CN103814001A - Processes and intermediates - Google Patents

Processes and intermediates Download PDF

Info

Publication number
CN103814001A
CN103814001A CN201280034618.9A CN201280034618A CN103814001A CN 103814001 A CN103814001 A CN 103814001A CN 201280034618 A CN201280034618 A CN 201280034618A CN 103814001 A CN103814001 A CN 103814001A
Authority
CN
China
Prior art keywords
formula
compound
alkyl
group
aliphatic series
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201280034618.9A
Other languages
Chinese (zh)
Inventor
G.J.塔诺里
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of CN103814001A publication Critical patent/CN103814001A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Abstract

A process for preparing enantioselectively a compound of formula la or lb: over a compound of formulas 1-2-Ih: as shown in the description.

Description

Method and intermediate
the cross reference of related application
The application requires the benefit of priority of the U.S. Provisional Application number 61/486,125 of submitting on May 13rd, 2011, and it is incorporated herein by reference.
Invention field
The present invention relates to method and intermediate for the preparation of proteinase inhibitor, particularly serpin.
background of invention
Being infected by hepatitis C virus (" HCV ") is a people's medical problem attracting people's attention.For the most cases of non-A type or non-hepatitis B, think that HCV is the medium that causes a disease, estimate the human serum positive rate (people such as A. Alberti that is 3% in the whole world, " Natural History of Hepatitis C (natural history of hepatitis C) " J. Hepatology, 31 (supplementary issues 1), 17-24 page (1999)).Only, in the U.S., nearly 4,000,000 individual possibilities are infected.(the people such as M.J. Alter, " The Epidemiology of Viral Hepatitis in the United States (at the epidemiology of U.S.'s viral hepatitis) " Gastroenterol. Clin. North Am., 23, the 437-455 pages (1994); M. J. Alter " Hepatitis C Virus Infection in the United States (at the infection with hepatitis C virus of the U.S.) " J. Hepatology, 31 (supplementary issues 1), 88-91 page (1999)).
In the time being exposed to HCV for the first time, only approximately 20% infected individual development goes out acute clinical hepatitis, and other seem the infection of spontaneously disappearing.But almost 70% in the situation that, virus is set up the chronic infection of sustainable many decades.(S. Iwarson, " The Natural Course of Chronic Hepatitis (natural process of chronic hepatitis) " FEMS Microbiology Reviews, 14, the 201-204 pages (1994); D. Lavanchy, " Global Surveillance and Control of Hepatitis C (whole world of hepatitis C is detected and controlled) " J. Viral Hepatitis, 6, the 35-47 pages (1999)).Long-term chronic infection can cause the liver inflammation of recurrent and progressive deterioration, and this causes more serious morbid state conventionally, for example sclerosis and hepatocellular carcinoma.(M.C. Kew, " Hepatitis C and Hepatocellular Carcinoma (hepatitis C and hepatocellular carcinoma) " FEMS Microbiology Reviews, 14, the 211-220 pages (1994); I. the people such as Saito, " Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carcinoma (infection with hepatitis C virus is relevant with the development of hepatocellular carcinoma) " Proc. Natl. Acad. Sci. USA, 87, the 6547-6549 pages (1990)).Regrettably, extensively effectively do not treat for the exhaustion progress of chronic hcv.
Proteinase inhibitor (particularly serpin) can be used for treating HCV to be infected, as disclosed in WO 02/18369.WO 02/18369 also discloses for the preparation of the method for these compounds and intermediate.These methods cause some space carbon center racemization.Referring to for example 223-22 page.As a result, still need to be for the preparation of the enantioselectivity method of these compounds.
summary of the invention
The present invention meets this requirement and other requirement, and it relates to method and intermediate for the preparation of proteinase inhibitor (particularly serpin).On the one hand, the invention provides method and the intermediate for the production of the bicyclic derivatives of formula Ia or Ib:
Wherein:
Ring A is C 3-12cyclic aliphatic ring;
Ring B is C 3-12heterocycle aliphatic series ring, it contains other 0-2 heteroatoms that is selected from independently of one another O, N and S, and it can optionally be replaced by 1-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group, aryl and hydroxyl;
R 1for H or protecting group; With
R 2for H, protecting group or C 1-12aliphatic series.
