CN1328546A - Pyrrolidines as inhibitors of neuraminidases - Google Patents

Pyrrolidines as inhibitors of neuraminidases Download PDF

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Publication number
CN1328546A
CN1328546A CN99807610A CN99807610A CN1328546A CN 1328546 A CN1328546 A CN 1328546A CN 99807610 A CN99807610 A CN 99807610A CN 99807610 A CN99807610 A CN 99807610A CN 1328546 A CN1328546 A CN 1328546A
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group
tetramethyleneimine
acetamido
hydrogen
alkenyl
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C·J·马林
顾禹归
陈慧如
陈元伟
D·A·德格伊
W·J·弗罗斯
V·L·吉兰达
D·J·格伦波弗尼克
W·M·卡迪
D·J·克姆普夫
L·L·克莱恩
A·C·克吕格尔
Z·林
D·L·马迪甘
K·F·麦丹尼尔
S·W·穆克莫雷
H·L·沈
K·D·斯图尔
V·S·斯托尔
孙明华
G·T·王
S·王
徐一波
M·C·杨
赵晨
A·肯尼迪
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Abbott Laboratories
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Abbott Laboratories
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Abstract

Disclosed are compounds of formula (I) which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

Description

Tetramethyleneimine as neuraminidase inhibitor
Technical field
The present invention relates to suppress new compound, composition and the method for neuraminidase, particularly neuraminidase influenza.The method and the synthetic intermediate that is used for these methods that the invention still further relates to the composition and the method for prevention and treatment influenza infection and prepare such compound.Background of invention
Many pathogenic microorganisms have the neuraminidase (being also referred to as sialidase) that participates in the microorganism reproduction process.Especially, the virus of orthomyxovirus and paramyxovirus group has neuraminidase.Comprise RSV (respiratory syncytial virus-relative disease), pneumonia and bronchiolitis (relevant) and laryngotracheobronchitis (relevant) with the paramyxovirus diseases associated with paramyxovirus 1 type with paramyxovirus 3 types.Some prior pathogenic microorganisms that have neuraminidase in people and/or animal comprise vibrio cholerae, clostridium perfringens, streptococcus pneumoniae.Genus arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Avian pneumo-encephalitis virus, avian influenza virus, equine influenza virus and Sendai virus.
Because of the mortality ratio due to the influenza is worldwide serious problems.This disease causes the havoc to people, rudimentary animal and some birds.Although can obtain to contain the vaccine of attenuated influenza virus, these vaccines only provide immunology protection to several parainfluenza virus strains, and to the crowd a little less than the immunizing power such as the elderly, child and to suffer from crowd's effect of chronic respiratory tract disease relatively poor.Because of the loss in productivity that causes absent from duty due to the influenza infection disease is estimated annual above 1,000,000,000 dollars.
Two kinds of main strains of influenza viruses (being called A and B) are arranged.At present, only there is several drugs to be approved for the treatment influenza.These medicines comprise amantadine and Rimantadine (they only have activity to suppressing A influenzae strain virus) and virazole (it be subjected to the toxicity dose limitation and influence it use).In the process with these pharmacological agenies, the mutant virus of resistance has appearred amantadine and Rimantadine are had soon.
Neuraminidase is a kind of by in the outstanding two kinds of main diseases toxalbumin of influenza virus tunicle.At progeny virus deenergized period from the cell that infects, neuraminidase gets off cracking on glycoprotein, glycolipid and the oligose of terminal sialic acid residue from the cell surface.The enzymic activity that suppresses neuraminidase causes progeny virus to be assembled from the teeth outwards.Such virus can not infect new cell, and therefore, virus replication is hindered or blocks.Research of X-radiocrystallography and sequence contrast show that the residue that directly contacts the sialic acid part of substrate is kept in the neuraminidase that derives from all A and B strains of influenza viruses by strictness.Therefore, in conjunction with the compound influenza virus A capable of blocking of sialic acid land and the duplicating of B strain of neuraminic acid zymophore.For the compound of neuraminidase influenza inhibitor will be useful to prevention and treatment influenza infection.
Following reference openly has the neuraminic acid derivatives of listing in every piece of described purposes in reference back: L.VonItzstein etc., and European Patent Application No. EP539204 announced on April 28th, 1993 (antiviral agent); T.Honda etc., European Patent Application No. EP823428 announced on February 11st, 1998 (sialidase inhibitor, the treatment of influenza); T.Honda etc., international patent application no WO98/06712 announced on February 19th, 1998 (sialidase inhibitor, the treatment of influenza); L VonItzstein etc., international patent application no WO95/20583 announces (viral neuraminidase inhibitor, the treatment of influenza) August 3 nineteen ninety-five; P.Smith, international patent application no WO95/18800 announces (viral neuraminidase inhibitor) July 13 nineteen ninety-five; P.Colman etc., international patent application no WO92/06691 announced on April 30th, 1992 (viral neuraminidase inhibitor); L.VonItzstein etc., U.S. Patent number mandate on July 15th, 5648379,1997 (treatment of influenza); P.Reece etc., international patent application no WO97/32214 announced on September 4th, 1997 (with combining of influenza neuraminidase reactive site); And P.Reece etc., international patent application no WO98/21243 announced on May 23rd, 1998 (antiviral drug).
Following reference openly has the sialic acid derivative of listing in every piece of described purposes in reference back: Y.Ohira etc., and international patent application no WO98/11083 announced on May 19th, 1998 (antiviral drug); Y.Ohira, European Patent Application No. EP882721 announced on December 9th, 1998 (antiviral drug); And B.Glanzer etc., Helvetica Chimica Acta74343-369 (1991) (VCN inhibitor).
Following reference openly has benzene derivative, cyclohexane derivant or the cyclohexene derivative of listing in every piece of described purposes in reference back: Y.Babu etc., U.S. Patent number mandate on February 11st, 5602277,1997 (neuraminidase inhibitor); M.Luo etc., U.S. Patent number 5453533 is authorized (neuraminidase influenza inhibitor September 26 nineteen ninety-five; The treatment of influenza); Y.Babu etc., international patent application no WO96/30329 announced on October 3rd, 1996 (neuraminidase inhibitor, the treatment of virus infection); N.Bischofberger etc., U.S. Patent number mandate on June 9th, 5763483,1998 (neuraminidase inhibitor); And K.Kent etc., international patent application no announcement on February 26th, 98/07685,1998 (intermediate of preparation neuraminidase inhibitor).
C.Kim etc., international patent application no WO98/17647 (announcement on April 30th, 1998) disclose the piperidine derivative as neuraminidase inhibitor.
N.Bischofberger etc., international patent application no WO96/26933 (announcement on September 6th, 1996) disclose the 6-membered ring compound as the various replacements of neuraminidase inhibitor.
Following reference openly is used as the dihydropyran derivatives of viral neuraminidase inhibitor:
D.Andrews etc., international patent application no WO97/06157 announced on February 20th, 1997; And
P.Cherry etc., international patent application no WO96/36628 announced on November 21st, 1996.
C.Kim etc., U.S. Patent number 5512596 (mandate on April 30th, 1996) are openly as the first aromatic derivatives of the 6-of neuraminidase inhibitor.
G.Diana etc., international patent application no WO98/03487 (announcement on January 29th, 1998) discloses the pyrazines derivatives of the replacement that is used for the treatment of influenza.
B.Horenstein etc., international patent application no WO99/06369 (announcement on February 11st, 1999) disclose the bridged piperazine derivatives as neuraminidase inhibitor.
Y.Babu etc., international patent application no WO97/47194 (announcement on December 18th, 1997) disclose as neuraminidase inhibitor and the cyclopentane derivatives that is used for the treatment of the replacement of influenza.
L.Czollner etc., Helvetica Chimica Acta 73 1338-1358 (1990) openly are used as the pyrrolidine analogue of the neuraminic acid of vibrio cholerae sialidase inhibitor.
Following reference openly is used as the siastatin category-B of neuraminidase inhibitor like thing: Y.Nishimura etc., Natural Product Letters 139-44 (1992); And Y.Nishimura etc., Natural Product Letters 133-38 (1992).
C.Penn, the open neuraminidase inhibitor of UK number of patent application GB2292081 (announcement on February 14th, 1996) with the influenza vaccines drug combination in purposes.
The purpose of this invention is to provide the neuraminidase that suppresses pathogenic microorganism, the compound of especially viral neuraminidase, particularly neuraminidase influenza.
The objective of the invention is also to provide the compound of the neuraminidase that suppresses influenza A and B strain.
Another object of the present invention provides the prevention to people and other mammiferous influenza infection.
Another object of the present invention provides the treatment to people and other mammiferous influenza infection.
A further object of the present invention provides and demonstrates the compound that suppresses influenza A virus and influenza B virus activity, and this compounds is when orally give, works by the inhibition neuraminidase influenza.
Another purpose of the present invention provides the compound that can be transported to from blood plasma effectively the pulmonary branches tracheae alveolar fluid in people and other Mammals, so that blocking-up influenza virus duplicating in this tissue.Of the present invention open
The present invention openly has the compound of formula I:
Figure A9980761000341
Or its pharmacy acceptable salt, ester or prodrug, wherein R 1Be selected from:
(a)-CO 2H，(b)-CH 2CO 2H，(c)-SO 3H，(d)-CH 2SO 3H，(e)-SO 2H，
(f)-CH 2SO 2H，(g)-PO 3H 2，(h)-CH 2PO 3H 2，(i)-PO 2H，(j)-CH 2PO 2H，
(k) tetrazyl, (l)-CH 2-tetrazyl, (m)-C (=O)-NH-S (O) 2-R 11,
(n)-CH 2C (=O)-NH-S (O) 2-R 11, (o)-SO 2N (T-R 11) R 12With
(p)-CH 2SO 2N(T-R 11)R 12，
Wherein T is selected from:
(i) key, (ii)-C (=O)-, (iii)-C (=O) O-, (iv)-C (=O) S-,
(v)-C (=O) NR 36-, (vi)-C (=S) O-, (vii)-C (=S) S-and
(viii)-C(＝S)NR 36，
R 11Be selected from:
(i) C 1-C 12Alkyl, (ii) C 2-C 12Alkenyl, (iii) cycloalkyl,
(iv) (cycloalkyl) alkyl,
(v) (cycloalkyl) alkenyl, (vi) cycloalkenyl group, (vii) (cycloalkenyl group) alkyl,
(viii) (cycloalkenyl group) alkenyl, (ix) aryl, (x) (aryl) alkyl, (xi)
(aryl) alkenyl,
(xii) heterocyclic radical, (xiii) (heterocyclic radical) alkyl and
(xiv) (heterocyclic radical) alkenyl; And
R 12And R 36Independently be selected from:
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) C 2-C 12Alkenyl, (iv) cycloalkyl,
(v) (cycloalkyl) alkyl, (vi) (cycloalkyl) alkenyl, (vii) cycloalkenyl group,
(viii) (cycloalkenyl group) alkyl, (ix) (cycloalkenyl group) alkenyl, (x) aryl,
(xi) (aryl) alkyl, (xii) (aryl) alkenyl, (xiii) heterocyclic radical,
(xiv) (heterocyclic radical) alkyl and (xv) (heterocyclic radical) alkenyl; X is selected from: (a)-C (=O)-N (R *)-, (b)-N (R *)-C (=O)-, (c)-C (=S)-N (R *)-, (d)-N (R *)-C (=S)-, (e)-N (R *)-SO 2-and (f)-SO 2-N (R *)-, be R wherein *Be hydrogen, C 1-C 3Low alkyl group or cyclopropyl; R 2Be selected from: (a) hydrogen, (b) C 1-C 6Alkyl, (c) C 2-C 6Alkenyl, (d) C 3-C 6Cycloalkyl, (e) C 5-C 6Cycloalkenyl group, (f) halo C 1-C 6Alkyl and (g) halo C 2-C 6Alkenyl; Or R 2-X-is
Figure A9980761000351
Y wherein 1For-CH 2-,-O-,-S-or-NH-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, amino methyl, 1-amino-ethyl, 2-amino-ethyl, thiol methyl, 1-thiol ethyl, 2-thiol ethyl, methoxymethyl, N-methylamino methyl and methylthiomethyl; R 3And R 4Independently be selected from (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl group, (d) heterocyclic radical, (e) aryl and (f)-Z-R 14Wherein Z is
(i)-C(R 37a)(R 37b)-，(ii)-C(R 47)＝C(R 48)-，(iii)-C≡C-、(iv)-C(＝O)-，
(v)-C(＝S)-，(vi)-C(＝NR 15)-，(vii)-C(R 37a)(OR 37c)-，(viii)
-C(R 37a)(SR 37c)-，
(ix)-C(R 37a)(N(R 37b)(R 37c))-，(x)-C(R 37a)(R 37b)-O-，
(xi)-C(R 37a)(R 37b)-N(R 37c)-，(xii)-C(R 37a)(R 37b)-N(O)(R 37c)-，
(xiii)-C(R 37a)(R 37b)-N(OH)-，(xiv)-C(R 37a)(R 37b)-S-，
(xv)-C(R 37a)(R 37b)-S(O)-，(xvi)-C(R 37a)(R 37b)-S(O) 2-，
(xvii)-C(R 37a)(R 37b)-C(＝O)-，(xviii)-C(R 37a)(R 37b)-C(＝S)-，
(xix)-C(R 37a)(R 37b)-C(＝NR 15)-，(xx)-C(R 37a)(OR 37c)-C(＝O)-，
(xxi)-C(R 37a)(SR 37c)-C(＝O)-，(xxii)-C(R 37a)(OR 37c)-C(＝S)-，
(xxiii)-C(R 37a)(SR 37c)-C(＝S)-，(xxiv)-C(＝O)-C(R 37a)(OR 37C)-，
(xxv)-C(＝O)-C(R 37a)(SR 37C)-，(xxvi)-C(＝S)-C(R 37a)(OR 37C)-，
(xxvii)-C(＝S)-C(R 37a)(SR 37C)-，(xxviii)-C(R 37a)(OR 37C)-C(R 37a)(OR 37C)-
(xxix)-C(R 37a)(SR 37C)-C(R 37a)(OR 37C)-，
(xxx)-C(R 37a)(OR 37C)-C(R 37a)(SR 37C)-，
(xxxi)-C(R 37a)(SR 37C)-C(R 37a)(sR 37C)-，(xxxii)-C(＝O)-C(＝O)-，
(xxxiii)-C(＝S)-C(＝S)-，(xxxiv)-C(＝O)-O-，(xxxv)-C(＝O)-S-，
(xxxvi)-C(＝S)-O-，(xxxvii)-C(＝S)-S-，(xxxviii)-C(＝O)-N(R 37a)-，
(xxxix)-C(＝S)-N(R 37a)-，(xl)-C(R 37a)(R 37b)-C(＝O)-N(R 37a)-，
(xli)-C(R 37a)(R 37b)-C(＝S)-N(R 37a)-，(xlii)-C(R 37a)(R 37b)-C(＝O)-O-，
(xliii)-C(R 37a)(R 37b)-C(＝O)-S-，(xliv)-C(R 37a)(R 37b)-C(＝S)-O-，
(xlv)-C(R 37a)(R 37b)-C(＝S)-S-，(xlvi)-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-，
(xlvii)-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-，(xlviii)-C(R 37a)(R 37b)-O-C(＝O)-
，(xlix)-C(R 37a)(R 37b)-S-C(＝O)-，
(l)-C(R 37a)(R 37b)-O-C(＝S)-，(li)-C(R 37a)(R 37b)-S-C(＝S)-，
(lii)-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-N(R 37a)-，
(liii)-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-N(R 37a)-，
(liv)-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-O-，
(lv)-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-S-，
(lvi)-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-O-，
(lvii)-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-S-，
(lviii)-C(R 37a)(R 37b)-O-C(＝O)-N(R 37a)-，
(lix)-C(R 37a)(R 37b)-S-C(＝O)-N(R 37a)-，
(lx)-C(R 37a)(R 37b)-O-C(＝S)-N(R 37a)-，
(lxi)-C(R 37a)(R 37b)-S-C(＝S)-N(R 37a)-，
(lxii)-C(R 37a)(R 37b)-O-C(＝O)-O-，
(lxiii)-C(R 37a)(R 37b)-S-C(＝O)-O-，(lxiv)-C(R 37a)(R 37b)-O-C(＝O)-S-，
(lxv)-C(R 37a)(R 37b)-S-C(＝O)-S-，(lxvi)-C(R 37a)(R 37b)-O-C(＝S)-O-，
(lxvii)-C(R 37a)(R 37b)-S-C(＝S)-O-，(lxviii)-C(R 37a)(R 37b)-O-C(＝S)-S-，
(lxix)-C (R 37a) (R 37b)-S-C (=S)-S-or (lxx)-C (R 37a) (R 37b)-C (R 37a) (OR 37c)-R 14For
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(the v) alkyl that replaces of thiol, (vi) R 37cThe alkyl that O-replaces,
(vii) R 37cThe alkyl that S-replaces, (viii) aminoalkyl group,
(ix) (R 37c) alkyl that replaces of NH-, (x) (R 37a) (R 37c) alkyl that replaces of N-,
(xi) R 37aThe alkyl that O-(O=) C-replaces, (xii) R 37aS-(O=) C-replaces
Alkyl, (xiii) R 37aThe alkyl that O-(S=) C-replaces,
(xiv) R 37aThe alkyl that S-(S=) C-replaces,
(xv) (R 37aO) 2-P (=O)-and the alkyl that replaces, (xvi) cyano group alkyl,
(xvii)) C 2-C 12Alkenyl, (xviii) halogenated alkenyl, (xix) C 2-C 12Alkynyl group,
(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl, (xxii) (cycloalkyl) alkenyl,
(xxiii) (cycloalkyl) alkynyl group, (xxiv) cycloalkenyl group,
(xxv) (cycloalkenyl group) alkyl,
(xxvi) (cycloalkenyl group) alkenyl, (xxvii) (cycloalkenyl group) alkynyl group, (xxviii) aryl,
(xxix) (aryl) alkyl, (xxx) (aryl) alkenyl, (xxxi) (aryl) alkynyl group,
(xxxii) heterocyclic radical, (xxxiii) (heterocycle) alkyl,
(xxxiv) (heterocycle) alkenyl or (xxxv) (heterocycle) alkynyl group,
Prerequisite is, when Z is
-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-O-，-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-O-，
-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-S-，-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-S-，
-C(R 37a)(R 37b)-O-C(＝O)-O-，-C(R 37a)(R 37b)-O-C(＝S)-O-，
-C(R 37a)(R 37b)-S-C(＝O)-O-，-C(R 37a)(R 37b)-S-C(＝S)-O-，
-C(R 37a)(R 37b)-O-C(＝O)-S-，-C(R 37a)(R 37b)-O-C(＝S)-S-，
-C (R 37a) (R 37b)-S-C (=O)-S-or-C (R 37a) (R 37b)-S-C (=S)-during S-,
R then 14Not hydrogen;
R 37a, R3 7b, R 47And R 48In each case, independently be selected from:
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(v) alkoxyalkyl, (vi) C 2-C 12Alkenyl, (vii) halogenated alkenyl,
(vii) C 2-C 12Alkynyl group, (ix) cycloalkyl,
(x) (cycloalkyl) alkyl, (xi) (cycloalkyl) alkenyl, (xii) (cycloalkyl) alkynyl group,
(xiii) cycloalkenyl group, (xiv) (cycloalkenyl group) alkyl, (xv) (cycloalkenyl group) alkenyl,
(xvi) (cycloalkenyl group) alkynyl group, (xii) aryl, (xviii) (aryl) alkyl,
(xix) (aryl) alkenyl, (xx) (aryl) alkynyl group, (xxi) heterocyclic radical,
(xxii) (heterocycle) alkyl, (xxiii) (heterocycle) alkenyl and
(xxiv) (heterocycle) alkynyl group;
R 37cIn each case, independently be selected from:
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) haloalkyl, (iv) C 2-C 12Alkenyl,
(v) halogenated alkenyl, (vi) C 2-C 12Alkynyl group, (vii) cycloalkyl,
(viii) (cycloalkyl) alkyl, (ix) (cycloalkyl) alkenyl, (x) (cycloalkyl) alkynyl group,
(xi) cycloalkenyl group, (xii) (cycloalkenyl group) alkyl, (xiii) (cycloalkenyl group) alkenyl,
(xiv) (cycloalkenyl group) alkynyl group, (xv) aryl, (xvi) (aryl) alkyl,
(xvii) (aryl) alkenyl, (xviii) (aryl) alkynyl group, (xix) heterocyclic radical,
(xx) (heterocycle) alkyl, (xxi) (heterocycle) alkenyl,
(xxii) (heterocycle) alkynyl group, (xxiii)-C (=O)-R 14, (xxiv)-C (=S)-R 14,
(xxv)-S (O) 2-R 14(xxvi) hydroxyalkyl;
Or as Z be-C (R 37a) (R 37b)-N (R 37c)-time, N (R then 37c) and R 14It in the time of together azido-;
Perhaps working as Z is-C (R 37a) (R 37b)-N (O) (R 37c)-time, N (O) (R then 37c) and R 14It in the time of together the 3-7 unit heterocycle of N-oxidation with theheterocyclic nitrogen atom of at least one N-oxidation;
Perhaps working as Z is-C (R 37a) (OR 37c)-,-C (R 37a) (SR 37c)-or-C (R 37a) (N (R 37b) (R 37c))-time, R then 37a, R 14The carbon atom that is connected with them (when together) forms cyclopentyl, cyclopentenyl, cyclohexyl or tetrahydrobenzene basic ring;
R 15Be selected from:
(i) hydrogen, (ii) hydroxyl is (iii) amino, (iv) C 1-C 12Alkyl, (v) haloalkyl,
(vi) C 2-C 12Alkenyl, (vii) halogenated alkenyl, (iii) cycloalkyl,
(ix) (cycloalkyl) alkyl, (x) (cycloalkyl) alkenyl,
(xi) cycloalkenyl group, (xii) (cycloalkenyl group) alkyl, (xiii) (cycloalkenyl group) alkenyl,
(xiv) aryl, (xv) (aryl) alkyl, (xvi) (aryl) alkenyl, (xii) heterocyclic radical,
(xviii) (heterocycle) alkyl and (xix) (heterocycle) alkenyl;
Perhaps R 3And R 4Common carbocyclic ring or the heterocycle that form of the atom that is connected with them with 3-8 annular atoms;
R 5Be selected from:
(a) hydrogen, (b)-CH (R 38) 2, (c)-O-R 40, (d) C 2-C 4Alkynyl group, (e) cyclopropyl,
(f) cyclobutyl, (g)-C (=Q 1)-R 17, and (h)-N (R 19) 2
Q wherein 1Be O, S or N (R 18);
R 17And R 18In each case, independently be selected from hydrogen, methyl and ethyl;
R 19, R 38And R 40In each case, independently be selected from:
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) haloalkyl, (iv) C 2-C 12Alkenyl,
(v) halogenated alkenyl, (vi) cycloalkyl, (vii) (cycloalkyl) alkyl,
(viii) (cycloalkyl) alkenyl, (ix) cycloalkenyl group, (x) (cycloalkenyl group) alkyl,
(xi) (cycloalkenyl group) alkenyl, (xii) aryl, (xiii) (aryl) alkyl,
(xiv) (aryl) alkenyl, (xv) heterocyclic radical, (xvi) (heterocycle) alkyl and
(xvii) (heterocycle) alkenyl; Y is selected from: (a) hydrogen, (b) C 1-C 5Alkyl, (c) C 1-C 5Haloalkyl, (d) C 2-C 5Alkenyl, (e) C 2-C 5Halogenated alkenyl, (f) C 2-C 5Alkynyl group, (g) C 3-C 5Cycloalkyl, (h) C 3-C 5Cycloalkyl-C 1-C 3Alkyl, (i) C 5Cycloalkenyl group, (j) C 5Cycloalkenyl group-C 1-C 3Alkyl, (k) C 5Cycloalkenyl group-C 2-C 3Alkenyl, (l)-(CHR 39) nOR 20, (m)-CH (OR 20)-CH 2(OR 20), (n)-(CHR 39) nSR 21, (o)-(CHR 39) nCN, (p)-(CHR 39) nN 3, (q) phenyl, (r) phenyl of halogen replacement, (s)-(CHR 39) nC (=Q 2) R 22, (t)-(CHR 39) nN (=Q 3), (u)-N (O)=CHCH 3, (v)-(CHR 39) nNR 23R 24, (w) halo and the heterocycle that (x) has 3-6 annular atoms; Wherein n is 0,1 or 2; Q 2Be O, S, NR 25Or CHR 26And Q 3Be NR 41Or CHR 42R 20Independently be in each case: (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) sec.-propyl, (vi) C 1-C 3Haloalkyl, (vii) vinyl, (viii) propenyl, (ix) pseudoallyl, (x) allyl group, (xi) C 2-C 3Halogenated alkenyl, (xii) amino, (xiii)-NHCH 3, (xiv)-N (CH 3) 2, (xv)-NHCH 2CH 3, (xvi)-N (CH 3) (CH 2CH 3), (xvii)-N (CH 2CH 3) 2Or (xviii)-N (=CH 2); R 21Be (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) sec.-propyl, (i) C 1-C 3Haloalkyl, (vii) vinyl, (viii) propenyl, (ix) pseudoallyl, (x) allyl group or (xi) C 2-C 3Halogenated alkenyl; R 22Be (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) sec.-propyl,
(vi) hydroxyl, (vii) thiol, (viii) methoxyl group, (ix) oxyethyl group, (x) positive propoxy,
(xi) isopropoxy, (xii) ring propoxy-, (xiii) methylthio group, (xiv) ethylmercapto group,
(xv) positive rosickyite base, (xvi) iprotiazem base, (xvii) ring rosickyite base, (xviii) vinyl,
(xix) propenyl, (xx) pseudoallyl, (xxi) allyl group, (xxii)-N (R 28a) (R 28b),
(xxiii)-CH 2R 29, (xxiv) amino methyl, (xxv) methylol, (xxvi) thiol methyl,
(xxvii)-NHNH 2, (xxviii)-N (CH 3) NH 2Or (xxix)-NHNH (CH 3);
R 23And R 39Independent is hydrogen or methyl;
R 41And R 42Independent is hydrogen, methyl or ethyl;
R 24Be selected from:
(i) hydrogen, (ii) C 1-C 4Alkyl, (iii) C 2-C 4Alkenyl, (iv) C 2-C 4Alkynyl group,
(v) cyclopropyl, (vi)-C (=Q 4)-R 30, (v)-OR 31, and (vi)-N (R 32) 2,
Q wherein 4Be O, S or N (R 33);
R 25For hydrogen, hydroxyl, methyl, ethyl, amino ,-CN or-NO 2
Radicals R 26Be hydrogen, methyl or ethyl;
R 28aFor hydrogen, hydroxyl, methyl, ethyl, amino ,-NHCH 3,-N (CH 3) 2, methoxyl group, oxyethyl group or-CN;
R 28bBe hydrogen, methyl or ethyl;
Perhaps R 28a, R 28bThe nitrogen that is connected with them the expression azetidinyl that combines;
Radicals R 29Be hydrogen, hydroxyl, thiol, methyl, ethyl, amino, methoxyl group, oxyethyl group, methylthio group, ethylmercapto group, methylamino or ethylamino;
R 30For hydrogen, methyl, ethyl ,-OR 34,-SR 34,-N (R 35) 2,-NHOH ,-NHNH 2,-N (CH 3) NH 2Or-N (CH 2CH 3) NH 2
Substituent R 31And R 32In each case, independent is hydrogen, methyl or ethyl;
Radicals R 33For hydrogen, hydroxyl, methyl, ethyl, amino ,-CN or-NO 2
Radicals R 34Be methyl or ethyl;
Radicals R 35Independent is hydrogen, methyl or ethyl; Prerequisite is to work as Q 2Be CHR 26The time, R then 22Be selected from hydrogen ,-CH 3,-C 2H 5,-C 3H 7,-OCH 3,-SCH 3,-O-C 2H 5With-S-C 2H 5Prerequisite is to work as R 3And R 4When doing for oneself hydrogen, then Y is not a hydrogen; R 6And R 7Independently be selected from:
(a) hydrogen, (b) C 1-C 12Alkyl, (c) C 2-C 12Alkenyl, (d) cycloalkyl,
(e) (cycloalkyl) alkyl, (f) (cycloalkyl) alkenyl, (g) cycloalkenyl group,
(h) (cycloalkenyl group) alkyl, (i) (cycloalkenyl group) alkenyl, (j) aryl, (k) (aryl) alkyl,
(l) (aryl) alkenyl, (m) heterocyclic radical, (n) (heterocycle) alkyl and (o) (heterocycle) alkenyl; With
R 8, R 9And R 10Independently be selected from:
(a) hydrogen, (b) C 1-C 6Alkyl, (c) C 2-C 6Alkenyl, (d) C 3-C 6Cycloalkyl,
(e) C 3-C 6Cycloalkenyl group and (f) fluorine, prerequisite is R 8, R 9And R 10In each no more than 6 atoms of total atom number (dehydrogenation outer).
Preferred compound of the present invention is the compound that has by the relative stereochemical structure shown in the formula II:
Figure A9980761000421
Or its pharmacy acceptable salt, ester or prodrug, wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y as above defines and R wherein 3And R 4Both are inequality.
Other preferred compound of the present invention is the compound that has by the relative stereochemical structure shown in the formula III:
Figure A9980761000431
Or its pharmacy acceptable salt, ester or prodrug, wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y as above defines and R wherein 3And R 4Both are inequality.
Other preferred compound of the present invention is the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1As above definition;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 2-C 3Alkenyl, or-X-R 2For
Figure A9980761000432
Y wherein 1For-CH 2-,-O-,-S-or-NH-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, amino methyl, 1-amino-ethyl, 2-amino-ethyl, thiol methyl, 1-thiol ethyl, 2-thiol ethyl, methoxymethyl, N-methylamino methyl and methylthiomethyl;
R 3And R 4Independently be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above definition and wherein R 3And R 4One of be not hydrogen;
R 5Be hydrogen or low alkyl group;
R 6And R 7Independent is hydrogen or low alkyl group;
R 8And R 9Independent is hydrogen, fluoro or low alkyl group;
R 10Be hydrogen, fluoro or low alkyl group; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl ,-C (=Q 2) R 22,-N (=Q 3) ,-N (O)=CHCH 3,-NR 23R 24Or have the heterocycle of 3-6 annular atoms, wherein a R 22, R 23, R 24, Q 2And Q 3As above definition.
The preferred compound of the present invention is the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1As above definition;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 2-C 3Alkenyl, or-X-R 2For
Figure A9980761000441
Y wherein 1For-CH 2-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl and 2-hydroxyethyl;
R 3And R 4Independently be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above definition and wherein R 3And R 4One of be not hydrogen;
R 5Hydrogen or low alkyl group;
R 6And R 7Independent is hydrogen or low alkyl group;
R 8And R 9Independent is hydrogen or low alkyl group;
R 10Be hydrogen or low alkyl group; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl ,-C (=Q 2) R 22,-N (=Q 3) ,-N (O)=CHCH 3Or have 5 annular atomses and also have the heterocycle of one or two pair key, R wherein 22, Q 2And Q 3As above definition.
Compound of the present invention even preferred is the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1As above definition;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 1-C 3Alkenyl, or-X-R 2For Y wherein 1For-CH 2-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl and 2-hydroxyethyl;
R 3And R 4Independently be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above definition and wherein R 3And R 4One of be not hydrogen;
R 5Be hydrogen or low alkyl group;
R 6And R 7Independent is hydrogen or low alkyl group;
R 8And R 9Independent is hydrogen or low alkyl group;
R 10Be hydrogen or low alkyl group; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
More highly preferred compound of the present invention is the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 3And R 4Independently be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above definition and wherein R 3And R 4One of be not hydrogen;
R 5Be hydrogen or low alkyl group;
R 6And R 7Independent is hydrogen or low alkyl group;
R 8And R 9Independent is hydrogen or low alkyl group;
R 10Be hydrogen or low alkyl group; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
Of the present invention even more highly preferred compound is the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen or low alkyl group R 3For heterocyclic radical or-Z-R 14, wherein Z and R 14As above definition;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
Other even more highly preferred compound of the present invention are the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen or low alkyl group R 3Be (a) heterocyclic radical, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl group, (g)-C (=O)-R 14, (h)-C (R 37a) (OR 37c)-R 14Or (i)-C (R 37a) (R 37b)-N (O) (R 37c) R 14, R wherein 14For:
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) halogenated alkenyl, (vii) aryl, (viii) aralkyl, (ix) heterocyclic radical,
(x) (heterocyclic radical) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyano group alkyl,
(xiv) (R 37aO)-(O=) alkyl that replaces of C-or
(xv) (R 37aO) 2-P (=O)-alkyl that replaces;
R 37aAnd R 37bIndependently be selected from:
(i) hydrogen, (ii) low alkyl group and (iii) low-grade alkenyl; And
R 37cFor:
Hydrogen, (ii) low alkyl group or (iii) low-grade alkenyl;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
The preferred compound of topnotch of the present invention is the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen R 3Be (a) heterocyclic radical, (b) alkyl or (c)-C (R 37a) (OR 37c)-R 14, R wherein 14For:
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) halogenated alkenyl, (vii) aryl, (viii) aralkyl, (ix) heterocyclic radical,
(x) (heterocyclic radical) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyano group alkyl,
(xiv) (R 37aO)-(O=) alkyl that replaces of C-or
(xv) (R 37aO) 2-P (=O)-alkyl that replaces;
R 37aAnd R 37bIndependently be selected from:
(i) hydrogen, (ii) low alkyl group and (iii) low-grade alkenyl; And
R 37cFor:
(i) hydrogen, (ii) C 1-C 3Low alkyl group or (iii) allyl group;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
The preferred compound of other topnotch of the present invention is the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen R 3Be (a) heterocyclic radical, (b) alkyl or (c)-C (R 37a) (OR 37c)-R 14, R wherein 14For:
(i) low alkyl group, (ii) low-grade alkenyl, the (iii) low alkyl group of hydroxyl-replacement or the (iv) low alkyl group of alkoxyl group-replacement;
R 37aFor:
(i) hydrogen, (ii) low alkyl group or (iii) low-grade alkenyl; And
R 37cFor:
(i) hydrogen, (ii) C 1-C 3Low alkyl group or (iii) allyl group;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
The preferred compound of other topnotch of the present invention is the compound with formula I or II or III, or its salt, ester or prodrug, wherein R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen R 3For-C (R 37a) (OR 37c)-R 14, R wherein 14For:
Low alkyl group or low-grade alkenyl;
R 37aFor:
Low alkyl group or low-grade alkenyl; And
R 37cFor:
Hydrogen, C 1-C 3Low alkyl group or allyl group;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
Preferred substituted R 1Comprise-CO 2H or its ester or prodrug.Preferred ester comprises C 2-C 6Benzyl ester lower alkyl esters or replacement or unsubstituted.Preferred substituted R 1Also comprise-S (O) 2NHC (=O) R 11, R wherein 11As above definition.
Topnotch preferred substituted R 1Comprise-CO 2H or its ester or prodrug.The preferred ester of topnotch comprises C 2-C 6Benzyl ester lower alkyl esters or replacement or unsubstituted.
Preferred substituted-X-R 2Comprise R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 2-C 3Alkenyl, or-X-R 2For Y wherein 1For-CH 2-,-O-,-S-or-NH-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, amino methyl, 1-amino-ethyl, 2-amino-ethyl, thiol methyl, 1-thiol ethyl, 2-thiol ethyl, methoxymethyl, N-methylamino methyl and methylthiomethyl.
More preferred substituents-X-R 2Comprise R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 2-C 3Alkenyl, or-X-R 2For
Figure A9980761000492
Y wherein 1For-CH 2-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl and 2-hydroxyethyl.
Even more preferred substituents-X-R 2Comprise R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 2-C 3Alkenyl.
More highly preferred substituting group-X-R 2Comprise R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group.
Even more highly preferred substituting group-X-R 2Comprise R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 2Low alkyl group or halo C 1-C 2Low alkyl group, and CH especially 3-C (=O)-NH-, CF 3-C (=O)-NH-, CH 3-SO 2-NH-or CF 3-SO 2-NH-.
Preferred substituted R 3And R 4Independently be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above generalized definition and wherein R 3And R 4One of be not hydrogen.
More highly preferred, substituent R 4Be hydrogen or low alkyl group R 3Comprise heterocyclic radical or-Z-R 14, wherein Z and R 14As above generalized definition.
Even more highly preferred, substituent R 4Be hydrogen or low alkyl group R 3Comprise: (a) heterocyclic radical, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl group, (g)-C (=O)-R 14, (h)-C (R 37a) (OR 37c)-R 14Or (i)-C (R 37a) (R 37b)-N (O) (R 37c) R 14, R wherein 14For:
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) halogenated alkenyl, (vii) aryl, (viii) aralkyl, (ix) heterocyclic radical,
(x) (heterocyclic radical) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyano group alkyl,
(xiv) (R 37aO)-(O=) alkyl that replaces of C-or
(xv) (R 37aO) 2-P (=O)-alkyl that replaces;
R 37aAnd R 37bIndependently be selected from:
(i) hydrogen, (ii) low alkyl group and (iii) low-grade alkenyl; And
R 37cBe (i) hydrogen, (ii) low alkyl group or (iii) low-grade alkenyl.
Topnotch is preferred, substituent R 4Be hydrogen R 3Comprise: (a) heterocyclic radical, (b) alkyl or (c)-C (R 37a) (OR 37c)-R 14, R wherein 14For:
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) halogenated alkenyl, (vii) aryl, (viii) aralkyl, (ix) heterocyclic radical,
(x) (heterocyclic radical) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyano group alkyl,
(xiv) (R 37aO)-(O=) alkyl that replaces of C-or
(xv) (R 37aO) 2-P (=O)-alkyl that replaces;
R 37aAnd R 37bIndependently be selected from:
(i) hydrogen, (ii) low alkyl group and (iii) low-grade alkenyl; And
R 37cBe (i) hydrogen, (ii) C 1-C 3Low alkyl group or (iii) allyl group.
Also topnotch is preferred, substituent R 4Be hydrogen R 3Comprise: (a) heterocyclic radical, (b) alkyl, or (c)-C (R 37a) (OR 37c)-R 14, R wherein 14For:
(i) low alkyl group, (ii) low-grade alkenyl, (iii) the low alkyl group of hydroxyl-replacement or
The (iv) low alkyl group of alkoxyl group-replacement;
R 37aBe (i) hydrogen, (ii) low alkyl group or (iii) low-grade alkenyl; And
R 37cBe (i) hydrogen, (ii) C 1-C 3Low alkyl group or (iii) allyl group.
Also topnotch is preferred, substituent R 4Be hydrogen R 3Comprise-C (R 37a) (OR 37c)-R 14, R wherein 14Be low alkyl group or low-grade alkenyl;
R 37aBe low alkyl group or low-grade alkenyl; And
R 37cBe hydrogen, C 1-C 3Low alkyl group or allyl group, particularly R wherein 37cBe hydrogen or methyl.
Preferred substituted R 5Comprise hydrogen or low alkyl group.The preferred R of topnotch 5Be hydrogen.
Preferred substituted R 6And R 7Independently comprise hydrogen and low alkyl group.The preferred R of topnotch 6And R 7Be hydrogen.
Preferred substituted R 8, R 9And R 10Independently comprise hydrogen, fluoro and low alkyl group.The preferred R of topnotch 8, R 9And R 10Be hydrogen.
Preferred substituted Y comprises C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl ,-C (=Q 2) R 22,-N (=Q 3) ,-N (O)=CHCH 3,-NR 23R 24Or have the heterocycle of 3-6 annular atoms, wherein a R 22, R 23, R 24, Q 2And Q 3As above definition.
More preferred substituents Y comprises C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl ,-C (=Q 2) R 22,-N (=Q 3) ,-N (O)=CHCH 3Or have 5 annular atomses and also have the heterocycle of one or two pair key, R wherein 22, Q 2And Q 3As above definition.
Even more preferred substituents Y comprises C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
For the representative substituting group Y of heterocyclic that has 5 annular atomses and also have one or two pair key comprises: furyl, the dihydrofuran base, two dehydrogenation dioxolanyls, the dithiole base, imidazolyl, imidazolinyl, isothiazolyl, isothiazoline base isoxazolyl isoxazoline-3-yl oxadiazole base oxadiazole quinoline base, oxathiolyl oxazolyl oxazolinyl, pyrazolyl, pyrazolinyl, pyrryl, the pyrrolin base, tetrazyl, tetrazolium quinoline base, thiadiazolyl group, the Thiadiazoline base, thiazolyl, thiazolinyl, thienyl, the dihydro-thiophene base, triazolyl, the triazoline base.
More highly preferred substituting group Y comprises cis-propenyl, trans-propenyl, isobutenyl, cis-2-chloro vinyl, vinyl, 2,2-difluoroethylene base, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
Topnotch preferred substituted Y comprises cis-propenyl, cis-2-chloro vinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
The preferred compound of the present invention comprises and is selected from following compound: (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-2-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate; (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (-)-(2R, 3S, 5R, 1, S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid ammonium salt; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-sec.-propyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-ethyl-N-methyl ammonia-Ji-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methylol-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-dimethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-(propylene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) butyl-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) amyl group-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-3-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(thiazole-4-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(thiazol-2-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(2,2-two fluoro-ethene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-3-base)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-5-base)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazol-4 yl)-tetramethyleneimine-5-formic acid; And (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-amino-tetramethyleneimine-5-formic acid;
Or its pharmacy acceptable salt, ester or prodrug.
The preferred compound of the present invention comprises and is selected from following compound: (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-2-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate; (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (-)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid ammonium salt; (±)-(2R, 3S, 5R, 1, R, 2 ' R)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-sec.-propyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-ethyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methylol-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-dimethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-(propylene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; And (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid;
Or its pharmacy acceptable salt, ester or prodrug.
Term used herein " acid protecting group " refers to be used to protect in building-up process acidic group (as-CO 2H ,-SO 3H ,-SO 2H ,-PO 3H 2,-PO 2H group etc.) to avoid the group of undesirable reaction.Acid protecting group commonly used is described in TH.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, second edition, John Wiley﹠amp; Sons is among the NewYork (1991).This type of the most frequently used acid protecting group is the ester class.
Such ester comprises:
Alkyl ester, especially lower alkyl esters includes, but is not limited to ethyl ester, n-propyl ester, isopropyl esters, n-butyl, sec-butyl ester, isobutyl, tertiary butyl ester, n-pentyl ester etc.;
Aralkyl ester includes, but is not limited to benzyl ester, phenethyl ester, 3-hydrocinnamyl ester, naphthalene methyl esters etc., and the aryl moiety of wherein said aralkyl is unsubstituted or by being substituted as preamble is defined;
Silyl ester, especially (three-low alkyl group) silyl ester, (two-low alkyl group) (aryl) silyl ester and (low alkyl group) (two-aryl) silyl ester include, but is not limited to the trimethyl silyl ester, the triethylsilyl ester, sec.-propyl dimetylsilyl ester, the t-butyldimethylsilyl ester, methyl di-isopropyl silyl ester, methyl two-tertiary butyl silyl ester, the triisopropyl silyl ester, methyldiphenyl base silyl ester, isopropyl diphenyl base silyl ester, the butyl diphenyl silyl ester, phenyl di-isopropyl silyl ester etc.
Preferred acid protecting group is a lower alkyl esters.
Term used herein " activatory hydroxy-acid group " refers to carboxylic acid halides such as acyl chlorides, refer to that also the activatory ester derivative includes, but is not limited to formic acid and acetate deutero-acid anhydrides, acid anhydrides derived from alkoxy carbonyl halogen such as isobutoxy carbonyl chloride etc., by carboxylic acid and N, the acid anhydrides that reactions such as N '-carbonyl dimidazoles obtain etc., N-hydroxy-succinamide deutero-ester, N-hydroxyl phthalimide deutero-ester, N-hydroxybenzotriazole deutero-ester, N-hydroxyl-5-norbornylene-2,3-diformamide deutero-ester, 2,4,5-Trichlorophenol deutero-ester, p-NP deutero-ester, phenol deutero-ester, pentachlorophenol deutero-ester, oxine deutero-ester etc.
Refer to have formula-C at this used term " acyl group " (=O)-R 95Group, R wherein 95Be the hydrogen or alkyl group.For R 95Preferred alkyl group be low alkyl group.The representative example of acyl group comprises the group such as formyl radical, ethanoyl, propionyl etc.
Refer to have formula-NHR at this used term " amido " 89Group, R wherein 89Be acyl group.The representative example of amido comprises kharophen, propionamido etc.
The straight or branched alkyl that refers to contain 2-15 carbon atom and also have at least one carbon-to-carbon double bond at this used term " alkenyl ".Term " low-grade alkenyl " refers to contain the straight or branched alkenyl of 2-6 carbon atom.The representative example of alkenyl comprises for example vinyl, 2-propenyl, 2-methyl isophthalic acid-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl etc.
Refer to by containing 2-15 carbon atom and also having the straight or branched hydrocarbon deutero-divalent group of at least one carbon-to-carbon double bond at this used term " alkylene group ".Term " rudimentary alkylene group " refers to by the straight or branched thiazolinyl deutero-divalent group that contains 2-6 carbon atom.The representative example of alkylene group comprise such as-CH=CH-,-CH 2CH=CH-,-C (CH 3)=CH-,-CH 2CH=CHCH 2-the group that waits.
Refer to have formula-OR at this used term " alkenyl oxy " 81Group, R wherein 81Be alkenyl.
Refer to have formula-OR at this used term " alkoxyl group " 99Group, R wherein 99Be alkyl group.Preferred R 99Be low alkyl group.The representative example of alkoxyl group comprises the group such as methoxyl group, oxyethyl group, tert.-butoxy etc.
Refer to have formula-O-R at this used term " alkoxyl group alkoxyl group " 96-O-R 97Group, R wherein 97Be low alkyl group as defined above, R 96Be low-grade alkylidene.The representative example of alkoxyl group alkoxyl group comprises the group such as methoxymethoxy, oxyethyl group methoxy base, tert.-butoxy methoxyl group etc.
Refer to be connected with on it alkyl of alkoxyl group, for example methoxymethyl, methoxy-propyl etc. at this used term " alkoxyalkyl ".
Refer to have formula-C at this used term " alkoxy carbonyl " (=O)-R 80Group, R wherein 80Be alkyl group.
This used term " alkoxy carbonyl alkyl " refer to have by the alkylene base key be connected in parent molecular moiety formula-C (=O)-R 79Group, R wherein 79Be alkoxy base.
The straight or branched alkyl that refers to have 1-12 carbon atom at this used term " alkyl ".Term " low alkyl group " refers to contain the straight or branched alkyl of 1-6 carbon atom.The representative example of alkyl comprises such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 1-methyl butyl, 2,2-dimethylbutyl, 2-methyl amyl, 2,2-dimethyl-propyl group, n-hexyl etc.Alkyl or contain hydrocarbon chain on the moieties of alkyl substituent and can choose wantonly by one or two heteroatoms or assorted group and be interrupted, described heteroatoms or assorted group independently be selected from oxygen ,-N (R 27)-and sulphur, wherein R 27In each case, independent for hydrogen, low alkyl group, cycloalkyl, cycloalkylalkyl or aralkyl and wherein two such heteroatomss or assorted group are separated by at least one carbon atom.
Refer to have formula-NHR at this used term " alkylamino " 91Group, R wherein 91Be alkyl group.Preferred group R 91Be low alkyl group.The representative example of alkylamino comprises methylamino, ethylamino etc.
Refer to by the straight or branched saturated hydrocarbyl deutero-divalent group that contains 1-15 carbon atom at this used term " alkylidene group ".Term " low-grade alkylidene " refers to by the straight or branched saturated hydrocarbyl deutero-divalent group that contains 1-6 carbon atom.The representative example of alkylidene group comprises such as methylene radical (CH 2-), ethylene (CH 2CH 2-), 1,1-ethylidene (CH (CH 3)-), trimethylene (CH 2CH 2CH 2-), 2,2-dimethyl propylidene (CH 2C (CH 3) 2CH 2-) etc. group.Alkylidene group or contain hydrocarbon chain on the substituent alkylene moiety of alkylidene group and can choose wantonly by one or two heteroatoms or assorted group and be interrupted, described heteroatoms or assorted group independently be selected from oxygen ,-N (R 27)-and sulphur, wherein R 27In each case, independent for hydrogen, low alkyl group, cycloalkyl, cycloalkylalkyl or aralkyl and wherein two such heteroatomss or assorted group are separated by at least one carbon atom.
Refer to have formula-SO at this used term " alkyl sulphonyl " 2-R 78Group, R wherein 78Be alkyl group.Preferred group R 78Be low alkyl group.
Refer to have by amino key at this used term " alkyl sulfonyl-amino " and (NH-) be connected in the formula-SO of parent molecular moiety 2-R 77Group, R wherein 77Be alkyl group.Preferred radicals R 77Be low alkyl group.
The straight or branched alkyl that refers to contain 2-15 carbon atom and also have at least one carbon-to-carbon triple bond at this used term " alkynyl group ".Term " alkynyl of low-grade chain " refers to contain the straight or branched alkynyl of 2-6 carbon atom, and the representative example of alkynyl group comprises for example ethynyl, 1-proyl, 2-propynyl, 3-butynyl, valerylene base, ethyl acetylene base etc.
Refer to by containing 2-15 carbon atom and also having the straight or branched hydrocarbon deutero-divalent group of at least one carbon-to-carbon triple bond at this used term " inferior alkynyl group ".Term " rudimentary inferior alkynyl group " refers to by the straight or branched alkynylene deutero-divalent group that contains 2-6 carbon atom, the representative example of inferior alkynyl group comprise such as-C ≡ C-,-CH 2-C ≡ C-,-C ≡ C-CH 2-,-CH (CH 3The group of)-C ≡ C-etc.
Refer to be connected with on it amino (NH at this used term " aminoalkyl group " 2) alkyl of group.
The carbocyclic ring system that refers to contain 6-10 annular atoms and one or two aromatic ring at this used term " aryl ".The representative example of aryl comprises such as phenyl, naphthyl, tetralyl, 2, the group of 3-indanyl, indenyl etc.
Described aryl can be unsubstituted or by one; two or three substituting groups replace, and each substituting group independently is selected from low alkyl group; halo; haloalkyl; halogenated alkoxy; hydroxyl; oxo (=O); hydroxyalkyl; alkenyl oxy; alkoxyl group; the alkoxyl group alkoxyl group; alkoxy carbonyl; alkoxy carbonyl alkyl; thio alkoxy; amino; alkylamino; alkyl sulphonyl; dialkyl amido; amido; unsubstituted aryl; unsubstituted aralkyl; unsubstituted aralkoxy; unsubstituted aryloxy; sulfydryl; cyano group; nitro; carboxyl; formaldehyde; NH 2C (=O)-, cycloalkyl, carboxyalkyl, alkyl sulfonyl-amino, unsubstituted heterocyclic, unsubstituted (heterocycle) alkyl, unsubstituted (heterocycle) alkoxyl group, unsubstituted (heterocycle) oxygen base and-SO 3H.The preferred aryl groups substituting group independently is selected from low alkyl group, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkenyl oxy, alkoxyl group, alkoxyl group alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, alkyl sulphonyl, amido, cyano group and nitro separately.The example of the aryl that replaces comprises 3-chlorophenyl, 3-fluoro phenyl, 4-chlorophenyl, 4-fluoro phenyl, 3,4-dichloro-phenyl, 3-chloro-4-fluoro phenyl, 4-methyl sulphonyl phenyl etc.
Term " (aryl) alkenyl " refers to have the low-grade alkenyl of aryl thereon.The representative example of (aryl) alkenyl comprises the group such as phenyl vinyl, phenyl propenyl etc.
Term " (aryl) alkyl " refers to have the low alkyl group of aryl thereon.The representative example of (aryl) alkyl comprises such as benzyl and phenylethyl.
Refer to have formula-O-R at this used term " (aryl) alkoxyl group " 76Group, R wherein 76Be aromatic alkyl group.
Term " (aryl) alkynyl group " refers to have the inferior alkynyl group of aryl thereon.The representative example of (aryl) alkynyl group comprises the group such as phenylacetylene base, phenyl proyl etc.
Used herein term " aryloxy " refers to have formula-O-R 72Group, R wherein 72Be aromatic yl group.
Refer to have formula-C at this used term " formamyl " (=O)-NH 2Group.
Refer to have formula-R at this used term " carboxyalkyl " 64The group of-COOH, wherein R 64Be lower alkylene groups.
Refer to thereon with cyano group (alkyl group CN) at this used term " cyano group alkyl ".
Refer to contain 5-10 carbon atom and on ring structure, contain the aliphatic member ring systems of 1 or 2 ring of at least one two key at this used term " cycloalkenyl group ".The representative example of cycloalkenyl group comprises such as tetrahydrobenzene, cyclopentenes, norbornylene etc.
Cycloalkenyl group can be unsubstituted or by one, two or three substituting groups replacements, described substituting group independently is selected from hydroxyl, halo, amino, alkylamino, dialkyl amido, alkoxyl group, alkoxyl group alkoxyl group, thio alkoxy, haloalkyl, sulfydryl, low-grade alkenyl and low alkyl group.Preferred substituted independently is selected from low alkyl group, low-grade alkenyl, haloalkyl, halo, hydroxyl and alkoxyl group.
The cycloalkenyl group that refers to be connected in low-grade alkenyl at this used term " (cycloalkenyl group) alkenyl ".The representative example of (cycloalkenyl group) alkenyl comprises such as cyclohexenyl ethene, cyclopentenyl ethene etc.
The cycloalkenyl group that refers to be connected in low alkyl group at this used term " (cycloalkenyl group) alkyl ".The representative example of (cycloalkenyl group) alkyl comprises such as cyclohexenyl methyl, cyclopentenyl methyl, cyclohexenyl ethyl, cyclopentenyl ethyl etc.
The cycloalkenyl group that refers to be connected in alkynyl of low-grade chain at this used term " (cycloalkenyl group) alkynyl group ".The representative example of (cycloalkenyl group) alkynyl group comprises such as cyclohexenyl ethynyl, cyclopentenyl proyl etc.
The aliphatic member ring systems that refers to contain 3-10 carbon atom and 1 or 2 ring at this used term " cycloalkyl ".Representational cycloalkyl comprises such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, norbornane (norbomane), dicyclo [2.2.2] octane etc.
Cycloalkyl can be unsubstituted or by one, two or three substituting groups replacements, described substituting group independently is selected from hydroxyl, halo, amino, alkylamino, dialkyl amido, alkoxyl group, alkoxyl group alkoxyl group, thio alkoxy, haloalkyl, sulfydryl, low-grade alkenyl and low alkyl group.Preferred substituted independently is selected from low alkyl group, low-grade alkenyl, haloalkyl, halo, hydroxyl and alkoxyl group.
The cycloalkyl that refers to be connected in low alkyl group at this used term " (cycloalkyl) alkyl ".The representative example of (cycloalkyl) alkyl comprises such as cyclohexyl methyl, cyclopentyl-methyl, cyclohexyl ethyl, cyclopentyl ethyl etc.
The cycloalkyl that refers to be connected in low-grade alkenyl at this used term " (cycloalkyl) alkenyl ".The representative example of (cycloalkyl) alkenyl comprises such as cyclohexyl ethene, cyclopentyl ethene etc.
The cycloalkyl that refers to be connected in alkynyl of low-grade chain at this used term " (cycloalkyl) alkynyl group ".The representative example of (cycloalkyl) alkynyl group comprises such as cyclohexyl-acetylene base, cyclopentyl proyl etc.
Refer to have formula-N (R at this used term " dialkyl amido " 90) 2Group, each R wherein 90Independent is low alkyl group.The representative example of dialkyl amido comprises dimethylamino, diethylamino, N-methyl-N-isopropyl propyl group amino etc.
Refer to fluorine, chlorine, bromine or iodine at this used term " halo ".
Refer to the low-grade alkenyl that wherein one or more hydrogen atoms are replaced by halogen at this used term " halogenated alkenyl ".The example of halogenated alkenyl comprises 2-fluorinated ethylene, 1-chloro ethene, 1,2-difluoroethylene, trifluoro-ethylene, 1,1,1-three fluoro-2-propylene etc.
Refer to have formula-OR at this used term " halogenated alkoxy " 69Group, R wherein 69Be haloalkyl as defined above.The example of halogenated alkoxy comprises chloro methoxyl group, fluoro methoxyl group, dichloro methoxyl group, trifluoromethoxy etc.
Refer to that at this used term " haloalkyl " wherein one or more hydrogen atoms are the low alkyl group that halogen replaces, include, but is not limited to trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoro methyl, chloro methyl, chloro ethyl, 2,2-Dichloroethyl, pentafluoroethyl group etc.
Refer to contain heteroatomic any 3-or the 4-unit ring that is selected from oxygen, nitrogen and sulphur at this used term " heterocyclic ring " or " heterocyclic " or " heterocycle "; Or contain following heteroatomic 5-, 6-or 7-unit ring: one, two, three or four nitrogen-atoms, a Sauerstoffatom, a sulphur atom, a nitrogen-atoms and a sulphur atom, two nitrogen-atoms and a sulphur atom, a nitrogen-atoms and a Sauerstoffatom, two nitrogen-atoms and a Sauerstoffatom, at non-conterminous locational two Sauerstoffatoms, at a non-conterminous locational Sauerstoffatom and a sulphur atom, or at non-conterminous locational two sulphur atoms.The first ring of described 5-has 0-2 two keys, and described 6-and 7-unit encircle has 0-3 two keys.Nitrogen heteroatom can be chosen wantonly by quaternized.Term " heterocyclic radical " also comprises two cyclic groups, wherein above-mentioned is any heterocyclic fused in phenyl ring or hexanaphthene or another heterocycle, for example, indyl, indolinyl, quinolyl, isoquinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, Decahydroisoquinolinpreparation base, benzofuryl, dihydro benzo furyl or benzothienyl etc.
Heterocyclic radical includes, but is not limited to group, for example, aziridinyl, azetidinyl, epoxide, oxa-cyclobutyl (oxetanyl), thia cyclobutyl (thienayl), pyrryl, pyrrolinyl, pyrrolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, tetrahydro pyridyl, piperidyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidyl, pyridazinyl oxazolyl oxazolinyl oxazolidinyl isoxazolyl isoxazole alkyl, morpholinyl, thio-morpholinyl, thiazolyl, thiazolinyl, thiazolidyl, isothiazolyl, the isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, benzothiazolyl benzoxazolyl, the oxa-cyclobutyl, the dihydrofuran base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl, thienyl, the dihydro-thiophene base, tetrahydro-thienyl, triazolyl, the triazoline base, tetrazyl, tetrazolium quinoline base isoxazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2,5-oxadiazole base oxadiazole quinoline base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, the Thiadiazoline base, 1,3-dithiolinyl, 1,2-dithiole base, 1,3-sulphur dioxide heterocyclic pentylene base, 1,3-dioxolinyl, two dehydrogenation dioxolanyls, 1,3-oxathiolinyl, oxathioyl, pyrimidyl, benzothienyl etc.Heterocyclic radical also comprises the compound of following formula
Figure A9980761000661
X wherein *For-CH 2Or-O-, Y *For-C (O)-or [C (R 92) 2-] v, R wherein 92Be hydrogen or C 1-C 4Alkyl, wherein v is 1,2 or 3, for example 1,3-benzo dioxane amyl group, 1,4-benzodioxan base etc.Heterocyclic radical also comprises dicyclo such as quinuclidinyl etc.
Heterocyclic radical can be for unsubstituted or replaced by 1-3 substituting group, and each substituting group independently is selected from low alkyl group, hydroxyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido and halogen.In addition, nitrogen heterocyclic ring can be a N-protected.
Refer to be connected in the heterocyclic radical of low-grade alkenyl at this used term " (heterocycle) alkenyl ", include, but is not limited to pyrrolidyl vinyl, morpholinyl vinyl etc.
Refer to have formula-OR at this used term " (heterocycle) alkoxyl group " 68Group, R wherein 68Be (heterocycle) alkyl.
Refer to be connected in the heterocyclic radical of low alkyl group at this used term " (heterocycle) alkyl ", include, but is not limited to pyrrolidyl methyl, morpholinyl methyl etc.
Refer to be connected in the heterocyclic radical of alkynyl of low-grade chain at this used term " (heterocycle) alkynyl group ", include, but is not limited to pyrrolidyl ethynyl, morpholinyl proyl etc.
Refer to (O-) be connected in the heterocyclic radical of parent molecular moiety at this used term " (heterocycle) oxygen base " by Sauerstoffatom.
Term " hydroxy-protective group " or " OH " blocking group refer to be used to protect hydroxyl to avoid the group of undesirable reaction in building-up process.Hydroxy-protective group commonly used is disclosed in T.H.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis second edition, John Wiley﹠amp; Sons is among the New York (1991).This type of hydroxy-protective group comprises:
Methyl ether,
The methyl ether that replaces, include, but is not limited to methoxymethyl ether, the methylthio group methyl ether, the t-butylthio methyl ether, (phenyl dimetylsilyl) methoxymethyl ether, the benzyloxy methyl ether, to methoxyl group benzyloxy base methyl ether, (4-methoxyl group phenoxy group) methyl ether, the tert.-butoxy methyl ether, 2-methoxy ethoxy methyl ether, 2,2,2-trichlorine oxyethyl group methyl ether, 2-(trimethyl silyl) oxyethyl group methyl ether, THP trtrahydropyranyl ether, tetrahydro thiapyran base ether, tetrahydrofuran base ether, tetrahydro-thienyl ether etc.
The ether that replaces includes, but is not limited to: 1-ethoxyethylether, 1-methyl isophthalic acid-methyl ethyl ether, 1-methyl isophthalic acid-benzyloxy ether, 2,2, and 2-three chlorethyl ethers, trimethyl silyl ether, tertbutyl ether etc.,
Benzylic ether
The benzylic ether that replaces includes, but is not limited to methoxy-benzyl ether, 3,4-dimethoxy-benzyl ether, adjacent nitrobenzyl ether, to halogeno-benzyl ether, to cyano group benzylic ether, phenylbenzene methyl ether, triphenyl methyl ether etc.,
Silyl ether, include, but is not limited to trimethyl silyl ether, triethylsilyl ether, triisopropyl silyl ether, dimethyl sec.-propyl silyl ether, diethyl sec.-propyl silyl ether, dimethylthexyhsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, tribenzyl silyl ether, triphenyl silyl ether, diphenyl methyl silyl ether etc.
Ester includes, but is not limited to manthanoate, acetic ester, chloracetic acid ester, dichloro acetic acid ester, trichloroacetic esters, trifluoro-acetate, methoxyacetic acid ester, phenylium ester, pivalate, benzoic ether etc.
Preferred hydroxyl protecting group comprises methyl ether, the benzylic ether of replacement, benzylic ether, silyl ether and the ester of replacement.
Refer to have formula-R at this used term " hydroxyalkyl " 65The group of-OH-, wherein R 65Be alkylidene group.
Refer to be easy to alternate group from compound at this used term " leavings group " by means of nucleophilic reagent.The example of leavings group comprises halogen (as chlorine, bromine or iodine) or sulphonate (for example methanesulfonates, p-toluenesulfonic esters, triflate etc.) etc.
Refer to be intended to protect in the synthesis step N-end of amino acid or peptide or protect amino at this used term " group of N-protected " or " N-protected " to avoid those groups of undesirable reaction.N-protected group commonly used is disclosed in T.H.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, second edition, John Wiley﹠amp; Sons is among the NewYork (1991).The N-protected group comprises acyl group for example formyl radical, ethanoyl, propionyl, valeryl, tertiary butyl ethanoyl, 2-chloro ethanoyl, 2-bromo ethanoyl, trifluoroacetyl group, tribromo-acetyl base, phthaloyl, ortho-nitrophenyl oxygen base ethanoyl, alpha-chloro butyryl radicals, benzoyl, 4-chlorinated benzene formyl radical, 4-bromobenzene formyl radical, 4-nitro benzoyl etc.; Alkylsulfonyl such as benzenesulfonyl, p-toluenesulfonyl etc.; Carbamate forms group such as benzyloxycarbonyl, to the chloro benzyloxy carbonyl, right-methoxyl group benzyloxy base carbonyl, to the nitro benzyloxycarbonyl, 2-nitro benzyloxycarbonyl, right-the bromo benzyloxycarbonyl, 3,4-dimethoxy benzyloxycarbonyl, 3,5-dimethoxy benzyloxycarbonyl, 2,4-dimethoxy benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro-4,5-dimethoxy benzyloxycarbonyl, 3,4,5-trimethoxy benzyloxycarbonyl, 1-(right-xenyl)-1-methyl ethoxy carbonyl, α, alpha-alpha-dimethyl-3,5-dimethoxy benzyloxycarbonyl, the hexichol methoxycarbonyl, tert-butoxycarbonyl, the di-isopropyl methoxycarbonyl, isopropoxy carbonyl, ethoxy carbonyl, methoxycarbonyl, allyloxy carbonyl, 2,2,2-trichlorine ethoxy carbonyl, phenyloxycarbonyl, 4-nitro-phenyloxycarbonyl, fluorenyl-9-methoxycarbonyl, the cyclopentyloxy carbonyl, the Buddha's warrior attendant alkoxy carbonyl, cyclohexyloxy carbonyl, thiophenyl carbonyl etc.; Alkyl such as benzyl, trityl, benzyloxymethyl etc.; And silyl such as trimethyl silyl etc.Preferred N-protected group is formyl radical, ethanoyl, benzoyl, valeryl, tertiary butyl ethanoyl, benzenesulfonyl, benzyl, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
Refer to have formula-SR at this used term " thio alkoxy " 98Group, R wherein 98Be alkyl.Preferred group R 98Be low alkyl group.
Refer to be connected with on it thiol group (alkyl SH) at this used term " alkylthio ".
As used in this, term " S " and " R " configuration define among Pure Appl.Chem. (1976) 45, the 13-30 as IUPAC 1974Recommendations for Section E.Fundamental Stereochemistry.
The compounds of this invention can comprise the carbon atom of asymmetric replacement.Therefore, all steric isomers of The compounds of this invention all plan to comprise in the present invention, comprise racemic mixture, non-enantiomer mixture and one optically active isomer, comprise the enantiomorph and the single diastereomer (not having its enantiomorph or other diastereomer substantially) of The compounds of this invention." there are not " other enantiomorph or diastereomer that a speech refers to surpass about 80% no described compound substantially, other enantiomorph or the diastereomer that more preferably surpass about 90% no described compound, even more preferably surpass other enantiomorph or the diastereomer of about 95% no described compound, even more preferred other enantiomorph or the diastereomer that surpasses about 98% no described compound, reach other enantiomorph or the diastereomer that most preferably surpass about 99% no described compound.
In addition, the compound that comprises the geometrical isomer of the two keys of possible carbon-to-carbon double bond and carbon-nitrogen also plans to comprise in the present invention.
The single stereoisomers of The compounds of this invention can be by any preparation in the whole bag of tricks in those of ordinary skills' ken.These methods comprise that stereospecificity is synthetic, the chromatography of the chromatographic separation of diastereomer, enantiomorph splits, the enantiomorph in the mixture of enantiomers is to the regeneration of the conversion of diastereomer and chromatographic separation diastereomer subsequently and single enantiomer, enzyme fractionation etc.
Stereospecificity is used suitable chiral raw material and is not caused racemization or the building-up reactions of the stereochemical conversion of chirality neutral synthetic comprising.
The non-enantiomer mixture of the compound that produces in the building-up reactions can separate by chromatographic technique well known to those skilled in the art usually.
The chromatography of enantiomorph splits and can finish on the chirality chromatographic resin.The chromatography column that contains the chirality resin can be from commercially available acquisition.In operation, be that racemic modification is placed solution and is splined on the post that contains chiral stationary phase.Then by the HPLC enantiomer separation.
The fractionation of enantiomorph also can be converted into diastereomer with the enantiomorph in the described mixture by the reaction with the chirality auxiliary material and realize.The diastereomer of Sheng Chenging can pass through column chromatography for separation then.When wanting isolated compound to contain can to form the carboxyl, amino of salt or covalent linkage or hydroxyl with the chirality auxiliary material, this technology is especially suitable.Chiral purity amino acid, organic carboxyl acid or organic sulfonic acid are useful especially as the chirality auxiliary material.In case described diastereomer is separated through chromatography, the single enantiomorph of then can regenerating.Described chirality auxiliary material can often reclaim and reuse.
Enzyme (as esterase, Phosphoric acid esterase and lipase) can be used for the fractionation of enantiomorph derivative in the mixture of enantiomers.The ester derivative that for example, can prepare carboxyl in the compound to be separated.Some enzyme is a kind of enantiomorph in this mixture of hydrolysis optionally.The acid of the enantiomer-pure of Sheng Chenging can separate with unhydrolysed ester then.
In addition, the solvate of formula I, II and III compound and hydrate all plan to comprise in the present invention.
As (the R for example of any variable in any substituting group or formula I or II or III compound or any other structural formula at this paper 1, R 2, R 3, m, n etc.) when occurring more than once, its definition in each case is independent of it in other definition under situation each time.In addition, substituent combination also allows, as long as so stable compound of combination results.Stable compound is for can separate the compound that obtains useful purity from reaction mixture.
This invention is intended to comprise compound with formula I, II and III by synthetic method or metabolic approach preparation.The compounds of this invention comprises the method that occurs in human body or animal body (in the body) or betides external method by the preparation of metabolic approach.
The compounds of this invention can be according to the method preparation of describing among the flow process 1-5 as follows.
By these flow processs, these methods will be described, wherein R 1Be carboxylic acid or carboxylicesters substituting group.It should be appreciated by those skilled in the art that other R 1Substituting group can (a) obtain from carboxylic acid or carboxylic acid ester groups, and (b) similar approach of the method by being used to introduce carboxylic acid or carboxylic acid ester groups is introduced, and perhaps (c) is by other method introducing well known in the art.
In addition, by these flow processs, these methods will be described, wherein R 4, R 6, R 7, R 8, R 9And R 10Be hydrogen.It should be appreciated by those skilled in the art that in these substituting groups wherein one or more for the compound of hydrogen can by with the similar method preparation of the method for describing on stream, perhaps prepare by other method well known in the art.
In addition, by these flow processs, explanation is obtained to have the preferred method of the The compounds of this invention of stereochemical structure relatively.It should be appreciated by those skilled in the art that have other relative stereochemical structure The compounds of this invention can by with the similar method preparation of disclosed method on stream, perhaps prepare by other method well known in the art.
In addition,, these methods will be described by these flow processs, wherein X be-C (=O)-NH-.It should be appreciated by those skilled in the art that other X group can by with the similar method preparation of disclosed method on stream, perhaps prepare by other method well known in the art.
Shown in flow process 1, in the presence of acid catalyst (as acetate etc.), in inert solvent (as toluene etc.), make the α-An Jisuanzhi 1 (P of propenal and N-protected 1Be the N-protected group, preferred benzyl etc.; P 2Be the carboxylic acid protective group, preferred tertiary butyl etc.) reaction, then with alkali (for example triethylamine etc.) balance and by chromatographic separation isomer, the tetramethyleneimine 2 that obtains replacing.In inert solvent (as methyl alcohol etc.), go back original reagent (as sodium borohydride etc.) with aldehyde-alcohol aldehyde radical is reduced to alcohol, then obtain alcohol 3 through the chromatographic separation isomer.Hydroxy-protective group P is used in the pure guard method of employing standard 3Protection such as (preferably use the silyl blocking group, as t-butyldimethylsilyl) alcohol 3 obtains 4.By making compound 4 and OsO4 and the reaction of N-methylmorpholine N-oxide compound obtain corresponding diol, realize the vinyl of compound 4 is oxidized to aldehyde.Handle this glycol with sodium periodate then, obtain aldehyde 5.By aldehyde 5 and a kind of Grignard reagent (as R 3MgBr etc.) reaction can be introduced substituent R 3, obtain alcohol 6.Oxidation alcohol 6 (as Swem oxidation etc.) obtains ketone 7.Reductive amination ketone 7 (for example, by with the reaction in methyl alcohol etc. of ammonium acetate and sodium cyanoborohydride) obtains amine 8.Amine 8 can be further functionalized to finish R 2The substituent introducing of-X-(for example by reactions such as amine and acylating agent such as diacetyl oxides, or by other process for acylating), then the chromatographic separation diastereomer obtains 9a.Other diastereomeric amine (9b) also can be separated and be further transformed according to the method for flow process 1.
Remove hydroxy-protective group P 3(for example, work as P 3During for the silyl blocking group, by with reactions such as fluoride sources such as tetrabutylammonium) obtain alcohol 10.The conversion of alcohol 10 hydroxyls can be introduced various substituting group Y.
For example, the alkylation of described hydroxyl obtains ether 11.N-removes protection (for example, P 1Be benzyl, by hydrogenation) obtain 12 ', then ester hydrolysis (for example, using sour example hydrochloric acid) obtains The compounds of this invention 12 ".
The hydroxyl of oxidation 10 (for example, Swem oxidation etc.) obtains aldehyde 13.Oxidation aldehyde 13 (is for example used NaClO 2Deng) obtain carboxylic acid 14.14 carboxylic acid substituent can be used to introduce various other functional groups on substituting group Y.For example, carboxylic acid can be esterified (for example, by with diazomethane or with reactions such as ethanol and DCC), perhaps carboxylic acid or its activatory derivative can obtain 15 with the amine reaction (wherein-C (=O)-R 22Expression ester or acid amides).N-deprotection (for example, P 1During for benzyl, by hydrogenation) obtain 16,, then ester hydrolysis (for example, using sour example hydrochloric acid) obtains The compounds of this invention 16 ".
According to method known to those skilled in the art and the specific method that exemplifies according to this paper, can be introduced as with the derivative of the carboxyl of 13 aldehyde radical or 14-CN's or various heterocyclic substituting group.
Make aldehyde 13 and low alkyl group-or low-grade alkenyl-Grignard reagent reaction, oxidation then (for example, Swern oxidation etc.) obtains ketone 17, wherein R 22Be low alkyl group or low-grade alkenyl.N-goes protection (for example, to work as P 1During for benzyl, by hydrogenation) obtain 18 ', ester hydrolysis (for example using acid as HCl) obtains compound 18 of the present invention then ".
Shown in flow process 2, can preparing wherein, substituting group Y is the compound of amino or amino derivative.Oxidation aldehyde 2 is (for example, with silver suboxide or NaClO 2Deng) obtain carboxylic acid 19.The Ku Ertisi of carboxylic acid 19 resets (for example, with reactions such as DPPA, triethylamine and benzyl alcohols), and then the chromatographic separation diastereomer obtains wherein P 4Acid amides 20 for N-protected group (for example, benzyloxycarbonyl etc.).Be similar to the method for transformation that in the flow process 1 compound 4 is converted into compound 9a and 9b, can be converted into 21a and 21b with 20, they can pass through chromatographic separation.Remove blocking group P 4(for example passing through selective hydration) obtains 22.Make amino further derivatize can be introduced as the substituting group Y of sulfonamide derivatives.N-removes protection (for example, P wherein 1During for benzyl, by hydrogenation), then ester hydrolysis (for example, with sour example hydrochloric acid etc.), obtaining wherein, Y is the The compounds of this invention of amino or sulfonamide derivatives.
Alkylene aldehyde 13 (is for example used Ph 3PCH 2Deng), then hydrogenation (causes that N-goes protection (as P 1During for benzyl) and alkene saturated, then ester hydrolysis (for example, with sour example hydrochloric acid etc.), obtaining wherein, Y is the The compounds of this invention of low alkyl group.
Shown in flow process 3, the vinyl of compound 4 is oxidized to glycol (for example uses OsO 4With N-methylmorpholine N-oxide compound etc.) obtain glycol 23.Remove N-protected group P 1(P for example 1During for benzyl, by hydrogenation) obtain tetramethyleneimine 24.With acid-unsettled N-protected group P 5(for example tert-butoxycarbonyl etc.) protection again obtains 25.To be similar to compound 4a is converted into compound 10 and compound 10 is converted into 13 mode shown in the flow process 1, can realize the conversion of compound 25 to aldehyde 26a and 26b.26a and 26b can pass through chromatographic separation.
Alkylene 26a is (as using Ph 3PCH 2Or triphenyl phosphine/methylene dichloride/n-Butyl Lithium or I -Ph 3p +CH 2CH 3/ KOtBu etc.) obtaining wherein, Y is an alkene substituent 27.Under acidic conditions, P 5The N-of blocking group goes protection and ester hydrolysis to obtain wherein, and Y is the substituent The compounds of this invention 28 of alkene.
In another alternative method shown in the flow process 4, the hydroxyl of alcohol 3 alkali-unsettled hydroxy-protective group P 6Protection such as (for example ethanoyl) obtains compound 29.Use OsO 4Obtain glycol 30 with the vinyl of N-methylmorpholine N-oxide compound oxidation 29, remove P 1Blocking group (for example by hydrogenation etc.) obtains tetramethyleneimine 31.With acid-unsettled N-protected group P 5(for example tert-butoxycarbonyl etc.) protection again obtains 32.Use hydroxy-protective group P 7(for example, silyl blocking group such as triisopropyl silyl etc.) optionally protects 32 primary alconol to obtain compound 33.Oxidation 33 (for example, Swern oxidation etc.) obtains ketone 34.Reduction amination ketone 34 (for example with the reaction in methyl alcohol etc. of ammonium acetate and sodium cyanoborohydride) obtains amine 35.Amine 35 can be further functionalized to finish R 2The substituent introducing of-X-(for example by reactions such as amine and acylating agent such as diacetyl oxides, or by other process for acylating), then the chromatographic separation diastereomer obtains 36a.Other diastereomeric amine (36b) also can be separated and be further transformed according to the method for this flow process.
Selectivity is removed the hydroxy-protective group P among the 36a 6(for example being used in the salt of wormwood in the methyl alcohol etc.) obtains alcohol 37.This alcohol is oxidized to aldehyde (as Swern oxidation etc.) obtains 38.This aldehyde can be used as the precursor of the various substituting group Y on the The compounds of this invention.For example, alkylene 38 is (as using Ph 3PCH 2Or triphenyl phosphine/methylene dichloride/n-Butyl Lithium or I -Ph 3P +CH 2CH 3/ KOtBu etc.) obtaining wherein, Y is an alkene substituent 39.Remove P 7Hydroxy-protective group (for example using fluoride sources such as tetrabutylammonium etc.) obtains alcohol 40.
Described alcohol can be used as the various R on the The compounds of this invention 3Substituent precursor.For example alcohol 40 can be oxidized to aldehyde (for example by Dess-Martin oxidation etc.) and obtain 41.Aldehyde 41 can with Grignard reagent (R 14MgBr etc.) or other organometallic reagent (for example organolithium reagent such as R 14Li etc.) reaction obtains being 42 of the non-enantiomer mixture of alcohol, and its chromatographic separation is obtained main isomer 42a and other isomer 42b.The mixture of isomer 42a or isomer 42 can oxidized (for example by Dess-Martin oxidation etc.) obtain ketone 43.Reductone 43 (for example, with sodium cyanoborohydride reaction in ethanol etc.) obtains the pure 42b as main isomer, and it can be through chromatographic separation.Under acidic conditions, P 5The N-of blocking group goes protection and ester hydrolysis to obtain wherein respectively, and Y is substituent The compounds of this invention 44a of alkene or 44b.
The alkylation of alcohol 42a or 42b obtains ether 45a or 42b respectively.Under acidic conditions, P 5The N-of blocking group goes protection and ester hydrolysis to obtain wherein respectively, and Y is substituent The compounds of this invention 48a of alkene or 48b.
Shown in flow process 5, ketone 43 can with Grignard reagent (R 37aMgBr etc.) or other organometallic reagent (for example organolithium reagent such as R 37aLi etc.) reaction obtains pure 46a and the 46b into the non-enantiomer mixture of alcohol, and it can be through chromatographic separation.Under acidic conditions, P 5The N-of blocking group goes protection and ester hydrolysis to obtain wherein respectively, and Y is substituent The compounds of this invention 47a of alkene or 47b.
The alkylation of alcohol 46a or 46b obtains ether 49a or 49b respectively.Under acidic conditions, P 5The N-of blocking group goes protection and ester hydrolysis to obtain wherein respectively, and Y is substituent The compounds of this invention 50a of alkene or 50b.
The ester of The compounds of this invention or prodrug can prepare by methods known in the art.Flow process 1
Figure A9980761000751
Flow process 1 (continuing) Flow process 1 (continuing)
Figure A9980761000771
Flow process 2
Figure A9980761000781
Flow process 3 Flow process 4
Figure A9980761000801
Flow process 4 (continuing)
Figure A9980761000811
Flow process 4 (continuing) Flow process 4 (continuing) Flow process 5
Figure A9980761000841
Flow process 5 (continuing)
Figure A9980761000851
Known technology can easily prepare other compound of the present invention by compound described here in the employing chemical literature.Required method is known and can be easily implemented by those of ordinary skills.
The important intermediate that is used to prepare The compounds of this invention comprises as follows: (1)
Figure A9980761000861
P wherein 1Be N-protected group (benzyl of preferred benzyl or replacement) and P 2Be carboxylic acid protective group (preferred low alkyl group, the especially tertiary butyl); Best P 1And P 2Can optionally go to protect/remove; Or its salt; (2) P wherein 1Be N-protected group (benzyl of preferred benzyl or replacement) and P 2Be carboxylic acid protective group (preferred low alkyl group, the especially tertiary butyl); P 3Be hydrogen or hydroxy-protective group (preferred acyl group blocking group such as ethanoyl etc., or silyl blocking group such as t-butyldimethylsilyl etc.); Best P 1, P 2And P 3Can optionally go to protect/remove; Or its salt; (3) P wherein 1Be N-protected group (benzyl of preferred benzyl or replacement) and P 2Be carboxylic acid protective group (preferred low alkyl group, the especially tertiary butyl); P 4Be hydrogen or N-protected group (preferred carbamate N-protected group such as benzyloxycarbonyl etc.); Best P 1, P 2And P 4Can optionally go to protect/remove; Or its salt; (4)
Figure A9980761000871
Or
Figure A9980761000872
P wherein 5Be N-protected group (unsettled N-protected group of preferred acid such as tert-butoxycarbonyl etc.) and P 2Be carboxylic acid protective group (preferred low alkyl group, the especially tertiary butyl); P 6Be hydrogen or hydroxy-protective group (unsettled hydroxy-protective group of preferred bases such as ethanoyl etc.); P 7Be hydroxy-protective group (preferred silyl blocking group such as triisopropyl silyl etc.); Best P 2, P 5, P 6And P 7Can optionally go to protect/remove; Or its salt; With Or
Figure A9980761000882
P wherein 5Be N-protected group (unsettled N-protected group of preferred acid such as tert-butoxycarbonyl etc.) and P 2Be carboxylic acid protective group (preferred low alkyl group, the especially tertiary butyl); P 6Be hydrogen or hydroxy-protective group (unsettled hydroxy-protective group of preferred bases such as ethanoyl etc.); P 7Be hydroxy-protective group (preferred silyl blocking group such as triisopropyl silyl etc.); R 2(preferred low alkyl group or junior alkyl halides, most preferable or trifluoromethyl) as defined herein; Best P 2, P 5, P 6And P 7Can optionally go to protect/remove; Or its salt.
All patents, patent application and the reference quoted in this specification sheets, it is attached to herein in full by reference.Under contradictory situation, will be as the criterion with the disclosure (comprising definition).
The synthetic required reagent that is used for The compounds of this invention is easy to obtain from some commercial source, for example, from Aldrich Chemical Co. (Milwaukee, WI, USA); SigmaChemical Co. (St.Louis, MO, USA); Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman ChemicalCompany (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brmswick, NJ 08901); (Waterbury CT.06708) obtains for Pfaltz and Bauer.Can not can prepare by adopting currently known methods by the compound that commerce obtains from chemical literature.
The following example will further specify the preparation of (but not limiting) The compounds of this invention.
Embodiment 1 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-formate hydrochlorate (1A. ±)-(2S, 3R, 5R)-and (±)-(2S, 3S, 5R)-1-benzyl-2-vinyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate (ratio 8: 1).
(8ml, (4.34g is 19.6mmol) and in toluene (100ml) solution of acetate (5) 120mmol) to add N-benzyl-tert-butyl glycinate with propenal.This solution of reflux.After 1 hour, make this reactant be cooled to about 50 ℃, add other 3ml propenal.This reactant of reflux is 2 hours again, vacuum concentration.Residue with 5% ethyl acetate/hexane wash-out, obtains (±)-(2S into oily matter through the silica gel column chromatography purifying; 3R, 5R)-and (±)-(2S, 3S; 5R)-1-benzyl-2-vinyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate (must measure: 2.78g, 45%).Under room temperature, by this crude product is stirred in ethyl acetate with triethylamine (0.5ml), make mixture balance under 8: 1 ratio of aldehyde, then evaporating solvent.
1H NMR (CDCl 3) (only being main isomer): δ 1.45 (s, 9H), 2.26 (m, 1H), 2.69 (m, 1H), 3.49 (dd, J=7.8,3.0Hz, 1H), 3.61 (d, J=13.5Hz, 1H), 3.93 (m, 1H), 3.94 (d, J=13.5Hz, 1H), 5.22-5.33 (two dd, 2H), 5.7 (ddd, J=17.7,10.2,7.8Hz, 1H), 7.21-7.35 (m, 5H), 9.71 (d, J=1.2 Hz, 1H).
MS(M＋H) +＝316。
Figure A9980761000901
(1B. ±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-(methylol)-tetramethyleneimine-5-t-butyl formate
Make (±)-(2S according to the preparation of method described in the embodiment 1A; 3R; 5R)-and (±)-(2S; 3S; 5R)-8: 1 mixture (6.0g of 1-benzyl-2-vinyl-3-carbonyl pyrrolidine-5-t-butyl formate; 19.0mmol) the 100ml methanol solution be cooled to 0 ℃ and with sodium borohydride (0.72g 19.0mmol) handles.This mixture was stirred 0.5 hour, be warmed to room temperature and restir 1 hour.With this reactant of aqueous ammonium chloride solution quencher, evaporating solvent.Residue is distributed between ethyl acetate and water,, filter and vacuum concentration through the dried over mgso organic layer.Residual oil with 20-30% ethyl acetate/hexane gradient liquid wash-out, obtains the title compound (must measure: 4.0g, 66%) for colorless oil through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ1.46(s，9H)，1.80(m，1H)，2.16(m，1H)，2.39(m，1H)，2.54(m，1H)，3.48-3.53(m，2H)，3.08(d，2H)，3.91(d，2H)，5.17-5.22(m，2H)，5.70(m，1H)，723-7.34(m，5H)。
MS(M＋H) +＝318。 (1C. ±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate
With (±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-(methylol)-tetramethyleneimine-5-t-butyl formate (3.6g, 11.4mmol), tert-butyldimethylsilyl chloride (3.7g, 24.5mmol) and imidazoles (2.8g, the solution among 80ml DMF 41.2mmol) at room temperature stirred 1.5 hours.Dilute this reactant with ethyl acetate, water and salt water washing are through dried over mgso and vacuum concentration.Residue with 5% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 3.5g, 71%).
1H?NMR(CDCl 3)：δ0.02(d，6H)，0.86(s，9H)，1.43(s，9H)，1.67(ddd，1H)，2.11(m，1H)，2.28(m，1H)，3.40-3.70(m，6H)，3.90(d，2H)，5.11-5.19(m，2H)，5.69(ddd，1H)，7.20-7.30(m，5H)。
MS(M＋H) +＝432。
Figure A9980761000911
(1D. ±)-(2R, 3R, 5R)-1-benzyl-2-formyl radical-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate
Perosmic anhydride (20ml) is added in (±)-(2S in 8: 1 acetone of 60ml, 3R, 5R)-1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (3.5g, 8.12mmol) and N-methylmorpholine N-oxide compound (3.0g is in the solution under room temperature 25.6mmol).At room temperature stir this reaction mixture 6 hours, and used saturated Na 2S 2O 3Aqueous solution quencher.With this mixture restir 10 minutes, remove and desolvate.Brown residue is distributed between methylene dichloride and water.Through dried over mgso organic layer and vacuum concentration, obtain intermediate glycol (about 3.8g) into oily matter, it can need not other purifying and use.
MS (crude product) (M+H) +=466.
This crude product glycol is dissolved in 6: 1 tetrahydrofuran (THF) (THF)/water (50ml), and (3.0g 14.0mmol) handles with sodium periodate.At room temperature stirred this mixture 1 hour, and, washed with water,, filter and vacuum concentration through dried over mgso with the ethyl acetate dilution.Crude product aldehyde with 3% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 1.6g, 46%).
1H?NMR(CDCl 3)：δ0.03(d，6H)，0.86(s，9H)，1.46(s，9H)，1.72(m，1H)，2.26-2.45(m，2H)，3.53-3.71(m，5H)，3.84(d，1H)，3.93(d，1H)，7.27-7.31(m，5H)，9.32(d，1H)。
MS(M＋H) +＝434。
Figure A9980761000921
(1E. ±)-(2R, 3R, 5R)-1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate
Under argon gas, the anhydrous THF of 10ml and 3 ethylene dibromides added fill magnesium (0.14g is in dry flask 5.83mmol).Then add 1-bromo-2-ethyl butane (0.95g, 5.83mmol).This reaction mixture of reflux 45 minutes reacts until most of magnesium.This reaction mixture is cooled to-30 ℃, drip (±) in THF (6ml)-(2R, 3R, 5R)-1-benzyl-2-formyl radical-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (0.5g, 1.15mmol).This reactant of chien shih slowly is warmed to-10 ℃ during with about 2 hours, uses the aqueous ammonium chloride solution quencher.With the slurry that the ethyl acetate dilution generates, water, salt water washing, through dried over mgso and concentrated.A kind of buttery crude product alcohol product (about 0.85g) can use without being further purified.
MS(M＋H) +＝520。
The 10ml anhydrous methylene chloride solution of preparation oxalyl chloride (2.5ml is in the 2M methylene dichloride) also remains under-78 ℃ and the nitrogen.(0.77ml 9.83mmol) slowly adds 2 and goes in this solution with DMSO.This mixture was stirred 15 minutes, with the 5ml anhydrous methylene chloride solution-treated of the about 0.85g crude product alcohol for preparing above.With this solution stirring 1 hour, (2.3ml 16.4mmol) slowly joined in this reaction mixture with triethylamine.Make this solution slowly be warmed to room temperature then, dilute with methylene dichloride.Wash organic layer with water, through dried over mgso and concentrated.Residue with 3% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 0.35g, 66%).
MS(M＋H) +＝518。 (1F. ±)-(2R, 3R, 5R, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate
With (±)-(2R, 3R, 5R)-1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (0.20g, 0.39mmol), the 5ml methanol solution reflux of ammonium acetate (30 equivalent) and sodium cyanoborohydride (10 equivalent) 24 hours, interim simultaneously other 60 equivalent ammonium acetates and the 20 equivalent sodium cyanoborohydrides of adding.Evaporating solvent.The residue of generation is distributed between methylene dichloride and water.Through the dried over mgso organic layer, filter and concentrate.Product with 30-50% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 130mg, 64%).
1H?NMR(CDCl 3)：δ7.30(m，5H)，4.91(s，1H)，3.53(m，2H)，3.08(m，1H)，2.88(m，1H)，2.35(m，1H)，1.85(m，1H)，1.44(s，9H)，1.20-1.40(m，7H)，0.88(s，9H)，0.85(m，6H)，0.03(s，6H)。
MS(M＋H) +＝519。
Figure A9980761000932
(1G. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate
With (±)-(2R, 3R, 5R, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (110mg, 0.21mmol) and diacetyl oxide (214mg, 10ml dichloromethane solution stirring 2.1mmol) 1 hour.Solvent removed in vacuo and excessive acetic anhydride via.Residue with 30% ethyl acetate/hexane wash-out, obtains the title compound (must measure: 85mg, 72%) for white solid through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ7.28(m，5H)，5.14(d，J＝14Hz，1H)，4.36(m，1H)，3.95(m，2H)，3.62(m，1H)，3.52(m，1H)，3.45(m，1H)，2.98(m，1H)，1.98(s，3H)，1.60(m，2H)，1.43(s，9H)，1.20-1.40(m，7H)，0.88(s，9H)，0.80(m，6H)，0.04(s，6H)
MS(M＋H) +＝561。
Figure A9980761000941
(1H. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(methylol)-tetramethyleneimine-5-t-butyl formate
Preparation (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (85mg, anhydrous THF (5ml) solution 0.15mmol) and remain in room temperature and nitrogen under.Tetrabutylammonium (among the 1M THF, 0.23ml) is slowly added in this solution.This reaction mixture was stirred 1 hour.Solvent removed in vacuo, residue with 30-50% ethyl acetate/hexane wash-out, obtain the title compound (must measure: 41mg, 61%) for the white foam thing through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ7.20-7.35(m，5H)，5.20(d，J＝14Hz，1H)，4.28(m，1H)，4.93(m，2H)，3.65(m，2H)，3.50(m，1H)，3.23(m，2H)，2.22(m，2H)，1.98(s，3H)，1.62(m，1H)，1.43(s，9H)，1.15-1.40(m，7H)，0.80(m，6H)
MS(M＋H) +＝447。
Figure A9980761000942
(1I. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate
With (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(methylol)-tetramethyleneimine-5-t-butyl formate (40mg, 0.09mmol) and silver suboxide (200mg, 0.90mmol) the mixture reflux in the 3ml methyl iodide is 3 hours.Cool off this reactant, filtration, vacuum evaporating solvent obtain title compound, are crude product oil.
MS(M＋H) +＝461。
Figure A9980761000951
(1J. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate
In the presence of 10% palladium that is stated from the catalytic amount on the gac, make crude product (±)-(2R according to the preparation of method described in the embodiment 1I, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl-tetramethyleneimine-5-t-butyl formate (32mg, 0.07mmol) and ammonium formiate (130mg, the ethanol of mixture 2.1mmol) (5ml) solution reflux 1.5 hours.Filter this reactant, vacuum concentration.Residue is used 50% ethyl acetate/hexane through the silica gel column chromatography purifying, then with 10% ethanol/methylene wash-out, obtains the title compound (must measure: 16mg, 47%) for colorless oil.
MS(M＋H) +＝371。
Figure A9980761000952
(1K. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-formate hydrochlorate
Make (±)-solution of (2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate (15mg) is dissolved in the aqueous solution (1ml) of 6N HCl, stirred 3 hours under room temperature.Under high vacuum, remove and desolvate, obtain title compound into white solid.
1H?NMR(d 6-DMSO)：δ8.10(d，J＝14Hz，1H)，4.28(m，1H)，4.18(m，1H)，3.45(m，1H)，3.22(s，3H)，2.47(m，1H)，2.38(m，1H)，1.90(m，1H)，1.88(s，3H)，1.15-1.42(m，7H)，0.82(t，J＝12.5Hz，3H)，0.79(t，J＝12.5Hz，3H)。
MS(M＋H) +＝315，(M-H) -＝313。
Embodiment 2 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-formate hydrochlorate
Figure A9980761000961
(2A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate.
The 5ml anhydrous methylene chloride solution of preparation oxalyl chloride (0.11ml is in the 2M methylene dichloride) also remains under-78 ℃ and the nitrogen.(32mg 0.42mmol) slowly adds in this solution with DMSO.This mixture was stirred 15 minutes, and (38mg, 5ml dichloromethane solution 0.085mmol) is handled with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-t-butyl formate.With this solution stirring 1 hour, (86mg 0.85mmol) slowly joined in this reaction mixture with triethylamine.Make this solution slowly be warmed to room temperature then, dilute with methylene dichloride.Water and salt water washing organic layer through dried over mgso, filter and concentrate.Residue with 3% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 39mg, 97%).
1H?NMR(CDCl 3)：δ9.68(d，J＝1.0Hz，1H)，7.28(m，5H)，5.06(d，J＝14Hz，1H)，4.38(m，1H)，4.10(m，1H)，3.75(m，2H)，3.45(m，1H)，2.62(m，1H)，2.20(m，2H)，1.98(s，3H)，1.42(s，9H)，1.25-1.40(m，7H)，0.82(m，6H)
MS(M＋H) +＝445。
Figure A9980761000971
(2B. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-carboxyl-tetramethyleneimine-5-t-butyl formate
In 0 ℃, with NaClO 2(0.16g) and NaH 2PO 4H 2Water (1ml) solution of O (0.17g) adds (±)-(2R; 3R; 5R; 1 ' S)-(35mg is 0.079mmol) and in the solution that is dissolved in the trimethyl carbinol (1.5ml) and acetonitrile (1.5ml) of 2-methyl-2-butene (0.5ml) for 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate.After 1 hour, use 10%Na 2S 2O 3Aqueous solution quencher should be reacted, and used dichloromethane extraction.Water and salt water washing organic layer, dry (sal epsom) also concentrates, and obtains title compound and (must measure: about 30mg).
MS(M＋H) +＝461。
Figure A9980761000972
(2C. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate
Maintain under 65 ℃, Diazald TM(0.5g, 5ml diethyl ether solution 2.33mmol) slowly add in potassium hydroxide aqueous solution (0.5g is in 1ml water) and the 1ml alcoholic acid solution.(30mg is in the reception flask of 3ml THF solution 0.065mmol) to filling (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-carboxyl-tetramethyleneimine-5-t-butyl formate with the diazomethane distillation.Make the reception flask in ice/water-bath, be cooled to 0 ℃.Use the dry ice/acetone cooler condenser, the 3ml ether is added in this matrass, become colourless until distillate.In this reactant of 0 ℃ of restir 0.5 hour.With this yellow reaction mixture of acetate (0.1ml) quencher, dilute with ethyl acetate.With 10% sodium bicarbonate and salt water washing organic layer, through dried over mgso and vacuum concentration.Residue with 50% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 20mg, 65%).
1H?NMR(CDCl 3)：δ7.25(m，5H)，5.10(d，J＝14Hz，1H)，4.23(m，1H)，4.08(m，1H)，3.85(m，1H)，3.72(m，1H)，3.69(s，3H)，3.40(m，1H)，2.75(m，1H)，2.33(m，1H)，2.15(m，1H)，1.98(s，3H)，1.42(s，9H)，1.20-1.40(m，7H)，0.83(m，6H)
MS(M＋H) +＝475。
Figure A9980761000981
(2D. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate
With (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate (14mg, 0.03mmol) and the mixture of ammonium formiate (0.3g) in the ethanol (1.5ml) of 10% palladium that contains the catalytic amount that is stated from the gac in about 75 ℃ the heating 1 hour.After removing by filter catalyzer, solvent removed in vacuo.Residue obtains the title compound (must measure: 8.5mg, 73%) for colorless oil through the silica gel column chromatography purifying.
MS(M＋H) +＝385。 (2E. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-formate hydrochlorate
(8.5mg, dioxane (1ml) solution of 4N HCl 0.022mmol) stirred under room temperature 24 hours with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl tetramethyleneimine-5-t-butyl formate.Under vacuum, remove and desolvate, obtain title compound (must measure: 8mg, 100%) for pale solid.
1H?NMR(d 6-DMSO)：δ8.02(d，J＝14Hz，1H)，4.40(m，1H)，4.22(m，1H)，3.85(t，J＝13Hz，1H)，3.70(m，1H)，3.65(s，3H)，3.15(m，1H)，2.55(mm，1H)，2.20(m，1H)，1.84(s，3H)，1.12-1.42(m，7H)，0.82(t，J＝12.5Hz，3H)，0.68(t，3H)
MS(M＋H) +＝329，(M－H)-＝327。
Embodiment 3 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-formate hydrochlorate
Figure A9980761000992
(3A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(oxyimino formyl radical)-tetramethyleneimine-5-t-butyl formate.
Method according to description such as Chelucci (Tetrahedron:Asymmetry 5:1973 (1994)); by making (±)-(2R; 3R; 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate and hydroxylamine hydrochloride and 10% wet chemical prepared in reaction title compound in methyl alcohol.
Figure A9980761001001
(3B. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate
Method according to description such as Chelucci (Tetrahedron:Asymmetry5:1973 (1994)); by making (±)-(2R; 3R; 5R; 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(oxyimino formyl radical)-tetramethyleneimine-5-t-butyl formate and 1,1 '-carbonyl dimidazoles is the prepared in reaction title compound in methylene dichloride.
Figure A9980761001002
(3C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate. (3D. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 4 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-propionyl-tetramethyleneimine-5-formate hydrochlorate
Figure A9980761001012
(4A. ±)-(2R, 3R, 5R, 1 ' S, 1 " R)-and (±)-(2R, 3R, 5R, 1 ' S, 1 " S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(1-hydroxyl) propyl group-tetramethyleneimine-5-t-butyl formate.
With ethyl-magnesium-bromide (0.070ml; 3M is in ether) adding (±)-(2R, 3R, 5R; 1 ' S)-(18mg is in 3ml tetrahydrofuran solution 0.041mmol) for 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate.This reaction mixture is remained on 0 ℃, stirred 1 hour.Should react with the aqueous ammonium chloride solution quencher, and between ethyl acetate and water, distribute.Through the dried over mgso organic layer, filter and the concentrated title compound (crude product must be measured: 20mg, 100%) that obtains.MS(M＋H) +＝475。 (4B. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-propionyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 2A, but with ((±)-(2R, 3R, 5R, 1 ' S, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S; 1 " S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(1-hydroxyl) propyl group-tetramethyleneimine-5-t-butyl formate (20mg, 0.041mmol) replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-t-butyl formate (must measure: 11mg, 56%).
MS(M＋H) +＝473。
Figure A9980761001022
(4C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-propionyl-tetramethyleneimine-5-t-butyl formate
In 70 ℃; with (±)-(2R; 3R; 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-propionyl-tetramethyleneimine-5-t-butyl formate (11mg; 0.023mmol), the mixture of ammonium formiate (250mg) and palladium (15mg, 10% is stated from the carbon) heated 20 minutes in ethanol (1.5ml).Filter this reactant, remove catalyzer, concentrate.Residue with 5% methyl alcohol/chloroform wash-out, obtains title compound (must measure: 8.5mg, 95%) through the silica gel column chromatography purifying.
MS(M＋H) +＝383。 (4D. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-propionyl-tetramethyleneimine-5-formate hydrochlorate
Make (±)-solution of (2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-propionyl-tetramethyleneimine-5-t-butyl formate (8mg) is dissolved in dioxane (1ml) solution of 4N HCl, stirred 24 hours under room temperature.This reactant of vacuum concentration obtains the title compound (must measure: 8mg, 100%) for pale solid.
1H?NMR(DMSO-d 6)：δ8.03(d，J＝14Hz，1H)，4.41(m，1H)，4.20(m，1H)，3.92(m，1H)，3.68(m，1H)，3.46(m，1H)，2.65(m，2H)，2.00(m，1H)，1.84(s，3H)，1.10-1.35(m，9H)，0.95(t，J＝Hz，3H)，0.81(t，J＝12.5Hz，3H)，0.75(t，J＝12.5Hz，3H)
MS(M－H) -＝325，(M＋35) +＝361，(2M－H) -＝651；(M＋H) +＝327，(2M＋1) +＝653，(2M＋Na) +＝675。
Embodiment 5 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-methylamino formyl radical)-tetramethyleneimine-5-formate hydrochlorate
Figure A9980761001032
(5A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(N-methyl-formamyl) tetramethyleneimine-5-t-butyl formate.
(18mg, 10ml tetrahydrofuran solution 0.175mmol) cools off on ice bath with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3 carboxyls-tetramethyleneimine-5-t-butyl formate (0.175mmol) and triethylamine.Add the carbonochloridic acid isobutyl ester (24mg, 0.175mmol) and stirred 30 minutes.Add then methylamine (among the 2.0M THF, 0.35ml, 0.70mmol).Stir this mixture, be warmed to ambient temperature overnight simultaneously.Dilute this reactant with ethyl acetate then.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 5% ethanol/methylene wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 17.2mg, 21%).
MS(M＋H) +＝474。 (5B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-methylamino formyl radical)-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 1J; but with (±)-(2R; 3R; 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(N-methylamino formyl radical) tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxyl group-methyl-tetramethyleneimine-5-t-butyl formate (must measure: 13mg, 94%).
MS(M＋H) +＝384。
Figure A9980761001042
(5C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-methylamino formyl radical)-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 1K; but with (±)-(2R; 3R; 5R; 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-methylamino formyl radical) tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(D 2O)：δ4.43(t，J＝10Hz，1H)，4.36(m，1H)，4.09(dd，1H)，3.08(q，J＝10Hz，1H)，2.75(m，4H)，2.25(m，4H)，2.02(s，3H)，1.5-1.15(br，7H)，0.80(m，6H)。
MS(M＋H) +＝328。
Embodiment 6 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(the amino formamyl of N-)-tetramethyleneimine-5-formate hydrochlorate (6A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(the amino formamyl of N-(tert-butoxycarbonyl))-tetramethyleneimine-5-t-butyl formate.
Under room temperature, with (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-carboxyl-tetramethyleneimine-5-t-butyl formate (60mg, 0.13mmol), tertiary butyl carbazates (carbazate) (21mg, 0.16mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC, 31mg, 0.16mmol) and I-hydroxybenzotriazole (9mg, 0.065mmol) 3ml anhydrous tetrahydrofuran solution stirred 6 hours.Dilute this reactant with ethyl acetate then.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 2% ethanol/methylene wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 45.6mg, 61%).
MS(M＋H) +＝575。
Figure A9980761001061
(6B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(the amino formamyl of N-(tert-butoxycarbonyl)) tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 1J; but with (±)-(2R; 3R; 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(the amino formamyl of N-(tert-butoxycarbonyl)) tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate (must measure: 28mg, 75%).
MS(M＋H) +＝484。
Figure A9980761001062
(6C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(the amino formamyl of N-)-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 1K; but with (±)-(2R; 3R; 5R; 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(the amino formamyl of N-(tert-butoxycarbonyl))-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(D 2O)：δ4.32(m，2H)，4.18(dd，1H)，3.14(q，J＝8.4Hz，1H)，2.75(m，1H)，2.26(m，1H)，2.01(s，3H)，1.50-1.15(m，7H)，0.80(q，J＝7.5Hz，6H)。
MS(M＋H) +＝329。
Embodiment 7 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethoxy carbonyl-tetramethyleneimine-5-formate hydrochlorate (7A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-ethoxy carbonyl-tetramethyleneimine-5-t-butyl formate.
Under room temperature, with (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-carboxyl-tetramethyleneimine-5-t-butyl formate (42mg, 0.091mmol), ethanol (0.5ml), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC, 36mg, 0.188mmol) and I-hydroxybenzotriazole (7mg, 0.05mmol) 2ml anhydrous tetrahydrofuran solution stir and spend the night.Dilute this reactant with ethyl acetate then.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 2% ethanol/methylene wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 36mg, 33%).
1H?NMR(CDCl 3)：δ7.50-7.20(br，5H)，5.12(d，J＝9Hz，1H)，4.60-4.30(br，2H)，4.14(q，J＝6Hz，2H)，4.08(m，1H)，3.85(br，1H)，3.72(m，1H)，3.40(m，1H)，2.75(m，1H)，2.32(m，1H)，1.97(s，3H)，1.40(s，9H)，1.37(t，J＝6Hz，3H)，1.20-1.50(m，7H)，0.83(m，6H)。
Mass spectrum: (M+H) +=489.
Figure A9980761001072
(7B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethoxy carbonyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl)-amyl group-3-ethoxy carbonyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.
Mass spectrum: (M+H) +=399. (7C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethoxy carbonyl-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 2E, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethoxy carbonyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(D 2O)：δ4.35(m，1H)，4.20(q，J＝7.5Hz，2H)，3.87-3.55(m，2H)，3.20(q，J＝7.5Hz，1H)，2.67(m，1H)，2.42(m，1H)，2.02(s，3H)，1.24(t，J＝7.5Hz，3H)，1.54-1.1?5(m，7H)，0.82(m，6H)。
Mass spectrum: (M+H) +=343, (M-H) -=341.
Embodiment 8 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethanoyl-tetramethyleneimine-5-formate hydrochlorate (8A. ±)-(2R, 3R, 5R, 1 ' S, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S, 1 ' ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(1-hydroxyl) ethyl-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 4A, but replace ethyl-magnesium-bromide with methylmagnesium-bromide. (8B. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-ethanoyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 2A, but with ((±)-(2R, 3R, 5R, 1 ' S, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S, 1 " S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(1-hydroxyl) ethyl-tetramethyleneimine-5-t-butyl formate (according to the described method preparation of embodiment 8A) replacement (±)-(2R, 3R; 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-hydroxyl-methyl-tetramethyleneimine-5-t-butyl formate. 1H?NMR(CDCl 3)：δ5.00(d，J＝9.7Hz，1H)，3.94(m，2H)，3.68(m，1H)，3.55(m，1H)，2.64(m，1H)，2.32(m，1H)，2.29(s，3H)，2.20(m，1H)，1.94(s，3H)，1.43(s，9H)，1.15-11.35(m，7H)，0.80(m，6H)。
MS:(M+H) +=459
Figure A9980761001101
(8C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethanoyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 4C; but with (±)-(2R; 3R; 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-ethanoyl-tetramethyleneimine-5-t-butyl formate (according to the described method preparation of embodiment 8B) replacement (±)-(2R; 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-propionyl-tetramethyleneimine-5-t-butyl formate.
MS(M＋H) +＝369。
Figure A9980761001102
(8D. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethanoyl-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 1K; but with (±)-(2R; 3R; 5R; 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethanoyl-5-t-butyl formate replacement (±)-(2R; 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.20(m，1H)，4.35(m，1H)，4.15(m，1H)，4.03(m，1H)，2.43(m，1H)，2.03(m，1H)，1.91(s，3H)，1.77(s，3H)，1.55(m，1H)，1.46(m，1H)，1.35(m，2H)，1.12(m，4H)，0.84(m，3H)，0.79(m，3H)。
MS(M＋H) +＝314，(M-H) -＝312。
Embodiment 9 (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-formate hydrochlorate (9A. ±)-(2S, 3R, 5R)-and (±)-(2S, 3 S, 5R)-1-benzyl-2-vinyl-3-carboxyl-tetramethyleneimine-5-t-butyl formate.
Preparation (±)-(2S, 3R, 5R)-and (±)-(2S, 3S, 5R)-1-benzyl-2-vinyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate (10g, 31.7mmol) the 39ml ethanolic soln of (ratio 8: 1).With silver suboxide (8.83g, 38.1mmol) and potassium hydroxide (10.86g, 194mmol) suspension in 65ml water is handled this solution.Under room temperature, stir this reactant 1 hour, pass through Celite Pad filters.Vacuum is removed ethanol.With acetate with this acidified aqueous solution to about pH4.With this acidic solution of ethyl acetate extraction.With salt water washing organic layer,, filter and concentrate the title compound (crude product must be measured: 8.2g, 77%) that obtains to brown oil through dried over sodium sulfate.This crude acid can be used for next step without being further purified.
MS(M＋H) +＝332，(M－H) -＝330。
Figure A9980761001112
(9B. ±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate
With (±)-(2S; 3R; 5R)-and (±)-(2S; 3S; 5R)-1-benzyl-2-vinyl-3-carboxyl-tetramethyleneimine-5-t-butyl formate (1.0g, 3.02mmol), diphenyl phosphoryl azide (0.83g, 3.32mmol), benzyl alcohol (0.36g; 4.53mmol) and triethylamine (0.32g, 3.32mmol) the mixture reflux in 30ml toluene is 16 hours.Evaporating solvent, residue with 10% ethyl acetate/hexane wash-out, obtain the title compound (must measure: 0.86g, 65%) for colorless oil through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ7.20-7.40(m，10H)，5.70(m，2H)，5.10-5.23(m，3H)，4.10(m，1H)，3.85(m，1H)，3.62(m，1H)，3.45(m，2H)，2.50(m，1H)，1.70(m，1H)，1.41(s，9H)。
MS(M＋H) +＝437。 (9C. ±)-(2R, 3R, 5R)-1-benzyl-2-formyl radical-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate
Perosmic anhydride (3 crystallization) is added in (±)-(2S in the 27ml acetone (8: 1), 3R, 5R)-1-benzyl-2-vinyl-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate (1.10g, 2.52mmol), N-methylmorpholine N-oxide compound (0.95g, being maintained in the stirred solution under room temperature 8.07mmol).After 6 hours, add 10% Na 2S 2O 3The aqueous solution also continues to stir other 15 minutes, with this reactant of dichloromethane extraction, concentrates organic layer, obtains crude product two alcohol intermediates.This diol product can need not other purifying and be used for next step.
MS(M＋H) +＝471。
(1.0g, 4.52mmol) gradation adds described crude product glycol (about 1.25g is in the solution of the stirring of 21ml THF/ water (6: 1) 2.66mmol) with sodium periodate.Stirred this reactant 1 hour, and diluted with ethyl acetate then.Water and salt water washing organic layer through dried over mgso, filter and concentrate.Residue with 15% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 0.66g, 60%).
1H?NMR(CDCl 3)：δ9.44(d，J＝1.2Hz，1H)，7.20-7.40(m，10H)，5.98(d，J＝14Hz，1H)，5.10(m，2H)，4.45(m，1H)，3.90(m，2H)，3.70(m，1H)，3.60(m，1H)，2.43(m，1H)，1.70(m，1H)，1.45(s，9H)。
MS(M＋H) +＝439。(9D. ±)-(2R, 3R, 5R, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-hydroxyl-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate
Under argon gas, (1.7g 10.3mmol) is added in and fills magnesium (0.25g is in the 15ml anhydrous THF solution of the ethylene dibromide in flask 10.3mmol) (3) with 1-bromo-2-ethyl butane.This reaction mixture of reflux 45 minutes reacts until most of magnesium.This solution is cooled to room temperature, is being maintained under-10 ℃ and the argon gas.Transfer to CuBrSMe by conduit 2(2.12g is 10.3mmol) in the suspension of 15ml dry THF.Stirred this mixture 0.5 hour, and changeed dark until solution colour.Drip (±)-(2R, 3R, 5R)-1-benzyl-2-formyl radical-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate (0.45g, 10ml THF solution 1.03mmol), and stirred 1.5 hours.Keep temperature in 0 ℃ simultaneously.Should reaction with the aqueous ammonium chloride solution quencher.With ethyl acetate dilution, water and salt water washing,, filter and concentrate through dried over mgso.Residue with 10% ethyl acetate/hexane wash-out, obtains alcohol adducts through the silica gel column chromatography purifying, is faint yellow oily thing (must measure: 160mg, 30%).
1H?NMR(CDCl 3)：δ7.20-7.40(m，10H)，6.10(d，J＝14Hz，1H)，5.10(m，2H)，4.22(m，1H)，4.01(m，1H)，3.71(m，1H)，3.65(m，2H)，3.55(m，1H)，3.20(m，1H)，2.00-2.30(m，2H)，1.45(s，9H)，1.15-1.40(m，7H)，0.84(m，6H)。
MS(M＋H) +＝525。
Figure A9980761001131
(9E. ±)-(2R, 3R, 5R)-1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate
The 5ml anhydrous methylene chloride solution of preparation oxalyl chloride (0.29ml is in the 2M methylene dichloride) also remains under-78 ℃ and the nitrogen.(90mg 1.14mmol) adds in this solution with DMSO.This mixture was stirred 15 minutes, and (150mg, 5ml dichloromethane solution 0.286mmol) are added drop-wise in above-mentioned cold (78 ℃) reaction mixture with the alcohol adducts for preparing above.This solution was stirred 1 hour in-78 ℃.Slow adding triethylamine (250mg, 2.29mmol).Make this reactant slowly be warmed to room temperature, dilute with methylene dichloride then.Water and salt water washing organic layer through dried over mgso, filter and concentrate.Residue with 5% ethyl acetate/hexane wash-out, obtains title compound (must measure: 100mg, 67%) through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ7.35(m，10H)，5.10(m，2H)，4.28(m，1H)，3.95(m，2H)，2.60(m，1H)，2.40(m，1H)，2.03(m，1H)，1.70(m，2H)，1.45(s，9H)，1.10-1.30(m，7H)，0.70(m，6H)。
MS(M＋H) +＝523。
Figure A9980761001141
(9F. ±)-(2S, 3R, 5R, 1 ' R)-and (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate.
With (±)-(2R, 3R, 5R)-1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate (90mg, 0.172mmol), ammonium acetate (400mg, 5.17mmol) and sodium cyanoborohydride (65mg, the 5ml methanol solution reflux of mixture 1.03mmol) 18 hours.The ammonium acetate and the sodium cyanoborohydride that add extra section continue other 2 hours of heating.Should react with the quencher of 1N sodium hydroxide, dilute with methylene dichloride.Water and salt water washing organic layer through dried over mgso, filter and concentrate.Product with 1: 1 ethyl acetate/hexane wash-out, then with 5% ethanol/methylene wash-out, obtains title compound (must measure: 58mg, 64%) through the silica gel column chromatography purifying.
MS(M＋H) +＝254。
Figure A9980761001151
(9G. ±)-(2S, 3R, 5R, 1 ' R)-and (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate.
Under room temperature, with (±)-(2S, 3R, 5R, 1 ' R)-and (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate (50mg, 0.096mmol) and diacetyl oxide (117mg, 1.15mmol) 5ml dichloromethane solution stirred 1 hour.Solvent removed in vacuo, residue with 30-50% ethyl acetate/hexane wash-out, obtain the title compound (must measure: 51mg, 97%) for colorless oil through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ7.72-7.35(m，10H)，5.82(d，J＝14Hz，1H)，5.10(m，2H)，4.38(m，1H)，4.15(m，2H)，3.63(m，1H)，3.38(m，1H)，3.10(m，1H)，2.15(m，1H)，2.00(s，3H)，1.65(m，1H)，1.42(s，9H)，1.20-1.35(m，7H)，0.80(m，6H)
MS(M＋H) +＝567。
Figure A9980761001152
(9H. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate.
With (±)-(2S, 3R, 5R, 1 ' R)-and (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate (49mg, 0.087mmol), ammonium formiate (150mg, 0.22mmol) and 10% the ethanol that is stated from the palladium on the activated carbon (5ml) solution in 80 ℃ of heating 45 minutes.After removing by filter catalyzer, remove and desolvate.Residue with 5-10% ethanol/methylene wash-out, obtains diastereomer, (±)-(2S through the silica gel column chromatography purifying, 3R, 5R, 1 ' S) (19mg) and (±)-(2S, 3R, 5R, 1 ' R) (8.6mg) 2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate.
1H?NMR(CDCl 3)：δ6.00(d，J＝14Hz，1H)，3.90(m，1H)，3.73(m，1H)，3.49(m，1H)，3.10(m，1H)，2.48(m，1H)，2.03(s，3H)，1.82(m，1H)，1.48(s，9H)，1.15-1.42(m，7H)，0.85(m，6H)
MS(M＋H) +＝342。
Figure A9980761001161
(9I. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-formic acid dihydrochloride.
Under room temperature, with (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate (17mg, 1ml 6N HCl solution stirring 0.050mmol) 3 hours.Under high vacuum, remove and desolvate, obtain title compound (must measure: 15mg, 100%) for white solid.
1H?NMR(d 6-DMSO)：δ8.28(bs，1H)，7.90(d，J＝Hz，1H)，4.71(d，J＝14Hz，1H)，4.39(m，1H)，4.10(m，1H)，3.92(m，1H)，3.08(m，1H)，2.64(m，1H)，2.31(m，1H)，1.95(m，1H)，1.88(s，3H)，1.50(m，1H)，1.10-1.40(m，7H)，0.72-0.90(m，6H)。
MS(M＋H) +＝286。
Embodiment 10 (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-acetamido-tetramethyleneimine-5-formate hydrochlorate. (10A. ±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate.
Under 1 normal atmosphere hydrogen, with (±)-(2S, 3R, 5R, 1 ' S)-(50mg is 0.88mmol) with 10% the solution stirring of palladium on carbon (5mg) in the 50ml ethyl acetate 45 minutes for 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate.Filter this reactant, concentrate the title compound (crude product must be measured: 35mg, 92%) that obtains to oily matter.
MS(M＋H) +＝431。 (10B. ±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-acetamido-tetramethyleneimine-5-t-butyl formate.
Make (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate (35mg, the 8ml dichloromethane solution reaction of solution 0.080mmol) and diacetyl oxide (0.05ml) 1 hour.Concentrate this reactant, residue is used 50% ethyl acetate/hexane through the silica gel column chromatography purifying, uses 3% ethanol/methylene wash-out then, obtains title compound (must measure: 30mg, 80%).
1H?NMR(CDCl 3)：δ7.20-7.35(m，5H)，6.62(d，J＝14Hz，1H)，5.34(d，J＝14Hz，1H)，4.42(m，2H)，4.20(m，1H)，3.68(m，1H)，3.42(m，1H)，3.10(m，1H)，2.18(m，2H)，2.02(s，3H)，1.96(s，3H)，1.45(s，9H)，1.25-1.42(m，7H)，0.85(m，6H)
MS(M＋H) +＝474。 (10C. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-acetamido-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-acetamido-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.Residue with 5% ethanol/methylene wash-out, obtains title compound (must measure: 11.5mg, 50%) through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ6.20(d，J＝14Hz，1H)，5.94(d，J＝14Hz，1H)，4.24(m，1H)，4.08(m，1H)，3.95(m，1H)，3.75(m，1H)，3.18(m，1H)，2.45(m，1H)，2.02(s，3H)，1.96(s，3H)，1.82(m，1H)，1.49(s，9H)，1.20-1.42(m，7H)，0.85(m，6H)
MS(M＋H) +＝384。
Figure A9980761001182
(10D. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-acetamido-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-acetamido-tetramethyleneimine-5-t-butyl formate (11.0mg, 0.029mmol) replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 11.0mg, 100%).
1H?NMR(d 6-DMSO)δ8.15(d，J＝14Hz，1H)，8.05(d，J＝14Hz，1H)，4.35(m，1H)，4.28(m，1H)，4.19(m，1H)，3.59(m，1H)，1.90(s，3H)，1.81(s，3H)，1.15-1.40(m，7H)，0.80(m，6H)
MS(M－H) -＝326，(M＋35) +＝362，(M＋H) +＝328，(M＋23) +＝350。Embodiment 11 (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl amino-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001191
(11A. ±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxyl group-carbonylamino-tetramethyleneimine-5-t-butyl formate.
Make (±)-solution of (2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate and methyl chlorocarbonate and triethylamine react in methylene dichloride.Reactant is distributed between methylene dichloride and water.Concentrated organic layer obtains title compound.
Figure A9980761001192
(11B. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl amino-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl amino-pyrrolidine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate. (11C. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl amino-tetramethyleneimine-5-formate hydrochlorate.
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl amino-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 12 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazol-4 yl)-5-formic acid dihydrochloride.
Figure A9980761001202
(12A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-diazonium ethanoyl-5-t-butyl formate.
In-10 ℃, make (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-carboxyl-tetramethyleneimine-5-t-butyl formate (405.3mg, 0.88mmol) and N-methylmorpholine (106 μ l, (20ml) solution of THF 0.96mmol) and carbonochloridic acid isobutyl ester (96 μ l, 0.93mmol) reaction 30 minutes.In reaction flask, import the ethereal solution (by the ethanol (15ml) and the preparation of water (15ml) solution reaction of diazald (2.4g) ether (60ml) solution and potassium hydroxide (2.4g)) of the diazomethane after distilling with conduit.Under room temperature, stirred this reactant 3 hours, dilute with ether then.With salt water washing organic layer, dry (sodium sulfate) also concentrates and obtains title compound, is thick oily matter (430.4mg). (12B. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-bromo ethanoyl-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3R; 5R; 1 ' S)-(427.4mg, (0.25ml, 2.2mmol) reaction is 0.5 hour for (50ml) solution of dioxane 0.88mmol) and Hydrogen bromide for 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-diazonium ethanoyl-5-t-butyl formate.Should reaction and vacuum concentration with saturated sodium bicarbonate aqueous solution (25ml) quencher.(3 * 50ml) extract residual water layer with methylene dichloride.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is through the silica gel column chromatography purifying, and the dichloromethane solution wash-out with 5% methyl alcohol obtains title compound, is white foam shape solid (379.3mg, 80.2%).
MS(M＋H) +＝539。
Figure A9980761001221
(12C. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(imidazol-4 yl)-5-t-butyl formate.
In 45 ℃, (120mg 1.15mmol) handles (±)-(2R in liquefied ammonia with formamidine acetate; 3R; 5R, 1 ' S)-(60mg 0.112mmol) and in the sealing test tube heated 20 hours in 45 ℃ 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-bromo ethanoyl-5-t-butyl formate.This reactant of vacuum concentration.Residue is handled with sodium bicarbonate aqueous solution, and (5 * 20ml) extract with methylene dichloride.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is through the silica gel column chromatography purifying, and the dichloromethane solution wash-out with 5% methyl alcohol obtains title compound, is white solid (21.2mg, 39.4%).