It is a kind of for the compound via formula Ic to Ih that aspect relates to, the method for the compound of enantioselectivity ground preparation formula Ia or Ib:
。
Under existing, the compound that described method is included in formula III makes the step of the compound carboxylation of formula IIa or IIb:
Figure 91558DEST_PATH_IMAGE003
，
Wherein R 1afor protecting group,
Figure 500149DEST_PATH_IMAGE004
；
Wherein R 3for protecting group or C 1-12aliphatic series, and R 4for H or C 1-4non-branching aliphatic series.
Another aspect relates to a kind of method of the compound for the preparation of formula 10:
，
Wherein R 2as above definition, and Z 2for H or protecting group;
Said method comprising the steps of:
A. under existing, the compound of formula III forms the 2-negatively charged ion of the compound of formula IIa:
Figure 136984DEST_PATH_IMAGE006
，
Wherein R 1aa as above defines with ring,
Figure 466334DEST_PATH_IMAGE007
，
Wherein R 3and R 4as above definition;
B. use the 2-negatively charged ion of carbon dioxide treatment step a, with the compound of enantioselectivity ground production Ia; With
C. make the compound of formula Ia react with the compound of formula 26:
Figure 665234DEST_PATH_IMAGE008
，
Wherein Z 3for protecting group.
detailed Description Of The Invention
Definition
For purposes of the present invention, determine chemical element according to the periodic table of elements (CAS version, Handbook of Chemistry and Physics (physics and chemistry handbook), the 75th edition).In addition, vitochemical generic principles is described in the Organic Chemistry(organic chemistry of Thomas Sorrell), University Science Books, the Advanced Organic Chemistry (Advanced Organic Chemistry) of Sausalito (1999) and M.B. Smith and J. March, the 5th edition, John Wiley & Sons, New York (2001), both are incorporated herein by reference.
Compound of the present invention described herein can optionally be replaced by one or more substituting groups, and described substituting group is summary description above for example, or as illustrated in specific category of the present invention, subclass and thing class.
Have to be noted that unless context clearly indicates other situation, herein and singulative " " and " being somebody's turn to do " of in claim, using comprise plural object.Therefore, for example, mention that " a kind of tackiness agent " comprises two or more tackiness agents, mention that " a kind of pharmaceutical agent " comprises two or more pharmaceutical agents, etc.
Term used herein " compound " refers to the compound being defined by the structural formula of corresponding drafting herein.In addition, unless otherwise indicated, otherwise term " compound " can comprise the salt of compound.
Term used herein " aliphatic series " comprises term alkyl, thiazolinyl, alkynyl and cyclic aliphatic, each optional as following being substituted wherein.
" alkyl " used herein refers to the radical of saturated aliphatic alkyl that contains 1-8 (for example, 1-6 or 1-4) carbon atom.Alkyl can be straight chain, ring-type or branching.The example of alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-heptyl or 2-ethylhexyl.Alkyl can be selected from following one or more substituting groups and be replaced (, optionally be substituted): halogen, cyclic aliphatic (for example, cycloalkyl or cycloalkenyl group), heterocycle aliphatic series (for example, Heterocyclylalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxyl group, aroyl, 4-hetaroylpyrazol, acyl group (for example, (aliphatic series) carbonyl, (cyclic aliphatic) carbonyl or (heterocycle aliphatic series) carbonyl), nitro, cyano group, amido (for example, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino, heteroaralkyl carbonylamino alkyl amino-carbonyl, cycloalkyl amino carbonyl, Heterocyclylalkyl aminocarboxyl, aromatic yl aminocarbonyl or heteroaryl amino carbonyl), amino (for example, aliphatic amino, cyclic aliphatic amino or heterocycle aliphatic amino), alkylsulfonyl (for example, aliphatic series-SO 2-), sulfinyl, sulfanyl, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo, carboxyl, formamyl, cyclic aliphatic oxygen base, heterocycle aliphatic series oxygen base, aryloxy, heteroaryloxy, aralkoxy, heteroaryl alkoxyl group, alkoxy carbonyl, alkyl-carbonyl oxygen base and hydroxyl.Some examples of substituted alkyl are not with restriction and are comprised carboxyalkyl (for example HOOC-alkyl, alkoxy carbonyl alkyl and alkyl carbonyl oxy alkyl), cyano group alkyl, hydroxyalkyl, alkoxyalkyl, acyl group alkyl, aralkyl, (alkoxy aryl) alkyl, (sulfuryl amino) alkyl (for example (alkyl-SO 2-amino) alkyl), aminoalkyl group, amidoalkyl, (cyclic aliphatic) alkyl and haloalkyl.