MS(M＋H) +＝483。
Figure A9980761001222
(12D. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazol-4 yl)-5-t-butyl formate.
According to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(imidazol-4 yl)-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxyl group-methyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 12.9mg, 66.2%).
1H?NMR(CDCl 3)：δ0.75-0.81(m，6H)，1.17-1.42(m，7H)，1.47(s，9H)，2.03(s，3H)，2.66(m，1H)，3.50(m，1H)，3.73(m，1H)，3.86(m，1H)，4.06(m，1H)，7.04(brs，1H)，7.86(brs，1H)。
MS(M＋H) +＝393。 (12E. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazol-4 yl)-5-formic acid dihydrochloride.
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazol-4 yl)-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate, obtain title compound solid (must measure: 12.0mg, 96.0%).
1H?NMR(DMSO-d 6)：δ0.67(t，J＝7Hz，3H)，0.75(t，J＝7Hz，3H)，1.11(m，3H)，1.23(m，4H)，1.78(s，3H)，2.33(m，1H)，2.70(m，1H)，3.69(dt，1H)，3.95(dd，1H)，4.29(m，1H)，4.48(dd，1H)，7.63(s，1H)，8.28(d，J＝9Hz，1H)，9.06(s，1H)。
MS(M＋H) +＝337。
Embodiment 13 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(oxazole-2-yl)-tetramethyleneimine-5-formic acid dihydrochloride. (13A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(N-(2-hydroxyethyl) formamyl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 5A, but replace the N-methylamine hydrochloride with thanomin. (13B. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(oxazoline-2-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature; make (±)-(2R; 3R; 5R, 1 ' S)-acetonitrile solution of 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(N-(2-hydroxyethyl) formamyl)-tetramethyleneimine-5-t-butyl formate, triethylamine (4eq.), tetracol phenixin (3.5eq.) and triphenyl phosphine (3.15eq.) reaction 16 hours.This reactant of vacuum concentration.Residue is distributed between ethyl acetate and water.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is used the ethyl acetate/hexane wash-out through the silica gel column chromatography purifying, obtains title compound. (13C. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(oxazole-2-yl)-tetramethyleneimine-5-t-butyl formate.
According to Meyer at J.Org.Chem.1979, method described in the 497-501, make (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(oxazoline-2-yl)-solution and the nickel peroxide of tetramethyleneimine-5-t-butyl formate react in hexanaphthene, obtains title compound.
Figure A9980761001251
(13D. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(oxazole-2-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(oxazole-2-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.
Figure A9980761001252
(13E. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(oxazole-2-yl)-tetramethyleneimine-5-formic acid dihydrochloride.
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-(oxazole-2-yl) tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.
Embodiment 14 (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(N-methylamino) tetramethyleneimine-5-formic acid dihydrochloride. (14A. ±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-(N-methyl-N-benzyloxycarbonyl amino)-tetramethyleneimine-5-t-butyl formate.
With (±)-(2S, 3R, 5R)-(2.08g 4.77mmol) is dissolved in the 50ml dry DMF and under nitrogen and keeps 1-benzyl-2-vinyl-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate.(0.32g 8mmol) handles this solution, stirs 30 minutes under room temperature with sodium hydride.(0.8ml 12.85mmol) handled this solution and restir 1 hour with methyl iodide.The water quencher should be reacted, and used ethyl acetate extraction.Concentrate the organic layer that merges and obtain crude product, this material obtains the title compound (must measure: 1.75g, 81%) for oily matter through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ7.36-7.20(m，10H)，5.75-5.50(br，1H)，5.25-5.07(m，4H)，4.75-4.50(br，1H)，3.97(d，J＝13.5Hz，1H)，3.75(m，1H)，3.61(d，J＝13.5Hz，1H)，3.50(m，1H)，2.93(s，3H)，2.45(m，1H)，1.75(m，1H)，1.46(s，9H)。
MS(M＋H) +＝451。 (14B. ±)-(2R, 3R, 5R)-1-benzyl-2-formyl radical-3-(N-methyl-N-benzyloxycarbonyl-amino) tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 9C, but with (±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-(N-methyl-N-benzyloxycarbonyl amino) tetramethyleneimine-5-t-butyl formate replacement (±)-(2S, 3R, R)-1-benzyl-2-vinyl-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate prepares title compound (must measure: 747mg, 42%).
MS(M＋H) +＝453。
Figure A9980761001271
(14C. ±)-(2R, 3R, 5R)-1-benzyl-2-(1-oxo-3-methyl) butyl-3-(N-methyl-N-benzyloxycarbonyl amino) tetramethyleneimine-5-t-butyl formate.
With about 12 minutes with chlorination isobutyl-magnesium (2.0M; in ether; 0.68ml) be added drop-wise to (±)-(2R; 3R; 5R)-1-benzyl-2-formyl radical-3-(N-methyl-N-benzyloxycarbonyl amino) tetramethyleneimine-5-t-butyl formate (196mg, being maintained in-78 ℃ 5ml anhydrous THF solution 0.43mmol).In-78 ℃ of yellow solutions that stir to generate 1 hour.With this solution of saturated aqueous ammonium chloride quencher, use ethyl acetate extraction.Concentrate organic layer, according to the crude product of method oxidation described in the embodiment 9D.Through purification by silica gel column chromatography,, obtain title compound (must measure: 78mg, 36%) with 10-25% ethyl acetate/hexane wash-out.
1H?NMR(CDCl 3)：δ7.46-7.25(m，10H)，5.09(br，2H)，4.90-4.60(m，1H)，3.97-3.65(m，4H)，3.00(s，3H)，2.60(br，1H)，2.20-1.80(m，3H)，1.46(s，9H)，0.80-0.67(m，7H)。
MS(M＋H) +＝509。 (14D. ±)-(2S, 3R, 5R, 1 ' R)-and (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-methyl) butyl-3-(N-methyl-N-benzyloxycarbonyl amino) tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 9F; but with (±)-(2R; 3R; 5R)-1-benzyl-2-(1-oxo-3-methyl) butyl-3-(N-methyl-N-benzyloxycarbonyl amino) tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R)-1-benzyl-2-formyl radical-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate.(must measure: 97mg, 65%).
MS(M＋H) +＝510。 (14E. ±)-(2S, 3R, 5R, 1 ' R)-and (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-(N-methyl-N-benzyloxycarbonyl amino) tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2S, 3R, 5R, 1 ' R)-and (±)-(2S, 3R, 5R, 1 ' S)-(47mg, solution 0.094mmol) and diacetyl oxide (0.15ml) reacted 2 hours in the 4ml dichloromethane solution 1-benzyl-2-(1-amino-3-methyl) butyl-3-(N-methyl-N-benzyloxycarbonyl amino) tetramethyleneimine-5-t-butyl formate.This reactant of vacuum concentration obtains title compound.
MS(M＋H) +＝552。 (14F. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(N-methylamino)-tetramethyleneimine-5-t-butyl formate.
With (±)-(2S, 3R, 5R, 1 ' R)-and (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-(N-methyl-N-benzyloxycarbonyl amino) tetramethyleneimine-5-t-butyl formate (0.094mmol), palladium (40mg, 10% is stated from the carbon) and the solution reflux of ammonium formiate (160mg) in 3ml ethanol 30 minutes.Add other palladium on carbon (15mg) and ammonium formiate (50mg).With this solution restir 15 minutes, filter this mixture then and remove solid and catalyzer.Evaporated filtrate, residue are through the silica gel column chromatography purifying, with 5% ethanol/methylene and 1% ammonium hydroxide wash-out, obtain (±)-(2S, 3R, 5R, 1 ' S) (15.4mg, hang down Rf) and (±)-(2S, 3R, 5R, 1 ' R) (5.4mg, high Rf)-2-(1-acetamido-3-methyl) butyl-3-(N-methylamino) tetramethyleneimine-5-t-butyl formate (must measure: 20.8mg, 68%).
Figure A9980761001291
(14G. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(N-methylamino) tetramethyleneimine-5-formic acid dihydrochloride.
The solution of (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(N-methylamino) tetramethyleneimine-5-t-butyl formate (9.4mg) was stirred 2 hours with the 4N HCl aqueous solution (about 1.5ml).This reactant of vacuum concentration obtains title compound (must measure: 10mg, 100%).
1H NMR (main peaks) (DMSO-d 6): δ 2.57 (s, 3H), 1.90 (s, 3H), 1.47 (m, 3H), 0.91 (d, J=7.5Hz3H), 0.83 (d, J=7.5Hz, 3H)
MS(M＋H) +＝272。
Embodiment 15 (±)-(2R, 3R, 5R, 1 " S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-formic acid dihydrochloride. (15A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate.
The ammonia bubbling is slowly fed (±)-(2R; 3R; 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate (20mg; 0.045mmol) and oxalic dialdehyde (6.2 μ l; 0.054mmol, 1.2 equiv.) be maintained in 0 ℃ the 5ml methanol solution 5 minutes.In 0 ℃ after 7 hours, add extra oxalic dialdehyde (10 μ l), and the ammonia bubbling was fed in this solution 5 minutes.Under room temperature, stirred this reactant 16 hours.Add oxalic dialdehyde (10 μ l) and ammonia as mentioned above at last, then under room temperature, react 4 hours again to finish this reaction.This reactant of vacuum concentration through the silica gel column chromatography purifying, with 50% ethyl acetate/hexane wash-out, is followed the methyl alcohol/chloroform wash-out with 10%, obtains title compound, is solid (must measure: 19.9mg, 91%).
1H?NMR(CDCl 3)：d?0.67(t，J＝7.2Hz，3H)，0.73(t，J＝7.2Hz，3H)，1.09-1.32(m，7H)，1.41(s，9H)，2.00(m，1H)，2.09(s，3H)，2.79(m，1H)，3.29(m，1H)，3.66(dd，J＝9.6，2.7Hz，1H)，3.77(m，1H)，3.92(d，J＝13.4Hz，1H)，4.04(d，J＝13.4Hz，1H)，4.22(dd，1H)，4.49(m，1H)，6.08(brs，1H)，7.00(s，2H)，7.21-7.34(m，5H)。
MS(M＋H) +＝483。
Figure A9980761001301
(15B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate.
With (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate (17mg, 0.035mmol), ammonium formiate (250mg) and the mixture reflux of 10% palladium on carbon (20mg) in 5ml ethanol 15 minutes.This reactant of vacuum concentration, residue with 5% ethanol/methylene and 0.25% ammonium hydroxide wash-out, obtain title compound through the silica gel column chromatography purifying, are white solid (must measure: 11.3mg, 81.9%).MS(M＋H) +＝393。
Figure A9980761001311
(15C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-formic acid dihydrochloride.
(11mg 0.028mmol) is dissolved among the 2ml 6N HCl, stirs 2 hours under room temperature with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate.This reactant of vacuum concentration obtains title compound, is pale solid (must measure: 11.3mg, 100%).
1H?NMR(DMSO-d 6)：δ0.71(t，J＝7Hz，3H)，0.75(t，J＝7Hz，3H)，1.09-1.28(m，7H)，1.74(s，3H)，2.43(m，1H)，2.80(m，1H)，3.85(m，1H)，4.04(m，1H)，4.29(m，1H)，4.52(m，1H)，7.64(s，2H)，8.07(br?d，J＝9Hz，1H)。
MS (M+H) +=337 and (M-H) -=335.
Embodiment 16 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N, N-formyl-dimethylamino)-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001312
(16A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(N, N-formyl-dimethylamino) tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 5A, but replace the N-methylamine, the preparation title compound with the N.N-dimethylamine.(must measure: 10mg, 23%).
Mass spectrum: (M+H) +=488. (16B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-methylamino formyl radical) tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1J; but with (±)-(2R; 3R, 5R, 1 " S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(N; N-formyl-dimethylamino) tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxyl group-methyl-tetramethyleneimine-5-t-butyl formate; preparation title compound (must measure: 5.5mg, 67%).
Mass spectrum (M+H) +=398.
Figure A9980761001322
(16C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N, N-formyl-dimethylamino)-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K; but with (±)-(2R; 3R; 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N, N-formyl-dimethylamino) tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R; 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate, the preparation title compound.
1H NMR (main peaks) (D 2O): d3.15 (s, 3H), 2.94 (s, 3H), 1.98 (s, 3H), 0.80 (m, 6H).
MS(M＋H) +＝342，(M－H) -＝340。
Embodiment 17 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-formate hydrochlorate. (17A. ±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-cyano group-tetramethyleneimine-5-t-butyl formate.
Method according to description such as Chelucci (Tetrahedron.Asymmetry 5:1973 (1994)); make (±)-(2S; 3S; 5R)-1-benzyl-2-vinyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate (8: 1 ratios) (5g; 15.9mmol) solution and oxammonium hydrochloride (1.28g; 18.5mmol) and 10% wet chemical (8ml) in 20ml methyl alcohol, react, obtain intermediate oxime product.
Under room temperature, make the crude product oxime and 1 for preparing above, 1 '-carbonyl dimidazoles (3.9,23.9mmol) in the 50ml methylene dichloride, reacted 3 hours.This reactant of vacuum concentration through the silica gel column chromatography purifying, with 2-10% ethyl acetate/hexane wash-out, obtains title compound (must measure: 2.5g, 50%).
MS：(M＋H) +＝313。 (17B. ±)-(2R, 3R, 5R)-1-benzyl-2-formyl radical-3-cyano group-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1D, but with (±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-cyano group-tetramethyleneimine-5-t-butyl formate replacement (±)-(2S, 3R, 5R)-and 1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 2.2g, 80%).
MS(M＋H) +＝315。 (17C. ±)-(2R, 3R, 5R)-1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1E; but with (±)-(2S; 3R; 5R)-1-benzyl-2-formyl radical-3-cyano group-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R; 5R)-and 1-benzyl-2-formyl radical-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.4g, 27%).
MS(M＋H) +＝399。
Figure A9980761001342
(17D. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1F, but with (±)-(2R, 3R, 5R)-1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R)-and 1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.215g, 50%).
MS(M＋H) +＝400。
Figure A9980761001351
(17E. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1G, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.210g, 90%).
1H?NMR(CDCl 3)：δ7.25(m，5H)，5.08(m，1H)，4.40(m，1H)，4.15(m，1H)，3.78(m，1H)，3.48(m，1H)，2.93(m，1H)，2.32(m，1H)，2.12(m，1H)，2.02(s，3H)，1.52(s，9H)，1.35(m，7H)，0.85(m，6H)。
MS(M＋H) +＝442。
Figure A9980761001352
(17F. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(CDCl 3)：δ5.35(bs，1H)，4.00(m，1H)，3.83(m，1H)，3.39(m，1H)，3.08(m，1H)，2.63(m，1H)，2.15(m，1H)，2.05(s，3H)，1.48(s，9H)，1.20-1.45(m，7H)，0.85(m，6H)。
MS(M＋H) +＝352。
Figure A9980761001361
(17G. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-formate hydrochlorate.
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(d 6-DMSO)：δ9.12(bs?1H)，8.05(m，1H)，4.38(m，1H)，4.23(m，1H)，3.88(m，1H)，3.68(m，1H)，3.00(m，1H)，2.55(m，1H)，2.05(m，1H)，1.88(s，3H)，1.10-1.40(m，7H)，0.80(m，6H)。
MS(M＋H) ＋＝296，(M－H) -＝294。
Embodiment 18 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethyl-tetramethyleneimine-5-formate hydrochlorate
Figure A9980761001362
(18A. ±)-(2R, 3S, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-vinyl-tetramethyleneimine-5-t-butyl formate.
Under nitrogen, to the Diethylaminoethyl triphenyl phosphonium (240mg, 0.67mmol) in the ice-cold suspension of 5ml THF, add potassium tert.-butoxide (60mg, 0.54mmol).Color is changed into glassy yellow immediately.After stirring 1 hour under the room temperature, (100mg 0.225mmol), stirs under room temperature and spends the night to be added in (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate among the 5ml THF.Should react with the saturated ammonium chloride quencher then, use ethyl acetate extraction, obtain crude product.This material with 30% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 55mg, 55%).
1H?NMR(CDCl 3)：δ7.45-7.20(m，5H)，5.94(ddd，1H)，5.24(d，J＝12Hz，1H)，4.98(d，J＝18Hz，1H)，4.93(d，J＝10.5Hz，1H)，4.37(m，1H)，4.06(d，J＝13.5Hz，1H)，3.80(d，J＝13.5Hz，1H)，3.41(dd，J＝9?Hz，J＝3Hz，1H)，3.31(q，J＝13.5Hz，1H)，2.60(m，1H)，2.26(m，1H)，2.00(s，3H)，1.45(s，9H)，1.40-1.25(m，7H)，0.82(m，6H)。
MS：(M＋H) +＝443。
Figure A9980761001371
(18B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethyl-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2R, 3S, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3--methoxymethyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(CDCl 3)：δ5.71(br，1H)，4.00(br，1H)，3.68(t，J＝8Hz，1H)，3.10(m，1H)，2.38(m，1H)，1.98(s，3H)，1.87(m，1H)，1.47(s，9H)，1.55-1.20(m，10H)，0.93(t，J＝7.5Hz，3H)，0.83(m，6H)。
MS(M＋H) +＝355。
Figure A9980761001381
(18C. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethyl-tetramethyleneimine-5-formate hydrochlorate.
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(D 2O)：δ4.30(br，1H)，4.25(t，J＝7.5Hz，2H)，3.58(br，1H)，2.61(m，1H)，2.23(br，1H)，2.05(s，3H)，1.90(m，1H)，1.70-1.20(m，9H)，0.92(t，J＝7.5Hz，3H)，0.81(m，6H)。
MS(M＋H) +＝299
Embodiment 19 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-propyl group-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001382
(19A. ±)-(2R, 3S, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate and (±)-(2R, 3S, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(trans-propylene-the 1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 18A, but replace the Diethylaminoethyl triphenyl phosphonium with bromination Yi base triphenyl phosphonium.
1H?NMR(CDCl 3)：δ7.24(m，5H)，5.59(m，1H)，5.36(dd，J＝11，7Hz，1H)，5.28(bs，1H)，4.32(m，1H)，4.06(d，J＝12.9Hz，1H)，3.80(d，J＝12.9Hz，1H)，3.42(dd，J＝8.5，2.0Hz，1H)，3.30(dd，J＝6.1，3.1Hz，1H)，2.88(m，1H)，2.29(m，2H)，2.01(s，3H)，1.64(dd，J＝6.8，1.7Hz，3H)，1.44(s，9H)，1.30(m，7H)，0.81(m，6H)。
MS：(M＋H) +＝457，(M＋Na) +＝479，(M－H) -＝455。
Figure A9980761001391
(19B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-propyl group-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1J, but with (±)-(2R, 3S, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate and (±)-(2R, 3S, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(trans-propylene-the 1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.5mg, 54%).
MS：(M＋H) +＝369，(M＋Na) +＝391，(M－H) -＝367。
Figure A9980761001392
(19C. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-propyl group-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-ethyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.5mg, 100%).
1H?NMR(DMSO-d 6)：δ8.10(d，J＝8.3Hz，1H)，4.24(m，1H)，4.17(m，1H)，2.43(m，1H)，2.19(m，1H)，1.89(s，3H)，1.70(m，1H)，1.50-1.20(m，12H)，0.87(t，J＝6.8Hz，3H)，0.84(t，J＝7.0Hz，3H)，0.79(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝313，(M＋Na) +＝335，(M－H) -＝311。
Embodiment 20 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001401
(20A. ±)-(2R, 3R, 5R, 1 ' RS)-1-benzyl-2-(1, the 2-dihydroxyl) ethyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
Perosmic anhydride is added in 8: 1 acetone and the N-methylmorpholine N-oxide compound (3.0g of 60ml, 25.6mmol) in (±)-(2S, 3R, 5R)-(3.5g is in the solution under room temperature 8.12mmol) for 1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.At room temperature stir this reaction mixture 6 hours, and used saturated Na 2S 2O 3Aqueous solution quencher.With this mixture restir 10 minutes, remove and desolvate.Brown residue is distributed between methylene dichloride and water.Through dried over mgso organic layer and vacuum concentration, obtain intermediate glycol (about 3.8g) into oily matter, it can need not other purifying and use.
MS：(M＋H) +＝466。 (20B. ±)-(2R, 3R, 5R, 1 ' RS)-2-(1, the 2-dihydroxyl) ethyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' RS)-1-benzyl-2-(1, the 2-dihydroxyl) ethyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (21.5g, 46.2mmol) replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.
MS(M＋H) +＝367。
Figure A9980761001411
(20C. ±)-(2R, 3R, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1, the 2-dihydroxyl)-ethyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
Make (±)-(2R, 3R, 5R, 1 ' RS)-2-(1, the 2-dihydroxyl) ethyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (deriving from the crude product of preceding step) is dissolved in 160ml3: in 1 the methanol, the adding tert-Butyl dicarbonate (14.0g, 64mmol).Under room temperature, stirred this mixture 72 hours.Remove then and desolvate, residue with 50% ethyl acetate/hexane wash-out, obtains the title compound (must measure: 15.4g, 70%) for faint yellow solid through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)：δ0.03(s，3H)，0.05(s，3H)，1.37(s，9H)，.42(s，9H)，1.47(s，9H)，1.93(d，1H)，2.30-2.50(m，2H)，3.28(d，1H)，3.66-3.43(m，4H)，3.85(dd，1H)，4.02-4.52(m，1H)。
MS(M＋H) +＝476。 (20D. ±)-(2R, 3R, 5R)-1-tert-butoxycarbonyl-2-formyl radical-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
Make (±)-(2R, 3R, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1, the 2-dihydroxyl) ethyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (6.0g, 12.6mmol) solution be dissolved in tetrahydrofuran (THF) (THF)/water (110ml) of 6: 1, (4.4g 20.6mmol) handles with sodium periodate.Stirred this mixture 3 hours under the room temperature, and, wash with water,, filter and vacuum concentration through dried over mgso with the ethyl acetate dilution.Residue, obtains being white wax sample solid title compound (must measure: 4.4g, 78.6%) with 20% ethyl acetate/hexane wash-out through the silica gel column chromatography purifying.
1H NMR (CDCl 3) (mixtures of two kinds of rotational isomers): δ 0.05 and 0.06 (two s, 6H), 0.88 and 0.90 (two s, 9H), 1.42 and 1.44 (two s, 9H), 1.47 and 1.48 (two s, 9H), 1.89-1.99 (m, 1H), and 2.37-2.43 (m, 2H), 3.54-3.67 (m, 2H), 4.02-4.34 (m, 2H), 9.43 and 9.53 (two d, 1H).MS(M＋H) +＝444。
Figure A9980761001421
(20E. ±)-(2R, 3R, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-hydroxy-3-methyl) butyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
In 0 ℃; make (±)-(2R; 3R; 5R)-1-tert-butoxycarbonyl-2-formyl radical-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate (7.1g; 16.03mmol) ether (75ml) solution and chlorination isobutyl-magnesium (24ml; 2.0M in the ether, 48mmol) reaction is 2.5 hours.Should react with the saturated ammonium chloride quencher, dilute with ethyl acetate.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue can be used for next step without being further purified.
MS(M＋H) +＝502。
Figure A9980761001431
(20F. ±)-(2R, 3R, 5R)-1-tert-butoxycarbonyl-2-(1-oxo-3-methyl) butyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
The 100ml anhydrous methylene chloride solution of preparation oxalyl chloride (16ml, 2M is in methylene dichloride) also remains under-78 ℃ and the nitrogen.(4.26ml 64.1mmol) slowly adds in this solution with DMSO.This mixture stirred 15 minutes and with (±)-(2R, 3R, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-hydroxy-3-methyl) butyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate reacts in the 30ml anhydrous methylene chloride.With this solution stirring 1 hour, (17ml 128mmol) slowly joined in this reaction mixture with triethylamine.Make this solution slowly be warmed to room temperature then, use the saturated sodium bicarbonate quencher,,, filter and vacuum concentration through dried over mgso with methylene dichloride dilution, water and salt water washing organic layer.Residue with 5-10% ethyl acetate/hexane wash-out, obtains title compound (must measure: 6.3g, 78.8%) through the silica gel column chromatography purifying.
1H NMR (CDCl 3): δ 0.07 (m, 6H), 0.81-0.96 (m, 15H), 1.40 and 1.42 (two s, 9H), 1.46 and 1.47 (two s, 9H), 1.72-1.82 (m, 1H), 2.15-2.45 (m, 4H), 3.47-3.69 (m, 1H), 4.28-4.46 (m, 2H).
MS(M＋H) +＝500。 (20G. ±)-(2R, 3R, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-amino-3-methyl) butyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1F, but with (±)-(2R, 3R, 5R)-1-tert-butoxycarbonyl-2-(1-oxo-3-methyl) butyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R)-and 1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.54g, 34.1%).
MS(M＋H) +＝501。
Figure A9980761001441
(20H. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1G, but with (±)-(2R, 3R, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-amino-3-methyl) butyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 462mg, 79.0%).
(±)-(2R, 3R, 5R, 1 ' S) 1H NMR (CDCl 3): δ 0.03 and 0.04 (two s, 6H), 0.86 (s, 9H), 0.89 and 0.95 (two d, 6H), 1.04 (m, 1H), 1.17-1.25 (m, 2H), 1.44 (s, 9H), 1.46 (s, 9H), 1.86 (m, 1H), 1.99 (s, 3H), 2.07 (m, 1H), 2.30 (m, 1H), 3.48 (m, 1H), 3.61 (m, 1H), 3.67 (m, 1H), 4.16 (m, 1H), 4.27 (m, 1H), 7.35 (brd, 1H).
MS(M＋H) +＝543。
Figure A9980761001442
(20I. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(methylol)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1H, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) butyl-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate.
MS(M＋H) +＝429。
Figure A9980761001451
(20J. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 2A, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-methylol-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 1.5g, 91%).
1H NMR (CDCl 3): δ 0.92 and 0.94 (two d, 6H), 1.07 (m, 1H), 1.23-1.33 (m, 2H), 1.43 (s, 9H), 1.44 (s, 9H), 1.64 (m, 1H), 2.03 (s, 3H), 2.39 (m, 1H), 2.46 (m, 1H), 3.18 (m, 1H), 4.19 (m, 1H), 4.32 (m, 1H), 4.39 (m, 1H), 7.12 (brd, 1H).
MS(M＋H) +＝427。
Figure A9980761001452
(20K. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
Under room temperature, (125.6mg, (1.0M is in THF, 0.31mmol) 0.35mmol) to drip potassium tert.-butoxide in the suspension in the 3ml dry toluene to the Diethylaminoethyl triphenyl phosphonium.Stir after 16 hours, drip (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate in 3ml toluene (30mg, 0.070mmol) and stirred 0.5 hour.Should react with the saturated ammonium chloride quencher, dilute with methylene dichloride.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is used eluent ethyl acetate through the silica gel column chromatography purifying, obtains title compound, is white foam shape solid (must measure: 23.7mg, 79.4%).
1H?NMR(CDCl 3)：δ0.92(m，6H)，1.26(m，2H)，1.44(s，9H)，1.47(s，9H)，1.65(m，1H)，1.97(s，3H)，2.43(m，2H)，3.56(m，1H)，4.15(m，2H)，4.32(m，1H)，5.11(m，1H)，5.15(m，1H)，5.75(m，1H)，7.35(br，1H)。
MS(M＋H) +＝425。
Figure A9980761001461
(20L. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 16.0mg, 99.1%).
1H?NMR(DMSO-d 6)：δ0.82(d，3H)，0.88(d，3H)，1.29(m，1H)，1.42(m，1H)，1.57(m，1H)，1.87(s，3H)，1.91(m，1H)，2.40(m，1H)，2.90(m，1H)，4.20(m，1H)，4.32(m，1H)，5.08(dd，1H)，5.17(dd，1H)，5.72(ddd，1H)，8.09(d，1H)，9.16(brs，1H)，9.28(brs，1H)。
MS：(M＋H) +＝269。
Embodiment 21 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001471
(21A. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-t-butyl formate.
(±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate.
MS(M＋H) +＝471。 (21B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-formate hydrochlorate.
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.15(d，J＝9Hz，1H)，4.28-4.15(m，2H)，3.95-3.45(m，4H)，2.35(m，1H)，1.98(m，1H)，1.89(s，3H)，1.50-1.45(m，7H)，0.81(t，J＝7.4Hz，3H)，0.77(t，J＝7.5Hz，3H)。
MS：(M＋H) +＝301，(M－H) -＝299。
Embodiment 22 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(pyrroles-1-yl)-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001481
(22A. ±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(2-trimethylsilylethoxy) carbonylamino)-tetramethyleneimine-5-t-butyl formate.
In 75 ℃; make (±)-(2R; 3R; 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-carboxyl-tetramethyleneimine-5-t-butyl formate (according to method described in embodiment 2B preparation) (80mg, 0.18mmol) with diphenyl phosphoryl azide (0.047ml, 0.216mmol), 2-trimethyl silyl ethanol (0.034ml; 0.234mmol) and triethylamine (0.030ml, 0.216mmol) in toluene (2ml) reaction 15 hours.This reactant of vacuum concentration, the residue that obtains with 25% ethyl acetate/hexane wash-out, obtain title compound through the silica gel column chromatography purifying, are faint yellow oily thing (must measure: 46mg, 45%).
MS：(M＋H) +＝576，(M＋Na) +＝598，(M－H) -＝574。
Figure A9980761001482
(22B. ±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1H, but with (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(2-trimethylsilylethoxy) carbonylamino)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
MS：(M＋H) +＝432，(M－H) -＝430。 (22C. ±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(pyrroles-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-amino-tetramethyleneimine-5-t-butyl formate (34mg, 0.078mmol) with the aqueous solution of 40% amber dialdehyde (50mg, 0.234mmol), acetate (0.00044ml, 0.0078mmol) and 4A molecular sieve (200mg) in toluene (2ml), reacted 3 hours.This reactant of vacuum concentration, the residue that obtains with 50% ethyl acetate/hexane wash-out, obtain title compound through the silica gel column chromatography purifying, are oily matter (must measure: 7.1mg, 19%).
MS：(M＋H) +＝482，(M＋Na) +＝504，(M－H) -＝480。
Figure A9980761001492
(22D. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(pyrroles-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1J, but with (±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(pyrroles-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.5mg, 61%).MS：(M＋H) +＝392，(M－H) -＝390。
Figure A9980761001501
(22E. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(pyrroles-1-yl)-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(pyrroles-1-yl) tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.5mg, 100%).
1H?NMR(D 2O)：δ7.48(bs，1H)，6.77(bs，2H)，5.97(bs，2H)，4.33(m，1H)，3.70(m，1H)，3.07(m，1H)，2.43(m，1H)，1.92(m，1H)，1.75(s，3H)，1.55(m，1H)，1.35-1.10(m，7H)，0.81(m，3H)，0.75(m，3H)。
MS：(M＋H) +＝336，(M－H) -＝334。
Embodiment 23 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(1-cis-N-oxyimino) ethyl-tetramethyleneimine-5-formate hydrochlorate
Figure A9980761001502
(23A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(1-cis-N-oxyimino) ethyl-tetramethyleneimine-5-t-butyl formate.
Make (±)-(2R; 3R; 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-ethanoyl-tetramethyleneimine-5-t-butyl formate (according to the preparation of method described in the embodiment 8B) (45mg; 0.1mmol) in ethanol/methylene (3/1) with hydroxylamine hydrochloride (21mg; 0.3mmol) and sodium hydroxide (12mg, methyl alcohol 0.3mmol) (2ml) solution reaction 2 hours.Dilute this reactant with ethyl acetate.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 40% ethyl acetate/hexane wash-out, obtains syn-oxime title compound (the last low Rf spot of TLC) through the silica gel column chromatography purifying, be oily matter (must measure: 35mg, 75%), and anti-oxime title compound (the last high Rf spot of TLC), be oily matter (must measure: 13mg, 25%).
MS:(M+H) +=474
Figure A9980761001511
(23B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(1-cis-N-oxyimino) ethyl-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(1-cis-N-oxyimino) ethyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(CDCl 3)：δ3.92(br，1H)，3.70(m，2H)，2.82(m，1H)，2.38(m，1H)，1.88(s，3H)，1.78(s，3H)，1.39(s，9H)，1.40-1.20(m，7H)，0.76(m，6H)。
MS：(M＋H) +＝384。
Figure A9980761001512
(23C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(1-cis-N-oxyimino) ethyl-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(1-cis-N-oxyimino) ethyl-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(D 2O)：δ4.35(m，1H)，4.00(m，1H)，3.80(m，1H)，3.71(m，1H)，3.63(m，1H)，3.13(q，J＝8.4Hz，1H)，2.64(m，1H)，2.18(m，1H)，1.97(s，3H)，1.85(s，3H)，1.50-1.10(m，7H)，0.77(m，6H)。
MS：(M＋H) +＝328
Embodiment 24
(±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-oxyimino) methyl-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001521
(24A. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-oxyimino) methyl-tetramethyleneimine-5-t-butyl formate.
In 25 ℃; make (±)-(2R; 3R; 5R; 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate (according to the preparation of method described in the embodiment 2A) (18mg; 0.051mmol) (7mg, 0.11mmol) solution reaction in the methanol solution (3ml) of 1N sodium hydroxide is 1.5 hours with hydroxylamine hydrochloride.Should reaction with aqueous ammonium chloride solution (3ml) and water (3ml) quencher.(2 * 10ml) absorb with methylene dichloride.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is through the silica gel column chromatography purifying, and the dichloromethane solution wash-out with 5% methyl alcohol obtains title compound, is oily matter (must measure: 6mg, 32%).
MS:(M+H) +=370 (24B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-oxyimino) methyl-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(N-oxyimino) methyl-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 25 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxyimino) methyl-tetramethyleneimine-5-formic acid.
Figure A9980761001532
(25A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(methoxyimino) methyl-tetramethyleneimine-5-formic acid.
In 0 ℃, make (±)-(2R, 3R, 5R, 1 ' S)-(20mg 0.045mmol) reacted 5 hours in ether (2ml) and methyl alcohol (0.1ml) with hydrogenchloride (0.45mmol) 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-cyano group-tetramethyleneimine-5-t-butyl formate (according to the preparation of method described in the embodiment 17E).With ammonium hydroxide aqueous solution this reactant that neutralizes, through the silica gel column chromatography purifying, the dichloromethane solution wash-out with 3% methyl alcohol obtains title compound, is white solid (must measure: 5mg, 26%).MS:(M+H) +=418
Figure A9980761001541
(25B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxyimino) methyl-tetramethyleneimine-5-formic acid.
According to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(imino--methoxymethyl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.9mg, 96%).
1H?NMR(DMSO-d 6)：δ7.52(d，J＝8.7Hz，1H)，7.15(s，1H)，6.77(s，1H)，3.68(m，1H)，3.61(s，3H)，3.22(m，1H)，2.51(m，1H)，2.23(m，1H)，1.82(m，1H)，1.78(s，3H)，1.40(m，1H)，1.26(s，3H)，1.13(m，3H)，0.78(t，J＝6.5Hz，3H)，0.72?(t，J＝6.5Hz，3H)
MS：(M＋H) +＝328
Embodiment 26 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(glycolyl)-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001542
(26A. ±)-(2R, 3R, 5R, 1 ' S, 1 " RS)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1, the 2-dihydroxyl) ethyl-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 20A, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2S, 3R, 5R)-1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxy ylmethyl)-tetramethyleneimine-5-t-butyl formate.
Figure A9980761001551
(26B. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(glycolyl)-tetramethyleneimine-5-t-butyl formate.
According to Kong at J.Carbohydrate Chem.1993, method in the 557th page, make (±)-(2R, 3R, 5R, 1 ' S, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1, the 2-dihydroxyl) ethyl-tetramethyleneimine-5-t-butyl formate and dibutyl tin oxide react in methyl alcohol.Concentrate this reactant, resistates be dissolved in the methylene dichloride, and as described in the above reference with bromine reaction, obtain title compound.
Figure A9980761001552
(26C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(glycolyl)-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 1K; but with (±)-(2R; 3R; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-glycolyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 27 (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-amino-tetramethyleneimine-5-formic acid dihydrochloride. (27A. ±)-(2S, 3R, 5R, 1 ' RS)-1-benzyl-2-(1-hydroxy-3-methyl) butyl-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 9D, but replace 3-amyl group magnesium bromide with bromination isobutyl-magnesium.
Figure A9980761001562
(27B. ±)-(2S, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 9E-H, but with (±)-(2R, 3R, 5R, 1 ' RS)-1-benzyl-2-(1-hydroxy-3-methyl) butyl-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate replaces in embodiment 9E process (±)-(2R as raw material, 3R, 5R, 1 ' RS)-1-benzyl-2-(1-hydroxyl-3-ethyl) amyl group-3-benzyloxycarbonyl amino-tetramethyleneimine-5-t-butyl formate. (27C. ±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-amino-tetramethyleneimine-5-formic acid dihydrochloride.
According to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-amino-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate, the preparation title compound.
1H?NMR(d 6-DMSO)：δ8.64(bs，1H)，8.32(bs，1H)，8.23(bs，1H)，8.18(d，J＝6Hz，1H)，4.79(d，J＝7Hz，1H)，4.42(m，1H)，4.33(m，1H)，4.21(m，1H)，4.07(m，1H)，3.76(m，2H)，2.73(m，2H)，1.92(m，3H)，0.80-0.97(m，7H)。
MS：(M＋H) +＝258
Embodiment 28 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-methoxycarbonyl-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761001571
(28A. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-carboxyl-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 2B; but with (±)-(2R; 3R; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate. (28B. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 2C, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-carboxyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-carboxyl-tetramethyleneimine-5-t-butyl formate.
Figure A9980761001582
(28C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-methoxycarbonyl-tetramethyleneimine-5-formate hydrochlorate.
Prepare title compound according to method described in the embodiment 2E, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.24，8.08(d，J＝9Hz，1H)，4.44，4.36(m，1H)，4.25，4.15(m，1H)，3.98，3.88(m，1H)，3.65，3.64(s，3H)，3.18，3.10(m，1H)，2.57，2.20(m，2H)，1.87，1.83(s，3H)，1.57(m，2H)，1.36(m，1H)，0.88(d，J＝7.5Hz，3H)，0.82(d，J＝7.5Hz，3H)。
MS：(M＋H) +＝301
Embodiment 29 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-formic acid dihydrochloride.
Figure A9980761001591
(29A. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 15A; but with (±)-(2R; 3R; 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R; 5R; 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 27.4mg, 83.%).
MS(M＋H) +＝455。
Figure A9980761001592
(29B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3 methyl) butyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 15B, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 19.1mg, 95.5%).
MS(M＋H) +＝365。
Figure A9980761001601
(29C. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-formic acid dihydrochloride.
Prepare title compound according to method described in the embodiment 15B, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ0.76(d，J＝6.6Hz，3H)，0.82(d，J＝6.6Hz，3H)，1.18(t，2H)，1.44(m，1H)，1.71(s，3H)，2.43-2.47(m，1H)，2.80(m，1H)，3.83(m，1H)，4.05(m，1H)，4.28(m，1H)，4.55(t，1H)，7.65(s，2H)，8.03(d，J＝8.4?Hz，1H)。
MS(M＋H) +＝326。
Embodiment 30 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazol-4 yl)-tetramethyleneimine-5-formic acid dihydrochloride.(30A. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-carboxyl-tetramethyleneimine-5-t-butyl formate
Figure A9980761001602
According to method described in the embodiment 2B; but with (±)-(2R; 3R; 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate (according to the preparation of method described in the embodiment 20J) replacement (±)-(2R, 3R; 5R; 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 129.5mg,＞100%).
MS(M＋H) +＝443。
Figure A9980761001611
(30B. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3 methyl) butyl-3-diazonium ethanoyl-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 12A, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-carboxyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-carboxyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 218.8mg, 100%).
MS(M＋H) +＝458。
Figure A9980761001612
(30C. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-bromo ethanoyl-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 12B; but with (±)-(2R; 3R; 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-diazonium ethanoyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R; 5R; 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-diazonium ethanoyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 107.2mg, 45.5%).
1H?NMR(CDCl 3)：δ0.90(d，6H)，1.26-1.35(m，3H)，1.42(s，9H)，1.95(s，3H)，2.25(m，2H)，3.11(m，1H)，3.54(dd，1H)，3.69(m，1H)，3.93(dd，2H)，4.11(d，1H)，4.27(m，1H)，4.35(d，1H)，5.05(brd，1H)，7.25-7.32(m，5H)。
MS(M＋H) +＝509。
Figure A9980761001621
(30D. ±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-(imidazol-4 yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 12C; but with (±)-(2R; 3R; 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-bromo ethanoyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R; 5R; 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-bromo ethanoyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 32.3mg, 60.4%).
MS(M＋H) +＝455。
Figure A9980761001622
(30E. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazol-4 yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 1J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-methyl) butyl-3-(imidazol-4 yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 23.9mg, 96.2%).
1H?NMR(CDCl 3)：δ0.87(d，3H)，0.89(d，3H)，1.26(m，1H)，1.41(m，2H)，1.46(s，9H)，1.59(m，1H)，1.93(s，3H)，2.62(m，1H)，3.30(m，1H)，3.54(m，1H)，3.79(m，1H)，41(m，1H)，6.11(brd，1H)，6.89(s，1H)，7.63(s，1H)。
MS(M＋H) +＝365。
Figure A9980761001631
(30F. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazol-4 yl)-tetramethyleneimine-5-formic acid dihydrochloride.
According to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazol-4 yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 24.4mg, 100%).
1H?NMR(DMSO-d 6)：δ0.76(d，J＝3.6Hz，3H)，0.88(d，J＝3.6Hz，3H)，1.22(m，1H)，1.28(m，1H)，1.48(m，1H)，1.79(s，3H)，2.32(dt，1H)，2.71(dt，1H)，3.68(m，1H)，3.96(m，1H)，4.28(m，1H)，4.51(t，1H)，7.63(s，1H)，8.23(d，J＝5.1Hz，1H)，9.10(s，1H)，9.67(brs，1H)，14.51(brs，1H)。
MS(M＋H) +＝309。
Embodiment 31 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(thiazole-4-yl)-tetramethyleneimine-5-formic acid dihydrochloride.
Figure A9980761001632
(31A. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(thiazole-4-yl)-tetramethyleneimine-5-t-butyl formate.
Reflux down, make (±)-(2R, 3R; 5R; 1 ' S)-(36.5mg, 0.07mmol) (21.4mg 0.35mmol) reacted 4 hours in ethanol (5ml) 1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-bromo ethanoyl-tetramethyleneimine-5-t-butyl formate with thioformamide.This reactant of vacuum concentration.Handle residue with the 5ml sodium bicarbonate aqueous solution, (4 * 5ml) extract with methylene dichloride.With salt water washing organic layer,, filter and vacuum concentration through dried over sodium sulfate.Residue is used eluent ethyl acetate through the silica gel column chromatography purifying, obtains title compound, is white solid (must measure: 23.8mg, 70.4%).
MS：(M＋H) +＝482。
Figure A9980761001641
(31B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(thiazole-4-yl)-tetramethyleneimine-5-formic acid dihydrochloride.
According to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(thiazole-4-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 18.5mg, 100%).
1H?NMR(DMSO-d 6)：δ0.62(d，J＝4.2Hz，3H)，0.72(d，J＝4.2Hz，3H)，1.05(m，1H)，1.12(m，1H)，1.30(m，1H)，1.72(s，3H)，2.14(dt，1H)，2.59(dt，1H)，3.69(m，1H)，3.92(bm，1H)，4.21(m，1H)，4.38(brm，1H)，7.46(d，J＝1.2Hz，1H)，8.02(d，J＝5.1Hz，1H)，9.04(d，J＝1.2Hz，1H)，9.39(brs，1H)，9.48(brs，1H)。
MS(M＋H) +＝326。
Embodiment 32 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(thiazol-2-yl)-tetramethyleneimine-5-formic acid dihydrochloride. (32A. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formamyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-carboxyl-tetramethyleneimine-5-t-butyl formate (0.258g, 0.584mmol) with the carbonochloridic acid isobutyl ester (80mg, 0.84mmol) and N-methylmorpholine (59mg 0.584mmol) reacted in THF (10ml) 0.25 hour.Add ammonium hydroxide aqueous solution (.39ml), stirred this reactant 0.5 hour in 0 ℃.Dilute this reactant with ethyl acetate.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 100% ethyl acetate-5% methyl alcohol-eluent ethyl acetate, obtains title compound through the silica gel column chromatography purifying, is glassy mass (must measure: 182mg, 70.7%).
1H NMR (CD 3OD): δ 4.70 (m, 1H), 4.36 (q, J=3Hz, 1H), 4.05 (m, 1H), 2.87 (q of t, J=9 and 3Hz, 1H), 2.52 (m, 1H), 2.36 (m, 1H), 1.94 (d, 3H), 1.63 (m, 1H), 1.41-1.53 (m, 18H), 1.3 (m, 2H), 0.9-0.18 (m, 6H).
MS(M＋H) +＝442。
Figure A9980761001652
(32B. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-thiocarbamoyl-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formamyl-tetramethyleneimine-5-t-butyl formate (70mg, 0.159mmol) and P 2S 10(8.5mg 0.019mmol) reacts in 4ml tetrahydrofuran (THF) and 1ml methylene dichloride.1.25 after hour, add 9.6mgP 2S 10After 2 hours, raw material is consumed.Dilute this mixture with ethyl acetate, water and salt water washing through dried over mgso, are filtered and are concentrated.Tlc analyzes and shows two spots, and mass spectrum shows that it is the mixture of monothio and dithio compound.This material can be used for next step without being further purified.
MS(M＋H) +＝458，474。
Figure A9980761001661
(32C. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(thiazol-2-yl)-tetramethyleneimine-5-t-butyl formate.
In 75 ℃; make (±)-(2R; 3R; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-thiocarbamoyl-tetramethyleneimine-5-t-butyl formate (73mg; 0.16mmol) (0.02ml 0.16mmol) reacts in 5ml acetone with chloro acetaldehyde (50% in water).After all feedstock conversion finish,, add sal epsom (0.9g) and extra sulfoacetoaldehyde at interval with 5 hours.Dilute this reactant with ethyl acetate.Water and salt water washing through dried over mgso, are filtered and vacuum concentration.Residue is used 100% eluent ethyl acetate through the silica gel column chromatography purifying, obtains title compound, is glassy mass (must measure: 12.6mg, 16.3%).
1H?NMR(CDCl 3)：δ7.69(m，1H)，7.45(m，1H)，4.44(m，1H)，4.28(m，2H)，3.52(m，1H)，2.7(m，1H)，2.5(m，1H)，1.99(s，3H)，1.44(s，9H)，1.37(s，9H)，1.27(m，3H)，0.95(m，6H)。
MS (M+H) +=482
Figure A9980761001671
(32D. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(thiazol-2-yl)-tetramethyleneimine-5-formic acid dihydrochloride.
According to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(thiazol-2-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 10.1mg, 82%).
1H?NMR(DMSO-d 6)：δ8.1(d，J＝10Hz，1H)，7.79(d，J＝4Hz，1H)，7.69(d，J＝4Hz，1H)，4.49(t，J＝7.5Hz，1H)，4.22(m，1H)，4.14(t，J＝9Hz，1H)，4.01(q，J＝10Hz，1H)，2.80(m，1H)，2.25(m，1H)，1.78(s，3H)，1.47(m，1H)，1.25(m，2H)，0.83(d，J＝6.2Hz，3H)，0.75(d，J＝6.2Hz，3H)
MS(M-H) -＝324，(2M－1) -＝649，(M＋335) +＝360
Embodiment 33 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (33A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate and (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(trans-2-chloro-ethene-the 1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 20K, but (chloro methyl) San Ben Phosphonium replaces Diethylaminoethyl San Ben Phosphonium with chlorination.The new spot of higher Rf0.73 (ethyl acetate) is accredited as cis-isomeride (must measure: 38.4mg, 40%), and lower Rf 0.57 (ethyl acetate) spot is accredited as trans-isomer(ide) (must measure: 42mg, 43%).
Cis-isomeride 1H NMR (CDCl 3): δ 7.44 (br, 1H), 6.13 (d, J=7.5Hz, 1H), 5.32 (dd, J=9Hz, J=7.5Hz, 1H), 4.31-4.16 (m, 2H), 3.65 (m, 1H), 3.12 (m, 1H), 2.50 (m, 1H), 1.98 (s, 3H), 1.62 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H), 1.30-1.07 (m, 2H), 0.82 (m, 6H)
MS(M＋H) +＝459
Trans-isomer(ide) 1H NMR (CDCl 3): δ 6.12-5.90 (m, 2H), 4.30-4.07 (m, 2H), 3.64 (m, 1H), 2.62-2.37 (m, 2H), 1.98 (s, 3H), 1.69 (m, 1H), 1.48 (s, 9H), 1.45 (s, 9H), 1.26 (m, 2H), 0.91 (m, 6H).
MS (M+H) +=459 (33B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' S)-(10mg 0.022mmol) reacted 7 hours in methylene dichloride (0.4ml) with trifluoroacetic acid (1.8ml) 1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate.This reactant of vacuum concentration.Residue obtains title compound through high vacuum dry.
1H?NMR(DMSO-d 6)：δ8.015(d，J＝7.63Hz，1H)，6.42(d，J＝7.02Hz，1H)，5.89(dd，J＝7.02Hz，J＝8.7Hz，1H)，4.42(m，1H)，4.17(m，1H)，3.59(m，1H)，3.31(m，1H)，2.47(m，1H)，1.88(s，3H)，1.84(m，1H)，1.58(m，1H)，1.39(m，1H)，1.29(m，2H)，0.885(d，J＝6.71Hz，3H)，0.83(d，J＝6.413H)。
MS(M＋H) +＝303
Embodiment 34 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(trans-2-chloro-ethene-the 1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001691
(34B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(trans-2-chloro-vinyl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 33B, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(trans-2-chloro-ethene-the 1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.04(d，J＝7.93Hz，1H)，6.355(d，J＝13.1Hz，1H)，5.93(dd，J＝13.1Hz，J＝9.32Hz，1H)，4.33(m，1H)，4.19(m，1H)，2.95(m，1H)，2.40(m，1H)，1.94(m，1H)，1.88(s，3H)，1.58(m，1H)，1.39(m，1H)，1.29(m，1H)，0.89(d，J＝6.7Hz，3H)，0.825(d，J＝6.7Hz，3H)。
MS(M＋H) +＝303
Embodiment 35 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001701
(35A. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Under room temperature, (479mg, (1.0M is in THF, 0.94mmol) 1.29mmol) to drip potassium tert.-butoxide in the suspension in the 3ml dry toluene to bromination Yi base triphenyl phosphonium.Stir after 2.5 hours, drip (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate in 5ml toluene (90mg, 0.211mmol) and stirred 1 hour.Should react with the saturated aqueous ammonium chloride quencher, dilute with ethyl acetate.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 50% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 70.6mg, 76%).
MS(M＋H) +＝439。
Figure A9980761001702
(35B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 33B, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-vinyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.04(d，J＝7.5Hz，1H)，5.51(m，1H)，5.26(m，1H)，4.32(m，1H)，4.18(m，1H)，3.45(m，1H)，3.18(m，1H)，2.39(m，1H)，1.88(s，3H)，1.73(m，1H)，1.63(dd，3H)，1.58(m，1H)，1.38(m，H)，1.28(m，1H)，0.88(d，J＝6Hz，3H)，0.81(dd，J＝6Hz，3H)。
MS(M＋H) +＝283
Embodiment 36 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(2,2-dimethyl-ethene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (36A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(2,2-dimethyl-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 20K, but replace Diethylaminoethyl San Ben Phosphonium, preparation title compound (must measure: 22.6mg, 33%) with iodate sec.-propyl San Ben Phosphonium.
1H?NMR(CDCl 3)：δ7.77(d，1H)，5.06(d，J＝10Hz，1H)，4.18(m，2H)，3.50(m，1H)，2.69(m，1H)，2.32(m，1H)，1.97(s，3H)，1.70(s，3H)，1.64(s，3H)，1.65(m，1H)，1.47(s，9H)，1.44(s，9H)，1.30-1.00(m，3H)，0.93(d，J＝6Hz，3H)，0.88(d，J＝6Hz，3H)。
MS (M+H) +=453 (36B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(2,2-dimethyl-ethene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 33B, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(2,2-dimethyl-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.01(d，J＝7.5Hz，1H)，4.99(d，J＝10Hz，1H)，4.30(m，1H)，4.14(m，1H)，3.40(m，1H)，3.06(m，1H)，2.36(m，1H)，1.86(s，3H)，1.66(s，3H)，1.63(s，3H)，1.57(m，1H)，1.39-1.20(m，3H)，0.88(d，J＝6Hz，3H)，0.81(d，J＝6Hz，3H)。
MS(M＋H) +＝297
Embodiment 37 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(2,2-two fluoro-ethene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001721
(37A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(2,2-two fluoro-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In-78 ℃, (1.6M is in hexane with n-Butyl Lithium, 0.61ml, 0.97mmol) be added in Diisopropylamine among the 4ml THF (136 μ l, 0.97mmol) in, stirred 30 minutes, add difluoro methylphosphonic acid diethyl ester (182mg, 0.97mmol), after 2 hours, colourless solution is yellowing slowly in-78 ℃ of stirrings.Be added in (±)-(2R, 3R, the 5R among the 3ml THF; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate (59mg; 0.138mmol), in-78 ℃ of stirrings 30 minutes, be warmed to room temperature then.With this mixture reflux 1.5 hours, under room temperature, stir and spend the night again.Should react with the saturated aqueous ammonium chloride quencher, dilute with ethyl acetate.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 50% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is faint yellow oily thing (must measure: 23.4mg, 37%).
1H?NMR(CDCl 3)：δ7.44(d，1H)，5.92(ddd，1H)，4.30-4.00(m，2H)，3.55(m，1H)，2.69(m，1H)，2.45(m，1H)，2.00(s，3H)，1.47(s，9H)，1.43(s，9H)，1.45-1.00(m，4H)，0.91(m，6H)。
MS (M+H) +=461 (37B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl--(2,2-two fluoro-ethene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 33B, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(2,2-two fluoro-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.04(d，J＝7.5Hz，1H)，4.59(ddd，1H)，4.23(m，1H)，4.14(m，1H)，3.48(m，1H)，3.39(m，1H)，2.91(m，1H)，2.43(m，1H)，1.85(s，3H)，1.58(m，1H)，1.40(m，1H)，1.31(m，1H)，1.22(m，1H)，0.89(d，J＝7.5Hz，3H)，0.83(d，J＝7.5Hz，3H)。
MS(M＋H) +＝305
Embodiment 38 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (38A. ±)-(2R, 3R, 5R, 1 ' S, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-hydroxyl-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 4A; but replace ethylmagnesium bromide with the 2-propynyl magnesium bromide; with (±)-(2R; 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate (250mg; 0.587mmol) replacement (±)-(2R; 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate.The gained crude product can be directly used in following reaction.
MS (M+H) +=453
Figure A9980761001742
(38B. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-oxo-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate.
In 0 ℃ to room temperature, make (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-hydroxyl-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate and Jones reagent (3.0M, in acetone, 0.33ml) in acetone (90ml), reacted 1 hour.Dilute this reactant with ethyl acetate.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 50% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is white solid (must measure: 143mg, 54%).
MS (M+H) +=451
Figure A9980761001751
(38C. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-oxo-1-ethynyl) methyl-tetramethyleneimine-5-t-butyl formate (140mg, 0.311mmol) (0.24ml 4.944mmol) reacted 4 hours in ethanol (12ml) with the hydrazine monohydrate.The vacuum concentration reactant.Residue is used eluent ethyl acetate through the silica gel column chromatography purifying, obtains title compound, is white solid (must measure: 131mg, 91%).
MS (M+H) +=465
Figure A9980761001752
(38D. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 33B, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-vinyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.13(d，J＝7.5Hz，1H)，7.65(d，J＝2.2Hz，1H)，6.20(d，J＝2.2Hz，1H)，4.39(m，1H)，4.25(m，1H)，3.94(m，1H)，3.56(q，J＝7.5Hz，1H)，2.62(m，1H)，2.17(m，1H)，1.87(s，3H)，1.42(m，1H)，1.21(m，1H)，1.11(m，1H)，0.80(d，J＝6.6Hz，3H)，0.71(d，J＝6.6Hz，3H)。
MS(M＋H) +＝309
Embodiment 39 (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-3-base)-tetramethyleneimine-5-methanoic acid trifluoro acetate and (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-5-base)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001761
(39A. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-3-base)-tetramethyleneimine-5-t-butyl formate and (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-5-base)-tetramethyleneimine-5-t-butyl formate.
Reflux down, make (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-oxo-1-ethynyl) methyl-tetramethyleneimine-5-t-butyl formate (31mg, 0.07mmol) with hydroxylamine hydrochloride (4.9mg, 0.07mmol) and yellow soda ash (3.7mg 0.035mmol) reacted in ethanol (3ml) 30 hours.This reactant of vacuum concentration.Residue with 3% ethanol/methylene wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 11.5mg, 36%).
MS (M+H) +=466
Figure A9980761001771
(39B. ±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-3-base)-tetramethyleneimine-5-methanoic acid trifluoro acetate and (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-5-base)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 33B, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-3-base)-tetramethyleneimine-5-t-butyl formate and (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-5-base)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-vinyl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ8.91，8.54(d，1H)，8.12，8.05(d，J＝7.5Hz，1H)，6.64，6.43(d，1H)，4.48，4.51(m，1H)，4.28(m，1H)，3.97，3.89(m，1H)，3.70，3.81(m，1H)，2.72(m，1H)，2.20，2.25(m，1H，1.83，1.80(s，3H)，1.48(m，1H)，1.34-1.10(m，2H)，0.83，0.84(d，J＝6Hz，3H)，0.77，0.78(d，J＝6Hz，3H)。
MS(M＋H) +＝310
Embodiment 40 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001772
(40A. ±)-(2R, 3R, 5R)-1-benzyl-2-vinyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3R, 5R)-1-benzyl-2-vinyl-3-(methylol)-tetramethyleneimine-5-t-butyl formate (54.2g, 0.17mol) and 4-(dimethylamino) pyridine (0.5g, 4.1mmol) (30ml, 0.32mol) reaction is 1 hour, is warmed to room temperature then with diacetyl oxide in anhydrous pyridine (400ml).With this reactant restir 16 hours.Remove pyridine in 30 ℃ of vacuum.Residue is distributed between ethyl acetate (100ml) and water (400ml).(3 * 100ml) extract water layer, and the ethyl acetate layer with the salt water washing merges through dried over mgso, filters and concentrates with ethyl acetate.Crude product with 10% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 49.6g, 81%).
1H?NMR(CDCl 3)：δ7.28(m，4H)，7.21(m，1H)，5.68(m，1H)，5.21(m，2H)，4.16(dd，J＝6.3，10.7Hz，1H)，4.10(dd，J＝7.3，10.7Hz，1H)，3.92(d，J＝13.7Hz，1H)，3.64(d，J＝13.7Hz，1H)，3.52(m，1H)，3.50(m，1H)，2.33(m，1H)，2.26(m，1H)，2.02(s，3H)，1.62(m，1H)，1.45(s，9H)。
MS (M+H) +=360
Figure A9980761001781
(40B. ±)-(2R, 3R, 5R, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1, the 2-dihydroxyl) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate.
Make (±)-(2R, 3R, 5R)-1-benzyl-2-vinyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (52.5g, 0.1 5mol) with 4-methylmorpholine N-oxide compound (54.7g, 0.47mol) (200mg 0.8mmol) reacts with perosmic anhydride in acetone (540ml) and water (60ml).After 24 hours, vacuum concentration should be reacted with 10% Sulfothiorine (250ml) quencher.(3 * 300ml) extract water layer, and the organic layer with the salt water washing merges through dried over mgso, filters and concentrates with ethyl acetate.Residue is through the silica gel column chromatography purifying, and the gradient liquid wash-out with ethyl acetate and methylene dichloride obtains title compound, is thickness oily matter (must measure: 41.2g, 72%).
1H?NMR(DMSO)：δ7.32(m，3H)，7.30(m，1H)，7.22(m，1H)，4.48(t，J＝5.4Hz，1H)，4.42(d，J＝5.4Hz，1H)，4.04(m，1H)，4.01(m，1H)，3.97(m，1H)，3.80(d，J＝13.2Hz，1H)，3.78(m，1H)，3.43(m，1H)，3.39(m，1H)，3.32(m，1H)，3.07(t，J＝4.9Hz，1H)，2.48(m，1H)，2.19(m，1H)，1.99(s，3H)，1.57(dt，J＝13.7，2.0Hz，1H)，1.38(s，9H)。
MS(M＋H) +＝394。
Figure A9980761001791
(40C. ±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-2-(1, the 2-dihydroxyl) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate.
Reflux down, make (±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1, the 2-dihydroxyl) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (24g, 61mmol) in ethanol (300ml) with ammonium formiate (38.5g, 0.61mol) and 10%Pd/C (2g) reaction 2 hours.Cool off this reactant, remove catalyzer by diatomite filtration.Vacuum concentrated filtrate obtains title compound (must measure: 16.7g, 90%).
1H?NMR(DMSO)：δ4.56(m，1H)，4.30(m，1H)，4.06(dd，J＝5.8，10.9Hz，2H)，3.79(dd，J＝8.8，10.5Hz，2H)，3.49(m，4H)，3.00(m，1H)，2.35(m，1H)，2.16(dt，J＝12.6，8.5Hz，1H)，2.01(s，3H)，1.52，(m，1H)，1.40(s，9H)。
MS(M＋H) +＝304。 (40D. ±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1, the 2-dihydroxyl) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-2-(1, the 2-dihydroxyl) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (33.4g, 0.11mol) (33.6g, 0.15mol) reaction is 48 hours with tert-Butyl dicarbonate in methyl alcohol (250ml) and water (50ml).Vacuum is removed methyl alcohol, and water (500ml) dilutes this residue, and (3 * 200ml) extract with ethyl acetate.Ethyl acetate layer with the salt water washing merges through dried over mgso, filters and concentrates.Residue is used the ethanol/methylene wash-out through silica gel column chromatography, obtains title compound, is white solid (must measure: 32.8g, 78%).
1H?NMR(DMSO)：δ4.80(m，1H)，4.45(m，1H)，4.08(m，1H)，3.91(m，2H)，3.82(m，1H)，3.71(m，1H)，3.28(m，2H)，2.48(m，1H)，2.07(m，2H)，2.01(m，3H)，1.39(m，18H)。
MS(M＋H) +＝404。 (40E. ±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-hydroxyl-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1, the 2-dihydroxyl) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (26.5g, 66mmol) (8.9g, 0.13mol) (19.0g, 99mmol) reaction is 4 hours with the triisopropyl silyl chloride with imidazoles in anhydrous dimethyl formamide (200ml).Solvent removed in vacuo also distributes residue between 300ml water and 150ml ethyl acetate.(2 * 100ml) extract water layer, and the ethyl acetate layer with saline water extraction merges through dried over mgso, filters and concentrates with ethyl acetate.Residue with 10% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 28.9g, 79%).
1H?NMR(CDCl 3)：δ4.22(m，1H)，4.04(m，3H)，3.87(t，J＝2.0Hz，1H)，3.74(dd，J＝4.9，9.8Hz，1H)，3.58(dd，J＝7.8，10.2Hz，1H)，3.39(bs，1H)，2.61(m，2H)，2.03(s，3H)，1.75(m，1H)，1.46(m，18H)，1.07(m，18H)。MS (M+H) +=560 (40F. ±)-(2R, 3R, 5R)-1-tert-butoxycarbonyl-2-(1-oxo-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate.
In-78 ℃, (6ml, (19.3ml is in anhydrous methylene chloride 38.6mmol) (70ml) solution 85mmol) slowly to add oxalyl chloride (2M) with dimethyl sulfoxide (DMSO).After 10 minutes, so that being no more than-70 ℃ speed, temperature is added in (±)-(2R in the anhydrous methylene chloride (75ml), 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-hydroxyl-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (14.4g, 26mmol).1.5 after hour, (18ml 0.13mol), makes temperature rise to 0 ℃ to add triethylamine.Should react with the ammonium chloride solution quencher, dilute with water, (3 * 100ml) extract with methylene dichloride.Dichloromethane layer with saline water extraction merges through dried over mgso, filters and concentrates.Residue with 10% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 11g, 77%).
1H?NMR(CDCl 3)：δ4.32(m，6H)，2.43(m，2H)，2.04(s，3H)，1.78(m，1H)，1.48(s，9H)，1.41(s，9H)，1.1(m，21H)。
MS(M＋H) +＝558。
Figure A9980761001812
(40G. ±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-amino-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate.
Reflux down, make (±)-(2R, 3R, 5R)-1-tert-butoxycarbonyl-2-(1-oxo-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (22g, 39mmol) in methyl alcohol (1L) with ammonium acetate (77g, 1.0mol) and sodium cyanoborohydride (24.8g, 0.39mol) reaction 2 hours.Vacuum evaporating solvent distributes residue between water (300ml) and methylene dichloride (300ml).(2 * 100ml) extract water layer, and the organic layer with the salt water washing merges through dried over mgso, filters and the concentrated title compound (crude product must be measured: 22.0g, 100%) that obtains with methylene dichloride. (40H. ±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3R, 5R, 1 ' R) and (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-amino-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (about 39mmol) in methylene dichloride (500ml) with diacetyl oxide (18ml, 0.19mol), triethylamine (27.5ml, 0.20mol) and dimethyl aminopyridine (50mg, 0.39mmol) reaction 18 hours.Should react with the ammonium chloride solution quencher, (3 * 100ml) extract water layers with methylene dichloride.Organic layer with saline water extraction merges through dried over mgso, filters and concentrates.Residue is through the silica gel column chromatography purifying, use the ethyl acetate/hexane wash-out, obtain title compound (±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (9.14g, 39%) and (±)-(2R, 3R, 5R, 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) second. base-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (9.75g, 41%) is white solid.
(±)-(2R，3R，5R，1’R) 1H?NMR(CDCl 3)：δ7.38(d，J＝8.3Hz，1H)，4.34(m，1H)，4.20(dd，J＝2.4，10.3Hz，1H)，4.09(dd，J＝8.8，10.2Hz，1H)，4.02(dd，J＝7.3，10.1Hz，1H)，3.88(m，1H)，3.71(dd，J＝4.4，10.3Hz，1H)，3.65(dd，J＝7.9，10.3Hz，1H)，2.74(m，1H)，2.60(m，1H)，2.04(s，3H)，1.98(s，3H)，1.69(dt，J＝14.1，2.5Hz，1H)，1.46(s，9H)，1.42(s，9H)，1.07(m，21H)。
MS(M＋H) +＝601。
(±)-(2R，3R，5R，1’S) 1H?NMR(CDCl 3)：δ6.82(d，1H)，4.10(m，4H)，3.81(m，3H)，2.55(m，2H)，1.98(m，7H)，1.46(s，9H)，1.42(s，9H)，1.07(m，21H)。
MS(M＋H) +＝601。
Figure A9980761001831
(40I. ±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-methylol-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-(acetoxy-methyl)-tetramethyleneimine-5-t-butyl formate (8.2g, 13.66mmol) (19g, 136mmol) reaction is 2 hours with salt of wormwood in methyl alcohol (200ml) and water (50ml).Solvent removed in vacuo makes residue (distribute between 3 * 100ml at water (100ml) and methylene dichloride.Through the dried over mgso organic extraction, filter and vacuum concentration, obtain title compound into colorless oil.
Figure A9980761001832
(40J. ±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 2A, but with (±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-methylol-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.9g, 78%).
1H?NMR(CDCl 3)：δ1.04-1.07(m，21H)，1.42(s，9H)，1.43(s，9H)，1.99(s，3H)，2.42(m，1H)，2.62(m，1H)，3.04(m，1H)，3.69(m，1H)，3.82(m，1H)，4.08(m，1H)，4.38(m，1H)，4.57(t，1H)，7.33(brd，1H)，9.65(s，1H)。
MS(M＋H) +＝557。
Figure A9980761001841
(40K. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 35A; but with (±)-(2R; 3R; 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R; 5R; 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.9g, 78%).
1H?NMR(CDCl 3)：δ1.03-1.10(m，21H)，1.44(s，9H)，1.47(s，9H)，1.55(m，1H)，1.64(dd，3H)，1.96(s，3H)，2.55(m，1H)，3.42(m，1H)，3.62-3.71(m，3H)，4.20(dd，1H)，4.30(m，1H)，5.39(m，1H)，5.48(m，1H)，7.73(brd，1H)。
MS(M＋H) +＝569。 (40L. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-triisopropyl siloxy-) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (4.85g, 8.54mmol) (12.8ml, 12.8mmol) reaction is 30 minutes with tetrabutylammonium (1M is in THF) in THF (100ml).Add entry (100ml), (2 * 100ml) extract to use methylene dichloride then.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 2/1: the ethyl acetate/hexane wash-out, obtain title compound, and be colorless solid (must measure: 3.1g, 89%).
1H?NMR(CDCl 3)：d?1.44(s，9H)，1.47(s，9H)，1.56(dd，3H)，1.80(m，1H)，2.02(s，3H)，2.67(m，1H)，3.11(t，3H)，3.44(dd，1H)，3.59(dd，1H)，3.74-3.84(m，2H)，4.15(dd，1H)，5.39(m，1H)，5.58(m，1H)，6.42(brd，1H)。
MS(M＋H) +＝413。 (40M. ±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 33B, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(trans-2-chloro-vinyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 18.0mg, 100%).
1H?NMR(DMSO-d 6)：d1.66(dd，3H)，1.71(dt，1H)，1.87(s，3H)，2.41(dt，1H)，3.18(m，1H)，3.43(dd，1H)，3.61(m，1H)，4.13(m，1H)，4.35(m，1H)，5.25(m，1H)，5.51(m，1H)，8.05(d，1H)，9.16(brs，2H)。
MS(M＋H) +＝257。
Embodiment 41 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001861
(41A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (600mg, 1.46mmol) (928mg, 2.18mmol) reaction is 1 hour with Dess-Martin Periodinane in methylene dichloride (50ml).Should react with 1M sodium thiosulfate solution (50ml) quencher, stir 20 minutes, (3 * 100ml) extract to use methylene dichloride then.Through dried over mgso organic layer, vacuum concentration.Residue is through the silica gel column chromatography purifying, with 2/1: the ethyl acetate/hexane wash-out obtains title compound (must measure: 547mg, 92%).
1H?NMR(CDCl 3)：δ9.40(d，J＝1Hz，1H)，7.88(bd)，5.69(m，1H)，5.27(m，1H)，4.78(dd，J＝9.5，1Hz，1H)，4.21(t，J＝8Hz，1H)，3.45(m，2H)，2.41(m，1H)，2.09(s，3H)，1.69(dd，J＝7.0，1Hz，3H)，1.55(m，1H)，1.46(s，9H)，1.40(s，9H)。
MS:(M+H) +=411, (M-H) -=409
Figure A9980761001862
(41B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature; with (±)-(2R; 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (780mg; 1.90mmol) THF (20ml) drips of solution be added to ethylmagnesium bromide (3M is in the ether) (3.17ml be in THF 9.51mmol) (15ml) solution and make it to react 40 minutes.Water (20ml) and saturated aqueous ammonium chloride (20ml) quencher should be reacted, and then extracted with methylene dichloride (3 * 50ml)).Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 2/1 ethyl acetate/hexane wash-out, obtain title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 472mg, 56%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 82mg, 10%), be colorless oil.
(±)-(2R，3S，5R，1’R，2’R)＝MS：(M＋H) +＝441，(M＋Na) +＝463，(M－H) -＝439。
(±)-(2R，3S，5R，1’R，2’S)＝MS：(M＋H) +＝441，(M＋Na) +＝463，(M－H) -＝439。 (41C. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-(300mg 0.68mmol) reacted 6 hours in methylene dichloride (2ml) with trifluoroacetic acid (8ml) 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.This reactant of vacuum concentration spends the night, and obtains title compound and (must measure: 311mmg), be colorless solid.
1H?NMR(500MHz，DMSO-d 6)：δ7.89(d，J＝8.7Hz，1H)，5.48(m，1H)，5.29(m，1H)，4.30(m，1H)，4.02(m，1H)，3.73(m，1H)，3.43(m，1H)，3.15(m，1H)，2.41(m，1H)，1.82(s，3H)，1.63(m，1H)，1.59(dd，J＝6.8，1.9Hz，3H)，1.55(m，1H)，1.27(m，1H)，0.85(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝285，(M＋Na) +＝307，(M－H) -＝283。
Embodiment 42 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001881
(42A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-(460mg, 1.05mmol) (666mg 1.57mmol) reacted 17 hours in methylene dichloride (30ml) 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate with Dess-Martin Periodinane.Should react with 1M sodium thiosulfate solution (50ml) quencher, stir 20 minutes.(3 * 100ml) extract this reactant with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 2: 1: the ethyl acetate/hexane wash-out, obtain title compound, and be colourless semisolid (must measure: 440mg, 96%).
MS：(M＋H) +＝439，(M＋Na) +＝461，(M－H) -＝437。
Figure A9980761001882
(42B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (435mg, 0.99mmol) (1 88mg, 4.97mmol) reaction is 0.5 hour with sodium cyanoborohydride in methyl alcohol (30ml) solution.Solvent removed in vacuo adds entry (30ml).Extract water layer with methylene dichloride (3 * 50ml)).Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 2: 1 ethyl acetate/hexane wash-outs, obtain title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 305mg, 70%) and compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 17mg, 4%). (42C. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-(300mg 0.68mmol) reacted 6 hours in methylene dichloride (2ml) with trifluoroacetic acid (8ml) 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.This reactant of vacuum concentration spends the night, and (2 * 5ml) grind, and obtain title compound and (must measure: 311mg), be colorless solid with acetonitrile.
1H?NMR(500?MHz，DMSO-d 6)：δ7.89(d，J＝8.7Hz，1H)，5.48(m，1H)，5.29(m，1H)，4.30(m，1H)，4.02(m，1H)，3.73(m，1H)，3.43(m，1H)，3.15(m，1H)，2.41(m，1H)，1.82(s，3H)，1.63(m，1H)，1.59(dd，J＝6.8，1.9Hz，3H)，1.55(m，1H)，1.27(m，1H)，0.85(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝285，(M＋ Na) +＝307，(M－H) -＝283。
Embodiment 43 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: .0065g, 100%).
1H NMR (DMSO-d 6): δ 7.90 (d, J=8.8Hz, 1H), 5.47 (m, 1H), 5.29 (t, J=9.8Hz, 1H), 4.29 (t, J=8.8Hz, 1H), 4.02 (q, J=6.8Hz, 1H), 3.71 (bt, J=8Hz, 1H), 3.43 (m, 1H), 3.15 (quintets, J=8.8Hz, 1H), 2.41 (dt, J=12.7,7.8Hz, 1H), 1.82 (s, 3H), 1.64 (m, 1H), 1.58 (dd, J=6.8,1.5Hz, 3H), 1.53 (m, 1H), 0.85 (t, J=7.3Hz 3H).
MS：(M＋H) +＝285，(M＋Na) +＝307，(M－H)-＝283，(M＋CF 3COOH) -＝397，(2M－1) -＝563
Embodiment 44 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001902
(44A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In-78 ℃; with (±)-(2R; 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (150mg; 0.37mmol) THF (10ml) drips of solution be added in enol lithium (1.83mmol, the 5 equivalents) solution of the acetonitrile in THF (15ml) and make it to react 15 minutes.Should react with saturated aqueous ammonium chloride (10ml) and water (10ml) quencher, then (2 * 50ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 2/1: the ethyl acetate/hexane wash-out, obtain title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 95mg, 58%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 30mg, 18%), be colorless oil.
(±)-(2R，3S，5R，1’R，2’R)＝MS：(M＋H) +＝452，(M－H) -＝450
(±)-(2R，3S，5R，1’R，2’S)＝ 1HNMR(CDCl 3)：δ8.14(d，J＝8.9Hz，1H)，5.51(m，1H)，5.38(m，1H)，4.25(m，1H)，4.19(m，1H)，3.94(m，1H)，3.74(m，1H)，3.22(m，1H)，2.54(m，1H)，2.47(m，2H)，2.04(s，3H)，1.69(m，1H)，1.65(dd，J＝6.5，1.8Hz，3H)，1.47(s，9H)，1.45(s，9H)。
MS:(M+H) +=452, (M-H) -=450 (44B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4.5mg, 95%).
1H?NMR(DMSO-d 6)：δ7.98(d，J＝10.0Hz，1H)，5.49(m，1H)，5.27(m，1H)，4.30(m，1H)，4.15(m，1H)，3.75(m，1H)，3.18(m，1H)，2.72-2.58(m，2H)，2.41(m，1H)，1.85(s，3H)，1.65(m，1H)，1.61(dd，J＝6.70，1.80Hz，3H)。
MS：(M＋H) +＝296，(M－H) -＝294
Embodiment 45 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761001921
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 8mg, 95%).
1H?NMR(DMSO-d 6)：δ7.75(d，J＝9.0Hz，1H)，5.47(m，1H)，5.25(m，1H)，4.46(m，1H)，4.20(m，1H)，4.13(m，1H)，3.56(m，1H)，3.15(m，1H)，2.55(m，2H)，2.42(m，1H)，1.82(s，3H)，1.72(m，1H)，1.55(dd，J＝6.71，1.83，3H)。
MS：(M＋H) +＝296，(M＋23) +＝318，(M－H) -＝294
Embodiment 46 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (46A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In-78 ℃; with (±)-(2R; 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (900mg; 2.187mmol) THF (40ml) drips of solution be added in enol lithium (8.75mmol, the 4 equivalents) solution of the ethyl acetate in THF (40ml) and make it to react 15 minutes.Should react with the saturated aqueous ammonium chloride quencher, then extract with methylene dichloride (3 *).Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1: 1 ethyl acetate/hexane wash-out, obtain title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 690mg, 63%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 246mg, 22.5%).
(±)-(2R，3S，5R，1’R，2’R) 1H?NMR(CDCl 3)：δ5.99(d，1H)，5.60(m，1H)，5.36(m，1H)，4.81(m，1H)，4.15(m，4H)，3.74(m，1H)，3.07(m，1H)，2.68(m，1H)，2.48(m，1H)，2.33(m，1H)，2.03(s，3H)，1.54(dd，3H)，1.47(s，9H)，1.46(s，9H)，1.24(t，J＝7.5Hz，3H)。
MS：(M＋H) +＝499
(±)-(2R，3S，5R，1’R，2’S) 1H?NMR(CDCl 3)：δ?7.93(d，1H)，5.44(m，2H)，4.19(m，4H)，4.03(m，1H)，3.72(m，1H)，3.37(m，1H)，2.63(m，1H)，2.48(m，2H)，2.01(s，3H)，1.65(dd，3H)，1.48(s，9H)，1.46(s，9H)，1.26(t，J＝7.5Hz，3H)。
MS:(M+H) +=499
Figure A9980761001941
(46B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ7.74(d，J＝9Hz，1H)，5.48(m，1H)，5.25(m，1H)，4.43(m，1H)，4.24(m，1H)，4.14(m，1H)，4.06(q，J＝7.5Hz，2H)，3.54(m，1H)，3.16(m，1H)，2.41(m，1H)，2.36(m，2H)，1.82(s，3H)，1.77(m，1H)，1.56(dd，3H)，1.18(t，J＝7.5Hz，3H)。
MS：(M＋H) +＝343
Embodiment 47 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ7.93(d，J＝9Hz，1H)，5.48(m，1H)，5.30(m，1H)，4.19(m，1H)，4.09(m，1H)，4.06(q，J＝7.5Hz，2H)，3.94(m，1H)，3.73(m，1H)，3.18(m，1H)，2.54(dd，1H)，2.40(m，1H)，2.27(m，1H)，1.82(s，3H)，1.65(m，1H)，1.60(dd，3H)，1.19(t，J＝7.5Hz，3H)。
MS：(M＋H) +＝343
Embodiment 48
Figure A9980761001951
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0030g, 100%).
1H NMR (DMSO-d 6): d8.97 (bs, 1H), 7.88 (d, J=8.5Hz, 1H), 5.45 (m, 1H), 5.28 (t, J=9.1Hz, 1H), 4.30 (t, J=8.6Hz, 1H), 3.94 (q, J=7.3Hz, 1H), 3.71 (t, J=8.0Hz, 1H), 3.62 (m, 1H), 3.15 (quintet, J=9.0Hz, 1H), 2.40 (dt, J=12.8,7.6Hz, 1H), 1.83 (s, 3H), 1.65 (m, 1H), 1.59 (dd, J=7.0,1.5Hz, 3H), 1.08 (d, J=5.5Hz, 3H).
MS：(M＋H) +＝271，(M＋Na) +＝293，(M－H) -＝269。
Embodiment 49
Figure A9980761001961
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0143g, 100%).
1H NMR (DMSO-d 6): δ 7.70 (d, J=9.1Hz, 1H), 5.49 (m, 1H), 5.25 (t, J=9.1Hz, 1H), 4.43 (t, J=8.6Hz, 1H), 4.03 (m, 1H), 3.92 (m, 1H), 3.55 (t, J=8.5Hz, 1H), 3.17 (quintet, J=8.5Hz, 1H), 2.42 (dt, J=12.8,7.3Hz, 1H), 1.85 (s, 3H), 1.72 (dt, J=12.8,10.0Hz, 1H), 1.57 (dd, J=6.7,1.8Hz, 3H), 1.04 (d, J=6.1Hz, 3H).
MS：(M＋H) +＝271，(M＋Na) +＝293，(M－H) -＝269
Embodiment 50 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (50A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with vinyl bromination magnesium, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 6.5mg, 18%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 22mg, 59%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝439，(M－H) -＝437。
(±)-(2R，3S，5R，1’R，2’R)MS：(M＋H) +＝439，(M－H) -＝437。 (50B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5mg, 96%).
1H?NMR(DMSO-d 6)：δ7.85(d，J＝9.1Hz，1H)，5.76(m，1H)，5.47(m，1H)，5.25(m，2H)，5.14(m，1H)，4.29(m，1H)，4.05(m，1H)，3.96(m，1H)，3.71(m，1H)，3.18(m，1H)，2.41(m，1H)，1.78(s，3H)，1.64(m，1H)，1.59(dd，J＝6.71，1.21Hz，3H)。
MS：(M＋H) +＝283，(M＋23) +＝305，(M－H) -＝281。
Embodiment 51 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6mg, 95%).
1H?NMR(DMSO-d 6)：δ7.84(d，J＝9.7Hz，1H)，5.78(m，1H)，5.48(m，1H)，5.23(m，34.43(m，1H)，4.26(m，1H)，4.20(m，1H)，3.55(m，1H)，3.18(m，1H)，2.43(m，1H)，1.81(s，3H)，1.73(m，1H)，1.57(dd，J＝6.72，1.83Hz，3H)。
MS：(M＋H) +＝283，(M＋23) -＝305，(M－H) -＝281，(2M－H) -＝563。
Embodiment 52 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (52A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with allyl group bromination magnesium, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 2.0mg, 5%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 9.0mg, 22%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝453，(M－H) -＝451。
(±)-(2R，3S，5R，1’R，2’R) 1H?NMR(DMSO-d 6)：δ7.70(d，J＝9.3Hz，1H)，5.80(m，1H)，5.51(m，1H)，5.30(m，1H)，5.00(m，2H)，4.58(brd，1H)，3.93(m，2H)，3.50(m，1H)，3.22(brt，1H)，2.02(m，3H)，1.88(s，3H)，1.56(m，4H)，1.41(s，9H)，1.36(s，9H)。
MS：(M－H) -＝451，(M＋H) +＝452，(M＋Na) +＝475。 (52B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 2mg, 100%).
1H?NMR(DMSO-d 6)：δ7.85(d，J＝9.3Hz，1H)，5.81(m，1H)，5.42(m，1H)，5.28(t，J＝7.3Hz，1H)，5.01(brd，2H)，3.99(m，2H)，3.57(m，2H)，3.08(m，1H)，2.33(m，1H)，2.26(m，1H)，2.07(m，1H)，1.81(s，3H)，1.57(dd，J＝1.4，5.4Hz，4H)。
MS：(M－H) -＝295，(M＋H) +＝297，(M＋Na) +＝319。
Embodiment 53 (±) 2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6mg, 100%).
1H?NMR(DMSO-d 6)：δ7.68(d，J＝9.2Hz，1H)，5.78(m，1H)，5.48(m，1H)，5.24(t，J＝7.8Hz，1H)，5.04(m，2H)，4.38(t，J＝7.0，1H)，4.09(t，J＝7.0，1H)，3.81(t，J＝4.7，1H)，3.53(t，J＝8.5，1H)，3.16(m，1H)，2.40(m，1H)，2.11(m，2H)，1.83(s，3H)，1.70(m，1H)，1.55(dd，J＝5.4，1.4Hz，3H)。
MS：(M－H) -＝295，(M＋H) +＝297，(M＋Na) +＝319。
Embodiment 54 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (52A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with the propyl group magnesium bromide, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 1mg, 1%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 32mg, 39%).
(±)-(2R，3S，5R，1’R，2’S) 1H?NMR(CDCl 3)：δ7.51(d，J＝8.2Hz，1H)，5.46(m，2H)，4.17(dd，J＝3.1，6.8Hz，1H)，4.05(m，1H)，3.81(t，J＝3.4Hz，1H)，3.54(m，1H)，3.21(m，1H)，2.60(m，1H)，2.02(s，3H)，1.70(dt，J＝3.0，7.4Hz，1H)，1.61(d，J＝5.4Hz，3H)，1.54(m，1H)，1.47(s，9H)，1.44(s，9H)，1.32(m，4H)，0.90(t，J＝7.1Hz，3H)
MS：(M＋H) +＝455，(M＋Na) +＝477；(M－H) -＝453。
(±)-(2R，3S，5R，1’R，2’R) 1H?NMR(CDCl 3)：δ5.98(d，J＝9.5Hz，1H)，5.60(t，J＝9.8Hz，1H)，5.36(m，1H)，4.16(m，1H)，3.75(d，J＝10.1Hz，1H)，3.64(m，1H)，3.51(m，1H)，3.09(brt，1H)，2.68(m，1H)，2.02(s，3H)，1.81(d，J＝13.9Hz，1H)，1.57(m，4H)，1.54(dd，J＝1.7，5.1Hz，3H)，1.46(s，9H)，1.45(s，9H)，0.88(t，J＝6.8Hz，3H)MS：(M－H) -＝453；(M＋H) +＝455。 (54B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 1mg, 100%).
1H?NMR(DMSO-d 6)：δ7.83(d，J＝9.2Hz，1H)，5.43(m，1H)，5.23(m，1H)，3.98(m，1H)，3.56(brt，1H)，3.46(m，1H)，3.08(m，2H)，2.32(m，1H)，1.80(s，3H)，1.57(dd，J＝1.4，5.4Hz，4H)，1.43(m，2H)，1.23(m，2H)，0.85(brt，3H)。
MS：(M＋H) +＝299，(M＋Na) +＝321。Embodiment 55 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0190g, 100%).
1H NMR (DMSO-d 6): δ 7.64 (d, J=9.3Hz, 1H), 5.48 (m, 1H), 5.24 (m, 1H), 4.38 (t, J=8.8Hz, 1H), 4.06 (m, 1H), 3.75 (m, 1H), 3.53 (t, J=8.5Hz, 1H), 3.16 (quintet, J=8.5Hz, 1H), 2.41 (dt, J=12.8,7.3Hz, 1H), 1.82 (s, 3H), 1.70 (dt, J=12.8,9.9Hz, 1H), 1.55 (dd, J=7.0,1.6Hz, 3H), 1.35 (m, 2H), 1.26 (m, 2H), 0.86 (t, J=6.7Hz, 3H).
MS：(M＋H) +＝299，(M＋Na) +＝321，(M－H) -＝297。
Embodiment 56 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002031
(56A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with sec.-propyl bromination magnesium, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0092g, 10%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0385g, 40%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝455，(M＋Na) +＝477，(2M＋Na) +＝931，(M－H) -＝453。
(±)-(2R，3S，5R，1’R，2’R)MS：(M＋H) +＝455，(M＋Na) +＝477，(2M＋Na) +＝931，(M－H) -＝453。
Figure A9980761002041
(56B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.010g, 100%).
1H NMR (DMSO-d 6): δ 7.63 (d, J=9.2Hz, 1H), 5.48 (m, 1H), 5.23 (m, 1H), 4.44 (m, 1H), 4.24 (m, 1H), 3.57 (t, J=8.7Hz, 1H), 3.33 (dd, J=8.5,2.5Hz, 1H), 3.21 (quintet, J=9.1Hz, 1H), 2.43 (dt, J=12.8,7.6Hz, 1H), 1.81 (s, 3H), 1.73 (dt, J=12.8,10.4Hz, 1H), 1.56 (dd, J=6.7,1.9Hz, 3H), 1.55 (m, 1H), 0.94 (d, J=6.7Hz, 3H), 0.78 (d, J=6.7Hz, 3H).
MS:(M+H) +=299, (M+Na) +=321, (M-H) -=297, (M+CF 3COOH) -=411, (2M-H) -=595 embodiment 57
Figure A9980761002042
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0433g, 100%).
1H NMR (DMSO-d 6): δ 7.88 (d, J=9.2Hz, 1H), 5.46 (m, 1H), 5.29 (m, 1H), 4.26 (t, J=8.5Hz, 1H), 4.11 (m, 1H), 3.67 (m, 1H), 3.39 (dd, J=9.8,1.8Hz, 1H), 3.15 (quintet, J=9.1Hz, 1H), 2.42 (dt, J=12.8,7.9Hz, 1H), 1.81 (s, 3H), 1.73 (m, 1H), 1.62 (m, 1H), 1.57 (dd, J=7.0,1.6Hz, 3H), 0.88 (d, J=6.7Hz, 3H), 0.75 (d, J=6.7Hz, 3H).
MS：(M＋H) +＝299，(M＋Na) +＝321，(M－H 2O) +＝281，(M－H) -＝297，(M＋CF 3COOH) -＝411，(2M－H) -＝595
Embodiment 58 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002051
(58A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with the butyl magnesium bromide, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 2.0mg, 8%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 6.0mg, 24%).
Figure A9980761002061
(58B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 2.0mg, 100%).
1H?NMR(DMSO-d 6)：δ8.34(d，J＝9.3Hz，1H)，5.24(m，1H)，5.12(m，1H)，3.90(m，1H)，3.78(m，1H)，3.23(m，1H)，2.90(m，1H)，2.14(m，1H)，1.80(m，1H)，1.75(s，3H)，1.52(m，3H)，1.45(m，1H)，1.08(br?s，6H)，0.83(brt，3H)。
MS：(M－H) -＝311，(M＋H) +＝313。Embodiment 59
Figure A9980761002062
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 6.0mg, 100%).
1H?NMR(DMSO-d 6)：δ7.60(d，J＝9.3Hz，1H)，5.46(m，1H)，5.24(t，J＝9.2Hz，1H)，4.21(t，J＝8.3Hz，1H)，4.02(t，J＝7.9Hz，1H)，3.74(m，1H)，3.47(t，J＝8.8，1H)，3.12(m，1H)，2.37(m，1H)，1.81(s，3H)，1.64(m，1H)，1.55(dd，J＝1.5，5.4Hz，3H)，1.29(m，6H)，0.86(t，J＝6.9，3H)。
MS：(M－H) -＝311；(M＋H) +＝313，(M＋Na) +＝335。
Embodiment 60 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002071
(60A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with isobutyl-bromination magnesium, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 31mg, 51%).
(±)-(2R，3S，5R，1’R，2’R) 1H?NMR(CDCl 3)：δ5.98(d，J＝9.5Hz，1H)，5.61(t，J＝8.2Hz，1H)，5.35(m，1H)，4.51(dd，J＝1.3，3.1Hz，1H)，4.15(m，1H)，3.74(d，J＝10.5Hz，1H)，3.61(m，2H)，3.09(t，J＝7.5Hz，1H)，2.71(m，1H)，2.02(s，3H)，1.81(d，J＝13.9Hz，1H)，1.58(br?s，1H)，1.54(dd，J＝1.7，5.1Hz，3H)，1.47(s，9H)，1.45(s，9H)，1.42(m，1H)，0.87(dd，J＝2.4，6.7Hz，6H)
MS：(M－H) -＝467；(M＋H) +＝469，(M＋Na) +＝491。
Figure A9980761002081
(60B. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-4-methyl-2-oxo) amyl group-3-cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-(8.0mg, 0.02mmol) (10mg 0.03mmol) reacted 1 hour in methylene dichloride (0.1ml) 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate with Dess-Martin Periodinane.Should react with 1M sodium thiosulfate solution (1ml) quencher, stir 20 minutes, (3 * 1ml) extract this reactant to use methylene dichloride then.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1: 1: the ethyl acetate/hexane wash-out, obtain title compound, and be colourless semisolid (must measure: 4.8mg, 61%).
Figure A9980761002082
(60C. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-4-methyl-2-oxo) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (4.8mg, 0.01mmol) (2.0mg, 0.05mmol) reaction is 0.5 hour with sodium borohydride in methyl alcohol (0.1ml) solution.Solvent removed in vacuo adds entry (1ml).Extract water layer with methylene dichloride (3 * 1ml)).Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1: 1 ethyl acetate/hexane wash-out, obtain title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 2.4mg, 51%).
Figure A9980761002091
(60D. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4.4mg, 100%).
1H?NMR(D 2O)：δ5.45(m，1H)，5.15(t，J＝11.0Hz，1H)，3.88(m，1H)，3.62(t，J＝8.0Hz，1H)，3.43(brt，1H)，2.98(m，1H)，2.36(m，1H)，1.81(s，3H)，1.60(m，1H)，1.51(m，1H)，1.45(dd，J＝1.3，5.4Hz，3H)，1.17(m，3H)，0.74(dd，J＝6.7，14Hz，6H)。
MS：(M－H) -＝311，(M＋H) +＝313，(M＋Na) +＝335。Embodiment 61 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 1.7mg, 85%).
1H?NMR(DMSO-d 6)：δ7.61(d，J＝9.8Hz，1H)，5.45(m，1H)，5.24(t，J＝7.4Hz，1H)，4.29(brt，1H)，4.0(brt，1H)，3.83(m，1H)，3.49?(t，J＝8.8Hz，1H)，3.13(m，1H)，2.39(m，1H)，1.82(s，3H)，1.68(m，2H)，1.55(dd，J＝1.4，5.4Hz，3H)，1.31(m，1H)，1.04(m，1H)，0.86(dd，J＝6.4，8.3Hz，6H)。
MS：(M－H) -＝311；(M＋H) +＝313，(M＋Na) +＝335。
Embodiment 62 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) penta-3-alkynyl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (62A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) penta-3-alkynyl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with propine-1-base zinc, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) penta-3-alkynyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0073g, 16%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) penta-3-alkynyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0349g, 77%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝451，(M＋Na) +＝473，(2M＋Na) +＝923，(M－H) -＝449。
(±)-(2R，3S，5R，1’R，2’R)MS：(M＋H) +＝451，(M＋Na) +＝473，(2M＋Na) +＝923，(M－H) -＝449。
Figure A9980761002111
(62B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) penta-3-alkynyl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) penta-3-alkynyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0052g, 100%).
1H NMR (DMSO-d 6): d 7.97 (d, J=8.3Hz, 1H), 5.48 (m, 1H), 5.25 (m, 1H), 4.35-4.20 (m, 3H), 3.67 (m, 1H), 3.18 (quintet, J=8.8Hz, 1H), 2.41 (dt, J=12.7,7.8Hz, 1H), 1.84 (s, 3H), 1.81 (d, J=1.9Hz, 3H), 1.63 (m, 1H), 1.59 (dd, J=6.9,2.0Hz, 3H).
MS：(M＋H) +＝295，(M＋Na) +＝317，(M－H) -＝293，(M＋CF 3COO -) -＝407，(2M－H) -＝587。Embodiment 63 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) penta-3-alkynyl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) penta-3-alkynyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0540g, 100%).
1H NMR (DMSO-d 6): d 7.90 (d, J=8.8Hz, 1H), 5.50 (m, 1H), 5.25 (m, 1H), 4.40-4.35 (m, 2H), 4.28 (m, 1H), 3.71 (t, J=8.0Hz, 1H), 3.18 (quintet, J=8.3Hz, 1H), 2.42 (dt, J=13.2,7.4Hz, 1H), 1.87 (s, 3H), 1.82 (d, J=1.9Hz, 3H), 1.71 (dt, J=12.7,10.0Hz, 1H), 1.57 (dd, J=6.9,1.5Hz, 3H).
MS：(M＋H) +＝295，(M＋Na) +＝31?7，(M－H) -＝293，(M＋CF 3COO -) -＝407。
Embodiment 64 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002121
(64A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In-78 ℃; make (±)-(2R; 3S; 5R, 1 ' R)-(41mg is 0.10mmol) with seven fluoropropyl iodide (0.144ml for 1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate; 1.0mmol; 10 equivalents) in THF (2ml) solution, reacted 5 minutes with 1M phenyl-magnesium-bromide (0.90ml, 0.90mmol, 9 equivalents).Made this reaction mixture be warmed to room temperature with 1 hour.Should react with saturated aqueous ammonium chloride (10ml) and water (10ml) quencher, then (3 * 25ml) extract with ethyl acetate.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/2: the ethyl acetate/hexane wash-out, obtain title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 12.6mg, 22%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝581，(M＋Na) +＝603，(2M＋Na) +＝1183，(M－H) -＝579。 (64B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.003g, 100%).
1H NMR (DMSO-d 6): δ 7.84 (d, J=9.3Hz, 1H), 5.45 (m, 1H), 5.26 (m, 1H), 4.71 (t, J=9.7Hz, 1H), 4.63 (d, J=22.0Hz, 1H), 4.51 (m, 1H), 3.59 (t, J=9.3Hz, 1H), 3.19 (quintet, J=8.3Hz, 1H), 2.43 (dt, J=12.7,7.3Hz, 1H), 1.76 (s, 3H), 1.74 (m, 1H), 1.53 (dd, J=6.8,1.4Hz, 3H).
MS：(M＋H) +＝425，(M＋Na) +＝447，(M－H) -＝423，(2M－1) -＝847。
Embodiment 65 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (65A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In 25 ℃, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-(35mg, 0.07mmol) (8mg 0.35mmol) reacted 3 hours in THF (5ml) 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate with lithium borohydride.Should react with saturated aqueous ammonium chloride (2ml) and water (2ml) quencher, then (2 * 10ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, dichloromethane solution wash-out with 5% methyl alcohol, obtain title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2, the 4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 14mg, 44%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝457，(M－H) -＝455。
Figure A9980761002141
(65B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2, the 4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)δ7.93(d，J＝9.0Hz，1H)，5.56(m，1H)，5.31(m，1H)，4.43(m，1H)，4.14(m，1H)，3.69(m，1H)，3.63(m，1H)，3.23(m，2H)，3.07(m，1H)，2.43(m，1H)，2.06(s，3H)，1.83(m，2H)，1.79(m，1H)，1.62(dd，J＝6.71，1.22Hz，3H)
MS：(M＋H) +＝301，(M－H) -＝299。
Embodiment 66 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002151
(66A. 2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 65A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 11mg, 70%).
1H?NMR(CDCl 3)δ5.58(m，1H)，5.38(m，1H)，4.16(m，1H)，4.05(m，1H)，3.97(m，1H)，3.78(m，2H)，3.20(m，1H)，2.66(m，1H)，2.54(m，1H)，2.04(s，3H)，1.80(m，1H)，1.55(m，2H)，1.47(s，9H)，1.44(s，9H)
MS:(M+H) +=457, (M-H) -=455 (66B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 8mg, 96%).
1H?NMR(DMSO-d 6)δ7.91(d，J＝9.1Hz，1H)，5.50(m，1H)，5.25(m，1H)，4.43(m，1H)，4.30(m，1H)，4.22(m，1H)，3.94(m，1H)，3.86(m，1H)，3.62(m，1H)，3.18(m，1H)，2.43(m，1H)，1.85(s，3H)，1.75(m，1H)，1.65(m，2H)，1.58(dd，J＝6.70，1.81Hz，3H)。
MS：(M＋H) +＝301，(M－H) -＝299。
Embodiment 67 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (67A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with the phenylacetylene lithium, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0010g, 4%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0050g, 21%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝513，(M＋Na) +＝535，(2M＋Na) +＝1047，(M－H) -＝511。
(±)-(2R，3S，5R，1’R，2’R)MS：(M＋H) +＝513，(M＋Na) +＝535，(2M＋Na) +＝1047，(M－H) -＝511。
Figure A9980761002171
(67B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 68 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (68A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(phenylacetylene-1-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0034g, 100%).
1H NMR (DMSO-d 6): δ 9.2 (bs, 1H), 8.04 (d, J=9.2Hz, 1H), 7.45-7.35 (m, 5H), 5.50 (m, 1H), 5.29 (m, 1H), 4.64 (d, J=4.9,1H), 4.5-4.4 (m, 2H), 3.81 (m, 1H), 3.22 (quintet, J=8.5Hz, 1H), 2.45 (dt, J=12.8,7.3Hz, 1H), 1.89 (s, 3H), 1.74 (dt, J=12.7,10.0Hz, 1H), 1.58 (dd, J=7.3,1.8Hz, 3H).
MS：(M＋H) +＝357，(M＋Na) +＝379，(M－H) -＝355。
Embodiment 69 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002181
(69A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 42A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-replacement of 5-t-butyl formate (2R, 3S, 5R, 1 ' R, 2 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 8mg, 81%).
MS:(M+H) +=481, (M-H) -=479
Figure A9980761002182
(69B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 42B, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-replacement of 5-t-butyl formate (2R, 3S, 5R, 1 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5mg, 63%).
MS:(M+H) +=483, (M-H) -=481 (69C. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4mg, 95%).
1H?NMR(DMSO-d 6)δ7.67(d，J＝8.9Hz，1H)，5.48(m，1H)，5.23(m，1H)，4.42(m，1H)，4.21(m，1H)，3.58(m，2H)，3.22(m，1H)，2.43(m，1H)，1.82(s，3H)，1.74(m，1H)，1.58(dd，J＝6.71，1.23Hz，3H)，1.52(m，1H)，1.38(m，1H)，1.29(m，2Hz)，1.13(m，1H)，0.80(m，6H)
MS：(M＋H) +＝327，(M－H) -＝325
Embodiment 70 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002201
(70A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 41B, but replace ethylmagnesium bromide, preparation title compound (must measure: 13mg, 45%) with 3-amyl group magnesium bromide.
MS:(M+H) +=483, (M-H) -=481
Figure A9980761002202
(70B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-ethyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3mg, 96%).
1H?NMR(DMSO-d 6)δ7.85(d，J＝9.2Hz，1H)，5.47(m，1H)，5.30(m，1H)，4.28(m，1H)，4.19(m，1H)，3.67(m，1H)，3.58(m，1H)，3.17(m，1H)，2.43(m，1H)，1.81(s，3H)，1.63(m，1H)，1.58(dd，J＝6.71，1.82Hz，3H)，1.40(m，2H)，1.28(m，1H)，1.10(m，1H)，1.05(m，1H)，0.83(m，6H)
MS：(M＋H) +＝327，(M－H) -＝325
Embodiment 71 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002211
(71A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 41B, but replace ethylmagnesium bromide, preparation title compound (must measure: 36mg, 60%) with phenyl-magnesium-bromide.
MS：(M＋H) +＝489，(M＋Na) +＝511，(M－H) -＝487。
Figure A9980761002212
(71B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.5mg, 100%).
1H?NMR(DMSO-d 6)：δ7.79(d，J＝9.2Hz，1H)，7.36(m，2H)，7.31(m，2H)，7.22(m，1H)，5.49(m，1H)，5.22(m，1H)，4.94(d，J＝3.0Hz，1H)，4.52(m，1H)，4.35(m，1H)，3.62(t，J＝8.5Hz，1H)，3.22(m，1H)，2.46(m，1H)，1.77(m，1H)，1.65(s，3H)，1.57(dd，J＝6.7，0.8Hz，3H)。
MS：(M＋H) +＝333，(M＋Na) +＝355，(M－H) -＝331。
Embodiment 72 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (72A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 42A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-replacement of 5-t-butyl formate (2R, 3S, 5R, 1 ' R, 2 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 24mg, 84%).
MS：(M＋H) +＝487，(M＋Na) +＝509，(M－H) -＝485。
Figure A9980761002222
(72B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 42B, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-replacement of 5-t-butyl formate (2R, 3S, 5R, 1 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 7.9mg, 52%).
MS：(M＋H) +＝489，(M＋Na) +＝520，(M-H) -＝487。
Figure A9980761002231
(72C. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 7.5mg, 100%).
1H?NMR(DMSO-d 6)：δ7.83(d，J＝9.2Hz，1H)，7.36(m，2H)，7.32(m，2H)，7.25(m，1H)，5.47(m，1H)，5.33(m，1H)，4.54(d，J＝9.8Hz，1H)，4.36(m，1H)，4.23(m，1H)，3.78(m，1H)，3.20(m，1H)，2.43(m，1H)，1.63(m，1H)，1.56(dd，J＝6.7，1.2Hz，3H)，1.53(s，3H)。
MS：(M＋H) +＝333，(M＋Na) +＝355，(M－H) -＝331。
Embodiment 73 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-(thiophene-2-yl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002232
(73A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(thiophene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In 25 ℃; will be at (±)-(2R among the THF (2ml); 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (40mg; 0.098mmol) be added drop-wise in THF (1ml) solution of 2-thiophene lithium (1M in THF, 0.505mmol, 5 equivalents) and make it to react 20 minutes.Should react with saturated aqueous ammonium chloride (2ml) and water (5ml) quencher, then (2 * 10ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/1: the ethyl acetate/hexane wash-out obtains title compound (must measure: 9.5mg, 20%).
MS：(M＋H) +＝495，(M＋Na) +＝517，(M－H) -＝493。 (73B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-(thiophene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(thiophene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 4.3mg, 100%).
1H?NMR(DMSO-d 6)δ7.86(d，J＝9.8Hz，1H)，7.63(dd，J＝5.4，1.0Hz，1H)，7.07(m，1H)，6.98(m，1H)，5.58(m，1H)，5.43(m，1H)，4.55(m，1H)，4.39(m，1H)，3.72(m，1H)，3.11(m，2H)，2.43(m，1H)，2.04(s，3H)，1.80(m，1H)，1.57(m，3H)。
MS：(M＋H) +＝339，(M＋Na) +＝361，(M－H) -＝337。
Embodiment 74 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-(4-methylthiazol-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002251
(74A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-(4-methylthiazol-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In-78 ℃, 1.6M n-Butyl Lithium (0.125ml, 0.20mmol, 4 equivalents) is added 2, in the 1ml THF solution of 4-dimethylthiazole (28.3mg, 0.25mmol, 5 equivalents) and make it to react 30 minutes.Will be at (±)-(2R among the THF (1ml); 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (20.5mg; 0.050mmol) be added drop-wise in the above solution and make it to react 30 minutes in-78 ℃, reaction 30 minutes under room temperature then.With saturated aqueous ammonium chloride (5ml) and this reaction mixture of water (5ml) quencher, then (3 * 25ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/2: the ethyl acetate/hexane wash-out, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-(4-methylthiazol-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 3.3mg, 13%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-(4-methylthiazol-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 7.5mg, 29%).
(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝524，(M＋Na) +＝546，(2M＋Na) +＝1069，(M－H) -＝522。
(2R，3S，5R，1’R，2’R)MS：(M＋H) +＝524，(M＋Na) +＝546，(2M＋Na) +＝1069，(M－H) -＝522。
Figure A9980761002261
(74B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-(4-methylthiazol-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-(4-methylthiazol-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0030g, 100%).
1H?NMR(DMSO-d 6)δ9.0(bs，1H)，8.10(d，J＝8.3Hz，1H)，7.11(d，J＝1.0Hz，1H)，5.48(m，1H)，5.30(m，1H)，4.30(m，1H)，4.10(m，1H)，3.88(dt，J＝9.4，2.6Hz，1H)，3.78(m，1H)，3.25-3.15(m，2H)，2.93(dd，J＝15.1，8.3Hz，1H)，2.41(dt，J＝12.3，7.3Hz，1H)，2.33(d，J＝1.0Hz，3H)，1.86(s，3H)，1.66(dt，J＝12.7，10.3Hz，1H)，1.61(dd，J＝6.8，1.5Hz，3H)。
MS：(M＋H) +＝368，(M＋Na) +＝390，(M－H) -＝366。
Embodiment 75 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3-(4-methylthiazol-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002262
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-(4-methylthiazol-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0030g, 100%).
1H?NMR(DMSO-d 6)d?9.0(bs，1H)，7.77(d，J＝9.3Hz，1H)，7.11(s，1H)，5.47(m，1H)，5.25(m，1H)，4.45(m，1H)，4.20(m，2H)，3.58(t，J＝9.1Hz，1H)，3.19(m，1H)，2.96(m，2H)，2.41(m，1H)，2.33(d，J＝1.0Hz，3H)，1.85(s，3H)，1.73(dt，J＝12.7，10.3Hz，1H)，1.54(dd，J＝6.9，1.5Hz，3H)。
MS：(M＋H) +＝368，(M＋Na) +＝390，(M－H) -＝366，(M＋CF 3COOH) -＝480，(2M－H) -＝733。
Embodiment 76 (±)-(2R, 3S, 5R, 1 ' R, 2 ' RS)-2-(1-acetamido-2-hydroxyl-3-(thiazoline-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002271
(76A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-(thiazoline-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In-78 ℃; will be at (±)-(2R among the THF (1ml); 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (20.5mg; 0.05mmol) be added drop-wise to (thiazoline-2-yl) lithium methide (0.20mmol, 4 equivalents, in-78 ℃ by the preparation of 0.025g 2-methylthiazol quinoline and 0.125ml 1.6M n-Butyl Lithium) THF (2ml) solution in and make it to react 30 minutes.Should react with saturated aqueous ammonium chloride (5ml) and water (5ml) quencher, then (3 * 20ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/1: the ethyl acetate/hexane wash-out, obtain title compound, and be mixture of isomers (must measure: 10mg, 40%).
MS：(M＋H) +＝512，(M＋Na) +＝534，(M－H) -＝510。
Figure A9980761002281
(76B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' RS)-2-(1-acetamido-2-hydroxyl-3-(thiazoline-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-(thiazoline-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.003g, 100%).
Main isomer 1H NMR (DMSO-d 6) δ 8.88 (m, 1H), 7.76 (d, J=8.8Hz, 1H), 5.46 (m, 1H), 5.19 (m, 1H), 4.69 (m, 1H), 3.90 (m, 1H), 3.85 (m, 1H), 3.49 (m, 2H), 3.35 (t, J=9.0Hz, 1H), 3.29 (dd, J=17.6,5.9Hz, 1H), 3.04 (t, J=8.9Hz, 1H), 2.78 (dd, J=17.6,8.1Hz, 1H), 2.7-2.55 (m, 2H), 1.75 (s, 3H), 1.70 (m, 1H), 1.56 (dd, J=6.8,1.5Hz, 3H).
MS：(M＋H) +＝356，(M＋Na) +＝378，(2M＋Na) +＝733，(M－H) -＝354。
Embodiment 77 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002291
(77A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In 0 ℃; will be at (±) among the THF (2ml)-(2R, 3S, 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (41mg; 0.10mmol) and 1,1-difluoro allyl iodide (94mg, 0.60mmol; 6 equivalents) with zinc powder (33mg; 0.50mmol, 5 equivalents) reacted 5 minutes, under room temperature, reacted 4 hours then.With saturated aqueous ammonium chloride (15ml) and this reaction mixture of water (15ml) quencher, then (3 * 25ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/3: the ethyl acetate/hexane wash-out obtains title compound (must measure: 35mg, 71%).
MS：(M＋H) +＝489，(M+Na) +＝511，(2M＋Na) +＝999，(M－H) -＝487。 (77B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0026g, 96%).
1H NMR (DMSO-d 6) d 7.68 (d, J=7.8Hz, 1H), 5.97 (m, 1H), 5.55-5.45 (m, 2H), 5.43 (m, 1H), 5.23 (m, 1H), 4.45 (m, 2H), 4.10 (m, 1H), 3.16 (quintet, J=9.1Hz, 1H), 2.41 (dt, J=12.8,7.3Hz, 1H), 1.72 (s, 3H), 1.70 (dt, J=12.8,10.3Hz, 1H), 1.61 (dd, J=6.7,1.2Hz, 3H).
MS：(M＋H) +＝333，(M＋Na) +＝355，(M－H) -＝331，(2M－H) -＝663。
Embodiment 78 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002301
(78A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 42A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, obtain (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0050g, 44%).
MS：(M＋H) +＝487，(M＋Na) +＝509，(M－2F) +＝448，(M－H) -＝485。
Figure A9980761002311
(78B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 42B, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate. (78C. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 79 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-(cis-butene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (79A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(cis-butene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
In 25 ℃; make (±)-(2R; 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (30mg; 0.073mmol) (0.75ml (0.5M), 0.37mmol) reaction is 45 minutes with cis-2-butene-2-base lithium in THF (5ml).Should react with saturated aqueous ammonium chloride (5ml) and water (5ml) quencher, then (2 * 10ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/1: the ethyl acetate/hexane wash-out obtains title compound (must measure 20mg, 59%).
1H?NMR(CDCl 3)δ6.19(d，J＝8.9Hz，1H)，5.61(m，1H)，5.35(m，1H)，5.27(m，1H)，4.48(m，1H)，4.18(m，1H)，4.77(m，2H)，3.10(m，1H)，2.72(m，1H)，1.99(s，3H)，1.82(m，1H)，1.73(m，3H)，1.55(m，6H)，1.47(s，9H)，1.44(s，9H)
MS:(M+H) +=467, (M-H) -=465 (79B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-(cis-butene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-(cis-butene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4mg, 96%).
1H?NMR(DMSO-d 6)δ8.09(d，J＝9.0Hz，1H)，5.50(m，1H)，5.32(m，1H)，5.16(m，1H)，4.50(m，1H)，4.38(m，1H)，4.19(m，1H)，3.43(m，1H)，3.20(m，1H)，2.43(m，1H)，1.88(s，3H)，1.74(m，1H)，1.70(s，3H)，1.62(m，3H)，1.58(m，3H)
MS：(M＋H) +＝311，(M－H) -＝309
Embodiment 80 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' R) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002331
(80A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' R) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature; will be at (±)-(2R among the THF (1ml); 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (60mg; 0.15mmol) (0.45ml is in solution 0.85mmol) and make it to react 40 minutes to be added drop-wise to 2-butyl magnesium bromide (3M is in ether).Should react with saturated ammonium chloride (1ml) quencher, then (3 * 1ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/4: the ethyl acetate/hexane wash-out, obtain title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate R f=0.65 (1: 1 ethyl acetate: hexane) (must measure 19mg, 27%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate R f=0.5 (1: 1 ethyl acetate: hexane) (must measure 19mg, 27%).
R f＝0.65? 1H?NMR(CDCl 3)δ5.98(d，J＝8.8Hz，1H)，5.62(t，J＝10.5Hz，1H)，5.35(m，1H)，4.66(d，J＝4.4Hz，1H)，4.16(d，J＝9.5Hz，1H)，3.78(m，3H)，3.12(m，2H)，2.73(m，1H)，2.0(s，3H)，1.81(d，J＝13.2Hz，1H)，1.54(brs，3H)，1.47(s，9H)，1.44(s，9H)，1.25(m，1H)，0.81(m，6H)。
MS：(M－H) -＝467，(M＋H) +＝469。
R f＝0.5? 1H?NMR(CDCl 3)δ6.00(d，J＝10.2Hz，1H)，5.61(brt，1H)，5.36(m，1H)，4.58(d，J＝4.7Hz，1H)，4.14(d，J＝8.8Hz，1H)，3.82(m，3H)，3.13(m，2H)，2.73(m，1H)，1.99(s，3H)，1.80(d，J＝13.9Hz，1H)，1.54(br?s，3H)，1.46(s，9H)，1.44(s，9H)，1.43(m，1H)，0.97(d，J＝6.8Hz，3H)，0.81(t，J＝7.2Hz，3H)
MS：(M－H) -＝467，(M＋H) +＝469。
Figure A9980761002341
(80B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' S)-(2.5mg 0.005mmol) reacted 6 hours in methylene dichloride (0.2ml) with trifluoroacetic acid (0.8ml) 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.This reactant vacuum concentration is spent the night, and (2 * 1ml) grind, and obtain title compound (must measure 2.0mg, 100%) with acetonitrile.
1H?NMR(DMSO-d 6)δ7.68(d，J＝8.8Hz，1H)，5.45(m，1H)，5.23(t，J＝7.3Hz，1H)，4.24(brt，1H)，4.18(m，1H)，3.52(t，J＝7.3Hz，1H)，3.45(m，1H)，3.16(m，1H)，2.38(m，1H)，1.83(s，3H)，1.68(m，1H)，1.58(dd，J＝2.0，4.8Hz，3H)，1.37(m，2H)，0.99(m，1H)，0.89(d，J＝6.8Hz，3H)，0.79(t，J＝7.4Hz，3H)
MS：(M－H) -＝311，(M＋H) +＝313，(M＋Na) +＝335。
Embodiment 81 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' R)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (R f=0.5,1: 1, ethyl acetate: hexane) replace (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 1.6mg, 76%).
1H?NMR(DMSO-d 6)δ7.55(d，J＝9.3Hz，1H)，5.45(m，1H)，5.23(m，1H)，4.31(brt，1H)，4.20(t，J＝8.3Hz，1H)，3.51(t，J＝9.3Hz，1H)，3.43(d，J＝7.4Hz，1H)，3.17(m，1H)，2.40(m，1H)，1.80(s，3H)，1.70(m，1H)，1.55(dd，J＝1.4，5.4Hz，3H)，1.36(m，2H)，1.14(m，1H)，0.84(t，J＝7.3Hz，3H)，0.73(d，J＝6.9Hz，3H)
MS：(M－H) -＝311，(M＋H) +＝313，(M＋Na) +＝335。
Embodiment 82 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002361
(82A. ±)-(2R, 3S, 5R, 1 ' R, 3 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 42A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R, 3 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 12mg, 63%). (82B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 42B, but with (±)-(2R, 3S, 5R, 1 ' R, 3 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (R f=0.5 and 0.65,1: 1, ethyl acetate: hexane) replace (2R, 3S, 5R, 1 ' R)-and 2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (R f=0.15,1: 1, ethyl acetate: hexane) (must measure: 6.0mg, 50%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (R f=0.10,1: 1, ethyl acetate: hexane) (must measure: 2.5mg, 63%).
Figure A9980761002371
(82C. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (R f=0.15,1: 1, ethyl acetate: hexane) replace (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6.0mg, 100%).
1H?NMR(DMSO-d 6)δ7.78(d，J＝9.2Hz，1H)，5.42(m，1H)，5.29(t，J＝10.3Hz，1H)，4.08(m，1H)，3.96(brt，1H)，3.51(m，2H)，3.08(m，1H)，2.33(m，1H)，1.78(s，3H)，1.56(d，J＝6.3Hz，3H)，1.52(m，1H)，1.40(m，1H)，1.29(m，1H)，1.21(m，1H)，0.84(t，J＝7.3Hz，3H)，0.73(d，J＝6.9Hz，3H)
MS：(M－H) -＝311，(M＋H) +＝313，(M＋Na) +＝335。
Embodiment 83 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' R)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002372
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (R f=0.10,1: 1, ethyl acetate: hexane) replace (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 2.5mg, 100%).
1H?NMR(DMSO-d 6)δ7.85(d，J＝8.7Hz，1H)，5.45(m，1H)，5.29(t，J＝9.3Hz，1H)，4.20(m，2H)，3.63(t，J＝8.3Hz，1H)，3.42(br?d，1H)，3.14(m，1H)，2.41(m，1H)，1.79(s，3H)，1.62(m，1H)，1.58(d，J＝5.4Hz，3H)，1.43(m，2H)，1.0(m，1H)，0.88(d，J＝6.8Hz，3H)，0.80(t，J＝7.3Hz，3H)
MS：(M－H) -＝311，(M＋H) +＝313，(M＋Na) +＝335。
Embodiment 84 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (84A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (22mg, 0.05mmol) with methyl-iodide (0.016ml, 0.25mmol), potassium hydroxide (14mg, 0.25mmol) and hexaoxacyclooctadecane-6-6 (0.7mg, 0.0025mmol) at N, reaction is 23 hours in the dinethylformamide (2ml).Then water (5ml) is added in this reaction mixture, then (2 * 10ml) extract with ether.The organic layer that water and salt water washing merge through dried over mgso, filters and vacuum concentration.Residue with 66% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is colorless oil (must measure: 5.2mg, 23%).
MS：(M＋H) +＝455，(M－H) -＝453。
Figure A9980761002391
(84B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4.7mg, 98%).
1H?NMR(DMSO-d 6)δ7.96(d，J＝9.2Hz，1H)，5.50(m，1H)，5.24(m，1H)，4.25(m，2H)，3.70(m，1H)，3.23(s，3H)，3.19(m，2H)，2.40(m，2H)，1.86(s，3H)，1.68(m，2H)，1.62(dd，J＝7.0，1.8Hz，3H)，1.39(m，1H)，0.77(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝299，(M＋Na) +＝321，(M－H) -＝297
Embodiment 85 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002392
(85A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (17mg, 0.04mmol) and methyl-iodide (28mg, 0.19mmol), potassium hydroxide (8mg, 0.19mmol) and hexaoxacyclooctadecane-6-6 (0.002mmol) at N, reaction is 6 hours in the dinethylformamide (1.5ml), then, water (5ml) is added in this reaction mixture, and then (2 * 10ml) extract with ether.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 50% ethyl acetate/hexane wash-out, obtains title compound (must measure: 5mg, 29%) through the silica gel column chromatography purifying.
MS：(M＋H) +＝455，(M－H) -＝453。
Figure A9980761002401
(85B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4mg, 95%).
1H?NMR(DMSO-d 6)δ8.00(d，J＝9.8Hz，1H)，5.57(m，1H)，5.35(m，1H)，4.42(m，1H)，4.28(m，1H)，3.95(m，1H)，3.54(m，1H)，3.28(s，3H)，2.80(m，1H)，2.30(m，1H)，1.92(s，3H)，1.65(m，1H)，1.60(m，3H)，1.43(m，2H)，0.82(t，J＝7.31Hz，3H)。
MS：(M＋H) +＝299，(M－H) -＝297
Embodiment 86 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002411
(86A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate. (86B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 87 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (87A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6.8mg, 33%).
MS：(M＋H) +＝469，(M＋Na) +＝491，(M－H) -＝467。 (87B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6.6mg, 100%).
1H?NMR(DMSO-d 6)：δ7.65(d，J＝9.2Hz，1H)，5.43(m，1H)，5.23(m，1H)，4.42(m，1H)，4.37(m，1H)，3.56(m，1H)，3.46(s，3H)，3.17(m，2H)，2.44(m，1H)，1.80(s，3H)，1.78(m，1H)，1.70(m，1H)，1.57(dd，J＝6.7，1.2Hz，3H)，0.94(d，J＝6.7Hz，3H)，0.82(d，J＝6.7Hz，3H)。
MS：(M＋H) +＝313，(M＋Na) +＝335，(M－H) -＝311。
Embodiment 88 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002431
(88A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 11.9mg, 36%).
MS：(M＋H) +＝469，(M＋Na) +＝491，(M－H) -＝467。 (88B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 11.5mg, 100%).
1H?NMR(DMSO-d 6)δ7.95(d，J＝9.8Hz，1H)，5.49(m，1H)，5.23(m，1H)，4.25(m，2H)，3.68(m，1H)，3.24(s，3H)，3.22(m，1H)，3.18(m，1H)，2.40(m，1H)，1.85(s，3H)，1.66(m，1H)，1.62(m，3H)，1.58(m，1H)，1.38(m，1H)，1.27(m，2H)，0.86(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝313，(M＋Na) +＝335，(M－H) -＝311。
Embodiment 89 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (89A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4.3mg, 21%).
MS：(M＋H) +＝469，(M＋Na) +＝491，(M－H) -＝467。
Figure A9980761002442
(89B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4.8mg, 100%).
1H?NMR(DMSO-d 6)δ7.70(d，J＝9.8Hz，1H)，5.45(m，1H)，5.24(m，1H)，4.40(m，1H)，4.25(m，1H)，3.57(t，J＝8.5Hz，1H)，3.40(m，1H)，3.35(s，3H)，3.17(m，1H)，2.42(m，1H)，1.82(s，3H)，1.69(m，1H)，1.56(dd，J＝7.1，1.2Hz，3H)1.24，(m，4H)，0.88(t，J＝7.0Hz，3H)。
MS：(M＋H) +＝313，(M＋Na) +＝335，(M－H) -＝311
Embodiment 90 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002451
(90A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 8mg, 31%).