" thiazolinyl " used herein refers to the aliphatic carbons group that contains 2-8 (for example, 2-6 or 2-4) carbon atom and at least one two key.As alkyl, thiazolinyl can be straight chain or branching.The example of thiazolinyl includes but not limited to allyl group, prenyl, crotyl and 2-hexenyl.Thiazolinyl can optionally be replaced by one or more substituting groups, such as halogen of described substituting group, cyclic aliphatic (for example, cycloalkyl or cycloalkenyl group), heterocycle aliphatic series (for example, Heterocyclylalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxyl group, aroyl, 4-hetaroylpyrazol, acyl group (for example, (aliphatic series) carbonyl, (cyclic aliphatic) carbonyl or (heterocycle aliphatic series) carbonyl), nitro, cyano group, amido (for example, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino, heteroaralkyl carbonylamino alkyl amino-carbonyl, cycloalkyl amino carbonyl, Heterocyclylalkyl aminocarboxyl, aromatic yl aminocarbonyl or heteroaryl amino carbonyl), amino (for example, aliphatic amino, cyclic aliphatic amino, heterocycle aliphatic amino or aliphatic sulfuryl amino), alkylsulfonyl (for example, alkyl-SO 2-, cyclic aliphatic-SO 2-or aryl-SO 2-), sulfinyl, sulfanyl, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo, carboxyl, formamyl, cyclic aliphatic oxygen base, heterocycle aliphatic series oxygen base, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, alkoxy carbonyl, alkyl-carbonyl oxygen base and hydroxyl.Some examples of substituted thiazolinyl are not with restriction and are comprised cyano group thiazolinyl, alkoxyl group thiazolinyl, acyl group thiazolinyl, hydroxyl thiazolinyl, arylalkenyl, (alkoxy aryl) thiazolinyl, (sulfuryl amino) thiazolinyl (for example (alkyl-SO 2-amino) thiazolinyl), amino thiazolinyl, amido thiazolinyl, (cyclic aliphatic) thiazolinyl and haloalkenyl group.
" alkynyl " used herein refers to the aliphatic carbons group that contains 2-8 (for example, 2-6 or 2-4) carbon atom and have at least one three key.Alkynyl can be straight chain or branching.The example of alkynyl includes but not limited to propargyl and butynyl.Alkynyl can optionally be replaced by one or more substituting groups, described substituting group for example aroyl, 4-hetaroylpyrazol, alkoxyl group, cycloalkyloxy, heterocycle alkoxyl group, aryloxy, heteroaryloxy, aralkoxy, nitro, carboxyl, cyano group, halogen, hydroxyl, sulfo group, sulfydryl, sulfanyl are (for example, aliphatic series sulfanyl or cyclic aliphatic sulfanyl), sulfinyl (for example, aliphatic series sulfinyl or cyclic aliphatic sulfinyl), alkylsulfonyl (for example, aliphatic series-SO 2-, aliphatic amino-SO 2-or cyclic aliphatic-SO 2-), amido (for example, aminocarboxyl, alkyl amino-carbonyl, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, Heterocyclylalkyl aminocarboxyl, cycloalkyl amino carbonyl, aromatic yl aminocarbonyl, aryl-amino-carbonyl, aromatic alkyl carbonyl amino, (Heterocyclylalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkyl carbonylamino, heteroaryl carbonylamino or heteroaryl amino carbonyl), urea, thiocarbamide, sulfamyl, sulphonamide, alkoxy carbonyl, alkyl-carbonyl oxygen base, cyclic aliphatic, heterocycle aliphatic series, aryl, heteroaryl, acyl group (for example, (cyclic aliphatic) carbonyl or (heterocycle aliphatic series) carbonyl), amino (for example, aliphatic amino), sulphur oxygen base, oxo, carboxyl, formamyl, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base and (heteroaryl) alkoxyl group.