MS:(M+H) +=467, (M-H) -=46590B. (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6mg, 96%).
1H?NMR(DMSO-d 6)δ8.02(d，J＝8.6Hz，1H)，5.75(m，1H)，5.51(m，1H)，5.24(m，1H)，5.05(m，2H)，4.27(m，1H)，4.22(m，1H)，3.74(m，2H)，3.26(s，3H)，3.18(m，1H)，2.47(m，1H)，2.39(m，1H)，2.17(m，1H)，1.87(s，3H)，1.67(m，1H)，1.63(dd，J＝6.71，1.23Hz，3H)。
MS：(M＋H) +＝311，(M－H) -＝309
Embodiment 91 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002461
(91A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4.0mg, 16%).
MS：(M＋H) +＝467，(M－H) -＝465。
Figure A9980761002471
(91B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3mg, 96%).
1H?NMR(DMSO-d 6)δ7.75(d，J＝9.2Hz，1H)，5.75(m，1H)，5.47(m，1H)，5.24(m，1H)，5.06(m，2H)，4.42(m，1H)，4.25(m，1H)，3.58(m，1H)，3.50(m，1H)，3.37(s，3H)，3.17(m，1H)，2.42(m，1H)，2.36(m，1H)，1.83(s，3H)，1.71(m，1H)，1.55(dd，J＝6.73，1.83Hz，3H)
MS：(M＋H) +＝311，(M－H) -＝309
Embodiment 92 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002472
(92A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with 1-butylene-4-base magnesium bromide, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0030g, 6%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 0.0145g, 28%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝467，(M＋Na) +＝489，(2M＋Na) +＝955，(M－H) -＝465。
(±)-(2R，3S，5R，1’R，2’R)MS：(M＋H) +＝467，(M＋Na) +＝489，(2M＋Na) +＝955，(M－H) -＝465。 (92B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0027g, 100%).
1H NMR (DMSO-d 6) δ 8.93 (bs, 1H), 7.90 (d, J=9.2Hz, 1H), 5.80 (m, 1H), 5.48 (m, 1H), 5.28 (m, 1H), 5.00 (dd, J=17.1,1.8Hz, 1H), 4.94 (dd, J=10.4,1.8Hz, 1H), 4.29 (bt, J=8.3Hz, 1H), 4.03 (m, 1H), 3.71 (m, 1H), 3.49 (m, 1H), 3.15 (quintet, J=8.5Hz, 1H), 2.41 (dt, J=12.8,7.3Hz, 1H), 2.16 (m, 1H), 2.05 (m, 1H), 1.83 (s, 3H), 1.79-1.75 (m, 1H), 1.64 (m, 1H), 1.58 (dd, J=6.7,1.8Hz, 3H), 1.34 (m, 2H).
MS：(M＋H) +＝311，(M＋Na) +＝333，(M－H) -＝309，(M＋CF 3COO -) -＝423
Embodiment 93 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002491
93A (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0027g, 100%).
1H NMR (DMSO-d 6) δ 7.68 (d, J=9.6Hz, 1H), 5.81 (m, 1H), 5.48 (m, 1H), 5.25 (m, 1H), 5.01 (dd, J=17.1,1.8Hz, 1H), 4.95 (dd, J=10.3,1.7Hz, 1H), 4.43 (t, J=8.5Hz, 1H), 4.10 (m, 1H), 3.74 (m, 1H), 3.56 (t, J=8.9Hz, 1H),, 3.16 (quintet, J=8.9Hz, 1H), 2.42 (dt, J=12.8,7.3Hz, 1H), 2.11 (m, 1H), 2.07 (m, 1H), 1.83 (s, 3H), 1.72 (dt, J=12.8,9.8Hz, 1H), 1.55 (dd, J=6.7,1.8Hz, 3H), 1.5-1.35 (m, 2H).
MS：(M＋H) +＝311，(M＋Na) +＝333，(M－H) -＝309，(M＋CF 3COO -) -＝423，(2M－H) -＝619。
Embodiment 94 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-2-(1-acetamido-2-methoxyl group-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002501
(94A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate. (94B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-2-(1-acetamido-2-methoxyl group-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 95 (±)-(2R, 3S, 5R, 1 ' RS)-2-(1-acetamido-2-oxo-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate. (95A. ±)-(2R, 3S, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 42A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6.8mg, 88%).
MS：(M＋H) +＝579，(M－H) -＝577。 (95B. ±)-(2R, 3S, 5R, 1 ' RS)-2-(1-acetamido-2-oxo-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0037g, 100%).
MS：(M＋H) +＝423，(M－H) -＝421。
Embodiment 96 (±)-(2R, 3 S, 5R, 1 ' RS)-2-(1-acetamido-2-oxo-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002521
(96A. ±)-(2R, 3S, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 42A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6.8mg, 88%).
MS：(M＋H) +＝579，(M－H) -＝577。
Figure A9980761002522
(96B. ±)-(2R, 3S, 5R, 1 ' RS)-2-(1-acetamido-2-oxo-2-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-seven fluoropropyls) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0037g, 100%).
MS：(M＋H) +＝423，(M－H) -＝421。
Embodiment 97 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002531
(97A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 42A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-replacement of 5-t-butyl formate (2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 14mg, 58%).
MS：(M＋H) +＝453，(M＋Na) +＝475；(M－H) -＝451。
Figure A9980761002532
(97B. ±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 1.4mg, 28%).
1H?NMR(DMSO-d 6)δ8.31(d，J＝8.3Hz，1H)，5.40(m，1H)，5.19(brt，1H)，4.26(t，J＝6.8Hz，1H)，3.63(t，J＝8.3Hz，1H)，3.35(m，1H)，2.97(m，1H)，2.45(m，1H)，，2.34(dt，J＝3.4，7.4Hz，1H)，2.20(m，1H)，1.84(s，3H)，1.58(dd，J＝2，4.3Hz，3H)，1.43(m，3H)，0.82(t，J＝7.3Hz，3H)
MS：(M－H) -=295，(M＋H) +＝297，(M＋Na) +＝319。
Embodiment 98 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but be used in (±)-(2R for preparing among the embodiment 42A, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.0mg, 100%).
1H?NMR(DMSO-d 6)：δ8.52(d，J＝8.6Hz，1H)，5.47(m，1H)，5.15(m，1H)，4.54(m，1H)，4.39(dd，J＝11.0，6.7Hz，1H)，3.84(t，J＝9.2Hz，1H)，3.17(m，1H)，2.50(m，1H)，2.38(m，1H)，，2.33(m，1H)，1.83(s，3H)，1.63(m，1H)，1.58(dd，J＝6.7，1.8Hz，3H)，0.94(t，J＝7.5Hz，3H)。
MS：(M＋H) +＝283，(M＋Na) +＝305，(M－H) -＝281。
Embodiment 99-115
Prepare title compound according to method described in embodiment 20 and the 40-42, but replace reactant.Embodiment 99 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ8.38(d，J＝8.5Hz，1H)，5.73(m，1H)，5.37(m，1H)，5.05(m，3H)，4.32(t，J＝7.9Hz，1H)，3.90(m，1H)，3.49(m，1H)，3.13(m，2H)，2.98(m，1H)，3.18(m，1H)，1.78(s，3H)，1.51(dd，J＝5.5，1.2Hz，3H)，1.44(m，1H)。
MS：(M＋H) +＝295，(M－H) -＝293。Embodiment 100
Figure A9980761002552
(±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ8.64(d，J＝8.5Hz，1H)，5.59(m，1H)，5.08(d，J＝17.1Hz，1H)，5.02(d，J＝9.8Hz，1H)，4.65(t，J＝8.6Hz，1H)，4.32(m，1H)，3.82(t，J＝9.2Hz，1H)，2.82(m，2H)，2.36(m，1H)，1.83(s，3H)，1.80(m，1H)，1.03(d，J＝6.7Hz，3H)，0.97(d，J＝6.7Hz，3H)。
MS：(M＋H) +＝283，(M＋Na) +＝305，(M－H) -＝281。Embodiment 101
Figure A9980761002561
(±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo) propyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)：δ8.96(d，J＝7.9Hz，1H)，5.71(m，1H)，5.27(d，J＝17.7Hz，1H)，5.17(d，J＝11.0Hz，1H)，4.38(m，1H)，4.29(m，1H)，3.81(m，1H)，2.61(m，1H)，2.22(m，1H)，2.13(s，3H)，2.01(s，3H)，1.24(m，1H)。
MS：(M＋H) +＝255，(M＋Na) +＝277，(M－H) -＝253。Embodiment 102
Figure A9980761002562
(±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo) butyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ8.61(d，J＝8.5Hz，1H)，5.60(m，1H)，5.10(d，J＝17.7Hz，1H)，5.03(dd，J＝10.4，1.2Hz，1H)，4.54(t，J＝8.5Hz，1H)，4.38(dd，J＝11.0，6.7Hz，1H)，3.86(m，1H)，2.84(m，1H)，2.52(m，1H)，2.37(m，2H)，1.85(s，3H)，1.82(m，1H)，0.94(t，J＝7.0Hz，3H)。
MS：(M＋H) +＝269，(M＋Na) +＝291，(M－H) -＝267。Embodiment 103 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo) amyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ8.60(d，J＝9.7Hz，1H)，5.60(m，1H)，5.07(m，2H)，4.65(m，1H)，4.54(m，1H)，4.38(m，1H)，3.86(m，1H)，2.84(m，1H)，2.45(m，1H)，2.36(m，1H)，1.86(s，3H)，1.82(m，1H)，1.47(m，2H)，0.87(t，J＝5.8Hz，3H)。
MS：(M＋H) +＝283，(M＋Na) +＝305，(M－H) -＝281。
Embodiment 104
Figure A9980761002572
(±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ8.00(d，J＝9.9Hz，1H)，5.63(m，1H)，5.08(m，1H)，4.98(m，1H)，4.35(m，1H)，4.25(m，1H)，4.08(m，1H)，3.55(m，1H)，3.45(m，1H)，3.38(m，1H)，2.83(m，1H)，2.33(m，1H)，1.78(s，3H)。
MS：(M＋H) +＝243，(M＋Na) +＝265，(M－H) -＝241。Embodiment 105 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) propyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.96(d，J＝9.7Hz，1H)，5.74(m，1H)，5.12(m，1H)，5.03(m，1H)，4.27(m，1H)，3.96(m，1H)，3.77(m，1H)，3.65(m，1H)，2.87(m，1H)，2.38(m，1H)，1.82(s，3H)，1.80(m，1H)，1.08(d，J＝6.0Hz，3H)。
MS：(M＋H) +＝257，(M＋Na) +＝279，(M－H) -＝255。
Embodiment 106
Figure A9980761002582
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.99(d，J＝9.0Hz，1H)，5.75(m，1H)，5.13(d，J＝17.1Hz，1H)，5.04(d，J＝10.5Hz，1H)，4.27(t，J＝8.4Hz，1H)，4.04(m，1H)，3.78(m，1H)，3.48(m，1H)，2.89(m，1H)，2.40(m，1H)，1.88(m，1H)，1.85(s，3H)，1.54(m，1H)，1.28(m，1H)，0.86(t，J＝7.2Hz，3H)。
MS：(M＋H) +＝271，(M＋Na) +＝293，(M－H) -＝269。Embodiment 107
Figure A9980761002591
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.99(d，J＝9.9Hz，1H)，5.75(m，1H)，5.08(m，2H)，4.28(m，1H)，4.03(m，1H)，3.77(m，1H)，3.52(m，1H)，2.88(m，1H)，2.40(m，1H)，1.86(s，3H)，1.75(m，1H)，1.45(m，2H)，1.25(m，2H)，0.87(t，J＝5.9Hz，3H)。
MS：(M＋H) +＝285，(M＋Na) +＝307，(M－H) -＝283。
Embodiment 108 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.97(d，J＝9.3Hz，1H)，5.75(m，1H)，5.12(d，J＝17.1Hz，1H)，5.04(d，J＝11.2Hz，1H)，4.24(m，1H)，4.13(m，1H)，3.74(dd，J＝9.8，6.1Hz，1H)，3.44(dd，J＝10.3，2.0Hz，1H)，2.87(m，1H)，2.40(m，1H)，1.84(m，1H)，1.83(s，3H)，1.75(m，1H)，0.89(d，J＝6.8Hz，3H)，0.75(d，J＝6.8Hz，3H)。
MS：(M＋H) +＝285，(M＋Na) +＝307，(M－H) -＝283。Embodiment 109 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-cyclopropyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)：δ7.81(d，J＝10.0Hz，1H)，5.73(m，1H)，5.05(m，2H)，4.39(m，1H)，4.20(m，1H)，3.90(m，1H)，3.61(m，1H)，3.08(m，1H)，2.86(m，1H)，2.42(m，1H)，1.85(s，3H)，0.88(m，1H)，0.45(m，1H)，0.35(m，2H)，0.11(m，1H)。
MS：(M＋H) +＝283，(M＋Na) +＝305，(M－H) -＝281。
Embodiment 110
Figure A9980761002602
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) propyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.77(d，J＝9.7Hz，1H)，5.72(m，1H)，5.07(m，2H)，4.40(m，1H)，4.03(m，1H)，3.95(m，1H)，3.57(m，1H)，2.86(m，1H)，2.43(m，1H)，1.88(m，1H)，1.84(s，3H)，1.04(d，J＝6.0Hz，3H)。
MS：(M＋H) +＝257，(M＋Na) +＝279，(M－H) -＝255。Embodiment 111
Figure A9980761002611
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) butyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)：δ7.72(d，J＝9.8Hz，1H)，5.73(m，1H)，5.08(d，J＝17.1Hz，1H)，5.03(d，J＝10.4Hz，1H)，4.41(m，1H)，4.13(m，1H)，3.68(m，1H)，3.63(m，1H)，2.88(m，1H)，2.44(m，1H)，1.90(m，1H)，1.83(s，3H)，1.38(m，2H)，0.84(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝271，(M＋Na) +＝293，(M－H) -＝269。
Embodiment 112
Figure A9980761002612
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) amyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.72(d，J＝9.9Hz，1H)，5.72(m，1H)，5.06(m，2H)，4.42(m，1H)，4.09(m，1H)，3.77(m，1H)，3.61(m，1H)，2.87(m，1H)，2.43(m，1H)，1.90(m，1H)，1.83(s，3H)，1.37(m，2H)，1.27(m，2H)，0.87(t，J＝5.9Hz，3H)。
MS：(M＋H) +＝285，(M＋Na) +＝307，(M－H) -＝283。Embodiment 113 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxy-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.71(d，J＝9.3Hz，1H)，5.70(m，1H)，5.08(d，J＝17.1Hz，1H)，5.03(d，J＝10.3Hz，1H)，4.42(m，1H)，4.25(m，1H)，3.61(m，1H)，3.35(dd，J＝8.3，2.5Hz，1H)，2.90(m，1H)，2.44(m，1H)，1.92(m，1H)，1.82(s，3H)，1.58(m，1H)，0.95(d，J＝6.8Hz，3H)，0.79(d，J＝6.4Hz，3H)。
MS：(M＋H) +＝285，(M＋Na) +＝307，(M－H) -＝283。
Embodiment 114
Figure A9980761002622
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-cyclopropyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.94(d，J＝9.6Hz，1H)，5.76(m，1H)，5.12(m，2H)，4.40(m，1H)，4.21(m，1H)，3.90(m，1H)，3.53(m，1H)，3.13(m，1H)，2.81(m，1H)，2.25(m，1H)，1.87(s，3H)，0.90(m，1H)，0.47(m，1H)，0.37(m，2H)，0.15(m，1H)。
MS：(M＋H) +＝283，(M＋Na) +＝305，(M－H) -＝281。Embodiment 115
Figure A9980761002631
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxy-4-methyl) amyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
1H?NMR(DMSO-d 6)δ7.71(d，J＝9.7Hz，1H)，5.83(m，1H)，5.06(d，J＝17.1Hz，1H)，5.02(d，J＝10.3Hz，1H)，4.41(m，1H)，4.06(m，1H)，3.83(m，1H)，3.59(t，J＝8.8Hz，1H)，2.84(m，1H)，2.42(m，1H)，1.90(m，1H)，1.82(s，3H)，1.71(m，1H)，1.34(m，1H)，1.07(m，1H)，0.89(d，J＝6.8Hz，3H)，0.86(d，J＝6.3Hz，3H)。
MS：(M＋H) +＝299，(M＋Na) +＝321，(M－H) -＝297。
Embodiment 116 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxy-2-methyl) propyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate. (116A. ±)-(2R, 3S, 5R, 1 ' R)-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl) propyl group-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 25 ℃, make (±)-(2R, 3S, 5R, 1 ' R)-(11mg, 0.027mmol) (0.05ml 0.134mmol) reacted 2 hours in THF (2ml) tert-butoxycarbonyl-2-(1-acetamido-2-oxo) propyl group-3-vinyl-tetramethyleneimine-5-t-butyl formate with methyl-magnesium-bromide (3M).Should react with saturated aqueous ammonium chloride (2ml) and water (2ml) quencher, then (2 * 5ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 2/1: the ethyl acetate/hexane wash-out obtains title compound (must measure 1.9mg, 17%).
MS：(M＋H) +＝427，(M－H) -＝425。 (116B. ±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxy-2-methyl) propyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl) propyl group-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 1.6mg, 99%).
1H?NMR(DMSO-d 6)δ?7.70(d，J＝9.9Hz，1H)，5.75(m，1H)，5.02(m，2H)，4.37(m，1H)，4.15(m，1H)，3.61(m，1H)，2.78(m，1H)，2.41(m，1H)，1.81(s，3H)，1.20(s，3H)，1.12(s，3H)。
MS：(M＋H) +＝271，(M＋23) +＝293，(M－H) -＝269
Embodiment 117 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxyl-2-ethyl) butyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate. (117A. ±)-(2R, 3S, 5R, 1 ' R)-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-ethyl) butyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 25 ℃, make (±)-(2R, 3S, 5R, 1 ' R)-(37mg, 0.087mmol) (0.15ml 0.44mmol) reacted 2 hours in THF (5ml) tert-butoxycarbonyl-2-(1-acetamido-2-oxo) butyl-3-vinyl-tetramethyleneimine-5-t-butyl formate with ethylmagnesium bromide (3M).Should react with saturated aqueous ammonium chloride (5ml) and water (5ml) quencher, then (2 * 10ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 2/1: the ethyl acetate/hexane wash-out obtains title compound (must measure 14mg, 35%).
MS：(M＋H) +＝455，(M－H) -＝453。
Figure A9980761002651
(117B. ±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxyl-2-ethyl) butyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-ethyl) butyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.8mg, 98%).
1H?NMR(DMSO-d 6)：δ7.62(d，J＝9.6Hz，1H)，5.75(m，1H)，5.03(m，2H)，4.39(m，1H)，4.31(m，2H)，3.87(m，1H)，3.38(m，1H)，2.88(m，1H)，2.40(m，1H)，1.83(s，3H)，1.55-1.30(m，4H)，0.86(m，6H)。
MS：(M＋H) +＝299，(M－H) -＝297
Embodiment 118 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido) allyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002652
(118A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido) allyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 20K; but with (±)-(2R; 3S; 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S; 5R; 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 15.3mg, 61.4%).
MS：(M＋H) +＝409。
Figure A9980761002661
(118B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido) allyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido) allyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 13.1mg, 100%).
1H?NMR(DMSO-d 6)：δ1.58(dd，3H)，1.74(dt，1H)，1.88(s，3H)，2.41(dt，1H)，3.17(m，1H)，3.56(dd，1H)，4.35(dd?1H)，4.70(dd，1H)，5.22-5.30(m，3H)，5.51(m，1H)，5.82(m，1H)，8.15(d，1H)，9.18(brs，2H)。
MS：(M＋H) +＝253。
Embodiment 119 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(cis and trans) butene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002671
(119A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(cis and trans) butene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 20K; but with (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate; replace first base three phenyl phosphonium bromides with the ethyl triphenyl phosphonium bromide; preparation title compound (must measure: 12.4mg, 48.2%).
MS:(M+H) +=423
Figure A9980761002672
(119B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(cis and trans) butene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(cis and trans) butene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 11.8mg, 100%).
1H?NMR(DMSO-d 6)：δ1.63(dd，3H)，1.66(dd，3H)，1.74(m，1H)，1.88(s，3H)，2.41(dt，1H)，3.17(m，1H)，3.50(dd，1H)，4.34(dd，1H)，4.95(m，1H)，5.23(m，1H)，5.39(m，1H)，5.53(m，1H)，5.68(m，1H)，8.21(d，1H)，9.18(br?s，2H)。
MS：(M＋H) +＝267
Embodiment 120 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3,3-dimethyl) allyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002681
(120A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3,3-dimethyl) allyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 20K; but with (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate; replace first base three phenyl phosphonium bromides with sec.-propyl three phenyl phosphonium bromides; preparation title compound (must measure: 8.2mg, 25.9%).
MS:(M+H) +=437
Figure A9980761002682
(120B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3,3-dimethyl) allyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3, the 3-dimethyl) allyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 7.5mg, 100%).
1H?NMR(DMSO-d 6)：δ1.53(dd，3H)，1.57(s，3H)，1.61(s，3H)，1.66(m，1H)，1.77(s，3H)，2.32(dt，1H)，3.07(m，1H)，3.39(dd，1H)，4.26(m，1H)，4.75(m，1H)，5.07(d，1H)，5.15(m，1H)，5.44(m，1H)，8.06(d，1H)。
MS：(M＋H) +＝281。
Embodiment 121 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(cis and trans) amylene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002691
(121A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(cis and trans) amylene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment; but with (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate; replace first base three phenyl phosphonium bromides with normal-butyl three phenyl phosphonium bromides; preparation title compound (must measure: 21.0mg, 66.2%).
MS：(M＋H) +＝437。
Figure A9980761002692
(121B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(cis and trans) amylene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(cis and trans) amylene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 16.0mg, 98.1%).
1H?NMR(DMSO-d 6)：δ0.93(t，3H)，1.62(dd，3H)，1.75(m，1H)，1.87(s，3H)，2.07(m，2H)，2.40(m，1H)，3.17(m，1H)，3.50(m，1H)，4.34(m?1H)，4.94(m，1H)，5.23(m，1H)，5.34(m，1H)，5.53(m，1H)，5.58(m，1H)，8.24(d，1H)，9.25(br?s，2H)。
MS：(M＋H) +＝281。
Embodiment 122 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-4-hydroxyl-2-(cis and trans) butene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002701
(122A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-4-(t-butyldimethylsilyloxy base)-2-(cis and trans) butene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment; but with (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate; replace first base three phenyl phosphonium bromides with 4-(t-butyldimethylsilyloxy base)-butyl triphenyl phosphonium bromide; preparation title compound (must measure: 23.1mg, 66.9%).
MS(M＋H) +＝567。 (122B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-4-hydroxyl-2-(cis and trans) butene-1-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-(cis and trans)-4-hydroxyl-butene-2-yl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 16.9mg,＞100%).
1HNMR(DMSO-d 6)：δ1.67(dd，3H)，1.78(dt，1H)，1.91(s，3H)，2.44(m，1H)，2.50(m，1H)，2.56(m，1H)，2.65(m，1H)，3.23(m，1H)，3.54(m，1H)，4.40(m，1H)，4.47(m，2H)，5.01(m，1H)，5.26(m，1H)，5.54(m，2H)，5.63(m，1H)，8.32(d，1H)，9.27(br?s，2H)。
MS：(M＋H) +＝297。
Embodiment 123 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido) butyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate. (123A. ±)-(2R, 3R, 5R)-1-benzyl-2-vinyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3R, 5R)-1-benzyl-2-vinyl-3-methylol-tetramethyleneimine-5-t-butyl formate (30.8g, 97.1mmol) (49.5ml 190.4mmol) reacted 1 hour in methylene dichloride (650ml) with imidazoles with t-butyldiphenylsilyl chlorine.Should react with the methyl alcohol quencher, then extract with methylene dichloride (600ml).Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 2/1: chloroform/hexane wash-out obtains title compound (must measure: 52.9g, 98%).
1H?NMR(CDCl 3)δ7.62-7.67(m，4H)，7.32-7.44(m，6H)，7.25-7.30(m，5H)，5.58-5.72(m，1H)，5.06-5.14(m，2H)，3.90(d，1H)，3.72-3.78(m，1H)，3.58-3.68(m，2H)，3.44-3.52(m，2H)，2.26-2.40(m，1H)，2.10-2.23(m，1H)，1.68-1.78(m，1H)，1.38(s，9H)，1.03(s，9H)。
MS:(M+H) +=556
Figure A9980761002721
(123B. ±)-(2R, 3R, 5R, 1 ' RS)-1-benzyl-2-(1, the 2-dihydroxyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3R, 5R)-1-benzyl-2-vinyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate (22.7g, 41mmol) with OsO4 (4%) (2.5ml, 0.7mol.%) (18.5g 2.77eq.) reacted 48 hours in acetone (500ml) and water (60ml) with N-methylmorpholine N-oxide compound.Use 10%Na 2S 2O 3The aqueous solution (200ml) quencher should be reacted, and this reactant of vacuum concentration distributes residue between ethyl acetate/water.Through the dried over mgso organic layer, filter and vacuum concentration.Residue with 35% ethyl acetate/hexane wash-out, obtains title compound (must measure: 11g, 55%) through purification by silica gel column chromatography.
1H?NMR(DMSO-d 6)：δ7.58-7.63(m，5H)，7.40-7.48(m，7H)，7.20-7.35(m，3H)，4.41-4.45(m，2H)，3.98(d，1H)，3.75-3.84(m，2H)，3.50-3.68(m，2H)，3.4-3.46(m，1H)，3.16-3.25(m，1H)，2.97-3.0(m，1H)，2.09-2.28(m，1H)，1.62-1.89(m，1H)，1.34-1.39(m，1H)，1.30(s，9H)，.98，.96(2s，9H)。
MS:(M+H) +=590
Figure A9980761002731
(123C. ±)-(2R, 3R, 5R, 1 ' RS)-2-(1, the 2-dihydroxyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.
Under 1 normal atmosphere hydrogen, make (±)-(2R, 3R, 5R, 1 ' RS)-1-benzyl-2-(1, the 2-dihydroxyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate (11g, 18.7mmol) with 20%Pd (OH) 2/ C (5g) reaction, under the room temperature in ethanol (40ml) vigorous stirring 2.5 days.Filter this reactant, with methyl alcohol (3 * 30ml) washing catalysts.Vacuum-evaporation filtrate obtains title compound (must measure: 8g, 94%), is oily matter. (123D. ±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1, the 2-dihydroxyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 40D, but with (±)-(2R, 3R, 5R, 1 ' RS)-2-(1, the 2-dihydroxyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (2R, 3R, 5R, 1 ' RS)-2-(1, the 2-dihydroxyl) ethyl-3-acetoxy-methyl-tetramethyleneimine-5-t-butyl formate.Residue with 35% ethyl acetate/hexane wash-out, obtains title compound (must measure: 20.5g, 60%) through purification by silica gel column chromatography.
1H?NMR(DMSO-d 6)δ7.57-7.60(m，4H)，7.38-7.48(m，6H)，4.85，4.77(2d，1H)，4.45-4.50(m，1H)，4.02-4.10(m，1H)，3.80-3.95(m，1H)，3.73，3.68(2s，1H)，3.45-3.67(m，2H)，3.18-3.28(m，2H)，2.36-2.46(m，2H)，1.86，1.70(2d，1H)，1.40，1.35(2s，9H)，1.32，1.26(2s，9H)，1.0，0.98(2s，9H)。
MS:(M+H) +=600 (123E. ±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-methylsulfonyl oxygen base-2-acetoxyl group) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3R, 5R, 1 ' R)-(20.5g is 34.2mmol) with diacetyl oxide (16.1ml for 1-tert-butoxycarbonyl-2-(1, the 2-dihydroxyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate, 171mmol) and triethylamine (47.7ml, 342mmol) in methylene dichloride (360ml) reaction 16 hours.
Handled this reactant 10 minutes with methyl alcohol (35ml), with methylene dichloride (1300ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.In 0 ℃, make residue and methylsulfonyl chloride (4.0ml, 51.3mmol) and triethylamine (14.3ml, 103mmol) in methylene dichloride (350ml) reaction 1.5 hours.Water (300ml) quencher should be reacted, with methylene dichloride (1200ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 30% ethyl acetate/hexane wash-out, obtains title compound (must measure: 23.8g, 97%) through the silica gel column chromatography purifying.
1H?NMR(DMSO-d 6)：δ7.58-7.62(m，4H)，7.38-7.50(m，6H)，5.12-5.26(2m，1H)，4.06-4.25(m，3H)，4.00(d，1H)，3.46-3.68(m，2H)，3.20，3.18(2s，3H)，2.40-2.48(m，1H)，2.02，1.99(2s，3H)，1.68-1.88(m，1H)，1.42，1.36(2s，9H)，1.31，1.25(2s，9H)，1.00，0.98(2s，9H)。
MS:(M+H) +=720, (M+NH 4) +=737
Figure A9980761002742
(123F. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.
In 25 ℃; make (±)-(2R; 3R; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-methylsulfonyl oxygen base-2-acetoxyl group) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate (23.8g; 33.1mmol) (10.1g 66.2mmol) reacted 18 hours in methyl alcohol (160ml) and THF (160ml) with salt of wormwood.This reactant of vacuum concentration is dissolved in the ethyl acetate residue, and water and salt water washing through dried over mgso, are filtered and vacuum concentration.Residue with 25% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 16.7g, 87%).
1H?NMR(CDCl 3)δ7.60-7.68(m，4H)，7.32-7.45(m，6H)，4.02-4.28(m，2H)，3.67-3.78(m，1H)，3.52-3.62(m，1H)，3.0-3.08(m，1H)，2.68-2.75(m，1H)，2.47-2.52(m，3H)，1.80-1.90(m，1H)，1.48，1.42(2s，9H)，1.37，1.35(2s，9H)，1.07，1.03(2s，9H)。
MS:(M+H) +=582 (123G. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-methylol-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate (4.17g, 7.2mmol) (14ml 14.0mmol) reacted 20 minutes in THF (7ml), then in 25 ℃ of reactions 1.5 hours with tetrabutylammonium (1M).This reactant of vacuum concentration is dissolved in the ethyl acetate residue, with damping fluid and the salt water washing of pH 7.0, through dried over mgso, filters and through vacuum concentration.Residue with 50% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying, is oily matter (must measure: 2.4g, 97%).
1H?NMR(DMSO-d 6)δ4.72-4.78(m，1H)，3.94-4.05(m，2H)，3.35-3.47(m，1H)，3.18-3.28(m，1H)，3.03-3.08(m，1H)，2.63-2.73(m，1H)，2.37-2.44(m，1H)，2.30-2.36(m，1H)，2.08-2.20(m，1H)，1.58-1.75(m，1H)，1.40(s，9H)，1.37，1.34(2s，9H)。
MS (M+H) +=344, (M+Na) +=366 (123H. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-formyl radical-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R in methylene dichloride (70ml), 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-methylol-tetramethyleneimine-5-t-butyl formate (2.4g, 7.0mmol) and triethylamine (3.9ml is 28.0mmol) with the sulfur trioxide pyridine complex (3.35g that drips, 21.0mmol) reaction in methyl-sulphoxide (21ml), then reacted other 3 hours.Water (50ml) quencher should be reacted, with ethyl acetate (200ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration, obtain title compound and (must measure: 2.2g).
1H NMR (DMSO-d 6) (rotational isomer) δ 9.58 and 9.56 (2s, 1H), 4.70 and 4.53 (2m, 1H), 3.96 (dd, J=1.4,9.2Hz, 1H), 3.25-3.20 (m, 1H), 2.91 (m, 1H), 2.71 (m, 1H), 2.50-2.28 (m, 3H), 1.42,1.37,1.34 and 1.30 (4s, 18H)
MS (M-H) -=340
Figure A9980761002762
(123I. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 25 ℃, by making first base three phenyl phosphonium bromide (12.63g, 35.4mmol) and potassium tert.-butoxide (1M) (17.6ml, 17.6mmol) inferior phosphoranyl (phosphoranylidene) the methyl inner salt (17.6mmol) of reaction preparation in 1 hour triphenyl in THF (70ml).In 0 ℃, will (2.2g be 6.5mmol) in the solution above adding and stirred 0.5 hour at (±) among the THF (10ml)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-formyl radical-tetramethyleneimine-5-t-butyl formate.Should react with saturated aqueous ammonium chloride (50ml) quencher, with ethyl acetate (200ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 10% ethyl acetate/hexane wash-out, obtains title compound (must measure: 2g, 84%) through the silica gel column chromatography purifying.
1H?NMR(DMSO-d 6)δ5.80-5.95(m，1H)，5.08(d，1H)，4.94-5.04(1H)，4.00-4.07(m，1H)，3.59，3.90(2t，1H)，3.07-3.16(m，1H)，2.73-2.81(m，1H)，2.65-2.72(m，1H)，2.35-2.48(m，1H)，1.59-1.76(m，1H)，1.42(s，9H)，1.38，1.35(2S，9H)。
MS:(M+H) +=340 (123J. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-methylsulfonyl oxygen base-3-azido-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 50 ℃, make (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-vinyl-tetramethyleneimine-5-t-butyl formate (1.72g, 5.1mmol) and ammonium chloride (1.36g, 25.4mmol) in ethanol (45ml) and water (5ml) with Lithium Azide (1.2g, 24.5mmol) reaction 7 hours.This reactant of vacuum concentration is with ethyl acetate (200ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue (2.15g) is dissolved in the methylene dichloride (50ml), in 0 ℃, with methylsulfonyl chloride (0.8ml, 10.2mmol) and triethylamine (2.8ml, 20.4mmol) reaction 0.5 hour.Should react with sodium bicarbonate aqueous solution (50ml) quencher, with ethyl acetate (200ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 10% ethyl acetate/hexane wash-out, obtains title compound (must measure: 1.87g, 80%) through the silica gel column chromatography purifying.
1H?NMR(DMSO-d 6)δ5.77-5.98(m，1H)，4.94-5.11(m，3H)，4.12-4.19(m，1H)，3.99-4.06(m，1H)，3.66，3.71(2d，1H)，3.25，3.22(2s，3H)，2.92-3.02(m，1H)，2.55-2.63(m，1H)，1.68-1.82(m，1H)，1.45，1.42(2s，9H)，1.38，1.36(2S，9H)。
MS:(M+H) +=461
Figure A9980761002781
(123K. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-aziridinyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 65 ℃; make (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-methylsulfonyl oxygen base-3-azido-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (2.12g; 4.6mmol) (1.81g 6.9mmol) reacted 1 hour in THF (30ml) and water (7.5ml) with triphenyl phosphine.This reactant of vacuum concentration, and be dissolved in again in the ethyl acetate (200ml).Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is through the silica gel column chromatography purifying, with the dichloromethane solution wash-out of 4% methyl alcohol, obtains 2g crude product title compound and (contains have an appointment 60% product and 40% Ph 3PO), can be directly used in acidylate.
1H?NMR(DMSO-d 6)δ5.78-5.5.98(m，1H)，4.12(d，1H)，3.42，3.19(2d，1H)，2.53-2.73(m，2H)，2.00-2.15(m，1H)，1.68-1.76(m，1H)，1.62-1.68(m，1H)，1.41(s，9H)，1.37，1.36(2s，9H)。
MS(M＋H) +＝339，(M＋Na) +＝361。
Figure A9980761002782
(123L. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(N-ethanoyl aziridinyl)-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 25 ℃, make (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-aziridinyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (1.03g, 3.1mmol) with diacetyl oxide (.42ml, 4.7mmol) and triethylamine (1.3ml 9.3mmol) reacted in methylene dichloride (30ml) 1 hour.Water (50ml) quencher should be reacted, with ethyl acetate (200ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 20% ethyl acetate/hexane wash-out, obtains title compound (must measure: .75g, 64%) through the silica gel column chromatography purifying.
1H?NMR(DMSO-d 6)δ5.78-5.98(m，1H)，5.05(d，1H)，4.98，4.94(2d，1H)，4.12-4.20(m，1H)，3.54，3.42(2dd，1H)，2.54-2.98(m，3H)，2.40，2.49(2d，1H)，2.15，2.19(2d，1H)，2.02，2.04(2s，3H)，1.68-1.82(m，1H)，1.42(s，9H)，1.48，1.45(2s，9H)。
MS:(2M+Na) +=783
Figure A9980761002791
(123M. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido) butyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, to cupric bromide (I)-methyl-sulfide mixture (0.051g, 0.248mmol) be added in the suspension in THF (1.0ml) ethylmagnesium bromide (1M) among the THF (1.0ml, 1.0mmol).In 0 ℃ stir 10 minutes after; this solution of portion (0.60ml) is added drop-wise to (±)-(2R; 3S; 5R; 1 ' S)-(0.020g is in-78 ℃ THF (0.40ml) solution 0.053mmol) for 1-tert-butoxycarbonyl-2-(N-ethanoyl aziridinyl)-3-vinyl-tetramethyleneimine-5-t-butyl formate.In-78 ℃ stir 20 minutes after, make this reactant be warmed to 0 ℃ and stirred 30 minutes.Should react with saturated aqueous ammonium chloride (1.0ml) quencher, with ethyl acetate (10ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is through the silica gel column chromatography purifying, and the gradient liquid wash-out with the 0-75% ethyl acetate/hexane obtains title compound (must measure: 0.004g, 19%).
1H NMR (DMSO-d 6) (rotational isomer) δ 7.48 (d, J=9.5Hz, 1H), 5.98-5.80 (m, 1H), 5.00-4.90 (m, 2H), 4.45-4.25 (m, 1H), 3.96-3.91 (m, 1H), and 3.60-3.57 and 3.53-3.50 (2m, 1H), 2.91-2.76 (m, 1H), 2.59-2.42 (m, 1H), 1.80 (s, 3H), 1.73-1.59 (m, 1H), 1.42 and 1.41 (2s, 9H), 1.40-1.15 (m, 4H), 1.37 and 1.34 (2s, 9H), 0.89-0.82 (m, 3H).
MS:(M-H) -=409, (M+H) +=411
Figure A9980761002801
(123N. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido) butyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido) butyl-3-vinyl-tetramethyleneimine-replacement of 5-t-butyl formate (2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.1mg, 99%).
1H?NMR(DMSO-d 6)：δ8.11(d，J＝7.3Hz，1H)，5.76-5.69(m，1H)，5.16(d，J＝17.1Hz，1H)，5.07(dd，J＝1.5，10.3Hz，1H)，4.30(dd，J＝7.3，9.8Hz，1H)，4.13(m，1H)，3.50(dd，J＝5.9，9.8Hz，1H)，2.90(m，1H)，2.39(m，1H)，1.92-1.85(m，1H)，1.87(s，3H)，1.52-1.18(m，4H)，0.85(t，J＝7.3，3H)
MS：(M－H) -＝253，(M＋H) +＝255
Embodiment 124-130
According to method described in embodiment 123M and the 123N,, but replace diethyl cuprate in the embodiment 123M step 1 and its preparation method with the reagent of pointing out and their preparation methods separately with the following title compound of two step preparations.Embodiment 124
Figure A9980761002811
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido) hexyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 123M, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grignard reagent and catalytic amount, but replace the 1M ethylmagnesium bromide with the 2M butylmagnesium chloride.
1H?NMR(MeOD-d 3)δ5.82-5.70(m，1H)，5.29(d，J＝17.0Hz，1H)，5.17(dd，J＝1.3，10.2Hz，1H)，4.35(dd，J＝7.5，10.2Hz，1H)，4.19(m，1H)，3.65(dd，J＝3.4，9.8Hz，1H)，3.01(m，1H)，2.55(m，1H)，2.08-1.97(m，1H)，2.04(s，3H)，1.62-1.31(m，8H)，0.91(t，J＝6.4Hz，3H)
MS：(M－H) -＝281，(M＋H) +＝283
Embodiment 125
Figure A9980761002812
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-4-methyl) amyl group-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 123M, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grignard reagent and catalytic amount, but replace ethylmagnesium bromide with isobutyl-chlorination magnesium.
1H?NMR(MeOD-d 3)δ5.83-5.71(m，1H)，5.29(dd，J＝0.7，17.0Hz，1H)，5.17(dd，J＝0.7，10.2Hz，1H)，4.34(dd，J＝7.5，10.2Hz，1H)，4.15(m，1H)，3.66(dd，J＝3.4，9.8Hz，1H)，3.01(m，1H)，2.55(m，1H)，2.08-1.97(m，1H)，2.04(s，3H)，1.65-1.10(m，5H)，0.91(t，J＝6.4Hz，3H)，0.91(d，J＝6.5Hz，3H)
(M＋H) +＝283
Embodiment 126
Figure A9980761002821
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3,3-dimethyl) butyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 123M, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grignard reagent and catalytic amount, but replace the 1M ethylmagnesium bromide with 1M tertiary butyl chlorination magnesium.
1H?NMR(MeOD-d 3)δ5.84-5.71(m，1H)，5.31(d，J＝17.0Hz，1H)，5.19(d，J＝10.2Hz，1H)，4.39-4.33(m，2H)，3.66(dd，J＝3.4，9.8Hz，1H)，3.02(m，1H)，2.57(m，1H)，2.08-1.97(m，1H)，2.02(s，3H)，1.55(dd，J＝9.5，14.6Hz，1H)，1.42(dd，J＝1.4，14.6Hz，1H)，0.95(s，9H)
(M＋H) +＝283
Embodiment 127
Figure A9980761002822
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-phenyl) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to Lipshutz, B.H. is at Organometallics in Synthesis; Schlosser, M. edits; Wiley and Sons:New York, 1994; Method described in 292 pages prepares phenylbenzene copper acid lithium.Use this cuprate according to method described in the embodiment 123M, but replace by diethyl cuprate mixture deutero-Grignard reagent with phenylbenzene copper acid lithium.
1H?NMR(MeOD-d 3)δ7.35-7.21(m，5H)，5.87-5.75(m，1H)，5.37(d，J＝16.6Hz，1H)，5.26(dd，J＝1.0，10.2Hz，1H)，4.53(m，1H)，4.37(dd，J＝7.5，9.8Hz，1H)，3.70(dd，J＝3.7，9.8Hz，1H)，3.11(m，1H)，2.97(dd，J＝6.1，14.2Hz，1H)，2.84(dd，J＝9.5，14.2Hz，1H)，2.59(m，1H)，2.08-1.99(m，1H)，1.93(s，3H)
(M－H) -＝301，(M＋H) +＝303
Embodiment 128
Figure A9980761002831
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-4-phenyl) butyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 123M, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grignard reagent and catalytic amount, but replace the 1M ethylmagnesium bromide with 1M styroyl magnesium chloride.
1H?NMR(MeOD-d 3)：δ7.29-7.13(m，5H)，5.77-5.65(m，1H)，5.24(d，J＝16.6Hz，1H)，5.13(dd，J＝1.0，9.8Hz，1H)，4.33(dd，J＝7.5，10.2Hz，1H)，4.22(m，1H)，3.62(dd，J＝3.4，9.8Hz，1H)，2.98(m，1H)，2.63(m，2H)，2.54(m，1H)，2.06-1.95(m，1H)，2.03(s，3H)，1.79-1.55(m，4H)(M－H) -＝329，(M＋H) +＝331
Embodiment 129 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-phenyl) butyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 123M, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grignard reagent and catalytic amount, but replace the 1M ethylmagnesium bromide with the 2M benzylmagnesium chloride.
1H?NMR(MeOD-d 3)δ7.30-7.17(m，5H)，5.82-5.70(m，1H)，5.28(d，J＝17.0Hz，1H)，5.17(d，J＝11.2Hz，1H)，4.33(dd，J＝7.5，10.2Hz，1H)，4.18(m，1H)，3.64(dd，J＝3.4，9.8Hz，1H)，3.01(m，1H)，2.78(m，1H)，2.66-2.50(m，2H)，2.07(s，3H)，2.07-1.85(m，3H)
(M－H) -＝315，(M＋H) +＝317
Embodiment 130 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-propylene-2-yl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002842
(130A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(N-tert-butoxycarbonyl aziridinyl)-3-vinyl-tetramethyleneimine-5-t-butyl formate.
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-aziridinyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (0.058g, 0.17mmol) with tert-Butyl dicarbonate (95mg, 0.44mmol) and triethylamine (0.12ml 0.86mmol) reacted in methylene dichloride (2.0ml) 1 hour.Should react with saturated sodium bicarbonate aqueous solution (1.0ml) quencher, with ethyl acetate (20ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is through the silica gel column chromatography purifying, and the gradient liquid wash-out with the 0-15% ethyl acetate/dichloromethane obtains title compound (must measure: 0.060g, 80%).
1H NMR (DMSO-d 6): (rotational isomer) δ 5.97-5.78 (m, 1H), 5.06-4.93 (m, 2H), 4.15 (dd, J=2.0,9.8Hz, 1H), 3.40-3.28 (m, 1H), 2.94-2.49 (m, 3H), 2.39 and 2.33 (2d, J=6.1,6.4Hz, 1H), 2.17 and 2.11 (2d, J=3.7,3.4,1H), 1.81-1.69 (m, 1H), 1.42-1.36 (m, 27H)
MS:(M+Na) +=461 (weak)
Figure A9980761002851
(130B. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-propylene-2-yl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, to cupric bromide (I)-methyl-sulfide mixture (0.026g, 0.127mmol) be added in the suspension in THF (1.0ml) pseudoallyl magnesium bromide (0.5M) among the THF (1.0ml, 0.50mmol).In 0 ℃ stir 10 minutes after, make this mixture be cooled to-78 ℃, and to wherein dripping (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(N-tert-butoxycarbonyl aziridinyl)-3-vinyl-tetramethyleneimine-5-t-butyl formate (0.030g, THF 0.068mmol) (1.0ml) solution.In-78 ℃ stir 10 minutes after, make this reactant be warmed to 0 ℃ and stirred 2 hours.Should react with saturated aqueous ammonium chloride (1.0ml) quencher, with ethyl acetate (10ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is through the silica gel column chromatography purifying, and the gradient liquid wash-out with the 0-10% ethyl acetate/dichloromethane obtains title compound (must measure: 0.026g, 79%).
1H NMR (DMSO-d 6) (rotational isomer) δ 6.64 (m, 1H), 5.96-5.76 (m, 1H), 4.98-4.89 (m, 2H), and 4.76-4.68 (m, 2H), 4.40-4.25 (m, 1H), 3.94 (m, 1H), 3.60-3.53 (m, 1H), 3.02-2.86 (m, 1H), 2.62-2.42 (m, 1H), 2.10-1.99 (m, 2H), 1.72 and 1.70 (2s, 3H), 1.72-1.55 (m, 1H), 1.44-1.34 (m, 27H)
MS:(M-H) -=479, (M+H) +=481
Figure A9980761002861
(130C. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-propylene-2-yl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In-25 ℃, make (±)-(2R, 3 S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-propylene-2-yl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (0.024g, 0.050mmol) (1M) (0.60ml 0.60mmol) reacted 1 hour in THF (2.0ml) solution with hexamethyl two silicon Lithium Azides (disilazide).In-25 ℃ of reactants upward, add then Acetyl Chloride 98Min. (0.085ml, 1.20mmol) and stirred this mixture 30 minutes.Should react and under room temperature, stir 30 minutes with saturated sodium bicarbonate aqueous solution (2.0ml) quencher.(20ml) dilutes this reactant with ethyl acetate.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is through the silica gel column chromatography purifying, and the gradient liquid wash-out with the 0-15% ethyl acetate/hexane obtains title compound (must measure: 0.015g, 58%) and unreacted raw material.
1H NMR (DMSO-d 6) (rotational isomer) δ 6.01-5.84 (m, 1H), 4.99-4.89 (m, 2H), 4.76-4.58 (m, 3H), 4.33 and 4.23 (2d, J=7.8,8.1Hz, 1H), 4.13-4.04 (m, 1H), 2.69 (m, 1H), 2.62-2.42 (m, 1H), 2.29 (br s, 3H), 2.35-2.14 (m, 2H), 1.76-1.55 (m, 1H), 1.60 (s, 3H), 1.50-1.35 (m, 27H)
MS:(M+H) +=523 (130D. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-propylene-2-yl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-propylene-2-yl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.(must measure: 12mg, 99%).
1H?NMR(MeOD-d 3)δ5.83-5.70(m，1H)，5.30(dd，J＝0.7，17.0Hz，1H)，5.19(d，J＝10.2Hz，1H)，4.79(s，1H)，4.71(s，1H)，4.46(m，1H)，4.30(dd，J＝7.8，9.8Hz，1H)，3.66(dd，J＝3.7，9.8Hz，1H)，3.03(m，1H)，2.56(m，1H)，2.40-2.19(m，2H)，2.08-1.96(m，1H)，2.01(s，3H)，1.76(s，3H)
(M－H) -＝265，(M＋H) +＝267
Embodiment 131-135
According to method described in the embodiment 130,, but replace pseudoallyl cuprate among the 130B and its preparation method with the reagent of pointing out in the step 1 and their preparation methods separately with the following title compound of 4 step preparations.Embodiment 131
Figure A9980761002881
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-1-(cis and trans)-propylene-1-yl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 130B, cupric bromide (I)-methyl-sulfide mixture by Grignard reagent and catalytic amount prepares the organic copper silicate reagent, but replaces 0.5M pseudoallyl magnesium bromide with 0.5M 1-propenyl magnesium bromide (mixture of cis and trans-isomer(ide)).
1H NMR (MeOD-d 3) (2: 1 are trans: the ratio of cis) δ 5.81-5.54 (m, 2H), 5.43-5.30 (m, 1H), (5.33-5.27 m, 0.33H, cis-isomeride), 5.31-5.25 (m, 0.66H, trans-isomer(ide)), and 5.20-5.15 (m, 1H), 4.26-4.17 (m, 2H), 3.65 (dd, J=3.4,9.8Hz, 1H), 2.98 (m, 1H), and 2.58-2.48 (m, 1H), 2.45-2.19 (m, 2H), 2.08-1.94 (m, 1H), 2.02 (s, 3H), (1.68 m, 2H, trans-isomer(ide)), (1.63 m, 1H, cis-isomeride)
(M－H) -＝265，(M＋H) +＝267
Embodiment 132
Figure A9980761002882
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-allyl group) methyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 130B, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grignard reagent and catalytic amount, but replace 0.5M pseudoallyl magnesium bromide with 1M vinyl bromination magnesium.
1H?NMR(MeOD-d 3)δ5.83-5.70(m，2H)，5.28(d，J＝17.0Hz，1H)，5.19-5.13(m，3H)，4.28(m，1H)，4.19(dd，J＝8.5，9.1Hz，1H)，3.66(dd，J＝3.4，9.5Hz，1H)，2.99(m，1H)，2.57-2.48(m，1H)，2.44-2.26(m，2H)，2.05-1.93(m，1H)，2.01(s，3H)
(M＋H) +＝253
Embodiment 133
Figure A9980761002891
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido)-2-(1-butylene-2-yl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 130B, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grinard reagent and catalytic amount, but replace 0.5M pseudoallyl magnesium bromide with 0.5M 1-butylene-2-base magnesium bromide.
1H?NMR(MeOD-d 3)δ5.81-5.73(m，1H)，5.30(d，J＝17.1Hz，1H)，5.19(d，J＝10.0Hz，1H)，4.93(s，1H)，4.83(s，1H)，4.45(m，1H)，4.31(dd，J＝7.6，9.8Hz，1H)，3.69(dd，J＝3.2，9.8Hz，1H)，3.03(m，1H)，2.59-2.53(m，1H)，2.38(dd，J＝5.9，14.9Hz，1H)，2.30(dd，J＝9.5，14.9Hz，1H)，2.07(q，J＝7.6Hz，2H)，2.05-1.99(m，1H)，2.01(s，3H)，1.05(t，J＝7.6Hz，3H)
(M+H) +=281 embodiment 134
Figure A9980761002892
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(trans-2-butene-2-yl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 130B, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grignard reagent and catalytic amount, but replace 0.5M pseudoallyl magnesium bromide with 0.5M 1-methyl isophthalic acid-propenyl magnesium bromide.
1H?NMR(MeOD-d 3)δ5.83-5.71(m，1H)，5.41(q，J＝6.8Hz，1H)，5.31(d，J＝17.3Hz，1H)，5.19(d，J＝10.2Hz，1H)，4.42(m，1H)，4.31(dd，J＝7.5，9.8Hz，1H)，3.61(dd，J＝4.0，9.8Hz，1H)，3.01(m，1H)，2.62-2.52(m，1H)，2.46(dd，J＝9.5，13.9Hz，1H)，2.26(dd，J＝5.8，13.9Hz，1H)，2.09-1.99(m，1H)，2.00(s，3H)，1.72(s，3H)，1.59(d，J＝6.8Hz，3H)
(M+H) +=281 embodiment 135
Figure A9980761002901
(±)-(2R, 3S, 5R, 1 ' S, 3 ' RS)-2-(1-acetamido-3-methyl) amyl group-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 130B, prepare the organic copper silicate reagent by cupric bromide (the I)-methyl-sulfide mixture of Grignard reagent and catalytic amount, but replace 0.5M pseudoallyl magnesium bromide with 2M sec-butyl bromination magnesium.
1H NMR (MeOD-d 3) (1: 1 methyl mixture of isomers) δ 5.82-5.69 (m, 1H), 5.27 (d, J=17.0Hz, 0.5H), 5.25 (d, J=17.0Hz, 0.5H), 5.15 (d, J=10.2Hz, 1H), 4.33 (m, 1H), 4.18 (dd, J=2.7,7.5Hz, 0.5H), 4.15 (dd, J=3.0,7.8Hz, 0.5H), 3.62 (dd, J=3.1,9.8Hz, 0.5H), 3.57 (dd, J=4.07,9.8Hz, 0.5H), 2.97 (m, 1H), 2.57-2.47 (m, 1H), 2.03-1.92 (m, 1H), 2.03 (s, 1.5H), 2.02 (s, 1.5H), 1.72-1.06 (m, 5H), 0.95-0.86 (m, 6H)
(M＋H) +＝283
Embodiment 136 (±)-(2R, 3S, 5R, 1 ' RS)-2-(1-acetamido-1-(N-methyl-N-benzylamino formyl radical) methyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002911
(136A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-carboxyl) methyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 2B; but with (±)-(2R; 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate.
Figure A9980761002912
(136B. ±)-(2R, 3S, 5R, 1 ' RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-benzylamino formyl radical) methyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 25 ℃, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-carboxyl) methyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (36mg, 0.09mmol) with N-methyl-N-benzylamine (32mg, 0.26mmol), dimethyl aminopyridine (1mg, 0.008mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (30mg, 0.16mmol) in DMF (3ml) reaction 16 hours.Water (3ml) quencher should be reacted, with ethyl acetate (20ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 50% ethyl acetate/hexane wash-out, obtains title compound through the silica gel column chromatography purifying.MS：(M＋H) +＝516，(M－H) -＝514。
Figure A9980761002921
(136C. ±)-(2R, 3S, 5R, 1 ' RS)-2-(1-acetamido-1-(N-methyl-N-benzylamino formyl radical) methyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C; but with (±)-(2R; 3S, 5R, 1 ' RS)-(1-acetamido-2-(N-methyl-N-benzylamino formyl radical) methyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R to 1-tert-butoxycarbonyl-2-; 3S; 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate; preparation title compound (must measure: 7mg, 95%).
1H?NMR(DMSO-d 6)：δ8.52(d，J＝9.7Hz，1H)，7.30(m，5H)，5.65(m，1H)，5.12(m，4H)，4.62(m，1H)，4.40(m，2H)，3.70(m，1H)，2.90(s，3H)，2.20(m，2H)，1.96(s，3H)。
MS：(M＋H) +＝360，(M＋23) +＝382
Embodiment 138 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-(N-phenyl-ketonic oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate. (138A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-N-phenyl-ketonic oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 25 ℃, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (18mg, 0.045mmol) with phenylcarbimide (16mg, 0.14mmol) and pyridine (0.1ml) in THF (3ml), reacted 16 hours.Water (2ml) quencher should be reacted, with ethyl acetate (10ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 50% ethyl acetate/hexane wash-out, obtains title compound (must measure: 7.5mg, 33%) through the silica gel column chromatography purifying.
MS:(M+H) +=518, (M-H) -=516 (138B. ±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-1-(N-phenylcarbonyl group oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-N-phenyl-ketonic oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4mg, 95%).
1H?NMR(DMSO-d 6)d?8.36(d，J＝9.7Hz，1H)，7.30(m，5H)，5.78(m，1H)，5.22(m，1H)，5.10(m，1H)，4.58(m，1H)，4.45(m，1H)，4.14(，2H)，3.58(m，1H)，2.88(m，1H)，2.27(m，1H)，2.12(m，1H)，1.88(s，3H)。
MS：(M＋H) +＝362，(M＋23) +＝384，(M－H) -＝360，(M＋35) -＝396
Embodiment 139 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-1-isobutyryl oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761002941
(139A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-isobutyryl oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (15mg, 0.04mmol) with isobutyryl chloride (8mg, 0.08mmol) and triethylamine (8mg 0.08mmol) reacted in ethylene dichloride (4ml) 2 hours.Water (3ml) quencher should be reacted, with ethyl acetate (20ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 30% ethyl acetate/hexane wash-out, obtains title compound (must measure: 11mg, 63%) through the silica gel column chromatography purifying.
MS:(M+H) +=469, (M-H) -=467
Figure A9980761002942
(139B. ±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-1-isobutyryl oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C; but with (±)-(2R; 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-isobutyryl oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3S; 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate; preparation title compound (must measure: 6.0mg, 96%).
1H?NMR(DMSO-d 6)δ8.00(d，J＝9.9Hz，1H)，5.63(m，1H)，5.08(m，1H)，4.98(m，1H)，4.35(m，1H)，4.25(m，1H)，4.08(m，1H)，3.55(m，1H)，3.45(m，1H)，3.38(m，1H)，2.83(m，1H)，2.33(m，1H)，1.78(s，3H)
MS：(M＋H) +＝243，(M＋23) +＝265，(M－H) -＝241
Embodiment 140 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-N-ethyl-thiocarbonyl oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate. (140A. ±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-N-ethyl-thiocarbonyl oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 70 ℃, make (±)-(2R, 3S, 5R, 1 ' R)-(17mg, 0.04mmol) (19mg 0.21mmol) reacted 17 hours in pyridine (2ml) 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate with ethyl mustard oil.Water (3ml) quencher should be reacted, with ethyl acetate (20ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 70% ethyl acetate/hexane wash-out, obtains title compound (must measure: 10mg, 48%) through the silica gel column chromatography purifying.
MS:(M+H) +=486, (M+23) +=508, (M-H) -=485 (140B. ±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-N-ethyl-thiocarbonyl oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-N-ethyl-thiocarbonyl oxygen base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 7mg, 94%).
1H?NMR(DMSO-d 6)δ830(d，J＝9.7Hz，1H)，5.78(m，1H)，5.25(m，1H)，5.12(m，1H)，4.50(m，1H)，4.33(m，1H)，4.18(m，2H)，3.72(m，1H)，3.55(m，2H)，2.30(m，1H)，2.10(m，1H)，1.82(s，3H)，1.17(m，3H)。
MS：(M＋H) +＝330，(M－H) -＝328
Embodiment 141 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-amino) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761002961
(141A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-tert-butoxycarbonyl amino) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 70 ℃, make (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-azido-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (9.5mg, 0.022mmol) (23.5mg 0.090mmol) reacted 30 minutes in ethanol (180 μ l) and water (45 μ l) with triphenyl phosphine.This reaction mixture of vacuum concentration.Residue is dissolved in the methylene dichloride (220 μ l), and in 25 ℃ to wherein add tert-Butyl dicarbonate (7.3mg, 0.034mmol) and N, the N-diisopropylethylamine (11.7ml, 0.067mmol).After 1 hour, this reaction mixture of dilute with water is used ethyl acetate extraction.Merge organic layer, use the salt water washing, through dried over mgso and vacuum concentration.Residue with 100% methylene dichloride to 50% dichloromethane/ethyl acetate wash-out, obtains title compound (must measure: 7.5mg, 67%) through the silica gel column chromatography purifying.
1H NMR (DMSO-d 6) (rotational isomer) δ 7.51 (d, J=10.5Hz, 1H), 6.80-6.66 (m, 1H), 5.90-5.76 (m, 1H), 5.02-4.90 (m, 2H), 4.38-4.19 (m, 1H), 3.98-3.94 (m, 1H), 3.68-3.62 (m, 1H), 3.09-2.73 (m, 2H), 2.60-2.42 (m, 1H), 1.80 (s, 3H), 1.72-1.62 (m, 1H), 1.42-1.34 (m, 27H).
MS:(M+H) +=498, (M+Na) +=520, (M-H) -=496, (M+Cl) -=532 (141B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-amino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-tert-butoxycarbonyl amino) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.65mg, 99%).
1H?NMR(DMSO-d 6)δ8.24(d，J＝7.9Hz，1H)，5.75-5.68(m，1H)，5.16(d，J＝17.1Hz，1H)，5.06(d，J＝10.4Hz，1H)，4.37-4.27(m，2H)，3.60-3.16(m，2H)，3.00-2.88(m，2H)，2.46-2.36(m，1H)，1.91-1.81(m，1H)，1.86(s，3H)。
MS：(M＋H) +＝242，(M＋Na) +＝264，(M－H) -＝240，(2M－H) -＝481
Embodiment 142 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-acetamido) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761002981
(142A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-acetamido) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3S, 5R, 1 ' S)-(9.4mg 0.024mmol) reacted 1 hour in methylene dichloride (0.23ml) with diacetyl oxide (11.2 μ l) and triethylamine (33.1 μ l) 1-tert-butoxycarbonyl-2-(1-acetamido-2-amino) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.Water (3ml) diluting reaction thing extracts with ethyl acetate (12ml), uses the salt water washing, through dried over mgso and vacuum concentration.Residue with 100% ethyl acetate to 90% ethyl acetate/methanol wash-out, obtains title compound (must measure: 6.8mg, 66%) through the silica gel column chromatography purifying.
1H NMR (DMSO-d 6) (rotational isomer) δ 7.79-7.74 (m, 1H), 7.54 (d, J=9.8Hz, 1H), 5.97-5.81 (m, 1H), and 5.01-4.91 (m, 2H), 4.36-4.27 (m, 1H), 3.97-3.90 (m, 1H), 3.68-3.63 (m, 1H), 3.21-3.15 (m, 1H), and 3.10-2.76 (m, 1H), 2.88-278 (m, 1H), 2.58-2.45 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H), and 1.76-1.64 (m, 1H), 1.42-1.36 (m, 18H).
MS (M+H) +=439, (M+Na) +=462, (M-H) -=438, (M+35) -=474
Figure A9980761002982
(142B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-acetamido) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S)-2-(1, the 2-diacetylamino) butyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate replaces (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.30mg, 80%).
MS：(M＋H) +＝284，(M－H) -＝282，(M＋Cl) -＝318
Embodiment 143 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-azido-) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761002991
(143A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-N-acetamido-2-azido-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 75 ℃; make (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(N-ethanoyl aziridinyl)-3-vinyl-tetramethyleneimine-5-t-butyl formate (21.6mg; 0.064mmol) with sodiumazide (41.6mg, 0.64mmol) and ammonium chloride (34.2mg 0.64mmol) reacted in ethanol (270 μ l) and water (30 μ l) 1 hour.Vacuum is removed ethanol then, with the remaining water liquid of ethyl acetate extraction.With the organism of salt water washing merging, through dried over mgso and vacuum concentration (crude product must be measured: 20mg, 82%).In 0 ℃ be added in 30 fens clockwise crude mixture diacetyl oxide in the methylene dichloride (330 μ l) (31 μ l, 0.33mmol) and triethylamine (92 μ l, 0.66mmol).This reaction mixture of vacuum concentration.Residue with 100% methylene dichloride to 50% dichloromethane/ethyl acetate wash-out, obtains title compound (must measure: 10mg, 60%) through the silica gel column chromatography purifying.
1H NMR (DMSO-d 6) (rotational isomer) δ 7.85 and 7.81 (d, J=9.5Hz and 9.8Hz, 1H), 5.94-5.80 (m, 1H), 5.04-4.93 (m, 2H), 4.58-4.38 (m, 1H), 4.04-3.96 (m, 1H), 3.72-3.66 (m, 1H), 3.41-3.21 (m, 2H), 3.09-2.79 (m, 1H), 2.59-2.46 (m, 1H), 1.84-1.82 (m, 3H), 1.79-1.53 (m, 1H), 1.43-1.35 (m, 18H).
MS:(M+H) +=424, (M+Na) +=446, (2M+Na) +=869, (M-H) -=422, (M+Cl) -=458
Figure A9980761003001
(143B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-azido-) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-azido-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 2.94mg, 93%).
1H?NMR(DMSO-d 6)δ8.24(d，J＝8.55Hz，1H)，5.74-5.67(m，1H)，5.14(d，J＝17.1Hz，1H)，5.06(d，J＝10.4Hz，1H)，4.41-4.35(m，2H)，3.57-3.36(m，3H)，2.93-2.90(m，1H)，2.44-2.38(m，1H)，1.96-1.84(m，1H)，1.84(s，3H)。
MS：(M＋H) +＝268，(M－H) -＝266，(M＋Cl) -＝302
Embodiment 144 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N-methylamino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride. (144A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-N-acetamido-2-N-methylamino) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, (.016g .53mmol) and N, O-is two-(.079g .39mmol) reacted 1 hour among DMSO (0.8ml) the trimethyl silyl ethanamide to make methylamine.Make (±)-(2R in 75 ℃ then; 3S; 5R, 1 ' S)-(.040g is .11mmol) with top reagent N-trimethyl silyl methylamine reaction 18 hours for 1-tert-butoxycarbonyl-2-(N-ethanoyl aziridinyl)-3-vinyl-tetramethyleneimine-5-t-butyl formate.(7ml) dilutes this reactant with ethyl acetate, and water and salt water washing through dried over mgso, are filtered and vacuum concentration.Residue with chloroform-methanol-ammonia wash-out, obtains title compound (must measure: .011g, 25%) through the silica gel column chromatography purifying.
1H?NMR(CDCl 3)δ5.78-5.98(m，1H)，5.90-5.04(2m，2H)，4.40-4.55(brm，1H)，3.90-4.02(m，1H)，3.64-3.75(2m，1H)，2.25-2.40(brm，3H)，2.83，2.85(2d，3H)，1.42，1.44(2s，9H)，1.34，1.37(2s，9H)。
MS:(M+H) +=412 (144B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N-methylamino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-N-methylamino) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 7.2mg, 99%).
1H?NMR(DMSO-d 6)δ8.25(d，1H)，5.70(m，1H)，5.10(m，2H)，4.50(m，1H)，4.40(m，1H)，2.55(s，3H)，1.85(s，3H)。
MS:(M+H) +=256 embodiment 145-164
Figure A9980761003012
Prepare following title compound according to method described in the embodiment 141-144, wherein R ' is a hydrogen.When R or R ' were not hydrogen, corresponding amine can the directly use without the intermediate steps of trimethyl silylization.Embodiment 145
Figure A9980761003021
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N-sec.-propyl amino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.30(d，1H)，5.70(m，1H)，5.10(m，2H)，4.40(br，2H)，3.52-3.68(br，1H)，3.10-3.20(br，1H)，2.82-2.97(br，1H)，2.37-2.47(br，1H)，1.88(s，3H)，1.25(d，6H)。
MS:(M+H) +=284 embodiment 146 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N-butyl amino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.25(d，1H)，5.70(m，1H)，5.10(m，2H)，4.50(m，1H)，4.38(m，1H)，3.60(m，1H)，2.90(m，3H)，2.40(m，2H)，1.87(s，3H)，1.62(m，2H)，1.33(m，2H)，0.90(t，3H)。
MS:(M+H) +=298 embodiment 147
Figure A9980761003031
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N-benzylamino) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(DMSO-d 6)δ7.56-7.43(m，5H)，5.74-5.67(m，1H)，5.1?5-4.99(m，2H)，4.56(m，1H)，4.27-3.93(m，3H)，3.66-3.15(m，3H)，2.91-2.88(m，1H)，2.64-2.34(m，2H)，1.86(s，3H)。
MS:(M+H) +=332, (M+Na) +=354, (M-H) -=330, (2M-H) -=661 embodiment 148
Figure A9980761003032
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N-styroyl amino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.25(d，1H)，7.30(m，5H)，5.70(m，1H)，5.10(m，2H)，4.50(br，1H)，4.35(br，1H)，3.61(m，1H)，3.17(m，3H)，2.98(m，3H)，2.42(m，1H)，1.88(s，3H)。
MS:(M+H) +=346 embodiment 149
Figure A9980761003041
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N, N-dimethylamino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.34(d，J＝9.2Hz，1H)，5.74-5.67(m，1H)，5.12(d，J＝17.1Hz，1H)，5.04(d，J＝10.4Hz，1H)，4.67-4.62(m，1H)，4.40(dd，J＝7.3，10.4Hz，1H)，3.60-3.11(m，3H)，2.96-2.83(m，1H)，2.50(s，6H)，2.44-2.38(m，1H)，1.92-1.84(m，1H)，1.84(s，3H)。
MS：(M＋H) +＝270，(M＋Na) +＝292，(M－H) -＝268。Embodiment 150 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N, N-diethylamino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.23(d，1H)，5.70(m，1H)，5.10(m，2H)，4.60(br，1H)，4.40(br，1H)，3.12(m，4H)，2.88(m，1H)，2.42(m，1H)，1.85(s，3H)，1.22(t，3H)。
MS:(M+H) +=298 embodiment 151
Figure A9980761003051
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-N, N-dibutylamino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.24(d，1H)，5.70(m，1H)，5.08(m，2H)，4.48-4.62(br，1H)，4.28-4.43(1H)，3.05(m，4H)，2.77-2.92(br，1H)，2.34-2.46(br，2H)，1.84(s，3H)，1.64(m，4H)，1.30(m，4H)，0.93(t，6H)。
MS (M+H) +=354 embodiment 152
Figure A9980761003052
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-2-hydroxyethylamino)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.20(d，1H)，5.70(m，1H)，5.15(d，1H)，5.08(d，1H)，4.50(brm，1H)，4.38(brm，1H)，3.68(m，1H)，3.0(brm，2H)，2.90(m，1H)，2.41(m，1H)，1.85(s，3H)。
MS:(M+H) +=286 embodiment 153 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-2-hydroxyethyl-N-ethylamino)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ5.81-5.74(m，1H)，5.38(d，J＝17.1Hz，1H)，5.22(d，J＝10.0Hz，1H)，4.92-4.88(m，1H)，4.48(dd，J＝7.6，9.8Hz，1H)，3.91(t，J＝4.9Hz，2H)，3.85(dd，J＝5.6，10.0Hz，1H)，3.63-3.53(m，2H)，3.46-3.39(m，4H)，3.16-3.13(m，1H)，2.66-2.61(m，1H)，2.08(s，3H)2.06-2.01(m，1H)，1.38(t，J＝7.33，3H)。
MS (M+H) +=314, (M+Na) +=336, (M-H) -=312, (M+C1) +=348, (2M-H) -=625 embodiment 154 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-2-hydroxyethyl-N-propyl group amino)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.36(d，J＝8.5Hz，1H)，5.75-5.68(m，1H)，5.13(d，J＝17.1Hz，1H)，5.04(d，J＝10.4Hz，1H)，4.62(m，1H)，4.36(m，1H)，3.77(t，J＝4.9Hz，2H)，3.63-3.59(m，1H)，3.50-3.23(m，3H)，3.22-3.19(m，2H)，3.08(t，J＝7.3Hz，2H)，2.91-2.87(m，1H)，2.44-2.39(m，1H)，1.99-1.88(m，1H)，1.84(s，3H)，1.75-1.70(m，2H)，0.90(t，J＝6.7Hz，3H)。
MS:(M+H) +=328, (M+Na) +=350, (M-H) -=326, (M+Cl) -=362 (2M-H) -=653 embodiment 155 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(imidazoles-1-yl)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(MeOD-d 3)δ9.06(s，1H)，7.72(s，1H)，7.58(s，1H)，5.84-5.76(m，1H)，5.39(d，J＝17.1Hz，1H)，5.23(d，J＝10.25Hz，1H)，4.70-4.66(m，1H)，4.52-4.43(m，2H)，3.92-3.89(m，1H)，3.20-3.17(m，1H)，2.67-2.62(m，1H)，2.11-2.04(m，1H)，1.95-1.89(m，1H)，1.91(s，3H)。
MS：(M＋H) +＝293，(M－H) -＝291，(M＋35) +＝327。Embodiment 156 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N, N-two-(2-hydroxyethylamino)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
MS:(M+H) +=330, (M+Na) +=352, (M-H) -=328, (M+Cl) -=364 embodiment 157
Figure A9980761003081
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-ethanoyl-N-methylamino) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(DMSO-d 6)δ8.01，7.95(2d，1H)，5.68-5.80(m，1H)，5.02-5.22(m，2H)，4.30-4.45(brm，2H)，3.26，3.21(2d，1H)，2.82-2.95(brm，1H)，2.38-2.48(m，1H)，1.98，2.02(2s，3H)，1.79，1.82(2s，3H)。
MS:(M+H) +=298 embodiment 158
Figure A9980761003082
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-2-hydroxyethyl-N-methylamino)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.35(d，J＝9.15Hz，1H)，5.74-5.67(m，1H)，5.12(d，J＝17.1Hz，1H)，5.04(d，J＝10.4Hz，1H)，4.70(m，1H)，4.39(dd，J＝7.3，10.4Hz，1H)，3.80-3.75(m，3H)，3.61-3.43(m，3H)，3.23-3.16(m，2H)，2.91-2.82(m，1H)，2.82(s，3H)，2.44-2.39(m，1H)，1.92-1.84(m，1H)，1.84(s，3H)。
MS:(M+H) +=300, (M+Na) +=322, (2M+H-H 2O) +=581 embodiment 159 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-propyl group-N-methylamino) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H NMR (DMSO-d 6) (broad peak) δ 8.3 (1H), 5.7 (1H), 5.12-5.04 (2H), 4.6 (1H), 4.35 (1H), 2.61-2.35 (11H), 1.9 (3H), 1.78-1.63 (2H), 1.9 (3H).
MS:(M+H) +=298, (M+Na) +=320, (M-H) -=296, (M+Cl) -=332 (2M-H) -=593 embodiment 160
Figure A9980761003092
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-cyclohexyl-N-methylamino)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(DMSO-d 6)δ8.26(m，1H)，5.75-5.65(m，1H)，5.08(d，J＝17.1Hz，1H)，5.02(d，J＝10.3Hz，1H)，4.62(m，1H)，4.43-4.40(m，1H)，3.62-3.58(m，1H)，3.46-3.16(m，2H)，2.89-2.84(m，1H)，2.72(s，3H)，2.44-2.39(m，1H)，2.07-1.80(m，5H)，1.81(s，3H)，163(m，1H)，1.45-1.06(m，6H)。
MS:(M+H) +=338, (M+Na) +=360, (M-H) -=336, (M+Cl) -=372 embodiment 161 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-benzyl-N-methylamino)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.36(m，1H)，7.61-7.46(m，5H)，5.69-5.64(m，1H)，5.07(d，J＝17.1Hz，1H)，4.99(d，J＝10.1Hz，1H)，4.77(m，1H)，4.44-4.39(m，2H)，4.25(d，J＝12.9，1H)，3.61(m，1H)，3.43(m，1H)，3.22(m，1H)，2.93-2.85(m，1H)，2.73(s，3H)，2.44-2.38(m，1H)，1.92-1.85(m，1H)，1.85(s，3H)。
MS:(M+H) +=346 embodiment 162
Figure A9980761003102
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-styroyl-N-methylamino)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.34(d，J＝8.55Hz，1H)，7.37-7.26(m，5H)，5.76-5.69(m，1H)，5.14(d，J＝17.1Hz，1H)，5.06(d，J＝10.4Hz，1H)，4.72(m，1H)，4.46-4.42(m，1H)，3.83-3.20(m，6H)，3.13-2.99(m，2H)，2.86(s，3H)，2.95-2.83(m，1H)，2.46-2.40(m，1H)，1.95-1.81(m，1H)，1.86(s，3H)。
MS:(M+H) +=360 embodiment 163
Figure A9980761003111
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-menaphthyl-N-methylamino)) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.41(d，J＝7.3Hz，1H)，8.32-7.59(m，7H)，5.60(m，1H)，5.04(d，J＝17.1Hz，1H)，4.91(d，J＝9.8Hz，1H)，4.97-4.73(m，3H)，4.39(m，1H)，3.70-3.13(m，3H)，2.90(m，1H)，2.72(s，3H)，2.43-2.41(m，1H)，2.01-1.74(m，1H)，1.87(s，3H)。
MS:(M+H) +=395, (M+Na) +=418, (M-H) -=394, (M+Cl) -=430 (2M-H) -=789 embodiment 164
Figure A9980761003112
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-morpholinyl) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
1H?NMR(DMSO-d 6)δ8.28(d，1H)，5.75-5.78(m，1H)，5.15(d，1H)，5.05(d，1H)，4.65(brm，1H)，4.42(m，1H)，3.72-3.98(brm，3H)，3.62(m，1H)，2.90(m，1H)，2.38-2.48(m，1H)，1.85(s，3H)。
MS：(M＋H) +＝312
Embodiment 165 (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-methyl-N-tertiary butyl amino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate. (165A. ±)-(2R, 3S, 5R, 1 ' S, 3 ' R) and (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-tertiary butyl amino-N-oxide compound)) ethyl-tetramethyleneimine-5-t-butyl formate.
In 0 ℃, make (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-tertiary butyl amino)) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (37mg, .08mmol) (20mg .08mmol) reacted 1 hour in methylene dichloride (0.9ml) with m-chloro benzoic acid.Residue directly through silica gel column chromatography, with the gradient liquid wash-out of acetone to acetone/30% methyl alcohol, is obtained title compound isomer (±)-(2R, 3S, 5R, 1 ' S, 3 ' R) (must measure: 0.10g, 27%) and isomer (±)-(2R, 3S, 5R, 1 ' S, 3 ' S) (must measure: .011g, 29%).
Figure A9980761003122
(165B. ±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-methyl-N-tertiary butyl amino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 15C, but with (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-tertiary butyl amino-N-oxide compound)) ethyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6mg, 80%).
1H?NMR(CD 3OD)δ5.72-5.87(m，1H)，5.40(d，1H)，5.20-5.28(m，2H)，4.44-4.53(dd，1H)，3.73-3.95(m，3H)，3.57(s，3H)，3.08-3.19(m，1H)，2.59-2.72(m，1H)，2.05-2.15(m，1H)，2.04(s，3H)，1.54(s，9H)。
MS:(M+H) +=328 embodiment 166-178
Figure A9980761003131
Prepare following title compound according to method described in the embodiment 165.Embodiment 166 (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-methyl-N-isopropyl propyl group amino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.87-5.74(m，1H)，5.46-5.40(m，1H)，5.27-5.23(m，1H)，5.21-5.18(m，1H)，4.50(dd，J＝8.1，9.8Hz，1H)，4.04-3.87(m，4H)，3.54(s，3H)，3.20-3.14(m，1H)，2.69-2.60(m，1H)，2.12-2.01(m，1H)，2.05(s，3H)，1.50(d，J＝6.4Hz，3H)，1.48(d，J＝6.4Hz，3H)。
MS：(M＋H) +＝314，(M＋Na) +＝336，(2M＋1) +＝627，(2M＋Na) +＝649。Embodiment 167
Figure A9980761003141
(±)-(2R, 3 S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-methyl-N-propyl group amino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.87-5.74(m，1H)，5.46-5.40(m，1H)，5.27-5.23(m，1H)，5.21-5.18(m，1H)，4.50(dd，J＝8.1，9.8Hz，1H)，4.04-3.87(m，4H)，3.54(s，3H)，3.20-3.14(m，1H)，2.69-2.60(m，1H)，2.12-2.01(m，1H)，2.05(s，3H)，1.50(d，J＝6.4Hz，3H)，1.48(d，J＝6.4Hz，3H)。
MS:(M+H) +=314, (M+H-H 2O) -=295 embodiment 168 (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-methyl-N-ethylamino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.82-5.75(m，1H)，5.44(d，J＝17.1Hz，1H)，5.26(d，J＝10.4Hz，1H)，5.14-5.11(m，1H)，4.48-4.45(m，1H)，4.9(d，J＝4.9Hz，2H)，3.87(dd，J＝4.9，10.4Hz，1H)，3.76(q，J＝6.7Hz，2H)，3.54(s，3H)，3.17-3.09(m，1H)，2.68-2.62(m，1H)，2.06(s，3H)，2.09-2.03(m，1H)，1.45(t，J＝7.3Hz，3H)。
MS:(M+H) +=300, (M+Na) +=322, (M+H-H 2O) +=282 embodiment 169
Figure A9980761003151
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N, N-dimethylamino-N-oxide compound) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(DMSO-d 6)δ8.58(d，1H)，5.67-5.78(m，1H)，5.20(d，1H)，5.08(d，1H)，4.62-4.78(brm，1H)，4.25-4.42(brm，1H)，4.06(d，1H)，3.85-3.95(brm，1H)，3.88-3.98(brm，1H)，3.35-3.50(brs，6H)，2.36-2.48(m，1H)，1.92(m，1H)，1.85(s，3H)。
MS:(M+H) +=286 embodiment 170 (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-methyl-N-benzylamino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ7.60-7.47(m，5H)，5.75-5.65(m，1H)，5.39(d，J＝6.35Hz，1H)，5.21(d，J＝8.8Hz，1H)，5.18-5.11(m，1H)，5.00-4.70(m，2H)，4.35-4.27(m，1H)，4.00-3.94(m，2H)，3.86-3.79(m，1H)，3.20(s，3H)，3.14-3.05(m，1H)，2.77-2.50(m，1H)，2.08(s，3H)，2.10-2.94(m，1H)。
MS (M+H) +=362, (M+Na) +=385, (M-H) -=360, (M+35) -=396 embodiment 171
Figure A9980761003161
(±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-methyl-N-tertiary butyl amino-N-oxide compound) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(CD 3OD)δ5.80(m，1H)，5.44(d，1H)，5.27(d，1H)，5.08(m，1H)，4.34-4.44(dd，1H)，3.83-3.94(m，3H)，3.38(s，3H)，3.02-3.18(m，1H)，2.58-2.72(m，1H)，2.08(s，3H)，1.97-2.08(m，1H)，1.55(s，9H)。
MS:(M+H) +=328 embodiment 172
Figure A9980761003162
(±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-methyl-N-isopropyl propyl group amino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.86-5.74(m，1H)，5.53-5.47(m，1H)，5.29-5.25(m，1H)，5.22-5.19(m，1H)，4.50(dd，J＝8.1，9.5Hz，1H)，4.13-4.04(m，2H)，3.96(dd，.J＝4.1，10.5Hz，1H)，3.87-3.82(m，1H)，3.39(s，3H)，3.23-3.17(m，1H)，2.70-2.61(m，1H)，2.11(s，3H)，2.08-2.00(m，1H)，1.50(d，J＝6.4Hz，3H)，1.49(d，J＝6.4Hz，3H)。
MS：(M＋H) +＝314，(M＋Na) +＝336，(2M＋1) +＝627，(2M＋Na) +＝649。Embodiment 173 (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-methyl-N-propyl group amino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.82-5.75(m，1H)，5.45(d，J＝17.1Hz，1H)，5.26(d，J＝10.4Hz，1H)，5.07-5.13(m，1H)，4.48-4.42(m，1H)，3.98(d，J＝5.5Hz，2H)，3.86(dd，J＝4.3，9.8Hz，1H)，3.67-3.64(m，2H)，3.46(s，3H)，3.16-3.01(m，1H)，2.68-2.62(m，1H)，2.09-2.02(m，1H)，2.06(s，3H)，1.92-1.86(m，2H)，1.04(t，J＝7.3Hz，3H)。
MS:(M+H) +=314, (M+H-H 2O) -=295 embodiment 174
Figure A9980761003172
(±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-methyl-N-ethylamino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.82-5.75(m，1H)，5.45(d，J＝17.1Hz，1H)，5.26(d，J＝10.4Hz，1H)，5.13-5.10(m，1H)，4.48-4.44(m，1H)，4.02-3.94(m，2H)，3.89(dd，J＝4.3，9.8Hz，1H)，3.82(q，J＝7.3Hz，2H)，3.46(s，3H)，3.18-3.10(m，1H)，2.68-2.62(m，1H)，2.09(s，3H)，2.07-2.02(m，1H)，1.46(t，J＝7.3Hz，3H)。
MS:(M+H) +=300, (M+Na) +=322, (M+H-H 2O) +=282 embodiment 175 (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-methyl-N-benzylamino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ7.60-7.47(m，5H)，5.75-5.65(m，1H)，5.39(d，J＝6.35Hz，1H)，5.21(d，J＝8.8Hz，1H)，5.18-5.11(m，1H)，5.00-4.70(m，2H)，4.35-4.27(m，1H)，4.00-3.94(m，2H)，3.86-3.79(m，1H)，3.40(s，3H)，3.14-3.05(m，1H)，2.77-2.50(m，1H)，2.08(s，3H)，2.10-2.94(m，1H)。
MS:(M+H) +=362, (M+Na) +=385, (M-H) -=360, (M+35) -=396 embodiment 176 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N, N-diethylamino-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.84-5.78(m，1H)，5.45(d，J＝16.85Hz，1H)，5.26(d，J＝10.0Hz，1H)，5.09-5.05(m，1H)，4.45-4.42(m，1H)，3.96-3.86(m，3H)，3.76(q，J＝6.6Hz，2H)，3.70(q，J＝7.3Hz，2H)，3.15-3.11(m，1H)，2.68-2.62(m，1H)，2.08-2.02(m，1H)，2.08(s，3H)，1.44-1.38(m，6H)。
MS:(M+H) +=314, (M+Na) +=336, (M+2Na) +=358 embodiment 177
Figure A9980761003191
(±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-pyrrolidyl-N-oxide compound)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(DMSO-d 6)δ8.74(d，1H)，5.65-5.80(m，1H)，5.28(d，1H)，5.10(d，1H)，4.82(m，1H)，4.40-4.50(dd，1H)，4.30(d，1H)，3.60-4.12(brm，5H)，2.98-3.15(m，1H)，2.38-2.48(m，1H)，2.05-2.20(brm，5H)，1.88-1.98(m，1H)，1.87(s，3H)。
MS:(M+H) +=312 embodiment 178 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-morpholinyl-N-oxide compound) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(DMSO-d 6)δ8.65(d，1H)，5.66-5.80(m，1H)，5.22(d，1H)，5.09(d，1H)，4.78(brs，1H)，4.32-4.42(dd，1H)，4.10-4.17(brm，2H)，3.50-4.02(brm，9H)，2.92-3.04(brm，1H)，2.37-2.48(m，1H)，1.88-1.96(m，1H)，1.87(s，3H)。
MS(M＋H) +＝328
Embodiment 179 (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-ethyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formate hydrochlorate. (179A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 123I, but replace first base three phenyl phosphonium bromides, preparation title compound (must measure: 350mg, 77%) with the ethyl triphenyl phosphonium bromide.
1H NMR (CDCl 3) (rotational isomer) δ 5.55-5.43 (m, 2H), 4.13-4.04 (m, 2H), 3.14-3.11 (m, 2H), 2.76-2.50 (m, 3H), 1.75-1.70 (m, 1H), 1.64 (d, 3H), 1.48-1.43 (m, 18H).
MS:(M+H) +=354, (M+Na) +=376, (2M+Na) +=729
Figure A9980761003202
179B (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-mesyloxy-3-azido-) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 123J, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido) butyl-3-vinyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 1.08g, 84%).
1H NMR (DMSO-d 6) (rotational isomer) δ 5.53-5.33 (m, 2H), 5.05-4.93 (m, 1H), 4.20-3.90 (m, 2H), 3.76-3.62 (m, 2H), 3.24 (s, 3H), 2.59-2.49 (m, 1H), 1.64-1.55 (m, 5H), 1.43-1.36 (m, 18H).
MS：(M＋H) +＝475，(M＋Na) +＝497，(2M＋Na) +＝971。
Figure A9980761003211
179C (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-aziridinyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 123K; but with (2R; 3S; 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-methylsulfonyl oxygen base-3-azido-) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-replacement of 5-t-butyl formate (2R, 3S; 5R; 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-methylsulfonyl oxygen base-3-azido-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 564mg, 71%).
1H NMR (DMSO-d 6) (rotational isomer) δ 5.45-5.30 (m, 2H), 4.15-3.99 (m, 1H), 3.30-3.08 (m, 1H), 3.07-2.84 (m, 1H), and 2.68-2.51 (m, 1H), 2.13-1.85 (m, 1H), 1.80-1.05 (m, 3H), 1.57 (d, J=5.4Hz, 3H), 1.41-1.35 (m, 18H).
MS:(M+H) +=352, (M+23) +=375, (2M+H) +=705, (2M+23) +=727
Figure A9980761003212
179D (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(N-ethanoyl aziridinyl)-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 123L, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-aziridinyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-and 1-tert-butoxycarbonyl-2-aziridinyl-3-vinyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 455mg, 72%).
1H NMR (DMSO-d 6) (rotational isomer) δ 5.74-5.34 (m, 2H), 4.17 (dd, J=2.4,6.35Hz, 1H), 3.41 (dd, J=1.95,6.35Hz, 1H), 3.14-2.99 (m, 1H), 2.73-2.58 (m, 2H), 2.40 (d, J=6.35Hz, 1H), 2.17-2.12 (m, 1H), 2.05-2.00 (m, 3H), and 1.66-1.55 (m, 1H), 1.56 (d, J=6.8Hz, 3H), 1.41-1.31 (m, 18H).
MS：(M＋H) +＝395，(M＋Na) +＝417，(M＋H＋Na) +＝418。
Figure A9980761003221
179E (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-N-ethyl-N-methylamino) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 150, but replace diethylamine, preparation title compound (must measure: 30mg, 87%) with N-ethyl-N-methylamine.
MS：(M＋H) +＝454，(M＋Na) +＝476，(M－H) -＝452，(M＋35) -＝488。
Figure A9980761003222
179E (±)-(2R, 3S, 5R, 1 ' S, 3 ' R) and (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-ethyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 165A, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-ethyl-N-methylamino)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-N-methyl-N-tertiary butyl amino) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 15.2mg, 51%).
Figure A9980761003231
179F (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-ethyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-ethyl-N-oxide compound)) ethyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 8.7mg, 29%).
1H?NMR(MeOD-d 3)δ5.75-5.69(m，1H)，5.37-5.30(m，1H)，5.07-5.04(m，1H)，4.49(dd，J＝7.8，10.2Hz，1H)，4.05-3.74(m，4H)，3.61-3.32(m，1H)，3.55(s，3H)，2.69-2.60(m，1H)，2.04(s，3H)，1.95-1.84(m，1H)，1.75(dd，J＝2.0，7.1Hz，3H)，1.44(t，J＝7.1Hz，3H)。
MS:(M+H) +=314, (M+35) +=348 embodiment 179-184
Figure A9980761003232
Prepare following title compound according to method described in the embodiment 179.Embodiment 180
Figure A9980761003233
(±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-ethyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.75-5.69(m，1H)，5.38-5.30(m，1H)，5.02-4.98(m，1H)，4.47(dd，J＝7.8，9.8Hz，1H)，4.02-3.77(m，4H)，3.56-3.39(m，1H)，3.47(s，3H)，2.69-2.59(m，1H)，2.07(s，3H)，1.95-1.84(m，1H)，1.76(dd，J＝1.7，7.1Hz，3H)，1.46(t，J＝7.1Hz，3H)。
MS:(M+H) +=314, (M+35) +=348 embodiment 181 (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-sec.-propyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.76-5.66(m，1H)，5.39-5.31(m，1H)，5.17-5.11(m，1H)，4.51(dd，J＝7.5，10.2Hz，1H)，4.07-3.76(m，4H)，3.55(s，3H)，3.52-3.39(m，1H)，2.69-2.60(m，1H)，2.02(s，3H)，2.08-1.84(m，1H)，1.75(dd，J＝1.7，7.1Hz，3H)，1.50(d，J＝6.1Hz，3H)，1.48(d，J＝6.4Hz，3H)。
MS:(M+H) +=314, (M+35) +=348 embodiment 182 (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-sec.-propyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.76-5.68(m，1H)，5.39-5.31(m，1H)，5.10-5.05(m，1H)，4.49(dd，J＝7.8，9.8Hz，1H)，4.12-3.84(m，4H)，3.55-3.44(m，1H)，3.41(s，3H)，2.69-2.60(m，1H)，2.08(s，3H)，2.07-1.84(m，1H)，1.76(dd，J＝1.7，6.8Hz，3H)，1.51(d，J＝2.4Hz，3H)，1.49(d，J＝2.4Hz，3H)。
MS:(M+H) +=314, (M+35) +=348 embodiment 183
Figure A9980761003251
(±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-isobutyl--N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.75-5.69(m，1H)，5.38-5.31(m，1H)，5.18-5.12(m，1H)，4.53(dd，J＝7.5，9.8Hz，1H)，4.25-3.42(m，6H)，3.65(s，3H)，2.68-2.58(m，1H)，2.44-2.36(m，1H)，2.05(s，3H)，1.94-1.87(m，1H)，1.76(d，J＝2.7Hz，3H)，1.14(d，J＝6.8Hz，6H)。
MS:(M+H) +=342, (M+Na) +=364, (M-H) -=340 embodiment 184 (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-2-(N-isobutyl--N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formate hydrochlorate.
1H?NMR(MeOD-d 3)δ5.75-5.69(m，1H)，5.38-5.31(m，1H)，5.06-5.02(m，1H)，4.48(dd，J＝7.5，9.8Hz，1H)，4.08-3.85(m，3H)，3.70-3.57(m，2H)，3.52(s，3H)，3.48-3.41(m，1H)，2.70-2.60(m，1H)，2.40-2.36(m，1H)，2.08(s，3H)，1.95-1.84(m，1H)，1.75(dd，J＝1.7，7.1Hz，3H)，1.14(d，J＝6.8Hz，6H)。
MS(M＋H) +＝342，(M＋Na) +＝364，(M－H) -＝340
Embodiment 185 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-sec.-propyl-N-hydroxyl amino)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
Figure A9980761003261
(185A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-sec.-propyl-N-hydroxyl amino)) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate.
(21mg 0.048mmol) is dissolved in the 0.95ml acetone ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate to make (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-sec.-propyl amino).Then in-45 ℃ with 0.14ml dimethyl ethylene oxide acetone soln (0.1M) titration 0.5 hour.Stop this reaction by this mixture of vacuum concentration.Residue with 100% methylene dichloride to 90% methylene chloride wash-out, obtains title compound (must measure: 5.3mg, 24%) through the silica gel column chromatography purifying, and reclaims raw material (must measure: 12mg, 57%).
1H?NMR(MeOD-d 3)δ5.95-5.89(m，1H)，5.08-4.94(m，2H)，4.75-4.68(m，1H)，4.13-3.83(m，2H)，2.85-2.47(m，4H)，1.96(s，3H)，1.82-1.76(m，1H)，1.52-1.44(m，18H)，1.45-1.29(m，1H)，1.07-1.04(m，6H)。
MS：(M＋H) +＝456，(M＋Na) +＝478，(M－H) -＝454，(M＋35) -＝490。
Figure A9980761003271
(185B. ±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(N-sec.-propyl-N-hydroxyl amino)) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate.
According to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(N-sec.-propyl-N-hydroxyl amino)) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.0mg, 87%).
1H?NMR(MeOD-d 3)δ5.83-5.71(m，1H)，5.40(d，J＝17.3Hz，1H)，5.24(d，J＝10.2Hz，1H)，4.48(dd，J＝7.8，10.2Hz，1H)，3.88-3.59(m，4H)，3.17-3.10(m，1H)，2.67-2.58(m，1H)，2.10-1.99(m，1H)，2.09(s，3H)，1.33-1.17(m，1H)，1.38(d，J＝6.4Hz，6H)。
MS:(M+H) +=300, (M-H) -=298, (2M-H) -=597 embodiment 186
Figure A9980761003272
(±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-2-phenyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.9mg, 100%).
1H?NMR(DMSO-d 6)δ8.62(d，J＝9.8Hz，1H)，7?93(m，2H)，7.68(m，1H)，7.55(t，J＝7.9Hz，2H)，5.61(m，1H)，5.48(m，1H)，5.19(m，1H)，4.50(m，1H)，3.98(t，J＝9.8Hz，1H)，3.30(m，1H)，2.38(m，1H)，1.73(m，1H)，1.71(s，3H)，1.59(m，3H)。
MS：(M＋H) +＝331，(M＋Na) +＝353，(M－H) -＝329。
Embodiment 187 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761003281
(187A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Prepare title compound according to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Figure A9980761003282
(187B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3.-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 188 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
Figure A9980761003291
(188A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
According to method described in the embodiment 84A, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0044g, 22%).
MS：(M＋H) +＝481，(M－H) -＝479。
Figure A9980761003292
(188B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3 S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0031g, 100%).
1H NMR (DMSO-d 6) δ 7.93 (d, J=9.2Hz, 1H), 5.81 (m, 1H), 5.49 (m, 1H), 5.26 (m, 1H), 5.1-4.9 (m, 2H), 4.29 (m, 1H), 4.03 (m, 2H), 3.68 (m, 1H), 3.26 (m, 1H), 3.25 (s, 3H), 3.18 (quintet, J=8.5Hz, 1H), 2.40 (dt, J=12.7,7.3Hz, 1H), 2.32 (m, 1H), 2.20 (m, 1H), 2.02 (m, 1H), 1.85 (s, 3H), 1.68 (m, 1H), 1.64 (m, 1H), 1.61 (dd, J=6.7,1.8Hz, 3H), and 1.55-1.40 (m, 2H).
MS：(M＋H) +＝325，(M＋Na) +＝347，(M－H) -＝323。
Embodiment 189 (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate (189A. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-mesyloxy-3-azido-) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 123J, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-and 1-Oxyranyle-3-vinyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 9.0g, 90%).
1H NMR (DMSO-d 6) (rotational isomer) δ 7.62-7.58 (m, 4H), 7.49-7.38 (m, 6H), 4.97-4.79 (m, 1H), 4.19-4.02 (m, 2H), 3.79-3.48 (m, 2H), 3.15 and 3.13 (2s, 3H), and 2.49-2.39 (m, 2H), 1.98-1.74 (m, 1H), 1.43-1.25 (m, 18H), 1.02 and 1.00 (2s, 9H).
MS:(M+H) +703, (M+Na) +=725
Figure A9980761003311
(189B. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-aziridinyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 123K, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-mesyloxy-3-azido-) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-and 1-tert-butoxycarbonyl-2-(1-mesyloxy-3-azido-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.9g, 79%).
1H NMR (DMSO-d 6) (rotational isomer) δ 7.60-7.56 (m, 4H), 7.49-7.39 (m, 6H), 4.11-4.05 (m, 1H), 3.67-3.48 (m, 2H), 3.42-3.30 (m, 1H), 2.49-2.39 (m, 1H), and 2.25-1.61 (m, 5H), 1.40,1.35,1.33 and 1.27 (4s, 18H), 0.99 and 0.98 (2s, 9H)
MS：(M＋H) +＝581，(M＋Na) +＝603。 (189C. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-N-ethanoyl aziridinyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 123L, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-aziridinyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' S)-and 1-tert-butoxycarbonyl-2-aziridinyl-3-vinyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.1g, 96%).
1H NMR (DMSO-d 6) (rotational isomer) δ 7.60-7.57 (m, 4H), 7.49-7.39 (m, 6H), 4.18-4.11 (m, 1H), 3.71-3.51 (m, 3H), 2.76-2.68 (m, 1H), 2.58-2.45 (m, 1H), 2.46 and 2.39 (2d, J=6.1,6.1Hz, 1H), 2.40 and 2.47 (2m, 1H), 2.08 and 2.05 (2d, J=3.1,3.1Hz, 1H), 2.02 and 1.99 (2s, 3H), 1.94-1.79 (m, 1H), 1.41,1.36,1.35 and 1.29 (4s, 18H), 0.99 and 0.98 (2s, 9H).
MS:(M+H) +=623, (M+Na) +=645 (189D. ±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-acetoxyl group) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.
In 100 ℃; make (±)-(2R; 3R; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-N-ethanoyl aziridinyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate (2.75g; 4.40mmol) with potassium acetate (2.49g, 25.37mmol) and acetate (1.45ml 25.37mmol) reacted in DMSO (45ml) 16 hours.Should react with 1N sodium bicarbonate (100ml) quencher, with ethyl acetate (300ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 100% methylene dichloride to 50% dichloromethane/ethyl acetate wash-out, obtains title compound (must measure: 2.45g, 81%) through the silica gel column chromatography purifying.
MS:(M+H) +=683, (M+Na) +=705, (M-H) -=681, (M+Cl) -=717
Figure A9980761003322
(189E. ±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
In 25 ℃, make (±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-acetoxyl group) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate (2.45g, 3.58mmol) (1.48g 10.73mmol) reacted 45 minutes in methyl alcohol (18ml) and THF (18ml) with salt of wormwood.Water (100ml) quencher should be reacted, with ethyl acetate (200ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 85% dichloromethane/ethyl acetate to 100% eluent ethyl acetate, obtains title compound (must measure: 2.05g, 90%) through the silica gel column chromatography purifying.
MS:(M+H) +=641, (M+Na) +=663, (2M+Na+H) +=1304, (M-H) -=639, (M+Cl) -=675 (189F. ±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 41A, but with (±)-(2R, 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H NMR (DMSO-d 6) (rotational isomer) 9.49 (d, J=16.3,1H), 8.33 and 8.29 (2d, J=8.8 and 8.8Hz, 1H), and 7.58-7.38 (m, 10H), 4.94 and 4.84 (2dd, J=4.4,8.8Hz with 4.4,8.8Hz, 1H), 4.26-3.37 (m, 4H), 2.47-2.30 (m, 1H), 1.97-1.83 (m, 1H), 1.92 (s, 3H), 1.42-1.18 (m, 18H), 1.42-1.18 (m, 1H), 1.00-0.97 (m, 9H).
MS:(M+H) +=639, (M-H) -=637 (189G. ±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-vinyl) methyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 118A; but with (±)-(2R; 3R; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H NMR (DMSO-d 6) (rotational isomer) δ 7.99-7.74 (m, 1H), 7.59-7.39 (m, 10H), 5.80-5.68 (m, 1H), 5.21-5.01 (m, 3H), 3.97-3.31 (m, 1H), 3.78-3.74 (m, 1H), 3.60-3.46 (m, 2H), 2.53-2.37 (m, 1H), 2.09-1.72 (m, 1H), 1.87 (s, 3H), 1.42-1.23 (m, 19H), 1.00-0.99 (m, 9H).
Figure A9980761003341
189 H. (±)-(2R, 3R, 5R, 1 ' R, 2 ' R) and (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 20A, but with (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-vinyl) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R)-1-benzyl-2-vinyl-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate, obtain (±)-(2R, 3R, 5R, 1 ' R, 2 ' S) isomer (must measure: 311mg, 24%) and (±)-(2R, 3R, 5R, 1 ' R, 2 ' R) isomer (must measure: 700mg, 54%).
(±)-(2R, 3R, 5R, 1 ' R, 2 ' S) 1H NMR (DMSO-d 6) (rotational isomer) 7.62-7.39 (m, 11H), 4.56 and 4.51 (d, J=4.8,1H), 4.46-4.39 (m, 2H), 3.97-3.82 (m, 1H), 3.74-3.47 (m, 3H), 3.28-3.21 (m, 2H), 2.89-2.64 (m, 1H), 2.51-2.45 (m, 1H), 2.05-1.8 (m, 1H), 1.87-1.86 (m, 3H), 1.43-1.23 (m, 19H), 0.99-0.98 (m, 9H).
(±)-(2R, 3R, 5R, 1 ' R, 2 ' R) 1H NMR (DMSO-d 6) (rotational isomer) 7.63-7.40 (m, 11H), 4.56 and 4.54 (d, J=4.8,1H), 4.47-4.33 (m, 2H), and 3.94-3.80 (m, 1H), 3.85-3.80 (m, 1H), 3.76-3.68 (m, 1H), 3.60-3.51 (m, 1H), 3.44-3.35 (m, 1H), and 3.30-3.21 (m, 1H), 2.78-2.62 (m, 1H), 2.46-2.31 (m, 1H), 2.07-1.98 (m, 1H), 1.83 (s, 3H), and 1.39-1.29 (m, 19H), 1.00-0.99 (m, 9H).
Figure A9980761003351
(189I. ±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
In 25 ℃, make (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2, the 3-dihydroxyl) propyl group-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate and 2, the 2-Propanal dimethyl acetal (1.1ml, 9.09mmol) and tosic acid (4.3mg, 0.023mmol) in tetrahydrofuran (THF) (4.5ml) reaction 45 minutes.Should reaction with triethylamine (3ml) quencher.Continue to stir other 10 minutes.Use 10% sodium bicarbonate (15ml) to dilute this reactant then, extract with ethyl acetate (45ml).Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue is used for next step,,, obtains title compound (must measure: 194mg, 91%) with 100% methylene dichloride to 94% methylene chloride wash-out through the silica gel column chromatography purifying. (189J. ±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-methylol-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 123G, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.The gained residue with 100% methylene dichloride to 94% methylene chloride wash-out, obtains title compound (must measure: 194mg, 91%) through the silica gel column chromatography purifying. (189JJ. ±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 123H, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-methylol-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-methylol-tetramethyleneimine-5-t-butyl formate. (189K. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-(cis-propylene-1-yl))-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 35A, but with (±)-(2R, 3R; 5R; 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1; 3-dioxolane-4-yl)) methyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R; 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate; preparation title compound (must measure: 11.5mg, 59%).
1H?NMR(CDCl 3)：δ6.62(d，1H)，5.56(m，1H)，5.40(m，1H)，4.43(m，1H)，4.25(m，1H)，4.16(m，1H)，4.02(m，1H)，3.88(m，1H)，3.54(m，1H)，3.14(m，1H)，2.54(m，1H)，2.04(s，3H)，1.71(m，1H)，1.60(dd，3H)，1.46(s，9H)，1.45(s，9H)，1.40(s，3H)，1.32(s，3H)。
MS:(M+H) +=483 (189L. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, the preparation title compound.
1H?NMR(DMSO-d 6)：δ7.84(d，J＝9Hz，1H)，5.49(m，1H)，5.27(m，1H)，4.47(m，1H)，4.25(m，1H)，4.17(m，1H)，3.75(m，1H)，3.59(m，1H)，3.35(m，1H)，3.18(m，1H)，2.43(m，1H)，1.81(s，3H)，1.55(dd，3H)。
MS：(M＋H) +＝287
Embodiment 190 (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003381
(190A. ±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 189I, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2,3-dihydroxyl)) propyl group-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate.
Figure A9980761003382
(190B. ±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-methylol-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 123G, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate. (190C. ±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 123H, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-methylol-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-methylol-tetramethyleneimine-5-t-butyl formate.
Figure A9980761003392
(190D. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-(cis-propylene-1-yl))-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 35A, but with (±)-(2R, 3R; 5R; 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1; 3-dioxolane-4-yl)) methyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R; 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate; preparation title compound (must measure: 42mg, 61%).
1H?NMR(CDCl 3)：δ7.88(d，1H)，5.52(m，1H)，5.34(m，1H)，4.33(m，1H)，4.21(m，1H)，3.96(m，2H)，3.83(m，1H)，3.60(m，1H)，3.40(m，1H)，2.53(m，1H)，1.98(s，3H)，1.66(dd，3H)，1.46(s，9H)，1.44(s，9H)，1.41(s，3H)，1.33(s，3H)。
MS:(M+H) +=483
Figure A9980761003401
(190E. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolane-4-yl)) methyl-3-(cis-propylene-1-yl))-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
1H?NMR(DMSO-d 6)：δ7.98(d，J＝9Hz，1H)，5.48(m，1H)，5.29(m，1H)，4.60(m，1H)，4.30(m，1H)，4.12(m，1H)，3.76(m，1H)，3.52(m，1H)，3.46(m，1H)，3.32(m，1H)，3.18(m，1H)，2.40(m，1H)，1.84(s，3H)，1.60(dd，3H)。
MS：(M＋H) +＝287
Embodiment 193 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003402
(193A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 88A, but replace methyl-iodide, preparation title compound (must measure: 3.6mg, 28%) with iodoethane.
MS：(M＋H) +＝483，(M＋Na) +＝505，(M－H) -＝481。 (193B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.2mg, 100%).
1H?NMR(DMSO-d 6)δ7.92(d，J＝9.2Hz，1H)，5.47(m，1H)，5.25(m，1H)，4.25(m，2H)，3.70(m，1H)，3.52(m，1H)，3.33(m，2H)，3.18(m，1H)，2.39(m，1H)，1.85(s，3H)，1.66(m，1H)，1.61(dd，J＝6.7，1.8Hz，3H)，1.56(m，1H)，1.37(m，1H)，1.28(m，2H)，1.13(m，3H)，0.86(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝327，(M＋Na) +＝349，(M－H) -＝325。
Embodiment 194 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003421
(194A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 88A, but replace methyl-iodide with iodoethane.
Figure A9980761003422
(194B. ±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 195 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-hydroxyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003431
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 19.9mg, 100%).
1H?NMR(DMSO-d 6)δ7.80(d，J＝8.8Hz，1H)，5.76(m，1H)，5.23(d，J＝17.1Hz，1H)，5.15(m，1H)，4.31(m，1H)，4.03(m，1H)，3.62(m，1H)，3.53(m，2H)，2.79(m，1H)，2.42(m，1H)，1.90(s，3H)，1.85(m，1H)。
MS(M＋H) +＝243，(M＋Na) +＝265，(M－H) -＝241。
Embodiment 196 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-dimethyl phosphine acyl group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003432
(196A. ±)-(2R, 3S, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-dimethyl phosphine acyl group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
In-78 ℃; will be at (±)-(2R among the THF (5ml); 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (78mg; 0.19mmol) (0.32ml is in THF 0.95mmol) (20ml) solution and make it to react 40 minutes to be added drop-wise to dimethyl phosphine acyl group lithium methide (3M).Water (10ml) and saturated aqueous ammonium chloride (10ml) quencher should be reacted, and then (2 * 50ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, and the dichloromethane solution wash-out with 5-10% methyl alcohol obtains title compound (±)-(2R, 3S, 5R, 1 ' R, 2 ' R) isomer (must measure: 27mg, 27%) and (±)-(2R, 3S, 5R, 1 ' R, 2 ' S) isomer (must measure: 5.5mg, 6%).
(±)-(2R，3S，5R，1’R，2’R) 1H?NMR(CDCl 3)δ5.98(m，1H)，5.58(m，1H)，5.35(m，1H)，4.94(m，1H)，4.14(m，2H)，3.74(m，8H)，3.06(m，1H)，2.64(m，1H)，2.03(s，3H)，1.95(m，1H)，1.83(m，3H)，1.53(s，9H)，1.46(s，9H)
MS：(M＋H) +＝535，(M－H) -＝533
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S) MS:(M+H) +=535, (M-H) -=533 196B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-dimethyl phosphine acyl group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C; but with (±)-(2R, 3S, 5R; 1 ' R; 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-dimethyl phosphine acyl group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R; 1 ' R; 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3mg, 96%).
1H?NMR(DMSO-d 6)δ7.98(d，J＝9.2Hz，1H)，5.48(m，1H)，5.28(m，1H)，4.36(m，1H)，4.30(m，1H)，4.08(m，2H)，3.70(m，2H)，3.60(m，6H)，3.18(m，1H)，2.40(m，1H)，2.05(m，1H)，1.85(s，3H)，1.60(dd，J＝6.2，1.2Hz，3H)
MS:(M+H) +=379, (M-H) -=377 embodiment 197
Figure A9980761003451
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-3-dimethyl phosphine acyl group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C; but with (±)-(2R, 3S, 5R; 1 ' R; 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-dimethyl phosphine acyl group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R; 1 ' R; 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 13mg, 96%).
1H?NMR(DMSO-d 6)δ7.72(d，J＝9.2Hz，1H)，5.48(m，1H)，5.24(m，1H)，4.44(m，1H)，4.15(m，2H)，3.62(m，7H)，3.54(m，1H)，3.15(m，1H)，2.40(m，1H)，1.95(m，1H)，1.82(s，3H)，1.72(m，1H)，1.54(dd，J＝6.7，1.2Hz，3H)
MS：(M＋H) +＝379，(M－H) -＝377
Embodiment 198 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-hydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate (198A. ±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-(cis and trans-2-methoxy-ethylene base)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
In 0 ℃; with 15 minutes with (±)-(2R; 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (113mg, 0.28mmol) add (methoxymethyl) three phenyl phosphonium bromides (240mg, 0.70mmol) and potassium tert.-butoxide (0.56ml; 0.56mmol 1M is in THF) toluene (3ml) solution in.Should react with saturated aqueous ammonium chloride (3ml) quencher, then (2 * 3ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/4: the ethyl acetate/hexane wash-out obtains title compound.
1H?NMR(CDCl 3)：δ8.65(br?d，1H)，6.01(d，J＝5.7Hz，1H)，5.40(m，3H)，5.11(brt，1H)，4.15(m，2H)，3.72(m，1H)，3.61(s，3H)，3.00(m，1H)，2.42(m，1H)，1.94(s，3H)，1.64(dd，J＝1.4，5.0Hz，3H)，1.45(m，9H)，1.25(m，9H)。
MS(M＋H) +＝439。 198B (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(cis and trans-2-methoxy-ethylene base)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (21mg, 0.048mmol) (37mg 0.43mmol) reacted 45 minutes in acetonitrile (2ml) and water (0.1ml) with AG50W-X2 ion exchange resin with LiBr.Filter this reactant, with saturated sodium bicarbonate aqueous solution (1ml) quencher, then (2 * 1ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/4: the ethyl acetate/hexane wash-out obtains title compound.
1H?NMR(CDCl 3)：δ9.70(dd，J＝1.3，2.4Hz，1H)，8.11(d，J＝7.8Hz，1H)，5.54(m，1H)，5.41(t，J＝5.8Hz，1H)，4.52(m，1H)，4.13(dd，J＝4.4，4.8Hz，1H)，3.75(dd，J＝2.7，3.1Hz，1H)，2.86(m，1H)，2.47(m，3H)，1.99(s，3H)，1.63(dd，J＝1.6，5.1Hz，3H)，1.46(s，9H)，1.45(m，1H)，1.44(s，9H)。
MS(M＋H) +＝425，(M－H) -＝423。 198C (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-hydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Under room temperature; make (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (9mg; 0.02mmol) (1mg 0.02mmol) reacted 20 minutes in methyl alcohol (0.1ml) with sodium borohydride.Should react with saturated aqueous ammonium chloride (1ml) quencher, then (2 * 1ml) extract with methylene dichloride.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is through purification by silica gel column chromatography, with 1/4: the ethyl acetate/hexane wash-out obtains title compound.
1H?NMR(CDCl 3)：δ8.45(d，J＝7.5Hz，1H)，5.55(m，1H)，5.34(t，J＝7.8Hz，1H)，4.20(dd，J＝3.0，5.4Hz，2H)，3.71(d，J＝6.1Hz，1H)，3.62(m，1H)，3.50(t，J＝9.1Hz，1H)，2.92(m，1H)，2.41(m，1H)，2.04(s，3H)，1.66(dd，J＝2.0，5.1Hz，3H)，1.62(m，1H)，1.47(s，9H)，1.45(m，1H)，1.43(s，9H)，1.22(m，2H)。
MS(M＋H) +＝427；(M－H) -＝425。 198D (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-hydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4.6mg, 100%).
1H?NMR(DMSO-d 6)δ9.25(br?s，1H)，8.13(d，J＝7.3Hz，1H)，5.52(m，1H)，5.28(brt，1H)，4.32(brt，1H)，4.22(m，1H)，3.49(m，4H)，3.18(m，1H)，2.40(m，1H)，1.90(s，3H)，1.73(m，1H)，1.63(dd，J＝1.8，5.5Hz，3H)，1.57(m，1H)
MS：(M－H) -＝269，(M＋H) +＝271。
Embodiment 199 (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-3-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003482
199A (±)-(2R, 3S, 5R, 1 ' S, 3 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-3-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Under room temperature; make (±)-(2R; 3S; 5R; 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (26mg; 0.061mmol) (0.122ml 0.367mmol) reacted 30 minutes in THF (4ml) with ethylmagnesium bromide (3.0M).Should react with saturated aqueous ammonium chloride (10ml) and water (10ml) quencher, then (3 * 25ml) extract with ethyl acetate.Through the dried over mgso organic layer, filter and vacuum concentration.Residue is used 1/1 ethyl acetate/hexane through purification by silica gel column chromatography, then with 2/1 ethyl acetate/hexane wash-out, obtains title compound (±)-(2R, 3S, 5R, 1 ' S, 2 ' S) (must measure 6.7mg, 24%) and (±)-(2R, 3S, 5R, 1 ' S, 2 ' R) (must measure: 6.8mg, 24%).
(±)-(2R，3S，5R，1’S，2’S)MS：(M＋H) +＝455，(M＋Na) +＝477，(M－H) -＝453。
(±)-(2R，3S，5R，1’S，2’R)MS：(M＋H) +＝455，(M＋Na) +＝477，(M－H) -＝453。 199B (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-3-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6.2mg, 100%).
1H?NMR(DMSO-d 6)δ9.20(bs，1H)，8.18(d，J＝7.3Hz，1H)，5.51(m，1H)，5.27(m，1H)，4.30(m，1H)，4.25(m，1H)，3.58(m，1H)，3.41(m，1H)，3.18(m，1H)，2.39(m，1H)，1.90(s，3H)，1.75(m，1H)，1.64(dd，J＝7.5，1.5Hz，3H)，1.51(m，1H)，1.38(m，1H)，1.32(m，1H)，0.83(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝299，(M＋Na) +＝321，(M－H) -＝297，(2M－H) -＝595。
Embodiment 200 (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-3-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003501
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-3-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 6.5mg, 100%).
1H NMR (DMSO-d 6) δ 9.25 (bs, 1H), 8.15 (d, J=7.3Hz, 1H), 5.52 (m, 1H), 5.27 (m, 1H), 4.31 (m, 2H), 3.52 (m, 1H), 3.36 (m, 1H), 3.19 (quintet, J=8.5Hz, 1H), 2.38 (m, 1H), 1.92 (s, 3H), 1.75 (m, 1H), 1.64 (dd, J=7.3,1.5Hz, 3H), 1.48 (m, 1H), 1.33 (m, 2H), 0.85 (t, J=7.3Hz, 3H).
MS：(M＋H) +＝299，(M＋Na) +＝321，(M－H) -＝297，(2M－H) -＝595。
Embodiment 201 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-oxo-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003511
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo-3,3-two fluoro-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0050g, 100%).
1H?NMR(DMSO-d 6)δ8.67(d，J＝8.5Hz，1H)，6.1-5.95(m，1H)，5.78(dd，J＝17.1，2.4Hz，1H)，5.71(d，J＝11.0Hz，1H)，5.45(m，1H)，5.12(m，1H)，4.94(t，J＝9.2Hz，1H)，4.51(dd，J＝12.2，6.1Hz，1H)，3.98(m，1H)，3.24(m，1H)，2.32(m，1H)，1.73(s，3H)，1.66(q，J＝11.9Hz，1H)，1.57(dd，J＝6.7，1.8Hz，3H)。
MS(M＋H) +＝331，(M＋H 2O) +＝349，(M＋Na) +＝353，(M－H) -＝329，(2M－H) -＝659。Embodiment 202
Figure A9980761003512
202A (±)-(2R, 3R, 5R, 1 ' R, 2 ' S) and (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 41B; but with (±)-(2R; 3R, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3S; 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-formyl radical) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, obtain (±)-(2R; 3R; 5R, 1 ' R, 2 ' S) isomer (must measure: 370mg; 17%) and (±)-(2R; 3R, 5R, 1 ' R; 2 ' R) isomer (must measure: 1.2g, 55%).
(±)-(2R，3R，5R，1’R，2’S) 1H?NMR(d 6-DMSO)δ7.4-7.65(m，10H)，4.47(d，1H)，4.32(m，1H)，3.87(m，2H)，3.68(m，1H)，3.55(m，1H)，3.25(m，1H)，2.7(m，1H)，2.45(m，1H)，2.0(m，1H)，1.83(d，3H)，1.28-1.4(m，18H)，0.95(d，9H)，0.83(dt.3H)
MS：(M－H) -＝667，(M＋35) +＝703，(M＋H) +＝669，(M＋Na) +＝691
(±)-(2R，3R，5R，1’R，2’R) 1H?NMR(d 6-DMSO)δ7.4-7.65(m，10H)，4.40(dd，1H)，4.12-4.32(m，1H)，3.82-3.96(m，1H)，3.66(m，2H)，3.52(t，1H)，2.6-2.8(m，1H)，2.45(m，1H)，1.76-2.0(m，1H)，1.87(d，3H)，1.25-1.4(m，1?8H)，0.95(d，9H)，0.83(dt.3H)。
MS:(M-H) -=667, (M+35) +=703, (M+H) +=669, (M+Na) +=691
Figure A9980761003521
202B (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
Under room temperature, make (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-(0.58g is 0.87mmol) with methoxymethyl chlorine (1.15ml for 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate, 10.07mmol) and diisopropylethylamine (3.5ml, 20.1mmol) in methylene dichloride (1ml) reaction 5 hours.Should react with saturated ammonium chloride solution (100ml) quencher, with ethyl acetate (200ml) dilution.Water and salt water washing organic layer through the dried over mgso organic layer, filter and vacuum concentration.Residue with 5% ethanol/methylene wash-out, obtains title compound (must measure 0.64g, 98%) through the silica gel column chromatography purifying.
1H?NMR(d 6-DMSO)δ7.4-7.65(m，10H)，4.70(s，1H)，4.62(s，1H)，4.35-4.55(m，2H)，3.75-3.95(m，2H)，3.68(m，1H)，3.55(m，1H)，3，25(m，1H)，3.24(s，3H)，2.55(m，1H)，2.45(m，1H)，2.0(m，1H)，1.85(s，3H)，1.28-1.4(m，18H)，0.99(d，9H)，0.8(dt.3H)
MS:(M-H) -=755, (M+35) +=791, (M+H) +=757, (M+Na) +=779
Figure A9980761003531
202C (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-methylol-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 123G, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure 0.416g, 95%).
1H?NMR(d 6-DMSO)δ7.45(t，1H)，4.62-4.74(m，3H)，4.48(m，1H)，3.85(m，2H)，3.55-3.6(m，2H)，3.45(t，1H)，3.2-3.4(m，2H)，3.25(d，3H)，2.4(m，2H)，1.82(d，3H)，1.58(m，3H)，1.32-1.45(m，18H)，0.82(dt.3H)。
MS:(M-H) -=517, (M+35) +=553, (M+H) +=519, (M+Na) +=541 202D (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 123H, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-methylol-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-methylol-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure 0.335g, 80.8%).
1H?NMR(d 6-DMSO)δ9.55(d，1H)，7.48(m，1H)，4.55-4.72(m，4H)，3.9(d，1H)，3.6(m，2H)，3.45(m，3H)，3.32(s，3H)，3.05(t，1H)，2.25-2.45(m，4H)，1.83(s，3H)，1.58(m，3H)，1.30-1.45(m，18H)，0.86(dt.3H)。
MS:(M-H) -=515, (M+35) +=551, (M+H) +=517
Figure A9980761003542
202E (±)-(2R, 3R, 5R, 1 ' R, 2 ' S, 1 " RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(1-hydroxyl-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 38A; but with (±)-(2R; 3R, 5R, 1 ' R; 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate; preparation title compound (must measure 0.27g, 83%).MS:(M-H) -=541, (M+35) +=577, (M+H) +=543, (M+Na) +=565
Figure A9980761003551
202F (±)-and (2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(1-oxo-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 38B, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' S; 1 " RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(1-hydroxyl-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S, 1 " RS)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-hydroxyl-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate; preparation title compound (must measure: 0.2g, 74%).
1H?NMR(d 6-DMSO)δ7.49(br?d，1H)，5.0(d，1H)，4.7(br?s，1H)，4.55-4.7(m，3H)，3.88(br?d，1H)，3.5-3.7(m，2H)，3.43(t，2H)，3.2-3.4(m，2H)，3.24(s，3H)，2.4-2.7(m，2H)，1.84(s，3H)，1.5-1.7(m，2H)，1.30-1.45(m，1?8H)，0.86(dt.3H)
MS:(M-H) -=539, (M+35) +=575, (M+H) +=541, (M+Na) +=563 202G (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 38C, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(1-oxo-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-oxo-2-acetylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 180mg, 87%).