" amido " used herein comprise " aminocarboxyl " and " carbonylamino " the two.These terms, while being combined with when independent use or with another group, in the time using endways, refer to amido for example-N (R x)-C (O)-R yor-C (O)-N (R x) 2, in the time using in inside they refer to amide group for example-C (O)-N (R x)-or-N (R x)-C (O)-, wherein R xand R yas give a definition.The example of amido comprises alkyl amido (for example alkyl-carbonyl-amino or alkyl amino-carbonyl), (heterocycle aliphatic series) amido, (heteroaralkyl) amido, (heteroaryl) amido, (Heterocyclylalkyl) alkyl amido, aryl amido, aralkyl amido, (cycloalkyl) alkyl amido and cycloalkyl amido.
" amino " used herein refer to-NR xr y, wherein R xand R yeach independently selected from hydrogen, aliphatic series, cyclic aliphatic, (cyclic aliphatic) aliphatic series, aryl, araliphatic, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, heteroaryl, carboxyl, sulfanyl, sulfinyl, alkylsulfonyl, (aliphatic series) carbonyl, (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic series) carbonyl, aryl carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl, (heteroaryl) carbonyl and (assorted araliphatic) carbonyl, wherein each is substituted as defined herein and optionally.Amino example comprises alkylamino, dialkyl amido and arylamino.For example, in the time that term " amino " is not end group (, alkyl-carbonyl-amino), its be expressed as-NR x-.R xthere is identical meanings as defined above.
Use or the part (as in " aralkyl ", " aralkoxy " or " aryloxy alkyl ") as larger part separately, " aryl " used herein refers to that monocycle (for example, phenyl), dicyclo (for example, indenyl, naphthyl, tetralyl, tetrahydro indenyl) and three rings are (for example, fluorenyl, tetrahydrofluorenyl or tetrahydrochysene anthryl, anthryl) member ring systems, wherein monocycle ring body is aromatics, or at least one ring that dicyclo or three encircles in member ring systems is aromatics.Dicyclo and three cyclic groups comprise 2 yuan of benzo-fused rings to 3 yuan of carbocyclic rings.For example, benzo-fused group comprises and two or more C 4-8the phenyl that isocyclic part condenses.Aryl is optionally replaced by one or more substituting groups, described substituting group for example aliphatic series (for example, alkyl, alkenyl or alkynyl), cyclic aliphatic, (cyclic aliphatic) aliphatic series, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, aryl, heteroaryl, alkoxyl group, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base, aryloxy, heteroaryloxy, (araliphatic) oxygen base, (assorted araliphatic) oxygen base, aroyl, 4-hetaroylpyrazol, amino, oxo (on the ring of the non-aromatic carbocyclic ring of benzo-fused dicyclo or three cyclophane bases), nitro, carboxyl, amido, acyl group (for example, aliphatic series carbonyl, (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic series) carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl or (assorted araliphatic) carbonyl), alkylsulfonyl (for example, aliphatic series-SO 2-or amino-SO 2-), sulfinyl (for example, aliphatic series-S (O)-or cyclic aliphatic-S (O)-), sulfanyl (for example, aliphatic series-S-), cyano group, halogen, hydroxyl, sulfydryl, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide and formamyl.Or aryl can not be substituted.
The limiting examples of substituted aryl comprises halogenated aryl (for example, (single halo) aryl, (dihalo) aryl is (for example, to dihalo aryl, between dihalo aryl) or (three halos) aryl), (carboxyl) aryl (for example, (alkoxy carbonyl) aryl, ((aralkyl) carbonyl oxygen base) aryl or (alkoxy carbonyl) aryl), (amido) aryl (for example, (aminocarboxyl) aryl, (((alkylamino) alkyl) aminocarboxyl) aryl, (alkyl-carbonyl) aminoaryl, (aromatic yl aminocarbonyl) aryl or (((heteroaryl) amino) carbonyl) aryl), aminoaryl (for example, ((alkyl sulphonyl) amino) aryl or ((dialkyl group) amino) aryl), (cyano group alkyl) aryl, (alkoxyl group) aryl, (sulfamyl) aryl (for example, (amino-sulfonyl) aryl), (alkyl sulphonyl) aryl, (cyano group) aryl, (hydroxyalkyl) aryl, ((alkoxyl group) alkyl) aryl, (hydroxyl) aryl, ((carboxyl) alkyl) aryl, (((dialkyl group) amino) alkyl) aryl, (4-nitro alkyl) aryl, (((alkyl sulphonyl) amino) alkyl) aryl, ((heterocycle aliphatic series) carbonyl) aryl, ((alkyl sulphonyl) alkyl) aryl, (cyano group alkyl) aryl, (hydroxyalkyl) aryl, (alkyl-carbonyl) aryl, alkylaryl, (tri haloalkyl) aryl, to an amino-alkoxy carbonyl aryl, to an amino-cyano-aryl, to a halo-aminoaryl and ((heterocycle aliphatic series)-adjacent (alkyl)) aryl.