1H?NMR(d 6-DMSO)δ7.57(brt，2H)，6.1(d，1H)，4.50-4.7(m，4H)，3.95(m，1H)，3.4-3.6(m，3H)，3.3-3.4(m，3H)，3.22(d，3H)，2.55-2.65(m，1H)，2.2(m，1H)，1.85(s，3H)，1.5-1.7(m，2H)，1.15-1.45(m，18H)，0.86(dt，3H)。
MS:(M-H) -=553, (M+35) +=589, (M+H) +=553, (M+Na) +=577
Figure A9980761003561
202H (±)-and (2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Prepare title compound according to method described in the embodiment 1K, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxymethyl-tetramethyleneimine-5-t-butyl formate.Use the 2-propyl alcohol: acetate: ethyl acetate: water (1: 1: 3: 1), then add 0.1% trifluoroacetic acid and carry out silica gel column chromatography, obtain title compound (must measure: 15mg, 55%) as eluent.
1H?NMR(d 6-DMSO)δ7.95(d，1H)，7.65(br?s，1H)，6.18(d，1H)，4.37(m，1H)，4.23(m，1H)，4.38(m，1H)，4.56(m，1H)，2.63(m，1H)，2.10(m，1H)，1.78(s，3H)，1.50(m，1H)，1.25(m，1H)，0.83(t.J＝7.46Hz，3H)。
MS：(M－H) -＝309，(M＋35) +＝345，(M＋H) +＝311，(M＋Na) +＝333
Embodiment 203 (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate 203B (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 202B, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.217g, 96%).
1H?NMR(d 6-DMSO)δ7.4-7.65(m，10H)，4.70(s，1H)，4.62(s，1H)，4.35-4.55(m，2H)，3.75-3.95(m，2H)，3.68(m，1H)，3.55(m，1H)，3.25(m，1H)，3.24(s，3H)，2.55(m，1H)，2.45(m，1H)，2.0(m，1H)，1.85(s，3H)，1.28-1.4(m，18H)，0.99(d，9H)，0.8(dt，3H)。
MS:(M-H) -=755, (M+35) +=791, (M+H) +=757, (M+Na) +=779
Figure A9980761003572
203C (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-methylol-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 123G, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-tert-butyl diphenyl siloxy-methyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.124g, 83%).
1H?NMR(d 6-DMSO)δ7.42(dd，1H)，4.62-4.8(m，3H)，4.48(m，1H)，3.6-3.85(m，3H)，3.35-3.6(m，4H)，3.25(s，3H)，2.25(m，1H)，2.4(m，1H)，2.28(m，1H)，1.82(s，3H)，1.58(m，3H)，1.32-1.45(m，18H)，0.9(dt，3H)。
MS:(M-H) -=517, (M+35) +=553, (M+H) +=519, (M+Na) +=541
Figure A9980761003581
203D (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 123H, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-methylol-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-Oxyranyle-3-methylol-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.106g, 86%).
1H?NMR(d 6-DMSO)δ9.58(d，1H)，7.58(dd，1H)，4.6-4.72(m，3H)，4.48(d，1H)，3.88(d，1H)，3.4-3.65(m，5H)，3.24(s，3H)，3.15(dd，1H)，2.20-2.48(m，4H)，1.86(s，3H)，1.58(m，3H)，1.30-1.40(m，18H)，0.86(t，3H)。
MS:(M-H) -=515, (M+35) +=551, (M+H) +=517 203E (±)-(2R, 3R, 5R, 1 ' R, 2 ' R, 1 " RS)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(1-hydroxyl-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 38A; but with (±)-(2R, 3R, 5R; 1 ' R; 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R; 1 ' S; 1 ' RS)-and 1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 32mg, 76%).
MS:(M-H) -=541, (M+35) +=577, (M+H) +=543, (M+Na) +=565
Figure A9980761003592
203F (±)-and (2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(1-oxo-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 38B, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(1-hydroxyl-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S; 1 " RS)-and 1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-oxo-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 25mg, 78%).
1H?NMR(d 6-DMSO)δ7.49(br?d，1H)，5.0(d，1H)，4.7(br?s，1H)，4.55-4.7(m，3H)，3.88(br?d，1H)，3.5-3.7(m，2H)，3.43(t，2H)，3.2-3.4(m，2H)，3.24(s，3H)，2.4-2.7(m，2H)，1.84(s，3H)，1.5-1.7(m，2H)，1.30-1.45(m，18H)，0.86(dt.3H)。
MS:(M-H) -=539, (M+35) +=575, (M+H) +=541, (M+Na) +=563
Figure A9980761003601
203G (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 38C, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(1-oxo-2-propine-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(1-oxo-2-acetylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 18mg, 72%).
1H?NMR(d 6-DMSO)δ7.57(m，2H)，6.1(d，1H)，4.40-4.7(m，4H)，3.93(m，1H)，3.4-3.6(m，3H)，3.3-3.4(m，3H)，3.22(d，3H)，2.55-2.65(m，1H)，2.2(m，1H)，1.85(s，3H)，1.5-1.7(m，2H)，1.15-1.45(m，18H)，0.86(m，3H)。
MS:(M-H) -=553, (M+35) +=589, (M+H) +=553, (M+Na) +=577 203H (±)-and (2R, 3R, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Prepare title compound according to method described in the embodiment 15B, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxymethoxy) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-(imidazoles-2-yl)-tetramethyleneimine-5-t-butyl formate.Use the 2-propyl alcohol: acetate: ethyl acetate: water (1: 1: 3: 1), then add 0.1% trifluoroacetic acid and carry out silica gel column chromatography, obtain title compound (must measure: 4mg, 45%) as eluent.
1H?NMR(d 6-DMSO)δ7.65(d，1H)，7.64(d，1H)，6.16(d，1H)，4.37(m，1H)，4.23(m，1H)，4.38(m，1H)，4.56(m，1H)，2.63(m，1H)，2.10(m，1H)，1.74(s，3H)，1.25-1.40(m，2H)，0.83(t，J＝7.46Hz，3H)。
MS：(M－H) -＝309，(M＋35) +＝345，(M＋H) +＝311，(M＋Na) +＝333
Embodiment 204 (±)-(2R, 3R, 5R)-2-acetamidomethyl-3-methoxycarbonyl-tetramethyleneimine-5-formate hydrochlorate (204A. ±)-(2R, 3R, 5R)-1-benzyl-2-amino methyl-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 1F; but with (±)-(2R; 3R; 5R)-1-benzyl-2-formyl radical-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R, 5R)-1-benzyl-2-(1-oxo-3-ethyl) amyl group-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate.
MS：(M＋H) +＝435。 (204B. ±)-(2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 1G, but with (±)-(2R, 3R, 5R)-1-benzyl-2-amino methyl-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' R)-and (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-amino-3-ethyl) amyl group-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(CDCl 3)：δ7.2-7.35(m，5H)，6.14(br，1H)，3.86(dd，J＝18Hz，13.5Hz，2H)，3.67(m，1H)，3.60(m，1H)，3.49(m，1H)，3.28(m，1H)，3.06(m，1H)，2.19(m，2H)，1.95(s，3H)，1.45(s，9H)，0.91(s，9H)，0.07(s，6H)。
MS:(M+H) +=477
Figure A9980761003622
(204C. ±)-(2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3-methylol-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 1H, but with (±)-(2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-t-butyldimethylsilyloxy ylmethyl-tetramethyleneimine-5-t-butyl formate.
Figure A9980761003631
(204D. ±)-(2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 2A, but with (±)-(2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3-methylol-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methylol-tetramethyleneimine-5-t-butyl formate.
1H?NMR(CDCl 3)：δ9.70(s，1H)，7.22-7.36(m，5H)，5.82(br，1H)，3.83(dd，J＝3.3Hz，13.5Hz，2H)，3.74(m，1H)，3.56(d，J＝9Hz，1H)，3.15(m，1H)，2.73(m，1H)，2.36-2.10(m，2H)，1.98(s，3H)，1.45(s，9H)。
MS (M+H) +=361
Figure A9980761003632
(204E. ±)-(2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in embodiment 2B and the 2C; but with (±)-(2R; 3R; 5R)-1-benzyl-2-acetamidomethyl-3-formyl radical-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3R; 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-formyl radical-tetramethyleneimine-5-t-butyl formate.
1H?NMR(CDCl 3)：δ7.45-7.20(m，5H)，5.96(br，1H)，3.90-3.73(m，4H)，3.71(s，3H)，3.52(dd，J＝9Hz，2Hz，1H)，3.13(m，1H)，2.84(m，1H)，2.36(m，1H)，2.18(m，1H)，1.97(s，3H)，1.45(s，9H)。MS：(M＋H) +＝391。
Figure A9980761003641
(204F. ±)-(2R, 3R, 5R)-2-acetamidomethyl-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 2D, but with (±)-(2R, 3R, 5R)-1-benzyl-2-acetamidomethyl-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-1-benzyl-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(CDCl 3)：δ6.19(br，1H)，3.72(m，2H)，3.70(s，3H)，3.43(m，1H)，3.28(m，1H)，2.74(m，1H)，2.44(m，1H)，2.21(m，1H)，2.00(s，3H)，1.48(s，9H)。
MS:(M+H)=301
Figure A9980761003642
(204G. ±)-(2R, 3R, 5R)-2-acetamidomethyl-3-methoxycarbonyl-tetramethyleneimine-5-formate hydrochlorate
Prepare title compound according to method described in the embodiment 2E, but with (±)-(2R, 3R, 5R)-2-acetamidomethyl-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-ethyl) amyl group-3-methoxycarbonyl-tetramethyleneimine-5-t-butyl formate.
1H?NMR(D 2O)：δ4.42(t，J＝8.25Hz，1H)，4.22(m，1H)，3.83(m，1H)，3.75(s，3H)，3.70-3.60(m，2H)，3.26(m，1H)，2.78(m，1H)，2.43(m，1H)，2.03(s，3H)。
MS:(M+H) +=245 embodiment 205-213
Embodiment 204C
According to method described in the embodiment 1-39, by the following title compound of intermediate preparation commonly used that described in embodiment 204C, prepares.
Embodiment 205
Figure A9980761003652
(±)-(2R, 3R, 5R)-2-acetamidomethyl-3-ethoxy carbonyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(D 2O)：δ4.30(t，J＝8.2Hz，1H)，4.21(m，3H)，3.62(dd，J＝2.4，3.4Hz，2H)，3.23(m，1H)，2.74(m，1H)，2.38(m，1H)，2.02(s，3H)，1.26(m，3H)
MS：(M＋H) +＝259；(M－H) -＝257。Embodiment 206
Figure A9980761003653
(±)-(2R, 3R, 5R)-2-acetamidomethyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-formate hydrochlorate
1H?NMR(D 2O)：δ7.46(s，2H)，4.53(dd，J＝9.5Hz，J＝8.5Hz，1H)，4.28(m，1H)，3.96(m，1H)，3.65(m，2H)，3.03(dt，J＝13.5Hz，J＝7.6Hz，1H)，2.46(m，1H)，1.94(s，3H)。
MS:(M+H) +=253; (M-H) -=251 embodiment 207
Figure A9980761003661
(±)-(2R, 3S, 5R)-2-acetamidomethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(D 2O)：δ5.74(m，1H)，5.24(m，2H)，4.20(dd，J＝1.7，8.1Hz，1H)，3.65(m，2H)，3.50(m，1H)，2.84(m，1H)，2.61(m，1H)，2.03(s，3H)，1.95(m，1H)
MS：(M＋H) +＝213。Embodiment 208
Figure A9980761003662
(±)-(2R, 3R, 5R)-2-acetamidomethyl-3-(2,2-dimethyl-vinyl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(D 2O)：δ5.01(br?d，1H)，4.18(dd，J＝2.1，8.1Hz，1H)，3.53(m，3H)，3.04(m，1H)，2.55(m，1H)，2.0(s，3H)，1.75(m，1H)，1.72(s，3H)，1.67(s，3H)
MS：(M＋H) +＝241，(M＋Na) +＝263，(M－H) -＝239。Embodiment 209
Figure A9980761003671
(±)-(2R, 3R, 5R)-2-acetamidomethyl-3-(N, N-formyl-dimethylamino)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(D 2O)δ4.60(t，J＝8.4Hz，1H)，4.23(m，1H)，3.56(d，J＝5.8Hz，2H)，3.50(m，1H)，3.10(s，3H)，2.94(s，3H)，2.88(m，1H)，2.19(m，1H)，2.00(s，3H)
MS：(M＋H) +＝258，(M－H) -＝256。Embodiment 210
Figure A9980761003672
(±)-(2R, 3R, 5R)-2-acetamidomethyl-3-(N-methylamino formyl radical)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(D 2O)δ4.49(t，J＝8.5Hz，1H)，4.10(m，1H)，3.57(d，J＝5.8Hz，2H)，3.03(m，1H)，2.76(m，1H)，2.74(s，3H)，2.29(m，1H)，2.00(s，3H)
MS：(M＋H) +＝244。Embodiment 211 (±)-(2R, 3R, 5R)-2-acetamidomethyl-3-propionyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(D 2O)δ4.24(m，2H)，3.55(d，J＝4.7Hz，1H)，3.40(m，1H)，2.85(m，1H)，2.64(m，3H)，2.16(m，1H)，2.01(s，3H)，1.02(t，J＝7.1Hz，，3H)
MS：(M＋H) +＝243，(M－H) -＝241。Embodiment 212
Figure A9980761003682
(±)-(2R, 3R, 5R)-2-acetamidomethyl-3-methoxymethyl-tetramethyleneimine-5-formate hydrochlorate
1H?NMR(D 2O)：δ4.44(t，J＝6Hz，2H)，3.77(m，1H)，3.65-3.48(m，3H)，3.35(s，3H)，2.64(m，1H)，2.56(m，1H)，2.03(s，3H)，2.00(m，1H)。
MS:(M+H) +=231; (M-H) -=229 embodiment 213
Figure A9980761003683
(±)-(2R, 3S, 5R)-2-acetamidomethyl-3-methyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(D 2O)：δ4.30(m，1H)，3.64(m，1H)，3.48(m，1H)，3.20(m，1H)，2.64(m，1H)，2.03(s，3H)，1.76(m，1H)，1.32(brt，，1H)，1.12(m，4H)。
MS：(M＋H) +＝201，(M＋Na) +＝223。
Embodiment 214 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate 214A (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-tert-butoxycarbonyl amino-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
In 0 ℃, to sulfur alcohol (0.047ml, add in THF 0.63mmol) (2ml) solution 2.5M n-Butyl Lithium/hexane (0.248ml, 0.62mmol).Stirred this reaction mixture 45 minutes, add (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(N-tert-butoxycarbonyl aziridinyl)-3-vinyl-tetramethyleneimine-5-t-butyl formate (0.08g, 0.182mmol) THF (0.5ml) solution, then add DMF (1.5ml) and under room temperature, stirred 2 hours.Should react with 1N sodium bicarbonate (10ml) quencher, with ethyl acetate (20ml) dilution.Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 10% ethyl acetate/hexane wash-out, obtains title compound (must measure: 61mg, 67%) through the silica gel column chromatography purifying.
1H?NMR(d 6-DMSO)：δ6.74(br，d，1H)，5.85(m，1H)，4.9-5.0(m，2H)，4.20(m，1H)，3.95(m，1H)，3.75(d，1H)，2.8-3.0(dd，1H)，2.5(m，3H)，1.65(m，1H)，1.32-1.45(m，27H)，1.17(dt，3H)。
MS:(M-H) -=499, (M+H) +=501, (M+Na) +=523
Figure A9980761003701
214B (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
In-78 ℃, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (58mg, 0.116mmol) (1.16ml 1.16mmol) reacts in THF (3ml) with hexamethyl dimethylamino silane Lithium Azide (1M).In-78 ℃ 0.5 hour and in-40 ℃ after 1 hour, (0.166ml is 2.33mmol) in-30 ℃ of reactions 0.3 hour to make top reaction mixture and Acetyl Chloride 98Min..Should react with 1N sodium bicarbonate (10ml) quencher, extract with ethyl acetate (20ml).Water and salt water washing organic layer through dried over mgso, filter and vacuum concentration.Residue with 10% ethyl acetate/hexane wash-out, obtains title compound (must measure: 28mg, 44%) through the silica gel column chromatography purifying.
1H?NMR(d 6-DMSO)：δ5.88(m，1H)，4.9-5.0(m，2H)，4.52(m，1H)，4.33(m，1H)，4.1(m，1H)，2.78(dd，1H)，2.3-2.5(m，6H)，1.7(m，1H)，1.32-1.5(m，27H)，1.11(t，3H)。
MS：(M＋H) +＝543。
Figure A9980761003702
214C (±)-(2R, 3R, 5R, 1 ' R)-2-(1-acetamido-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 7mg, 95%).
1H?NMR(d 6-DMSO)δ8.15(d，1H)，5.72(m，1H)，5.05-5.2(m，2H)，4.2-4.4(m，2H)，4.33(m，1H)，2.93(m，1H)，2.7-2.8(2d，1H)，2.3-2.6(m，3H)，1.85-1.95(m，1H)，1.93(s，3H)，1.17(t，J＝7.46Hz，3H)
MS：(M＋H) +＝287。
Embodiment 215 (±)-(2R, 3S, 5R, 1 ' R, 3 ' S)-2-(1-acetamido-2-ethyl sulfinyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate 215A (±)-(2R, 3S, 5R, 1 ' R, 3 ' S) and (±)-(2R, 3S, 5R, 1 ' R, 3 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethyl sulfinyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
In 40 ℃, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (72mg, 0.132mmol) and 55%-chlorine peroxybenzoic acid (41mg, 0.132mmol) in chloroform (1.5ml) reaction 30 minutes.This reactant of vacuum concentration.Residue is used eluent ethyl acetate through the silica gel column chromatography purifying, obtains title compound (±)-(2R, 3S, 5R, 1 ' R, 3 ' S) isomer (must measure: 14mg, 18.9%) and (±)-(2R, 3S, 5R, 1 ' R, 3 ' R) (must measure: 45mg, 60.7%).
(2R，3S，5R，1’R，3’S) 1H?NMR(d 6-DMSO)：δ5.88(m，1H)，4.9-5.0(m，2H)，4.50(m，1H)，4.0-4.15(m，1H)，2.7-2.9(m，3H)，2.55(m，1H)，2.37(s，3H)，1.7(m，1H)，1.32-1.5(m，27H)，1.12(t，3H)
MS：(M＋H) +＝559，(M＋Na) +＝581
(2R，3S，5R，1’R，3’R) 1H?NMR(d 6-DMSO)δ5.88(m，1H)，4.9-5.0(m，2H)，4.50(m，1H)，4.03-4.15(m，1H)，3.2(m，1H)，3.1(dd，1H)，2.5-2.7(m，2H)，2.38(s，3H)，1.75(m，1H)，1.32-1.5(m，27H)，1.12(t，3H)
MS:(M+H) +=559, (M+Na) +=581
Figure A9980761003721
215B (±)-(2R, 3S, 5R, 1 ' R, 3 ' S)-2-(1-acetamido-2-ethyl sulfinyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C; but with (±)-(2R, 3S, 5R; 1 ' R; 3 ' S)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethyl sulfinyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R; 1 ' R; 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 9mg, 86%).
1H?NMR(d 6-DMSO)δ8.39(d，1H)，5.72(m，1H)，5.15-5.2(dd，2H)，4.5(m，1H)，4.37(m，1H)，3.65(m，1H)，2.85-3.04(m，3H)，2.6-2.85(m，2H)，2.4(m，1H)，1.83-1.95(m，1H)，1.86(s，3H)，1.20(t，J＝7.46Hz，3H)。
MS：(M－H) -＝301，(M＋H) +＝303，(M＋Na) +＝325
Embodiment 216 (±)-(2R, 3S, 5R, 1 ' R, 3 ' R)-2-(1-acetamido-2-ethyl sulfinyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003722
According to method described in the embodiment 41C; but with (±)-(2R, 3S, 5R; 1 ' R; 3 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethyl sulfinyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R; 1 ' R; 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 12mg, 94%).
1H?NMR(d 6-DMSO)δ8.39(d，1H)，5.72(m，1H)，5.15-5.2(dd，2H)，4.53(m，1H)，4.41(t，1H)，3.65(m，1H)，3.2(dd，1H)，2.9-3.0(m，2H)，2.65-2.9(m，2H)，2.4(m，1H)，1.83-1.95(m，1H)，1.83(s，3H)，1.20(t，J＝7.46Hz，3H)
MS：(M－H) -＝301，(M＋H) +＝303，(M＋Na) +＝325
Embodiment 217 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-N-tert-butoxycarbonyl acetamido-2-ethylsulfonyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate 217A (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethylsulfonyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
In 0 ℃; make (±)-(2R; 3S; 5R; 1 ' R; 3 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethyl sulfinyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (25mg, 0.0448mmol) and 55%-chlorine peroxybenzoic acid (14mg, 0.0448mmol) in chloroform (1.5ml) reaction 1 hour.This reactant of vacuum concentration.Residue with 25% ethyl acetate/hexane wash-out, obtains title compound (must measure: 23.7mg, 92%) through the silica gel column chromatography purifying.
1H?NMR(d 6-DMSO)：δ5.88(m，1H)，4.85-5.0(m，2H)，4.38(m，1H)，4.15(m，1H)，3.7(m，1H)，3.45(dd，1H)，2.9-3.2(m，3H)，2.5-2.7(m，1H)，2.3-2.4(m，3H)，1.6-2.04(m，1H)，1.35-1.55(m，27H)，1.15(t，3H)
MS:(M+H) +=575 217B (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethylsulfonyl) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C; but with (±)-(2R; 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-ethylsulfonyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3S; 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate; preparation title compound (must measure: 12mg, 94%).
1H?NMR(d 6-DMSO)δ8.34(d，1H)，5.72(m，1H)，5.05-5.25(dd，2H)，4.68(m，1H)，4.39(dd，1H)，3.7(2d，1H)，3.48(dd，1H)，3.3-3.4(dd，2H)，3.08(q，2H)，2.95(m，1H)，2.42(m，1H)，1.9(m，1H)，1.84(s，3H)，1.23(t，J＝7.46Hz，3H)。
MS:(M-H) -=317, (M+35) +=353, (M+H) +=319, (M+Na) +=341 embodiment 218,220
Figure A9980761003741
According to method described in the embodiment 214, with the following title compound of 3 steps preparation.
Embodiment 218 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-iprotiazem base) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003742
218A (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-iprotiazem base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 214A, but replace sulfur alcohol, preparation title compound (must measure: 22mg, 62%) with isopropyl mercaptan.
1H?NMR(d 6-DMSO)：δ6.73(d，1H)，5.85(m，1H)，4.9-5.0(m，2H)，4.18(m，1H)，3.95(m，1H)，3.75(br?d，1H)，2.8-3.0(m，2H)，1.65(m，1H)，1.32-1.45(m，27H)，1.18(dd，6H)
MS:(M-H) -=513, (M+H) +=515, (M+Na) +=537 218B (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-(N-tert-butoxycarbonyl-N-acetamido)-2-iprotiazem base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 214B, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-iprotiazem base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R)-and 1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 12mg, 50%).
1H?NMR(d 6-DMSO)：δ5.86(m，1H)，4.88-5.0(m，2H)，4.54(m，1H)，4.33(m，1H)，4.13(d，1H)，3.05(m，1H)，2.73-2.84(m，2H)，2.38(br?s，3H)，1.72(m，1H)，1.32-1.5(m，27H)，1.14(dd，6H)。
MS:(M+H) +=557, (M+Na) +=579 218C (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-iprotiazem base) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 15B, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-iprotiazem base) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 8mg, 97%).
1H?NMR(d 6-DMSO)δ8.14(d，1H)，5.72(m，1H)，5.05-5.2(dd，2H)，4.2-4.4(m，2H)，3.68(dd，1H)，2.93(m，2H)，2.74(dd，1H)，2.58(dd，1H)，1.93(m，1H)，1.87(s，3H)，1.2(t，6H)
MS：(M－H) -＝299，(M＋H) +＝301，(M＋Na) +＝323
Embodiment 219 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-thiophenyl) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate
Figure A9980761003761
219A (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-amino-2-thiophenyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-aziridinyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (20.3mg, 0.06mmol) with thiophenol (19.9mg, 0.18mmol) and triethylamine (0.047ml 0.34mmol) reacted in methyl alcohol (0.06ml) 3.5 hours.This reaction solution of vacuum concentration.Residue launches with ethyl acetate/methanol/ammonium hydroxide (99/0.05/0.05) through preparation property silica gel thin-layer chromatography purifying, obtains title compound (must measure: 20.7mg, 77%).
1H?NMR(d 6-DMSO)：δ7.31(m，4H)，7.17(m，1H)，5.87(m，1H)，5.03(d，J＝17Hz，0.4H)，5.01(d，J＝17Hz，0.6H)，4.91(d，J＝11Hz，0.4H)，4.90(d，J＝11Hz，0.6H)，4.15(m，1H)，3.82(m，0.6H)，3.76(m，0.4H)，3.39(m，1H)，2.92(m，2H)，2.55(m，1H)，1.64(m，2H)，1.42(s，5.4H)，1.37(s，3.6H)，1.34(s，5.4H)，1.22(s，3.6H)
MS:(M+H) +=449, (M+Na) +=471
Figure A9980761003771
219B (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-thiophenyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
Under room temperature, make (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-amino-2-thiophenyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate (17.2mg, 0.04mmol) with diacetyl oxide (0.011ml, 0.11mmol) and triethylamine (0.032ml 0.23mmol) reacted in methylene dichloride (0.3ml) 4.25 hours.The vacuum concentration reaction soln.Residue launches with 5% ethanol/methylene through preparation property silica gel thin-layer chromatography purifying, obtains title compound.
1H?NMR(d 6-DMSO)：δ7.75(d，J＝9Hz，0.6H)，7.73(d，J＝9Hz，0.4H)，7.32(m，4H)，7.19(m，1H)，5.87(m，1H)，5.04(d，J＝17Hz，0.4H)，5.00(d，J＝17Hz，0.6H)，4.95(d，J＝10Hz，0.6H)，4.93(d，J＝10Hz，0.4H)，4.59(m，0.4H)，4.45(m，0.6H)，3.99(dd，J＝10Hz，2Hz，0.6H)，3.94(dd，J＝10Hz，2.5Hz，0.4H)，3.84(m，0.6H)，3.77(m，0.4H)，3.07(dd，13Hz，5Hz，0.6H)，2.95(m，1.8H)，2.83(brt，J＝8Hz，0.6H)，2.48(m，1H)，1.84(s，1.2H)，1.81(s，1.8H)，1.68(m，1H)，1.41(s，5.4H)，1.36(s，3.6H)，1.34(s，5.4H)，1.26(s，3.6H)
MS:(M-H) -=489, (M+35) -(M+H) +=490, (M+Na) +=513 219C (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-thiophenyl) ethyl-3-vinyl-tetramethyleneimine-5-formate hydrochlorate
According to method described in the embodiment 1K, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-thiophenyl) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3R, 5R, 1 ' S)-and 2-(1-acetamido-3-ethyl) amyl group-3-(methoxymethyl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 14.6mg, 100%).
1H NMR (d 4-methyl alcohol): δ 7.43 (m, 2H), 7.31 (m, 3H), 5.75 (ddd, J=17Hz, 10Hz, 8Hz, 1H), 5.32 (br d, J=17Hz, 1H), 5.19 (dd, J=10Hz, 1.4Hz, 1H), 4.58 (m, 2H), 3.89 (dd, J=10Hz, 3Hz, 1H), 3.19 (dd, J=14Hz, 6Hz, 1H), 3.09 (dd, J=14Hz, 9Hz, 1H), 3.04 (m, 1H), 2.57 (dt, J=13Hz, 7Hz, 1H), 2.04 (s, 3H), 2.03 (m, 1H)
MS：(M－H) -＝333；(M＋H) +＝335，(M＋Na) +＝357
Embodiment 220 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-benzylthio-) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003781
220A (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-benzylthio-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 214A, but replace sulfur alcohol, preparation title compound (must measure: 28mg, 72%) with benzyl mercaptan.
1H?NMR(d 6-DMSO)：δ7.2-7.35(m，5H)，6.80(br?d，1H)，5.84(m，1H)，4.86-4.96(m，2H)，4.25(m，1H)，3.95(m，1H)，3.7-3.8(m，3H)，2.76-2.94(m，1H)，2.35-2.45(m，2H)，1.65(m，1H)，1.32-1.45(m，27H)
MS:(M-H) -=561, (M+H) +=563, (M+Na) +=585
Figure A9980761003791
220B (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-(N-tert-butoxycarbonyl-acetamido)-2-benzylthio-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 214B, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-benzylthio-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R)-and 1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl amino-2-ethylmercapto group) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 3.3mg, 61%).
1H?NMR(d 6-DMSO)：δ7.2-7.35(m，5H)，5.84(m，1H)，4.86-4.96(m，2H)，4.55(m，1H)，4.32(d，1H)，4.05(d，1H)，3.56-3.65(m，2H)，2.9(m，1H)，2.3-2.65(m，3H)，2.42(s，3H)，1.76(d，1H)，1.25-1.55(m，27H)
MS:(M+H) +=605, (M+Na) +=627 220C (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-benzylthio-) ethyl-3-vinyl-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-N-tert-butoxycarbonyl acetamido-2-benzylthio-) ethyl-3-vinyl-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 2.2mg, 95%).
1H?NMR(d 6-DMSO)δ8.18(d，1H)，7.2-7.32(m，5H)，5.68(m，1H)，5.02-5.2(m，2H)，4.3-4.45(m，2H)，3.76(s，2H)，3.68(dd，1H)，2.92(m，1H)，2.62(dd，1H)，2.32-2.55(m，2H)，1.85-1.95(m，1H)，1.89(s，3H)。
MS (M-H) -=347, (M+H) +=349, (M+Na) +=371 embodiment 221 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-(4-pyridylthio) ethyl-3-vinyl-tetramethyleneimine-5-formic acid dihydrochloride.
Prepare title compound according to method described in the embodiment 219A-C, but replace thiophenol as the reagent among the embodiment 219A with 4-sulfo-pyridine.
1H NMR (d 4-methyl alcohol): d 8.57 (d, J=7Hz, 2H), 7.97 (d, J=7Hz, 2H), 5.85 (ddd, J=17Hz, 10Hz, 9Hz, 1H), 5.40 (br d, J=17Hz, 1H), 5.25 (dd, J=17Hz, 10Hz, 1H), 4.67 (dt, J=10Hz, 4Hz, 1H), 4.47 (dd, J=10Hz, 8Hz, 1H), 4.01 (dd, J=10Hz, 4Hz, 1H), 3.68 (dd, J=14Hz, 5Hz, 1H), 3.45 (dd, J=14Hz, 10Hz, 1H), 3.16 (m, 1H), 2.65 (dt, J=14Hz, 7Hz, 1H), 2.07 (m, 1H), 2.04 (s, 3H)
MS:(M-H) -=334; (M+H) +=336, (M+Na) +=358 embodiment 222
Figure A9980761003802
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-ethyl formate.
In 0 ℃, (1.49ml is 20.5mmol) with ethanol (25ml) reaction 10 minutes to make thionyl chloride.Will be at (±)-(2R in the ethanol (50ml), 3S, 5R, 1 ' R, 2 ' S)-(815mg 2.05mmol) reacted 17 hours in the solution above the adding and under room temperature 2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate.This reactant of vacuum concentration, residue with 90/10/0.5 methylene chloride/ammonium hydroxide wash-out, obtain title compound through the silica gel column chromatography purifying, are white solid (must measure: 462mg, 72%).
1H?NMR(DMSO-d 6)：δ7.49(d，J＝9.8Hz，1H)，5.31(m，2H)，4.11(m，2H)，3.72(t，J＝7.7Hz，1H)，3.69(m，1H)，3.42(m，1H)，3.07(m，1H)，2.85(m，1H)，2.22(m，1H)，1.76(s，3H)，1.54(d，J＝5.6Hz，3H)，1.45(m，1H)，1.39(m，1H)，1.21(m，1H)，1.19(t，J＝7.0Hz，3H)，0.83(t，J＝7.3Hz，3H)。
MS：(M＋H) +＝313，(M＋Na) +＝335，(M－H) -＝311。Embodiment 223 (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-ethyl formate.
According to method described in the embodiment 222, but with (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate, preparation title compound (must measure: 32mg, 52%).
1H?NMR(d 6-DMSO)：δ7.6(br?s，1H)，6.1(br?s，1H)，4.08(q，J＝7.12Hz，2H)，3.78(m，1H)，3.65(m，1H)，3.55(m，1H)，3.45(m，1H)，3.25(m，1H)，3.45(m，1H)，1.72(s，3H)，1.45(m，1H)，1.2(m，1H)，1.16(t，J＝7.12Hz，3H)，0.82(t，J＝7.46Hz，3H)。
MS:(M-H) -=337, (M+35) +=373, (M+H) +=339, (M+Na) +=361 embodiment 224 (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-sec.-propyl-N-methylamino-N-oxide compound) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-ethyl formate
According to method described in the embodiment 222, but with (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-and 2-(1-acetamido-2-(N-sec.-propyl)-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate, preparation title compound (must measure: 25mg, 34%).
1H?NMR(MeOD-d 3)：δ5.51-5.43(m，1H)，5.34-5.27(m，1H)，4.36-4.30(m，1H)，4.18(q，J＝7.1Hz，2H)，3.88(dd，J＝6.8，8.8Hz，1H)，3.82-3.67(m，2H)，3.49-3.42(m，1H)，3.34(s，3H)，3.14-2.96(m，1H)，2.42-2.33(m，1H)，1.92(s，3H)，1.64-1.52(m，1H)，1.63(dd，J＝1.7，6.8Hz，3H)，1.41-1.24(m，1H)，1.39(d，J＝6.4Hz，3H)，1.31(d，J＝6.4Hz，3H)，1.26(t，J＝7.1Hz，3H)。
MS：(M＋H) +＝356，(M＋Na) +＝378，(M－H) -＝354，(M＋35) +＝390。Embodiment 225 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-ethyl formate
According to method described in the embodiment 222, but with (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate, preparation title compound (must measure: 838mg, 94%).
1H?NMR(CDCl 3)：δ5.50(m，1H)，5.41(m，1H)，5.28(m，1H)，4.21(q，J＝7.5Hz，2H)，4.06(m，1H)，3.87(t，J＝7.5Hz，1H)，3.10(m，1H)，2.97(m，1H)，2.39(m，1H)，1.97(s，3H)，1.66(dd，3H)，1.60(m，1H)，1.40(m，2H)，0.94(d，J＝7.5Hz，3H)，0.93(d，J＝7.5Hz，3H)。
MS:(M+H) +=311 embodiment 226
Figure A9980761003831
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-ethyl formate
According to method described in the embodiment 222, but with (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate, preparation title compound (must measure: 28mg, 46%).
1H?NMR(CDCl 3)：δ6.05(d，J＝7.5Hz，1H)，5.90(dd，J1＝9Hz，J2＝6Hz，1H)，5.31(d，J＝9Hz，1H)，4.19(q，J＝7.5Hz，2H)，4.06(m，1H)，3.82(t，J＝7.5Hz，1H)，3.17(m，2H)，2.45(m，1H)，1.98(s，3H)，1.67(m，1H)，1.60(m，1H)，1.37(m，2H)，1.27(t，J＝7.5Hz，3H)，0.91(d，J＝7.5Hz，3H)，0.89(d，J＝7.5Hz，3H)。MS：(M＋H) +＝331
Embodiment 227 has a mind to blank.
Embodiment 228
Figure A9980761003841
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(2,2-two fluoro-vinyl)-tetramethyleneimine-5-ethyl formate
According to method described in the embodiment 222, but with (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(2,2-two fluoro-vinyl)-tetramethyleneimine-5-methanoic acid trifluoro acetate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate, preparation title compound (must measure: 28mg, 57%).
1H?NMR(CDCl 3)：δ4.22(q，J＝7.5Hz，2H)，4.14(m，1H)，4.03(m，1H)，3.29(br，1H)，2.85(m，1H)，2.52(m，1H)，2.01(s，3H)，1.77(m，2H)，1.64(m，2H)，1.49(m，1H)，1.38(m，1H)，1.29(t，J＝7.5Hz，3H)，0.93(d，J＝7.5Hz，3H)，0.90(d，J＝7.5Hz，3H)。
MS:(M+H) +=333 embodiment 229
Figure A9980761003842
(±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-ethyl formate
According to method described in the embodiment 222, but with (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate, preparation title compound (must measure: 48mg, 75.5%).
1H?NMR(CDCl 3)：δ7.49(d，1H)，7.26(s，1H)，6.18(d，1H)，4.18(q，J＝7.5Hz，2H)，4.12(m，1H)，3.91(t，J＝7.5Hz，1H)，3.51(t，J＝7.5Hz，1H)，3.40(q，J＝9Hz，1H)，2.64(m，1H)，2.00(m，1H)，1.82(s，3H)，1.75(m，1H)，1.36(m，1H)，1.26(t，J＝9Hz，3H)，0.855(d，3H)，0.84(d，3H)。
MS：(M＋H) +＝337
Embodiment 230 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003851
230A (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 41B; but with (±)-(2R; 3S; 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S; 5R; 1 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, obtain title compound (must measure: 0.021g, 51%).
MS：(M＋H) +＝469，(M＋Na) +＝491，(2M＋Na) +＝959，(M－H) -＝467。
Figure A9980761003861
230B (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0039g, 100%).
1H NMR (DMSO-d 6) δ 7.52 (d, J=10.3Hz, 1 H), 5.45 (m, 1H), 5.28 (m, 1H), 4.32 (m, 2H), 3.68 (t, J=8.8Hz, 1H), 3.16 (quintets, J=8.5Hz, 1H), 2.41 (dt, J=13.2,8.3Hz, 1H), 1.81 (s, 3H), 1.59 (m, 1H), 1.53 (dd, J=6.8,1.5Hz, 3H), 1.52-1.42 (m, 3H), 1.30 (m, 1H), 0.86 (t, J=7.3Hz, 3H), 0.83 (t, J=7.3Hz, 3H).
MS：(M＋H) +＝313，(M＋Na) +＝335，(M－H) -＝311，(2M－H) -＝623。
Embodiment 231 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-2-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate 231A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 41B; but with (±)-(2R; 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R; 3S; 5R; 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate and replace ethylmagnesium bromide with methyl-magnesium-bromide; obtain title compound (must measure: 0.0285g, 45%).
MS：(M＋H) +＝469，(M＋Na) +＝491。 231B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-2-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0040g, 100%).
1H NMR (DMS0-d 6) δ 9.25 (bs, 1H), 8.75 (bs, 1H), 7.54 (d, J=10.3Hz, 1H), 5.45 (m, 1H), 5.29 (m, 1H), 4.37 (bt, J=8.3Hz, 1H), 4.22 (t, J=9.7Hz, 1H), 3.62 (t, J=8.8Hz, 1H), 3.12 (quintets, J=8.5Hz, 1H), 2.41 (dt, J=12.7,7.8Hz, 1H), 1.78 (s, 3H), 1.59 (m, 1H), 1.53 (dd, J=6.8,2.0Hz, 3H), 1.4-1.25 (m, 4H), 1.17 (s, 3H), 0.81 (t, J=6.5Hz, 3H).
MS：(M＋H) +＝313，(M＋Na) +＝335，(M－H) -＝311，(2M－H) -＝623。
Embodiment 232 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003881
232A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 41B; but with (±)-(2R; 3S; 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S; 5R; 1 ' R)-and 1-tert-butoxycarbonyl-2-(1-acetamido-1-formyl radical) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, obtain title compound (must measure: 0.0222g, 33%).
MS：(M＋H) +＝483，(M＋Na) +＝505，(M－H) -＝481。 232B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0035g, 100%).
1H NMR (DMSO-d 6) δ 9.1 (bs, 1H), 8.75 (bs, 1H), 7.53 (d, J=9.8Hz, 1H), 5.44 (m, 1H), 5.28 (m, 1H), 4.35-4.25 (m, 2H), 3.67 (m, 1H), 3.16 (quintet, J=8.5Hz, 1H), 2.41 (dt, J=12.8,7.9Hz, 1H), 1.81 (s, 3H), 1.60 (m, 1H), 1.53 (dd, J=6.7,1.8Hz, 3H), 1.46 (m, 2H), 1.4-1.20 (m, 4H), 0.86 (t, J=7.3Hz, 3H), 0.82 (t, J=6.7Hz, 3H).
MS:(M+H) +=327, (M-H) -=325, (M+CF 3COOH) -=439, (2M-H) -=651 embodiment 233 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-propyl group-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Prepare title compound according to method described in the embodiment 232, but replace ethylmagnesium bromide with the propyl group magnesium bromide.
1H?NMR(DMSO-d 6)δ0.81(t，3H)，0.91(t，3H)，1.24-1.49(m，8H)，1.54(dd，3H)，1.60(m，1H)，1.81(s，3H)，2.41(m，1H)，3.15(m，1H)，3.69(t，1H)，4.28(t，1H)，4.35(t，1H)，5.17(br?s，1H)，5.28(td，1H)，5.45(dq，1H)，7.54(d，1H)，8.80(br?s，1H)，9.12(br?s，1H)。
MS：(M＋H) +＝341。
Embodiment 234 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethyl-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate 234A (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-(methylthio group) methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
According to Marshall, J.A is at J.Org.Chem.1979, the 44th volume, method described in 2994 pages, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate and methyl-sulphoxide and acetic anhydride obtain title compound.
Figure A9980761003901
234A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
According to Marshall, J.A is at J.Org.Chem. 1979, the 44th volume, method described in 2994 pages, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-(methylthio group) methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate and Raney nickel reaction obtain title compound. (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-ethyl-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Prepare title compound according to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 235 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-ethyl-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Prepare title compound according to method described in the embodiment 234, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, the 3S among the embodiment 234A, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate.
Embodiment 236 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methylol-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003912
236A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-((1-oxyethyl group) ethoxyl methyl)-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
According to Still, W.C (J.Am.Chem.Soc., 100,1481 (1978)) method, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-(50mg is 0.11mmol) with (ethoxy ethoxy methyl) tributyl stannane (260mg, 0.66mmol) reaction for 1-tert-butoxycarbonyl-2-(1-acetamido-2-oxo) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, obtain title compound (must measure: 26.8mg, 43.8%).
1H?NMR(CDCl 3)δ0.89(t，3H)，1.19(m，3H)，1.29(dd，3H)，1.45(s，9H)，1.46(s，9H)，1.52-1.73(m，8H)，1.99(s，3H)，2.44(m，1H)，3.24-3.74(m，5H)，3.91-4.22(m，3H)，4.49(m，1H)，4.62(m，1H)，5.37(m，1H)，5.64(m，1H)，5.97-6.41(m，1H)。
MS：(M＋H) +＝557。 236B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methylol-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-(1-oxyethyl group-2-ethoxyl methyl)-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (13.5mg, 0.024mmol) be dissolved among the THF (1ml), under room temperature, handled 1 hour with 0.5N HCl (1ml).Remove and desolvate, in the white solid and the trifluoroacetic acid (0.8ml) that obtain were reacted 6 hours in methylene dichloride (0.2ml).This reactant of vacuum concentration spends the night, and the title compound that obtains to pale solid (must be measured: 10.7mg).
1H?NMR(DMSO-d 6)δ0.81(t，3H)，1.24-1.38(m，4H)，1.52(dd，3H)，1.62(m，1H)，1.78(s，3H)，2.41(m，1H)，3.11(m，1H)，3.51(qAB，2H)，3.77(t，1H)，4.23?(t，1H)，4.40(m，1H)，5.27(t，1H)，5.45(m，1H)，7.55(d，1H)，8.87(br?s，1H)，9.26(br?s，1H)。
MS：(M＋H) +＝329。
Embodiment 237 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-allyloxy-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003931
237A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 84A, make (2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate reaction, but replace methyl-iodide (must measure: 28mg, 80%) with allyl iodide.
MS：(M＋H) +＝479，(M－H) -＝477。
Figure A9980761003932
237B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-allyloxy-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4mg, 100%).
1H?NMR(DMSO-d 6)δ7.98(d，J＝7.8Hz，1H)，5.90(m，1H)，5.55(m，1H)，5.48(m，1H)，5.32(m，2H)，5.26(m，2H)，5.16(m，1H)，4.28(m，2H)，3.96(m，1H)，3.79(m，1H)，3.73(m，1H)，3.66(m，1H)，3.26(m，1H)，2.40(m，1H)，1.81(s，3H)，1.70(m，1H)，1.64(dd，J＝6.9，1.5Hz，3H)。
MS：(M＋H) +＝323，(M－H) -＝321。
Embodiment 238 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(2,5-dihydrofuran-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate 238A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(2,5-dihydrofuran-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Under 25 ℃ and nitrogen, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-(21mg, 0.044mmol) (7.5mg 0.009mmol) reacted 2 hours in methylene dichloride (5ml) 1-tert-butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (according to method described in embodiment 237A preparation) with two (tricyclohexyl phosphine) chloro-benzal rutheniums (IV) [Grubb ' s catalyzer].This reactant of vacuum concentration, gained residue with 75% ethyl acetate/hexane wash-out, obtain title compound (must measure: 18mg, 90%) through the silica gel column chromatography purifying.
MS：(M＋H) +＝451，(M－H) -＝449。
Figure A9980761003942
238B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(2,5-dihydrofuran-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(2,5-dihydrofuran-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 7mg, 100%).
1H?NMR(DMSO-d 6)δ8.09(d，J＝8.8Hz，1H)，6.10(m，1H)，5.87(m，1H)，5.50(m，1H)，5.27(m，1H)，4.68(m，2H)，4.58(m，1H)，4.33(m，1H)，4.06(m，1H)，3.68(m，1H)，3.18(m，1H)，2.40(m，1H)，1.85(s，3H)，1.68(m，1H)，1.60(dd，J＝6.8，1.5Hz，3H)。
MS：(M＋H) +＝295，(M－H) -＝293。
Embodiment 239 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-allyloxy-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003951
239A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 84A, make (2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate reaction, but replace methyl-iodide (must measure: 19mg, 36%) with allyl iodide.
MS：(M＋H) +＝493，(M－H) -＝491。
Figure A9980761003952
239B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-allyloxy-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-allyl group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.7mg, 100%).
1H?NMR(DMSO-d 6)δ8.06(dd，J＝8.8Hz，1H)，6.92(m，1H)，6.77(m，1H)，5.50(m，1H)，5.29(m，2H)，5.17(m，1H)，5.05(m，2H)，4.27(m，2H)，4.10(dd，J＝12.2，5.4Hz，1H)，3.83(m，1H)，3.78(m，1H)，3.40(m，1H)，3.20(m，1H)，2.46(m，1H)，2.38(m，1H)，2.20(m，1H)，1.88(s，3H)，1.69(m，1H)，1.63(dd，J＝6.8，1.5Hz，3H)。
MS：(M＋H) +＝337，(M＋Na) +＝359，(M－H) -＝335。
Embodiment 240 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
Figure A9980761003961
240A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Under 25 ℃ and nitrogen, make (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (according to the preparation of method described in the embodiment 239A) (11.5mg is 0.023mmol) with two (tricyclohexyl phosphine) chloro-benzal ruthenium (IV) Grubb ' s catalyzer] (3.8mg is 0.005mmol) methylene dichloride (3ml) reaction 3 hours.This reactant of vacuum concentration, gained residue with 75% ethyl acetate/hexane wash-out, obtain title compound (must measure: 5.7mg, 53%) through the silica gel column chromatography purifying.
MS：(M＋H) +＝465，(M＋Na) +＝487，(M－H) -＝463。
Figure A9980761003971
240B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replaces (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 5.9mg, 100%).
1H?NMR(DMSO-d 6)δ8.04(d，J＝8.8Hz，1H)，5.77(m，2H)，5.50(m，1H)，5.25(m，1H)，4.21(m，2H)，4.14(m，1H)，4.04(m，1H)，3.81(m，1H)，3.40(m，1H)，3.23(m，1H)，2.41(m，1H)，2.09(m，1H)，1.88(s，3H)，1.83(m，1H)，1.70(m，1H)，1.63(d，J＝6.8Hz，3H)。
MS：(M＋H) +＝309，(M＋Na) +＝331，(M－H) -＝307。
According to the synthetic following compounds embodiment 241 of preceding method among the embodiment 1-240
Figure A9980761003972
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)δ7.90(d，9.1Hz，1H)，5.79(m，2H)，5.48(m，1H)，5.23(m，1H)，4.43(m，1H)，4.24(m，2H)，4.17(m，2H)，3.73(m，1H)，3.64(m，1H)，3.19(m，1H)，2.42(m，1H)，2.02(m，1H)，1.85(s，3H)，1.78(m，1H)，1.75(m，1H)，1.56(dd，J＝7.5，1.5Hz，3H)。
MS：(M＋H) +＝309，(M＋Na) +＝331，(M－H) -＝307。Embodiment 242
Figure A9980761003981
(±)-(2R, 3S, 5R, 1 ' S, 2 ' RS)-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO)δ7.7(d，J＝9.8Hz，1H)，5.61(m，1H)，5.19(dt，J＝1.8，11.0Hz，1H)，4.33(dd，J＝6.7，10.3Hz，1H)，3.81(m，1H)，3.70(dd，J＝1.8，10.3Hz，1H)，3.54(q，J＝6.1Hz，1H)，3.10(m，1H)，2.35(dt，J＝12.8，6.8Hz，1H)，1.90(s，3H)，1.7(m，1H)，1.59(dd，J＝0.7，7.3Hz，3H)，1.4(m，3H)，1.2(m，2H)，0.90(t，J＝6.7Hz，3H)。
MS:(M+H) +=299 embodiment 243
Figure A9980761003982
(±)-(2R, 3S, 5R, 1 ' S, 2 ' RS)-2-(1-acetamido-2-hydroxyl-3-ethoxy carbonyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO)δ7.75(m，1H)，5.60(m，1H)，5.29(m，1H)，4.55-4.25(m，3H)，4.15-4.0(m，3H)，3.9-3.6(m，3H)，3.15(m，1H)，2.45-2.3(m，2H)，1.9(s，3H)，1.8-1.5(m，5H)，1.2(m，3H)。
MS:(M+H) +=343 embodiment 244
Figure A9980761003991
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)d?7.91(d，J＝8.05Hz，1H)，5.50(m，2H)，5.30(m，3H)，4.27(m，1H)，4.23(m，1H)，3.75(m，1H)，3.48(m，1H)，3.23(m，1H)，3.15(s，3H)，2.40(m，1H)，1.80(s，3H)，1.68(m，1H)，1.64(dd，J＝1.83，7.32Hz，3H)
MS:(M+H) +=297, (M-H) -=295 embodiment 245
Figure A9980761003992
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)d?7.90(d，J＝7.85Hz，1H)，5.57(m，2H)，5.48(m，3H)，4.27(m，1H)，4.22(m，1H)，3.77(m，1H)，3.60(m，1H)，3.46(m，1H)，3.23(m，2H)，2.39(m，1H)，1.80(s，3H)，1.70(m，1H)，1.64(dd，J＝1.47，6.73Hz，3H)，1.12(t，J＝6.83Hz，3H)
MS:(M+H) +=311, (M-H) -=309 embodiment 246
Figure A9980761004001
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-(propylene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)δ7.69(d，J＝9.75Hz，1H)，5.47(m，1H)，5.28(m，1H)，5.03(m，1H)，4.86(m，1H)，4.40(m，1H)，4.30(m，1H)，4.18(m，1H)，3.97(m，1H)，3.68(m，1H)，3.21(m，1H)，2.43(m，1H)，1.82(m，1H)，1.73(s，3H)，1.64(s，3H)，1.59(m，3H)
MS:(M+H) +297, (M-H) -=295 embodiment 247 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl-2-(propylene-2-yl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H NMR (DMSO-d 6) δ 7.65 (d, J=9.80Hz, 1H), 5.48 (m, 1H), 5.23 (m, 1H), 4.99 (s, 1H), 4.88 (s, 1H), 4.46 (m, 1H), 4.30 (m, 1H), 4.19 (m, 1H), 3.55 (m, 1H), 3.22 (m, 1H), 2.44 (m, 1H), 1.78 (s, 3H), 1.75 (m, 1H), 1.65 (s, 3H), 1.58 (dd, J=1.23,6.70Hz, 3H) MS:(M+H) +=297, (M-H) -=295 embodiment 248
Figure A9980761004011
(±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-(propylene-2-yl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)d?7.77(d，J＝9.8Hz，1H)，5.49(m，1H)，5.25(m，1H)，5.07(m，1H)，4.94(m，1H)，4.32(m，1H)，4.25(m，1H)，3.75(m，1)，3.48(m，1H)，3.25(m，1H)，3.08(s，3H)，2.40(m，1H)，1.77(s，3H)，1.68(m，1H)，1.64(dd，J＝1.22，6.71Hz，3H)，1.56(s，3H)
MS:(M+H) +=311, (M-H) -=309 embodiment 249
Figure A9980761004012
(±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)δ7.62(d，J＝9.21Hz，1H)，5.58(m，1H)，5.28(m，1H)，4.37(m，1H)，3.98(m，1H)，3.57(m，1H)，3.10(m，1H)，2.45(m，1H)，1.92(s，3H)，1.76(m，1H)，1.62(dd，J＝1.83，6.72Hz，3H)，1.24(m，5H)，0.84(t，J＝7.61Hz，3H)，0.77(t，J＝7.61Hz，3H)
MS：(M＋H) +＝297，(M－H) -＝295
Embodiment 250 (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)δ7.76(d，J＝9.2Hz，1H)，5.46(m，1H)，5.29(m，1H)，4.23(m，1H)，3.63(m，1H)，3.15(m，1H)，3.01(m，1H)，2.38(m，1H)，1.87(s，3H)，1.71(m，1H)，1.60(m，3H)，1.36(m，1H)，1.20(m，4H)，0.83(t，J＝7.3Hz，6H)。
MS：(M＋H) +＝297，(M－H) -＝295
Embodiment 251 (-)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-ethyl formate and (+)-(2S, 3S, 5S, 1 ' R)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-ethyl formate
To carry out chromatography on the disposable chirality HPLC post that is expelled to 5 * 30cm size of (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-ethyl formate (100mg).Described post is adorned post with the Chiralpak AD chiral stationary phase weighting material that derives from Chiral Technologies.Moving phase is 1: 9 ethanol of 117ml/min. by flow rate: hexane is formed.Minute observe two peaks at (24-36) minute with (66-96), be respectively (-)-(2R, 3S, 5R, 1 ' S) (must measure: 45mg) and (+)-(2S, 3S, 5S, 1 ' R) (must measure: 45mg).
(-)-(2R, 3S, 5R, 1 ' S) [α] D=-26 ℃ (c=0.78, methylene dichloride)
Embodiment 252 (-)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid ammonium salt
Figure A9980761004031
In 0 ℃, make (-)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-ethyl formate (according to the method preparation of embodiment 251) (4.9mg, 0.0157mmol) (0.75mg 0.0314mmol) reacted 7 hours in the mixture of methyl alcohol (0.75ml) and water (0.25ml) with lithium hydroxide.Add 0.1N aqueous hydrochloric acid (1ml) then, this reactant of vacuum concentration, the residue that obtains pass through the ion exchange chromatography purifying on Aldrich Dowex 50WX8-400 highly acidic resin.With this residue upper prop, water (5ml) washing then with 0.5N ammonium hydroxide aqueous solution wash-out, obtains title compound, is colorless solid (must measure: 3.9mg, 83%).[α] D=-40 ℃, c=0.08 (water).
1H?NMR(DMSO-d 6)δ7.71(d，J＝9.2Hz，1H)，5.38(m，1H)，5.29(m，1H)，3.92(m，1H)，3.65(t，J＝8.5Hz，1H)，3.43(m，1H)，3.33(m，1H)，2.98(m，1H)，2.23(m，1H)，1.76(s，3H)，1.54(dd，J＝6.7，1.8Hz，3H)，1.46(m，2H)，1.23(m，1H)，0.84(t，J＝7.3Hz，3H)。
MS：(M＋H)＝285，(M＋Na) +＝307，(M－H) -＝283。
[α] D=-40 ℃, (c=0.08, water).Embodiment 253
Figure A9980761004032
(±)-(2R, 3S, 5R, 1, R, 2 ' S)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(MeOD-d 3)δ7.8(d，J＝9.3Hz，1H)，5.49-5.43(m，1H)，5.25(dd，J＝1.95，9.3Hz，1H)，4.38-4.31(m，2H)，3.57-3.50(m，1H)，3.46(dd，J＝4.9，10.3Hz，1H)，3.42(s，3H)，3.35-3.32(m，2H)，3.27(s，3H)，3.16-3.09(m，1H)，2.46-2.40(m，1H)，1.80(s，3H)，1.72-1.65(m，1H)，1.55(d，J＝6.8Hz，3H)。
MS：(M＋H) +＝315，(M＋Na) +＝337，(M－H) -＝313，(M＋Cl) -＝349，(2M－H) -＝627。
Embodiment 254
Figure A9980761004041
(±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(MeOD-d 3)δ8.04(d，J＝8.5Hz，1H)，5.52-5.48(m，1H)，5.27-5.22(m，1H)，4.32-4.25(m，2H)，3.74-3.71(m，1H)，3.53(dd，J＝2.4，10.1Hz，1H)，3.33-3.25(m，2H)，3.31(s，3H)，3.25(s，3H)，3.21-3.17(m，1H)，2.42-2.36(m，1H)，1.86(s，3H)，1.71-1.63(m，1H)，1.62(d，J＝7.3Hz，3H)。
MS：(M＋H) +＝315，(M＋Na) +＝337，(M－H) -＝313，(M＋Cl) -＝349，(2M－H) -＝627。
Embodiment 255 (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)δ7.60(m，1H)，5.46(m，1H)，5.30(m，1H)，4.54(m，1H)，4.35(m，1H)，4.03(m，1H)，3.96(m，1H)，3.69(m，1H)，3.15(m，1H)，2.40(m，1H)，1.98(m，2H)，1.80(s，3H)，1.70-1.50(m，5H)，1.38(m，3H)，0.83(m，3H)。
MS：(M＋H) +＝343，(M－H) -＝341
Embodiment 256 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-(3-pentyloxy)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(MeOD-d 3)δ5.69-5.59(m，1H)，5.33-5.25(m，1H)，4.39(m，1H)，4.34(dd，J＝7.8，10.2Hz，1H)，3.73(dd，J＝4.8，10.2Hz，1H)，3.58-3.47(m，2H)，3.38-3.24(m，1H)，3.27-3.20(m，1H)，2.61-2.52(m，1H)，2.02(s，3H)，1.90-1.78(m，1H)，1.70(dd，J＝1.7，6.8Hz，3H)，1.60-1.50(m，4H)，0.92(t，J＝7.5Hz，6H)
(M＋H) +＝327，(M＋Na) +＝349
Embodiment 257
Figure A9980761004061
(±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-(3-pentyloxy)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(MeOD-d 3)δ5.73-5.66(m，1H)，5.32-5.25(m，1H)，4.36(dd，J＝7.8，10.2Hz，1H)，4.09(m，1H)，3.68(dd，J＝6.1，10.2Hz，1H)，3.61(d，J＝4.4Hz，2H)，3.35-3.23(m，1H)，3.24-3.16(m，1H)，2.65-2.55(m，1H)，2.03(s，3H)，1.92-1.80(m，1H)，1.70(dd，J＝2.0，7.1Hz，3H)，1.59-1.47(m，4H)，0.94-0.88(m，6H)
(M＋H) +＝327，(M＋Na) +＝349
Embodiment 258 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)δ8.01(d，J＝8.6Hz，1H)，5.76(m，1H)，5.49(m，1H)，5.25(m，1H)，5.05(m，2H)，4.28(m，1H)，4.02(m，1H)，3.77(m，1H)，3.62(m，1H)，3.36(m，1H)，3.29(m，1H)，3.18(m，1H)，2.43(m，1H)，2.38(m，1H)，2.16(m，1H)，1.87(s，3H)，1.69(m，1H)，1.63(dd，J＝6.7，1.2Hz，3H)，1.12(t，J＝6.7Hz，3H)。
MS：(M＋H) +＝325，(M－H) -＝323。
Embodiment 259 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-allyloxy) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(DMSO-d 6)δ9.16(m，2H)，8.13(d，J＝7.5Hz，1H)，5.88(m，1H)，5.50(m，1H)，5.15-5.32(m，3H)，4.35(m，2H)，3.95(m，2H)，3.61(m，1H)，3.40(m，2H)，3.20(m，1H)，2.40(m，1H)，1.87(s，3H)，1.72(m，1H)，1.62(d，J＝6.2，3H)
MS：(M＋1)＝297，(M＋23)＝319，(2M＋23)＝615
Embodiment 260 (±)-(2R, 3S, 5R, 1 ' R, 2 ' RS)-2-(1-acetamido-2-hydroxyl-2-(2-ethoxy carbonyl)) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1HNMR(DMSO-d 6)δ7.57(d，J＝10Hz，1H)，5.45(m，1H)，5.29(m，1H)，4.35(m，1H)，4.09(m，1H，3.68(m，1H)，3.44(m，1H)，3.17(m，1H)，2.87(m，1H)，2.64(m，1H)，2.39(m，1H)，1.80(s，3H)，1.65-1.56(m，2H)，1.53(m，3H)，1.50-1.30(m，3H)，1.21(t，J＝7.5Hz，3H)，0.80(t，J＝7.5Hz，3H)。
MS：(M＋H) +＝385，(M－H) -＝383
Embodiment 261 (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-3,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(CD 3OD)δ5.58-5.70(m，1H)，5.24-5.38(m，1H)，4.34-4.50(m，2H)，3.58-3.72(m，2H)，3.42-3.48(d，2H)，2.50-2.63(m，1H)，2.04(s，3H)，1.77-1.95(m，1H)，1.65-1.76(m，4H)，1.50-1.63(m，1H)。
MS：(M＋H) +＝301
Embodiment 262 (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-3,4-dihydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
1H?NMR(CD 3OD)δ5.58-5.72(m，1H)，5.25-5.37(m，1H)，4.30-4.45(m，2H)，3.63-3.77(m，2H)，3.44-3.49(d，2H)，2.50-2.63(m，1H)，2.03(s，3H)，1.76-1.95(m，2H)，1.65-1.75(m，4H)。
MS：(M＋H) +＝301。
Embodiment 263 (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-methoxyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate 263A (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
According to method described in the embodiment 84A, with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 4.2mg, 20%).
MS：(M＋H) +＝427，(M＋Na) +＝449，(M－H) -＝425。
Figure A9980761004092
263B (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-methoxyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R)-1-tert-butoxycarbonyl-2-(1-acetamido-2-methoxyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 0.0031g, 100%).
1H?NMR(DMSO-d 6)δ8.12(d，J＝7.9Hz，1H)，5.50(m，1H)，5.23(m，1H)，4.33(m，1H)，3.56(dd，J＝9.7，8.0Hz，1H)，3.4-3.3(m，2H)，3.26(s，3H)，3.19(m，1H)，2.39(dt，J＝12.8，7.3Hz.1H)，1.86(s，3H)，1.71(m，1H)，1.61(dd，J＝6.7，1.8Hz，3H)。
MS：(M＋H) +＝271，(M＋Na) +＝293。
Embodiment 264 (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-dimethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate 264A (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-dimethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate
Prepare title compound according to method described in the embodiment 41B, but replace ethylmagnesium bromide with tert-butyl lithium, obtain (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-dimethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate (must measure: 2.5mg, 11%).
(±)-(2R，3S，5R，1’R，2’S)MS：(M＋H) +＝469，(M－H) -＝467。
Figure A9980761004102
264B (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate
According to method described in the embodiment 41C, but with (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl-3-dimethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate replacement (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-and 1-tert-butoxycarbonyl-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-t-butyl formate, preparation title compound (must measure: 2.3mg, 100%).
1H?NMR(D 2O)δ5.40(m，1H)，5.10(t，J＝5.5Hz，1H)，4.13(t，J＝9.2Hz，1H)，3.46(m，1H)，3.22(d，J＝7.3Hz，1H)，3.00(m，1H)，2.41(m，1H)，1.70(s，3H)，1.45(m，1H)，1.39(d，J＝4.9Hz，3H)，1.07(t，J＝5.5Hz，1H)，0.70(s，9H)
MS：(M＋H) +＝313。
Adopt aforesaid method and those skilled in the art's general knowledge; can prepare the The compounds of this invention (wherein Ac is an ethanoyl) of taking from parent nucleus of table 1 and representing; take from a Y substituting group of table 2, take from a R substituting group of table 3 and take from a R who shows 4a, 4b, 4c, 4d, 4e, 4f or 4g 3Substituting group.Table 1 Table 2
Figure A9980761004122
Figure A9980761004131
Figure A9980761004151
Table 3-H 1
Figure A9980761004182
Figure A9980761004183
Table 4a
Figure A9980761004191
Figure A9980761004201
Table 4b
Figure A9980761004251
Figure A9980761004261
Figure A9980761004281
Figure A9980761004301
Figure A9980761004331
Figure A9980761004341
Table 4d
Figure A9980761004351
Table 4e
Figure A9980761004371
Table 4f
Figure A9980761004391
Figure A9980761004411
Figure A9980761004421
Figure A9980761004431
Table 4g
Figure A9980761004451
Figure A9980761004461
Figure A9980761004471
Figure A9980761004481
Figure A9980761004491
Figure A9980761004501
Can determine the ability of The compounds of this invention according to following method at the vitro inhibition neuraminidase.
The neuraminic acid EIA:
Make influenza virus A/N1/PR/8/34 grow in the allantoic cavity of zygote and by sucrose density gradient centrifugation purifying (Laver, W.G. (1969) " Fundamental Techniques inVirology " (K.Habel and N.P.Salzman edit) 92-86 page or leaf, Academic Press, New York).From grow in mdck cell, obtain influenza virus A/N2/Tokyo/3/67 in the tissue culture supernatant liquor of virus.(Air, G.M., Laver as discussed previously, W.G., Luo, M., Stray, S.J., Legrone, G. and Webster, R.G. (1990) .Virology.177., 578-587), by with the described virus of TPCK-tryptic digestion, then centrifugal, also dialysing with sucrose density gradient centrifugation purifying nerve propylhomoserin enzyme catalysis fragment then prepares the neuraminidase of B/Memphis/3/89 virus.
The enzymic activity of the neuraminidase that the employing of neuraminic acid EIA and A/N1/PR/8/34 or A/N2/Tokyo/3/67 totivirus or a B/Memphis/3/89 catalysis fragment are relevant.Testing the same day, with suitable described totivirus of dilution of the damping fluid of 20mMN-ethyl morpholine, 10mM calcium chloride, pH7.5 or catalytic fragment.Neuraminidase suppresses to be determined at 20mMN-ethyl morpholine, 10mM calcium chloride, contain in the pH7.5 damping fluid of 5%DMSO and carry out.Reaction mixture comprises neuraminidase, inhibitor (testing compound) and 20-30 μ M4-methyl-umbelliferone base (unbelliferyl) sialic acid substrate (in cumulative volume 200 μ l), and makes it to place 96 holes white U-shape flat board.In general, use the inhibitor of 5-8 concentration for each Ki pH-value determination pH.Come initiation reaction by adding enzyme, and make and at room temperature carried out 30-60 minute.During reaction, by be equipped be respectively 355+/-35nm and 460+/-25nm excite dull and stereotyped readout meter (ICN Biomedical) with the Fluoroskan11 of emission filter, per minute measure once should each hole of flat board fluorescence.Described dull and stereotyped readout meter is subjected to the control of DeltaSoftII software (Biometallics) and macintosh computer.If this compound during reaction demonstrates linear response speed, the speed of reaction that then is used for dose-response research is suitable for using the equation 1 of non-linear regression (Kaleidagraph), to determine total Ki value (Segel, I.H. (1975) enzyme kinetics, the 105-106 page or leaf, Wiley-Interscience, New York).
(1-Vi/Vo)=[I]/[I]+Ki (1+[S]/Km) equation 1 in equation 1, speed of reaction that Vi and Vo represent respectively to suppress and that do not suppress, Km=16-40 μ M (bacterial strain that depends on neuraminidase to be measured).To demonstrating slowly-combination inhibition (Morrison, J.F. (1982) Trends Biochem.Sci.7, those compounds 102-105), with with test for the first time identical mode and carry out second time and test, but neuraminidase and inhibitor should and not have substrate in room temperature exists preincubation down 2 hours, causes this reaction with substrate then.The data analysis of gained linear velocity such as above-mentioned carrying out.
Equation 2 be used to measure inferior nmole scope the Ki value (Morrison, J.F and Stone, S.R. (1985) Comments Mol.Cell Biophys.2,347-368).
V=A{sqrt{ (Ki '+It-Et) A2+4Ki ' Et}-(Ki '+It-Et) equation 2 in equation 2, V=speed; A=α kcat[S]/2 (Km+[S]); α is for being converted to flat fluorescent the factor of volumetric molar concentration; Ki '=Ki (1+[S]/Km); It=inhibitor total concn, and the gross activity concentration of Et=neuraminidase.
The compounds of this invention suppresses to have A type neuraminidase influenza and the Type B neuraminidase influenza of Ki value between about 0.1 nmole and about 500 micromoles.Preferred compound of the present invention suppresses to have A type neuraminidase influenza and the Type B neuraminidase influenza of Ki value between about 0.1 nmole and about 3.5 micromoles.
The compounds of this invention suppresses the ability that plaque forms in the cell cultures and can determine by following method.
The cell cultures plaque forms inhibition test
Cell cultures: feasible mdck cell from American Type Culture Collection grows among high glucose (GibcoBRL) Dulbecco ' the sModified Eagle Medium (DMEM) that is supplemented with 10% foetal calf serum (JRH Biosciences), 40mM HEPES damping fluid (GibcoBRL) and microbiotic (GibcoBRL).Under 37 ℃ and 5% carbonic acid gas, make cell in flask or revolving bottle, carry out routine and cultivate.When merging, cell is reduced to the density of 500000 cell/ml, carries out the individual layer processing with trypsinase/EDTA (GibcoBRL), then carries out cell centrifugation, resuspending and dilutes in growth medium.With 1ml/1cm 2The volume of growth area is to the ratio inoculating cell of surface-area.
The plaque measurement scheme: remove the growth medium on the 6 hole flat boards after mdck cell converges, the mensuration substratum (having 1% foetal calf serum, 40mM HEPES damping fluid and antibiotic DMEM) that contains pre-mixing virus (influenza A/Tokyo/3/67[H2N2]) (40-100 plaque forming unit) and 2 * concentration testing compound with 1.5ml covers cell.Place vibrator (rocker) to go up and incubation 2 hours under room temperature this flat board.Between viral adsorption cycle, the substratum that preparation agar covers.In microwave oven, melt the 2 * agarose (agarose of final concentration 0.6%) that covers substratum (DMEM), place 48 ℃ of water-bath holding temperature balances then with 40mM HEPES damping fluid.After viral adsorption cycle, add substratum that 1.5ml agar covers and mix with substratum that 1.5ml in every hole contains virus and testing compound.
With culture in required time (being generally a couple of days) of 35 ℃ of incubations to produce plaque.With the formalin fixed plaque among 3.7% the PBS 20 minutes, then remove the agar coverture and with the violet staining in 0.1% the distilled water 15 minutes.The counting plaque is also determined EC50 concentration with regression analysis by the testing compound of a plurality of different concns.
Virus stock solution: converge in the rotation glass bottle at the MDCK that DMEM (being supplemented with 1%FCS, 40mM HEPES damping fluid and microbiotic) is housed and to prepare stock solution in 37 ℃ of incubations.About 0.1 plaque forming unit inoculation glass bottle with the multiple infection in every hole.After the cytopathic effect of observing virus is near completion, the results revolving bottle.From the supernatant liquor of the substratum that derives from low-speed centrifugal and cellular lysate, prepare stock solution.Titration stock solution and in-80 ℃ of storages.
The compounds of this invention provides plaque to form restraining effect to influenza virus A/N2/Tokyo in mdck cell, and its EC50 value is between about 100 micromoles and Yue 1 nmole.The preferred compound of the present invention provides plaque to form restraining effect with the EC50 value between its about 1 micromole and Yue 1 nmole to the influenza virus A/N2/Tokyo in the mdck cell.
Adopt following method can test The compounds of this invention antiviral activity in vivo.
Interior resisting virus effect measuring method
Anesthesia (Ultane) female BALB/c mouse is also used 10 of 0.1mlA type influenza VR-95 (PuertoRico PR8-34) -2Diluent (by freezing stock solution dilution) intranasal vaccination (IN).This virus concentration can be guaranteed to make mouse invasion in inoculating 5 days.Preceding 4 hours of infection and infect and handled mouse in back 4 hours, after this regularly handle with one of following therapy: nothing is treated; Testing compound (100,25,6.25,1.39mg/kg/ days BD, PO); Or solvent (sterilized water BD, PO).Inoculate one group of 10 animal (being appointed as contrast) with 0.9% salt solution.Determine the percentage survival rate.Collected lung at the 5th day, weigh and according to consolidation (consolidatio) per-cent (0,10-20,25-50,50-75,75-100%) respectively scoring be 0,1,2,3 or 4.In addition, to every pair of lung imaging analysis, to determine the actual consolidation per-cent of lung.
The compounds of this invention can be to use derived from mineral acid or organic acid salt form.These salt include, but is not limited to following salt: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, bisul-phate, butyrates, camphorate, camsilate, two sugar limes, cyclopentane propionate, dodecyl sulfate, esilate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-hydroxyl-esilate (isethionate), lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, right-tosylate and undecane hydrochlorate.Can make also with such reagent such as low alkyl group halogen (as muriate, bromide and the iodide of methyl, ethyl, propyl group and butyl), sulfuric acid dialkyl (as dimethyl, diethyl, dibutyl and diamyl sulfuric ester), long-chain halogenide (as muriate, bromide and the iodide of decyl, dodecyl, tetradecyl and octadecyl), aralkyl halogen (as benzyl and phenethyl bromide) etc. that to contain the basic nitrogen group quaternized.Can obtain water-soluble or oil soluble or dispersible products thus.
The example that can be used to form the acid of pharmaceutically-acceptable acid addition comprises such mineral acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid and such organic acid, for example oxalic acid, toxilic acid, succsinic acid and citric acid.Other salt comprises the salt that become with basic metal or alkaline-earth metal such as sodium, potassium, lithium, calcium or magnesium or salt that is become with ammonium or N (R *) 4 +Salt (R wherein *Be low alkyl group).
In addition, also plan comprises the salt that The compounds of this invention is become with one of naturally occurring amino acid.
The preferred salt of The compounds of this invention comprises hydrochloride, mesylate, sulfonate, phosphoric acid salt and isethionate.
Formula I of the present invention, II and III compound can have for acidic-group (for example ,-CO 2H ,-SO 3H ,-SO 2H ,-PO 3H 2,-PO 2H) substituting group.Formula I substituent of the present invention, the II and the III compound that have for the ester of this type of acidic-group are also included among the present invention.Such ester can be used as prodrug.Prodrug of the present invention can provide the acid substituting group of above-mentioned formula I, II or III parent compound in vivo through metabolism.Prodrug also can be used to increase these solubility of substances and/or GI absorption.These prodrugs also can be used for increasing solubleness so that intravenously gives described compound.Prodrug also can be used to increase the hydrophobicity of described compound.Prodrug also can be by increasing absorption and/or weakening the first oral administration biaavailability that (first-pass) mechanism improves described compound of crossing.Prodrug also can work aspect the tissue permeability that increase compound, causes improving in infected tissue active and/or reduction clearance rate therefrom.
This type of ester of the present invention's design comprises:
Alkyl ester, especially lower alkyl esters include, but is not limited to ethyl ester, n-propyl, isopropyl ester, positive butyl ester, secondary butyl ester, isobutyl ester, the tert-butyl ester, n-pentyl ester etc.;
Alkoxy alkyl, especially lower alkoxy lower alkyl esters include, but is not limited to methoxyl group methyl esters, 1-ethoxy ethyl ester, 2-methoxyl group ethyl ester, isopropoxy methyl esters, tert.-butoxy methyl esters etc.;
Alkoxy alkoxy alkyl ester, the especially lower alkyl esters of alkoxyl group alkoxyl group-replacement include, but is not limited to 2-methoxy ethoxy methyl esters etc.;
Aryloxy alkyl ester, the especially lower alkyl esters of aryloxy-replacement include, but is not limited to phenoxy group methyl esters etc., and wherein said aryl is unsubstituted or is substituted as this paper is previously defined;
Halogenated alkoxy alkyl ester, the especially lower alkyl esters of halogenated alkoxy-replacement include, but is not limited to 2,2,2-trichlorine oxyethyl group methyl esters etc.;
Alkoxy carbonyl alkyl ester, the especially lower alkyl esters of elementary alkoxy carbonyl-replacement include, but is not limited to methoxycarbonyl methyl esters etc.;
Cyano group alkyl ester, the especially lower alkyl esters of cyano group-replacement include, but is not limited to cyano group methyl esters, 2-cyano group ethyl ester etc.;
The thio alkoxy methyl esters, the methyl esters of especially rudimentary thio alkoxy-replacement includes, but is not limited to methylthio group methyl esters, ethylmercapto group methyl esters etc.;
Alkyl sulphonyl alkyl ester, the especially lower alkyl esters of low alkyl group alkylsulfonyl-replacement include, but is not limited to 2-methylsulfonyl ethyl ester etc.;
Aryl sulfonyl alkyl ester, the especially lower alkyl esters of aryl sulfonyl-replacement include, but is not limited to 2-benzenesulfonyl ethyl ester and 2-tosyl group ethyl ester etc.;
Acyloxy alkyl ester, the especially lower alkyl esters of low alkyl group acyloxy-replacement include, but is not limited to methanoyl methyl esters, acetoxyl group methyl esters, new pentane acyloxy methyl esters, acetoxyl group ethyl ester, new pentane acyloxy ethyl ester etc.;
Naphthene base carbonyl oxygen base alkyl ester includes, but is not limited to cyclopentylcarbonyl oxygen base methyl esters, cyclohexyl-carbonyl oxygen base methyl esters, cyclopentylcarbonyl oxygen base ethyl ester, cyclohexyl-carbonyl oxygen base ethyl ester etc.;
Aryl carbonyl oxygen base alkyl ester includes, but is not limited to benzoyloxy methyl esters etc.;
(alkoxy-carbonyl oxy) alkyl ester, the lower alkyl esters of especially (elementary alkoxy carbonyl oxygen base)-replacement includes, but is not limited to methoxycarbonyl oxygen base methyl esters, ethoxy carbonyl oxygen base methyl esters, 1-(methoxycarbonyl oxygen base) ethyl ester, 2-(ethoxy carbonyl oxygen base) ethyl ester etc.;
The lower alkyl esters of (cyclo alkoxy carbonyl oxygen base) alkyl ester, especially (cyclo alkoxy carbonyl oxygen base)-replacement includes, but is not limited to cyclohexyloxy carbonyl oxygen base methyl esters, cyclopentyloxy ketonic oxygen base ethyl ester, cyclohexyloxy carbonyl oxygen base propyl ester etc.;
Oxo dioxolyl methyl esters includes, but is not limited to (5-phenyl-2-oxo-1,3-dioxole-4-yl) methyl esters, [5-(4-aminomethyl phenyl)-2-oxo-1,3-dioxole-4-yl] methyl esters, [5-(4-p-methoxy-phenyl)-2-oxo-1,3-dioxole-4-yl] methyl esters, [5-(4-fluoro phenyl)-2-oxo-1,3-dioxole-4-yl] methyl esters, [5-(4-chlorophenyl)-2-oxo-l, 3-dioxole-4-yl] methyl esters, (2-oxo-1,3-dioxole-4-yl] methyl esters, (5-methyl-2-oxo-l, 3-dioxole-4-yl] methyl esters, (5-ethyl-2-oxo-1,3-dioxole-4-yl] methyl esters, (5-propyl group-2-oxo-1,3-dioxole-4-yl] methyl esters, (5-sec.-propyl-2-oxo 1,3-dioxole-4-yl] methyl esters, (5-butyl-2-oxo-1,3-dioxole-4-yl] methyl esters etc.;
The phthalidyl ester, wherein the phenyl ring of phthalidyl is unsubstituted or is substituted as this paper is previously defined, includes, but is not limited to phthalidyl ester, dimethyl phthalidyl ester, dimethoxy phthalidyl ester etc.;
Aryl ester includes, but is not limited to phenyl ester, naphthalene ester, 2,3-indanyl ester etc.;
Aralkyl ester, the especially lower alkyl esters of aryl-replacement include, but is not limited to benzyl ester, styroyl ester, 3-phenyl propyl ester, naphthalene methyl esters etc., and wherein the aryl moiety of aralkyl is unsubstituted or is substituted as this paper is previously defined;
Dialkyl aminoalkyl ester, the especially lower alkyl esters of dialkyl amido-replacement include, but is not limited to 2-(N, N-dimethylamino) ethyl ester, 2-(N, N-diethylamino) ethyl ester etc.;
(heterocycle) alkyl ester, the especially lower alkyl esters of heterocycle-replacement, wherein heterocycle is a nitrogen heterocyclic ring, includes, but are not limited to (heterocycle) methyl esters etc., wherein the heterocyclic moiety of (heterocycle) alkyl is unsubstituted or is substituted as this paper is previously defined; With
The carboxyalkyl ester, especially the lower alkyl esters of carboxyl-replacement includes, but is not limited to carboxyl ester etc.;
And other or the like.
The prodrug ester that contains acid compound of preferred formula I, II or III is a lower alkyl esters, include, but is not limited to ethyl ester, n-propyl, isopropyl ester, positive butyl ester, secondary butyl ester, isobutyl ester, the tert-butyl ester, n-pentyl ester and benzyl ester, wherein phenyl ring is unsubstituted or is substituted as this paper is previously defined.
The method of the prodrug ester of preparation formula I, II or III compound is well known in the art, comprising:
Make described acid reaction in inert solvent (for example, DMF, acetonitrile, N-Methyl pyrrolidone etc.) with corresponding halogenide (for example, muriate or acyl chlorides) and alkali (for example, triethylamine, DBU, N, N-dimethyl aminopyridine etc.);
Make the activated derivatives (for example, acyl chlorides, SULPHURYL CHLORIDE, a clodronic acid ester etc.) and reactions such as corresponding alcohol or alkoxide of described acid.
Other example of prodrug of the present invention comprises formula I, II that hydroxyl replaces or the ester of III compound, and it can be by the following groups acidylate: amino-acid residue sealing or untight, phosphate functional group, hemisuccinic acid ester residue, formula R 100C (O)-or R 100C (S)-acyl residue (R wherein 100Be hydrogen, low alkyl group, haloalkyl, alkoxyl group, thio alkoxy, alkoxyalkyl, thio alkoxy alkyl or halogenated alkoxy) or formula R a-C (R b) (R d)-C (O)-or R a-C (R b) (R d)-C (S)-acyl residue (R wherein bAnd R dIndependently be selected from hydrogen or low alkyl group, and R aFor-N (R e) (R f) ,-OR eOr-SR e(R wherein eAnd R fIndependently be selected from hydrogen, low alkyl group and haloalkyl), or have formula R 101NH (CH 2) 2NHCH 2C (O)-or R 101NH (CH 2) 2OCH 2C (O)-amino-acyl residue (R wherein 101Be hydrogen, low alkyl group, (aryl) alkyl, (cycloalkyl) alkyl, acyl group, benzoyl or alpha-amino group acyl group).The amino acid ester of particularly important is glycinate and Methionin ester; Yet, also can use other amino-acid residue, comprise any naturally occurring amino acid, comprise also that wherein aminoacyl is-C (O) CH 2NR 102R 103(R wherein 102And R 103Independently be selected from hydrogen and low alkyl group) or group-NR 102R 103(R wherein 102And R 103Form nitrogen heterocyclic ring together) amino acid.
Other prodrug comprises formula I, II or the III compound that hydroxyl replaces, and wherein hydroxyl is by formula-CH (R 104) OC (O) R 105Or-CH (R 104) OC (S) R 105Functionalized (the R wherein of substituting group 105Be low alkyl group, haloalkyl, alkoxyl group, thio alkoxy or halogenated alkoxy and R 104Be hydrogen, low alkyl group, haloalkyl, alkoxy carbonyl, aminocarboxyl, alkyl amino-carbonyl or dialkyl amino carbonyl).This type of prodrug can be according to the method for Schreiber (Tetrahedron Lett.1983,24,2363), by the ozonolysis of corresponding methallyl ethers in methyl alcohol, then handles with diacetyl oxide and prepares.
The preparation of the ester by the formula I, the II that formula I, II that hydroxyl replaces or III compound and activatory aminoacyl, phosphoryl, half succinyl or acyl derivative are reacted carry out the hydroxyl replacement or III compound.
The prodrug of the compound that hydroxyl of the present invention replaces also can be by formula I, II or the III alkylation that hydroxyl is replaced with (halo) alkyl ester; with two-(alkanoyl) or make formula I, the II that hydroxyl replaces or the III compound produces the ethanoyl transferance or with activatory aldehyde and hydroxyl condensation, intermediate hemiacetal acylations is prepared.
In preparation during prodrug, for avoiding unwanted side reaction, other the functional group of reaction often needs protection.After the group of reaction is protected, can make required group functionalization.Make the functionalized products that obtains go protection then, to remove adding to stop the blocking group of unwanted side reaction.So just obtain required prodrug.The reaction conditions that is fit to of preparation blocking group is well known in the art.A source of reaction conditions can be at T.H.Greene and P.G.M.Wuts, the blocking group of organic synthesis, the 2nd edition, John Wiley ﹠amp; Find among the Sons, New York (1991).
The present invention also is included as ester or prodrug and is the formula I of salt, II or III compound.For example, The compounds of this invention can be a carboxylicesters, also can be amine or nitrogenous substituent acid salt on the same compound.
The compounds of this invention is used to suppress the neuraminidase from the pathogenic microorganism that contains neuraminidase.The disease that The compounds of this invention is used for (at human body, in other animal and the poultry) treatment or prevents to be caused by the microorganism that contains neuraminidase.
The compounds of this invention is used for neuraminidase of (particularly Mammals, especially in the people) inhibition A type influenza virus in external or body and the neuraminidase of Type B influenza virus.The compounds of this invention also is used for suppressing in vivo influenza virus, orthomyxovirus and paramyxovirus, particularly suppresses A type influenza virus and Type B influenza virus in people and other Mammals.The compounds of this invention also is used for treating in vivo the infection that is caused by influenza virus, orthomyxovirus and paramyxovirus, particularly the human body diseases that is caused by A type influenza virus and Type B influenza virus.The compounds of this invention also is used for the infection that prevention is caused by influenza virus, orthomyxovirus and paramyxovirus in people and other mammalian body, particularly prevent A type influenza and Type B influenza virus sexuality to dye, especially prevention be in take place with influenza infection concurrent or dye as other respiratory tract disease high risk population of influenza infection sequela or A type influenza virus and the Type B influenza virus sexuality of suffering among chronic respiratory tract disease (as asthma, pulmonary emphysema or the Cysticfibrosis) crowd.
Total per daily dose with single dose or divided dose administration of human or other mammalian hosts can be, for example, the 0.001-300mg/kg body weight/day, more common is the amount of 0.1-10mg/kg body weight/day.Dosage unit compositions can contain the sub-doses of this tittle, to constitute per daily dose.
The amount that can mix the active ingredient that produces unit dosage with carrier substance will change according to host to be treated and concrete route of administration.
But, should be appreciated that, for any concrete patient, specific dosage level will depend on multiple factor, comprise the severity of disease specific of activity, age, body weight, physical integrity, sex, diet, administration number of times, route of administration, discharge rate, drug combination situation and the treatment of the particular compound of use.
Before infection or after the symptom of determining occurs and/or make a definite diagnosis infection, begin to give The compounds of this invention.
The compounds of this invention can be to give in the dosage unit preparations per os that contains conventional nontoxic pharmaceutically acceptable carrier, auxiliary and solvent (if desired), parenteral, hypogloeeis, the nose, in lung, give, as solution, suspension or dry powder (for example, mode with spraying) suck or be blown into, or per rectum gives.Comprise subcutaneous injection, intravenously, intramuscular, breastbone inner injection or infusion techniques at this used term parenteral.
Injection, for example aseptic injection water-based or oily suspensions can use the preparation of suitable dispersion agent or wetting agent and suspension agent according to known technology.Aseptic injection also can be at aseptic injectable solution or the suspension in nontoxic, parenteral acceptable diluent or the solvent, for example, for 1, the solution in the ammediol.Operable acceptable solvent and solvent have water, Ringer ' s solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil is usually as solvent or suspension medium.For this purpose, can use the fixed oil of any gentleness, comprise synthetic one-or two glyceryl ester.In addition, find that lipid acid such as oleic acid can be used for the preparation of injection.
The suppository of rectal administration can prepare by described medicine and suitable non-irritating excipient such as theobroma oil and polyoxyethylene glycol are mixed, and these materials are liquid under rectal temperature for solid at normal temperatures, thereby can melt in rectum and discharge medicine.
The solid dosage of oral administration can comprise capsule, tablet, pill, powder and granule.In these solid dosages, active compound can mix with at least a inert diluent such as sucrose, lactose or starch.These formulations also can comprise the material such as the lubricant (as Magnesium Stearate) of other non-inert diluent, and this is common convention.Under the situation of capsule, tablet and pill, these formulations also can comprise buffer reagent.Tablet and pill can also be used the enteric coating dressing in addition.
That the liquid dosage form of oral administration can comprise is pharmaceutically acceptable, contain this area inert diluent commonly used such as emulsion, solution, suspension, syrup and the elixir of water.This based composition also can comprise auxiliary, for example wetting agent, emulsifying agent, suspension agent, sweeting agent, seasonings and perfume compound.
The compounds of this invention also can liposome form give.As known in the art, liposome is usually derived from phosphatide or other lipid material.Liposome can form by being scattered in the single or multiple lift hydration liquid crystal in the water-bearing media.Can use acceptable and metabolizable fat on any nontoxic, the physiology that can form liposome.Except The compounds of this invention, the composition of liposome form of the present invention also can contain stablizer, sanitas, vehicle etc.Preferred lipid is phosphatide and phosphatidylcholine (Yelkin TTS), comprises natural and synthetic.
The method that forms liposome is known in the art.Referring to, for example, Prescott edits, the method for cytobiology, XIV volume, Academic Press, New York, N.Y. (1976), 33 pages etc.
The compounds of this invention can be used as independent active medicine and gives, but they also can be used for the treatment of other medication combined use acute or chronic respiratory tract disease with one or more anti-infection agents and/or other.Comprise with the other medicines of The compounds of this invention Combined Preparation: influenza vaccines; Other influenza inhibitor such as amantadine, Rimantadine, ribavirin etc.; Another kind of neuraminidase influenza inhibitor such as zanamivir or GS4104 etc.; Be used for the treatment of respiratory tract bacterial infection and bronchitic medicine, as erythromycin, clarithromycin, Azythromycin etc.; Be used for the treatment of steroid of the medicine of asthma such as zileuton, salbutamol, Salmeterol, formoterol, ipratropium bromide, suction etc., or be used for the treatment of the antiphlogiston of asthma such as beclometasone, beclomethasone dipropionate, FLUTICASONE PROPIONATE, budesonide, Triamcinolone Acetonide, flunisolide, Cromoglycic Acid, zafirlukast, montelukast.
When drug combination, therapeutical agent can be formulated as the composition that separates that gives in identical time or different time, or therapeutical agent is given as single composition.
Above-mentioned only is to be explanation the present invention, and does not mean that the present invention is limited to disclosed compound.Apparent for a person skilled in the art, in the essential scope of the present invention that various variations and change all should be considered as defining in appended claims.

Claims (56)

1. the compound of following formula: Or its pharmacy acceptable salt, ester or prodrug, wherein R 1Be selected from:
(a)-CO 2H，(b)-CH 2CO 2H，(c)-SO 3H，(d)-CH 2SO 3H，(e)-SO 2H，
(f)-CH 2SO 2H，(g)-PO 3H 2，(h)-CH 2PO 3H 2，(i)-PO 2H，(j)-CH 2PO 2H，
(k) tetrazyl, (l)-CH 2-tetrazyl, (m)-C (=O)-NH-S (O) 2-R 11,
(n)-CH 2C (=O)-NH-S (O) 2-R 11, (o)-SO 2N (T-R 11) R 12With
(p)-CH 2SO 2N(T-R 11)R 12，
Wherein T is selected from:
(i) key, (ii)-C (=O)-, (iii)-C (=O) O-, (iv)-C (=O) S-,
(v)-C (=O) NR 36-, (vi)-C (=S) O-, (vii)-C (=S) S-and
(viii)-C(＝S)NR 36，
R 11Be selected from:
(i) C 1-C 12Alkyl, (ii) C 2-C 12Alkenyl, (iii) cycloalkyl,
(iv) (cycloalkyl) alkyl,
(v) (cycloalkyl) alkenyl, (vi) cycloalkenyl group, (vii) (cycloalkenyl group) alkyl,
(viii) (cycloalkenyl group) alkenyl, (ix) aryl, (x) (aryl) alkyl, (xi)
(aryl) alkenyl,
(xii) heterocyclic radical, (xii) (heterocyclic radical) alkyl and
(xiv) (heterocyclic radical) alkenyl; And
R 12And R 36Independently be selected from:
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) C 2-C 12Alkenyl, (iv) cycloalkyl,
(v) (cycloalkyl) alkyl, (vi) (cycloalkyl) alkenyl, (vii) cycloalkenyl group,
(viii) (cycloalkenyl group) alkyl, (ix) (cycloalkenyl group) alkenyl, (x) aryl,
(xi) (aryl) alkyl, (xii) (aryl) alkenyl, (xii) heterocyclic radical,
(xiv) (heterocyclic radical) alkyl and (xv) (heterocyclic radical) alkenyl; X is selected from: (a)-C (=O)-N (R *)-, (b)-N (R *)-C (=O)-, (c)-C (=S)-N (R *)-, (d)-N (R *)-C (=S)-, (e)-N (R *)-SO 2-and (f)-SO 2-N (R *)-, be R wherein *Be hydrogen, C 1-C 3Low alkyl group or cyclopropyl; R 2Be selected from: (a) hydrogen, (b) C 1-C 6Alkyl, (c) C 2-C 6Alkenyl, (d) C 3-C 6Cycloalkyl, (e) C 5-C 6Cycloalkenyl group, (f) halo C 1-C 6Alkyl and (g) halo C 2-C 6Alkenyl; Or R 2-X-is
Figure A9980761000031
Y wherein 1For-CH 2-,-O-,-S-or-NH-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, amino methyl, 1-amino-ethyl, 2-amino-ethyl, sulphomethyl, 1-thio-ethyl, 2-thio-ethyl, methoxymethyl, N-methylamino methyl and methylthiomethyl; R 3And R 4Independently be selected from (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl group, (d) heterocyclic radical, (e) aryl and (f)-Z-R 14Wherein Z is
(i)-C(R 37a)(R 37b)-，(ii)-C(R 47)＝C(R 48)-，(iii)-C≡C-、(iv)-C(＝O)-，
(v)-C(＝S)-，(vi)-C(＝NR 15)-，(vii)-C(R 37a)(OR 37c)-，(viii)
-C(R 37a)(SR 37c)-，
(ix)-C(R 37a)(N(R 37b)(R 37c))-，(x)-C(R 37a)(R 37b)-O-，
(xi)-C(R 37a)(R 37b)-N(R 37c)-，(xii)-C(R 37a)(R 37b)-N(O)(R 37c)-，
(xiii)-C(R 37a)(R 37b)-N(OH)-，(xiv)-C(R 37a)(R 37b)-S-，
(xv)-C(R 37a)(R 37b)-S(O)-，(xvi)-C(R 37a)(R 37b)-S(O) 2-，
(xvii)-C(R 37a)(R 37b)-C(＝O)-，(xviii)-C(R 37a)(R 37b)-C(＝S)-，
(xix)-C(R 37a)(R 37b)-C(＝NR 15)-，(xx)-C(R 37a)(OR 37c)-C(＝O)-，
(xxi)-C(R 37a)(SR 37c)-C(＝O)-，(xxii)-C(R 37a)(OR 37c)-C(＝S)-，
(xxiii)-C(R 37a)(SR 37c)-C(＝S)-，(xxiv)-C(＝O)-C(R 37a)(OR 37C)-，
(xxv)-C(＝O)-C(R 37a)(SR 37C)-，(xxvi)-C(＝S)-C(R 37a)(OR 37C)-，
(xxvii)-C(＝S)-C(R 37a)(SR 37C)-，(xxviii)-C(R 37a)(OR 37C)-C(R 37a)(OR 37C)-
(xxix)-C(R 37a)(SR 37C)-C(R 37a)(OR 37C)-，
(xxx)-C(R 37a)(OR 37C)-C(R 37a)(SR 37C)-，
(xxxi)-C(R 37a)(SR 37C)-C(R 37a)(sR 37C)-，(xxxii)-C(＝O)-C(＝O)-，
(xxxiii)-C(＝S)-C(＝S)-，(xxxiv)-C(＝O)-O-，(xxxv)-C(＝O)-S-，
(xxxvi)-C(＝S)-O-，(xxxvii)-C(＝S)-S-，(xxxviii)-C(＝O)-N(R 37a)-，
(xxxix)-C(＝S)-N(R 37a)-，(xl)-C(R 37a)(R 37b)-C(＝O)-N(R 37a)-，
(xli)-C(R 37a)(R 37b)-C(＝S)-N(R 37a)-，(xlii)-C(R 37a)(R 37b)-C(＝O)-O-，
(xliii)-C(R 37a)(R 37b)-C(＝O)-S-，(xliv)-C(R 37a)(R 37b)-C(＝S)-O-，
(xlv)-C(R 37a)(R 37b)-C(＝S)-S-，(xlvi)-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-，
(xlvii)-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-，(xlviii)-C(R 37a)(R 37b)-O-C(＝O)-
，(xlix)-C(R 37a)(R 37b)-S-C(＝O)-，
(l)-C(R 37a)(R 37b)-O-C(＝S)-，(li)-C(R 37a)(R 37b)-S-C(＝S)-，
(lii)-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-N(R 37a)-，
(liii)-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-N(R 37a)-，
(liv)-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-O-，
(lv)-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-S-，
(lvi)-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-O-，
(lvii)-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-S-，
(lviii)-C(R 37a)(R 37b)-O-C(＝O)-N(R 37a)-，
(lix)-C(R 37a)(R 37b)-S-C(＝O)-N(R 37a)-，
(lx)-C(R 37a)(R 37b)-O-C(＝S)-N(R 37a)-，
(lxi)-C(R 37a)(R 37b)-S-C(＝S)-N(R 37a)-，
(lxii)-C(R 37a)(R 37b)-O-C(＝O)-O-，
(lxiii)-C(R 37a)(R 37b)-S-C(＝O)-O-，(lxiv)-C(R 37a)(R 37b)-O-C(＝O)-S-，
(lxv)-C(R 37a)(R 37b)-S-C(＝O)-S-，(lxvi)-C(R 37a)(R 37b)-O-C(＝S)-O-，
(lxvii)-C(R 37a)(R 37b)-S-C(＝S)-O-，(lxviii)-C(R 37a)(R 37b)-O-C(＝S)-S-，
(lxix)-C (R 37a) (R 37b)-S-C (=S)-S-or (lxx)-C (R 37a) (R 37b)-C (R 37a) (OR 37c)-; R 14For
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(the v) alkyl that replaces of thiol, (vi) R 37cThe alkyl that O-replaces,
(vii) R 37cThe alkyl that S-replaces, (viii) aminoalkyl group,
(ix) (R 37c) alkyl that replaces of NH-, (x) (R 37a) (R 37c) alkyl that replaces of N-,
(xi) R 37aThe alkyl that O-(O=) C-replaces, (xii) R 37aS-(O=) C-replaces
Alkyl, (xiii) R 37aThe alkyl that O-(S=) C-replaces,
(xiv) R 37aThe alkyl that S-(S=) C-replaces,
(xv) (R 37aO) 2-P (=O)-and the alkyl that replaces, (xvi) cyano group alkyl,
(xvii) C 2-C 12Alkenyl, (xviii) halogenated alkenyl, (xix) C 2-C 12Alkynyl group,
(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl, (xxii) (cycloalkyl) alkenyl,
(xxiii) (cycloalkyl) alkynyl group, (xxiv) cycloalkenyl group,
(xxv) (cycloalkenyl group) alkyl,
(xxvi) (cycloalkenyl group) alkenyl, (xxvii) (cycloalkenyl group) alkynyl group, (xxviii) aryl,
(xxix) (aryl) alkyl, (xxx) (aryl) alkenyl, (xxxi) (aryl) alkynyl group,
(xxxii) heterocyclic radical, (xxxiii) (heterocycle) alkyl,
(xxxiv) (heterocycle) alkenyl or (xxxv) (heterocycle) alkynyl group,
Prerequisite is, when Z is
-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-O-，-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-O-，
-C(R 37a)(R 37b)-N(R 37b)-C(＝O)-S-，-C(R 37a)(R 37b)-N(R 37b)-C(＝S)-S-，
-C(R 37a)(R 37b)-O-C(＝O)-O-，-C(R 37a)(R 37b)-O-C(＝S)-O-，
-C(R 37a)(R 37b)-S-C(＝O)-O-，-C(R 37a)(R 37b)-S-C(＝S)-O-，
-C(R 37a)(R 37b)-O-C(＝O)-S-，-C(R 37a)(R 37b)-O-C(＝S)-S-，
-C (R 37a) (R 37b)-S-C (=O)-S-or-C (R 37a) (R 37b)-S-C (=S)-during S-,
R then 14Not hydrogen;
R 37a, R 37b, R 47And R 48In each case, independently be selected from:
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(v) alkoxyalkyl, (vi) C 2-C 12Alkenyl, (vii) halogenated alkenyl,
(vii) C 2-C 2-C 12Alkynyl group, (ix) cycloalkyl,
(x) (cycloalkyl) alkyl, (xi) (cycloalkyl) alkenyl, (xii) (cycloalkyl) alkynyl group,
(xiii) cycloalkenyl group, (xiv) (cycloalkenyl group) alkyl, (xv) (cycloalkenyl group) alkenyl,
(xvi) (cycloalkenyl group) alkynyl group, (xvii) aryl, (xviii) (aryl) alkyl,
(xix) (aryl) alkenyl, (xx) (aryl) alkynyl group, (xxi) heterocyclic radical,
(xxii) (heterocycle) alkyl, (xxiii) (heterocycle) alkenyl and
(xxiv) (heterocycle) alkynyl group;
R 37cIn each case, independently be selected from:
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) haloalkyl, (i) C 2-C 12Alkenyl,
(v) halogenated alkenyl, (vi) C 2-C 12Alkynyl group (vii) cycloalkyl,
(viii) (cycloalkyl) alkyl, (ix) (cycloalkyl) alkenyl, (x) (cycloalkyl) alkynyl group,
(xi) cycloalkenyl group, (xii) (cycloalkenyl group) alkyl, (xiii) (cycloalkenyl group) alkenyl,
(xiv) (cycloalkenyl group) alkynyl group, (xv) aryl, (xvi) (aryl) alkyl,
(xvii) (aryl) alkenyl, (xviii) (aryl) alkynyl group, (xix) heterocyclic radical,
(xx) (heterocycle) alkyl, (xxi) (heterocycle) alkenyl,
(xxii) (heterocycle) alkynyl group, (xxiii)-C (=O)-R 14, (xxiv)-C (=S)-R 14,
(xxv)-S (O) 2-R 14(xxvi) hydroxyalkyl;
Or as Z be-C (R 37a) (R 37b)-N (R 37c)-time, N (R then 37c) and R 14It in the time of together azido-;
Perhaps working as Z is-C (R 37a) (R 37b)-N (O) (R 37c)-time, N (O) (R then 37c) and R 14It in the time of together the 3-7 unit heterocycle of N-oxidation with theheterocyclic nitrogen atom of at least one N-oxidation;
Perhaps working as Z is-C (R 37a) (OR 37c)-,-C (R 37a) (SR 37c)-or-C (R 37a) (N (R 37b) (R 37c))-time, R then 37a, R 14The carbon atom that is connected with them (when together) forms cyclopentyl, cyclopentenyl, cyclohexyl or tetrahydrobenzene basic ring;
R 15Be selected from:
(i) hydrogen, (ii) hydroxyl is (iii) amino, (iv) C 1-C 12Alkyl, (v) haloalkyl,
(vi) C 2-C 12Alkenyl, (vii) halogenated alkenyl, (viii) cycloalkyl,
(ix) (cycloalkyl) alkyl, (x) (cycloalkyl) alkenyl,
(xi) cycloalkenyl group, (xii) (cycloalkenyl group) alkyl, (xiii) (cycloalkenyl group) alkenyl,
(xiv) aryl, (xv) (aryl) alkyl, (xvi) (aryl) alkenyl, (xvii) heterocyclic radical,
(xviii) (heterocycle) alkyl and (xix) (heterocycle) alkenyl;
Perhaps R 3And R 4Common carbocyclic ring or the heterocycle that form of the atom that is connected with them with 3-8 annular atoms;
R 5Be selected from:
(a) hydrogen, (b)-CH (R 38) 2, (c)-O-R 40, (d) C 2-C 4Alkynyl group, (e) cyclopropyl,
(f) cyclobutyl, (g)-C (=Q 1)-R 17, and (h)-N (R 19) 2
Q wherein 1Be O, S or N (R 18);
R 17And R 18In each case, independently be selected from hydrogen, methyl and ethyl;
R 19, R 38And R 40In each case, independently be selected from:
(i) hydrogen, (ii) C 1-C 12Alkyl, (iii) haloalkyl, (iv) C 2-C 12Alkenyl,
(v) halogenated alkenyl, (xi) cycloalkyl, (vii) (cycloalkyl) alkyl,
(viii) (cycloalkyl) alkenyl, (ix) cycloalkenyl group, (x) (cycloalkenyl group) alkyl,
(xi) (cycloalkenyl group) alkenyl, (xii) aryl, (xiii) (aryl) alkyl,
(xiv) (aryl) alkenyl, (xv) heterocyclic radical, (xvi) (heterocycle) alkyl and
(xvii) (heterocycle) alkenyl;
Y is selected from:
(a) hydrogen, (b) C 1-C 5Alkyl, (c) C 1-C 5Haloalkyl, (d) C 2-C 5Alkenyl,
(e) C 2-C 5Halogenated alkenyl, (f) C 2-C 5Alkynyl group, (g) C 3-C 5Cycloalkyl,
(h) C 3-C 5Cycloalkyl-C 1-C 3Alkyl, (i) C 5Cycloalkenyl group, (j) C 5Cycloalkenyl group-C 1-
C 3Alkyl, (k) C 5Cycloalkenyl group-C 2-C 3Alkenyl, (l)-(CHR 39) nOR 20,
(m)-CH (OR 20)-CH 2(OR 20), (n)-(CHR 39) nSR 21, (o)-(CHR 39) nCN, (p)-(CHR 39) nN 3, (q) phenyl, (r) phenyl of halogen replacement, (s)-(CHR 39) nC (=Q 2) R 22, (t)-(CHR 39) nN (=Q 3), (u)-N (O)=CHCH 3, (v)-(CHR 39) nNR 23R 24, (w) halo and the heterocycle that (x) has 3-6 annular atoms; Wherein n is 0,1 or 2; Q 2Be O, S, NR 25Or CHR 26And Q 3Be NR 41Or CHR 42R 20Independently be in each case: (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) sec.-propyl, (vi) C 1-C 3Haloalkyl, (vii) vinyl, (viii) propenyl, (ix) pseudoallyl, (x) allyl group, (xi) C 2-C 3Halogenated alkenyl, (xii) amino, (xiii)-NHCH 3, (xiv)-N (CH 3) 2, (xv)-NHCH 2CH 3, (xvi)-N (CH 3) (CH 2CH 3), (xvii)-N (CH 2CH 3) 2Or (xviii)-N (=CH 2); R 21Be (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) sec.-propyl, (vi) C 1-C 3Haloalkyl, (vii) vinyl, (viii) propenyl, (ix) pseudoallyl, (x) allyl group or (xi) C 2-C 3Halogenated alkenyl; R 22For: (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) sec.-propyl, (i) hydroxyl, (vii) thiol, (viii) methoxyl group, (ix) oxyethyl group, (x) positive propoxy, (xi) isopropoxy (vii) encircles propoxy-, (viii) methylthio group, (xiv) ethylmercapto group, (xv) positive rosickyite base, (xvi) iprotiazem base, (xvii) ring rosickyite base, (xvii) vinyl, (xix) propenyl, (xx) pseudoallyl, (xxi) allyl group, (xxii)-N (R 28a) (R 28b), (xxiii)-CH 2R 29, (xxiv) amino methyl, (xxv) methylol, (xxvi) sulphomethyl, (xxvii)-NHNH 2, (xxviii)-N (CH 3) NH 2Or (xxix)-NHNH (CH 3); R 23And R 39Independent is hydrogen or methyl; R 41And R 42Independent is hydrogen, methyl or ethyl; R 24Be selected from: (i) hydrogen, (ii) C 1-C 4Alkyl, (iii) C 2-C 4Alkenyl, (iv) C 2-C 4Alkynyl group,
(v) cyclopropyl, (vi)-C (=Q 4)-R 30, (v)-OR 31, and (vi)-N (R 32) 2,
Q wherein 4Be O, S or N (R 33);
R 25For hydrogen, hydroxyl, methyl, ethyl, amino ,-CN or-NO 2
Radicals R 26Be hydrogen, methyl or ethyl;
R 28aFor hydrogen, hydroxyl, methyl, ethyl, amino ,-NHCH 3,-N (CH 3) 2, methoxyl group, oxyethyl group or-CN;
R 28bBe hydrogen, methyl or ethyl;
Perhaps R 28a, R 28bThe nitrogen that is connected with them the expression azetidinyl that combines;
Radicals R 29Be hydrogen, hydroxyl, thiol, methyl, ethyl, amino, methoxyl group, oxyethyl group, methylthio group, ethylmercapto group, methylamino or ethylamino;
R 30For hydrogen, methyl, ethyl ,-OR 34,-SR 34,-N (R 35) 2,-NHOH ,-NHNH 2,-N (CH 3) NH 2Or-N (CH 2CH 3) NH 2
Substituent R 31And R 32In each case, independent is hydrogen, methyl or ethyl;
Radicals R 33For hydrogen, hydroxyl, methyl, ethyl, amino ,-CN or-NO 2
Radicals R 34Be methyl or ethyl;
Radicals R 35Independent is hydrogen, methyl or ethyl; Prerequisite is to work as Q 2Be CHR 26The time, R then 22Be selected from hydrogen ,-CH 3,-C 2H 5,-C 3H 7,-OCH 3,-SCH 3,-O-C 2H 5With-S-C 2H 5Prerequisite is to work as R 3And R 4When respectively doing for oneself hydrogen, then Y is not a hydrogen; R 6And R 7Independently be selected from:
(a) hydrogen, (b) C 1-C 12Alkyl, (c) C 2-C 12Alkenyl, (d) cycloalkyl,
(e) (cycloalkyl) alkyl, (f) (cycloalkyl) alkenyl, (g) cycloalkenyl group,
(h) (cycloalkenyl group) alkyl, (i) (cycloalkenyl group) alkenyl, (j) aryl, (k) (aryl) alkyl,
(l) (aryl) alkenyl, (m) heterocyclic radical, (n) (heterocycle) alkyl and (o) (heterocycle) alkenyl;
R 8, R 9And R 10Independently be selected from:
(a) hydrogen, (b) C 1-C 6Alkyl, (c) C 2-C 6Alkenyl, (d) C 3-C 6Cycloalkyl,
(e) C 3-C 6Cycloalkenyl group and (f) fluorine, prerequisite is R 8, R 9And R 10In each no more than 6 atoms of total atom number (dehydrogenation outer).
2. the compound that is expressed from the next according to claim 1 with relative stereochemical structure:
Figure A9980761000101
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
3. the compound that is expressed from the next according to claim 1 with relative stereochemical structure:
Figure A9980761000102
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
4. according to the compound of claim 1: wherein
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 2-C 3Alkenyl, or-X-R 2For
Figure A9980761000103
Y wherein 1For-CH 2-,-O-,-S-or-NH-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, amino methyl, 1-amino-ethyl, 2-amino-ethyl, thiol methyl, 1-thiol ethyl, 2-thiol ethyl, methoxymethyl, N-methylamino methyl and methylthiomethyl;
R 3And R 4Independently be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above definition and wherein R 3And R 4One of be not hydrogen;
R 5Be hydrogen or low alkyl group;
R 6And R 7Independent is hydrogen or low alkyl group;
R 8And R 9Independent is hydrogen, fluoro or low alkyl group;
R 10Be hydrogen, fluoro or low alkyl group; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl ,-C (=Q 2) R 22,-N (=Q 3) ,-N (O)=CHCH 3,-NR 23R 24Or have the heterocycle of 3-6 annular atoms, wherein a R 22, R 23, R 24, Q 2And Q 3As defined herein.
5. the compound that is expressed from the next according to claim 4 with relative stereochemical structure:
Figure A9980761000111
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
6. the compound that is expressed from the next according to claim 4 with relative stereochemical structure:
Figure A9980761000112
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
7. according to the compound of claim 1: wherein
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 2-C 3Alkenyl, or-X-R 2For Y wherein 1For-CH 2-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl and 2-hydroxyethyl;
R 3And R 4Independently be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above definition and wherein R 3And R 4One of be not hydrogen;
R 5Be hydrogen or low alkyl group;
R 6And R 7Independent is hydrogen or low alkyl group;
R 8And R 9Independent is hydrogen or low alkyl group;
R 10Be hydrogen or low alkyl group; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl ,-C (=Q 2) R 22,-N (=Q 3) ,-N (O)=CHCH 3Or have 5 annular atomses and also have the heterocycle of one or two pair key, R wherein 22, Q 2And Q 3As defined herein.
8. the compound that is expressed from the next according to claim 7 with relative stereochemical structure: R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
9. the compound that is expressed from the next according to claim 7 with relative stereochemical structure: R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
10. according to the compound of claim 1: wherein
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH, wherein R 2Be C 1-C 3Low alkyl group, halo C 1-C 3Low alkyl group, C 2-C 3Alkenyl or halo C 1-C 3Alkenyl, or-X-R 2For Y wherein 1For-CH 2-and Y 2For-C (=O)-or-C (R Aa) (R Bb)-, be R wherein AaAnd R BbIndependently be selected from hydrogen, C 1-C 3Low alkyl group, methylol, 1-hydroxyethyl and 2-hydroxyethyl;
R 3And R 4Independently be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above definition and wherein R 3And R 4One of be not hydrogen;
R 5Be hydrogen or low alkyl group;
R 6And R 7Independent is hydrogen or low alkyl group;
R 8And R 9Independent is hydrogen or low alkyl group;
R 10Be hydrogen or low alkyl group; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
11. the compound that is expressed from the next according to claim 10 with relative stereochemical structure:
Figure A9980761000141
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
12. the compound that is expressed from the next according to claim 10 with relative stereochemical structure:
Figure A9980761000142
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
13. the compound according to claim 1: wherein
R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 3And R 4Upright be selected from hydrogen, heterocyclic radical and-Z-R 14, wherein Z and R 14As above definition and wherein R 3And R 4One of be not hydrogen;
R 5Be hydrogen or low alkyl group;
R 6And R 7Independent is hydrogen or low alkyl group;
R 8And R 9Independent is hydrogen or low alkyl group;
R 10Be hydrogen or low alkyl group; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle 3 of one or two pair key
14. the compound that is expressed from the next according to claim 13 with relative stereochemical structure:
Figure A9980761000151
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
15. the compound that is expressed from the next according to claim 13 with relative stereochemical structure: R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
16. the compound according to claim 1: wherein
R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen or low alkyl group R 3For heterocyclic radical or-Z-R 14, wherein Z and R 14As above definition;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
17. the compound that is expressed from the next according to claim 16 with relative stereochemical structure:
Figure A9980761000161
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
18. the compound that is expressed from the next according to claim 16 with relative stereochemical structure: R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
19. according to the compound of claim 1, wherein
R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen or low alkyl group R 3Be (a) heterocyclic radical, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl group, (g)-C (=O)-R 14, (h)-C (R 37a) (OR 37c)-R 14Or (i)-C (R 37a) (R 37b)-N (O) (R 37c) R 14, R wherein 14For:
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) halogenated alkenyl, (vii) aryl, (viii) aralkyl, (ix) heterocyclic radical,
(x) (heterocyclic radical) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyano group alkyl,
(xiv) (R 37aO)-(O=) alkyl that replaces of C-or
(xv) (R 37aO) 2-P (=O)-alkyl that replaces;
R 37aAnd R 37bIndependently be selected from:
(i) hydrogen, (ii) low alkyl group and (iii) low-grade alkenyl; And
R 37cFor:
(i) hydrogen, (ii) low alkyl group or (iii) low-grade alkenyl;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
20. the compound that is expressed from the next according to claim 19 with relative stereochemical structure:
Figure A9980761000171
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
21. the compound that is expressed from the next according to claim 19 with relative stereochemical structure:
Figure A9980761000181
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
22. according to the compound of claim 1, wherein
R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-, R 2-NH-C (=O)-, R 2-NH-SO 2-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen R 3Be (a) heterocyclic radical, (b) alkyl or (c)-C (R 37a) (OR 37c)-R 14, R wherein 14For:
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) halogenated alkenyl, (vii) aryl, (viii) aralkyl, (ix) heterocyclic radical,
(x) (heterocyclic radical) alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyano group alkyl,
(xiv) (R 37aO)-(O=) alkyl that replaces of C-or
(xv) (R 37aO) 2-P (=O)-alkyl that replaces;
R 37aAnd R 37bIndependently be selected from:
(i) hydrogen, (ii) low alkyl group and (iii) low-grade alkenyl; And
R 37cFor:
(i) hydrogen, (ii) C 1-C 3Low alkyl group or (iii) allyl group;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
23. the compound that is expressed from the next according to claim 22 with relative stereochemical structure:
Figure A9980761000191
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
24. the compound that is expressed from the next according to claim 22 with relative stereochemical structure:
Figure A9980761000192
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
25. according to the compound of claim 1, wherein
R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen R 3Be (a) heterocyclic radical, (b) alkyl or (c)-C (R 37a) (OR 37c)-R 14, R wherein 14For:
(i) low alkyl group, (ii) low-grade alkenyl, the (iii) low alkyl group of hydroxyl-replacement or the (iv) low alkyl group of alkoxyl group-replacement;
R 37aFor:
(i) hydrogen, (ii) low alkyl group or (iii) low-grade alkenyl; And
R 37cFor:
(i) hydrogen, (ii) C 1-C 3Low alkyl group or (iii) allyl group;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
26. the compound that is expressed from the next according to claim 25 with relative stereochemical structure:
Figure A9980761000201
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
27. the compound that is expressed from the next according to claim 25 with relative stereochemical structure: R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
28. according to the compound of claim 1, wherein
R 1For-CO 2H;
-X-R 2Be R 2-C (=O)-NH-or R 2-SO 2-NH-, wherein R 2Be C 1-C 3Low alkyl group or halo C 1-C 3Low alkyl group;
R 4Be hydrogen R 3For-C (R 37a) (OR 37c)-R 14, R wherein 14For:
Low alkyl group or low-grade alkenyl;
R 37aFor:
Low alkyl group or low-grade alkenyl; And
R 37cFor:
Hydrogen, C 1-C 3Low alkyl group or allyl group;
R 5Be hydrogen;
R 6And R 7Be hydrogen;
R 8And R 9Be hydrogen;
R 10Be hydrogen; And
Y is C 2-C 5Alkenyl, C 2-C 5Halogenated alkenyl or have 5 annular atomses and also have the heterocycle of one or two pair key.
29. the compound that is expressed from the next according to claim 28 with relative stereochemical structure:
Figure A9980761000211
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
30. the compound that is expressed from the next according to claim 29 with relative stereochemical structure:
Figure A9980761000221
R wherein 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X and Y R as defined herein and wherein 3And R 4Both are inequality.
31. compound is selected from: (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-2-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate; (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-1-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (-)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid ammonium salt; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-sec.-propyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-ethyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S3 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methylol-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-dimethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-(propylene-2-yl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) butyl-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2-hydroxyl) amyl group-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-hydroxyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(cis-2-chloro-ethene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' R)-2-(1-acetamido-3-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(thiazole-4-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-1-tert-butoxycarbonyl-2-(1-acetamido-3-methyl) butyl-3-(thiazol-2-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-vinyl-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(2,2-two fluoro-ethene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-3-base)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(isoxazole-5-base)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazoles-2-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-(imidazol-4 yl)-tetramethyleneimine-5-formic acid; And (±)-(2S, 3R, 5R, 1 ' S)-2-(1-acetamido-3-methyl) butyl-3-amino-tetramethyleneimine-5-formic acid;
Or its pharmacy acceptable salt, ester or prodrug.
32. compound is selected from: (±)-(2R, 3S, 5R, 1 ' R)-2-(1-acetamido-2-ethyl-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxy-2-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-ethyl-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-methanoic acid trifluoro acetate; (±)-(2R, 3R, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dihydroxyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (-)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid ammonium salt; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-vinyl) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S)-2-(1-acetamido-2-ethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-sec.-propyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' S, 3 ' S)-2-(1-acetamido-2-(N-ethyl-N-methylamino-N-oxide compound)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3R, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(pyrazole-3-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' R)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl)) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-2-allyl group) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S, 3 ' S)-2-(1-acetamido-2-hydroxy-3-methyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methoxyl group-4-vinyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-cyano group) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-1-(3,6-dihydro-2-H-pyrans-2-yl) methyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2,3-dimethoxy) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-methylol-2-hydroxyl) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group) amyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-3-dimethyl) butyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-oxyethyl group-3-vinyl) propyl group-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl-2-(propylene-2-yl)) ethyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid; And (±)-(2R, 3S, 5R, 1 ' R, 2 ' S)-2-(1-acetamido-2-hydroxyl) hexyl-3-(cis-propylene-1-yl)-tetramethyleneimine-5-formic acid;
Or its pharmacy acceptable salt, ester or prodrug.
33. suppress the medicinal compositions of neuraminidase influenza, it comprises the compound of the claim 1 of pharmaceutical carrier and treatment significant quantity.
34. the medicinal compositions of treatment influenza infection, it comprises the compound of the claim 1 of pharmaceutical carrier and treatment significant quantity.
35. the medicinal compositions that flu-prevention infects, it comprises the compound of the claim 1 of pharmaceutical carrier and treatment significant quantity.
36. suppress the medicinal compositions of neuraminidase influenza, it comprises the compound of the claim 31 of pharmaceutical carrier and treatment significant quantity.
37. the medicinal compositions of treatment influenza infection, it comprises the compound of the claim 31 of pharmaceutical carrier and treatment significant quantity.
38. the medicinal compositions that flu-prevention infects, it comprises the compound of the claim 31 of pharmaceutical carrier and treatment significant quantity.
39. suppress the method from the neuraminidase of pathogenic microorganism, this method comprises the compound of the claim 1 of the people that needs this treatment or other Mammals treatment significant quantity.
40. the method for claim 39, wherein said pathogenic derivative are virus.
41. the method for claim 40, wherein said virus is influenza virus.
42. treatment is by the method for disease due to the microorganism with neuraminidase, this method comprises the compound of the claim 1 of the people that needs this treatment or other Mammals treatment significant quantity.
43. the method for claim 42, wherein said pathogenic derivative are virus.
44. the method for claim 43, wherein said virus is influenza virus.
45. prevention is by the method for disease due to the microorganism with neuraminidase, this method comprises the compound of the claim 1 of the people that needs this treatment or other Mammals treatment significant quantity.
46. the method for claim 45, wherein said pathogenic derivative are virus.
47. the method for claim 46, wherein said virus is influenza virus.
48. suppress the method from the neuraminidase of pathogenic microorganism, this method comprises the compound of the claim 31 of the people that needs this treatment or other Mammals treatment significant quantity.
The method of 49 claims 48, wherein said pathogenic microorganism are virus.
50. the method for claim 49, wherein said virus is influenza virus.
51. treatment is by the method for disease due to the microorganism with neuraminidase, this method comprises the compound of the claim 31 of the people that needs this treatment or other Mammals treatment significant quantity.
52. the method for claim 51, wherein said pathogenic microorganism are virus.
53. the method for claim 52, wherein said virus is influenza virus.
54. prevention is by the method for disease due to the microorganism with neuraminidase, this method comprises the compound of the claim 31 of the people that needs this treatment or other Mammals treatment significant quantity.
55. the method for claim 54, wherein said pathogenic microorganism are virus.
56. the method for claim 55, wherein said virus is influenza virus.
CN99807610A 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases Pending CN1328546A (en)

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