" araliphatic " used herein group for example " aralkyl " refers to aliphatic group (for example, the C being replaced by aryl 1-4alkyl).Aliphatic series, alkyl and aryl are as defined herein.An example of araliphatic (for example aralkyl) is benzyl.
" aralkyl " used herein refers to alkyl (for example, the C being replaced by aryl 1-4alkyl).Alkyl and aryl as above define.An example of aralkyl is benzyl.Aralkyl is optionally replaced by one or more substituting groups, and for example aliphatic series of described substituting group (for example, is substituted or unsubstituted alkyl, alkenyl or alkynyl, comprises carboxyalkyl, hydroxyalkyl or haloalkyl, for example trifluoromethyl), cyclic aliphatic (for example, be substituted or unsubstituted cycloalkyl or cycloalkenyl group), (cycloalkyl) alkyl, Heterocyclylalkyl, (Heterocyclylalkyl) alkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, heterocycle alkoxyl group, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, aroyl, 4-hetaroylpyrazol, nitro, carboxyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, amido (for example, aminocarboxyl, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino or heteroaralkyl carbonylamino), cyano group, halogen, hydroxyl, acyl group, sulfydryl, alkyl alkylthio base, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" dicyclo member ring systems " used herein comprises 8 yuan to 12 yuan (for example, 9 yuan, 10 yuan or 11 yuan) structures that form two rings, and wherein two rings have at least one common atom (for example, 2 common atoms).Dicyclo member ring systems comprises dicyclo aliphatic series (for example, bicyclic alkyl or bicyclic alkenyl), dicyclo heterolipid family, bicyclic aryl and bicyclic heteroaryl.
" cyclic aliphatic " used herein group comprises " cycloalkyl " and " cycloalkenyl group ", and wherein each is as described belowly optionally substituted.
" cycloalkyl " used herein refers to the saturated carbon ring monocycle of 3-10 (for example, 5-10) carbon atom or dicyclo (condense or bridging) ring.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, adamantyl, norborneol alkyl, cube alkyl (cubyl), octahydro-indenyl, decahydro-naphthyl, dicyclo [3.2.1] octyl group, dicyclo [2.2.2] octyl group, dicyclo [3.3.1] nonyl, dicyclo [3.3.2.] decyl, dicyclo [2.2.2] octyl group, adamantyl, azacycloalkyl and ((aminocarboxyl) cycloalkyl) cycloalkyl." cycloalkenyl group " used herein refers to the ring of the non-aromatic carbocyclic ring of 3-10 (for example, the 4-8) carbon atom with one or more pairs of keys.The example of cycloalkenyl group comprises cyclopentenyl, 1，4-cyclohexadiene base, cycloheptenyl, cyclooctene base, six hydrogen-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, dicyclo [2.2.2] octenyl and dicyclo [3.3.1] nonene base.Cycloalkyl or cycloalkenyl group can optionally be replaced by one or more substituting groups, and described substituting group is aliphatic series (for example, alkyl for example, alkenyl or alkynyl), cyclic aliphatic, (cyclic aliphatic) aliphatic series, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, aryl, heteroaryl, alkoxyl group, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base, aryloxy, heteroaryloxy, (araliphatic) oxygen base, (assorted araliphatic) oxygen base, aroyl, 4-hetaroylpyrazol, amino, amido (for example, (aliphatic series) carbonylamino, (cyclic aliphatic) carbonylamino, ((cyclic aliphatic) aliphatic series) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycle aliphatic series) carbonylamino, ((heterocycle aliphatic series) aliphatic series) carbonylamino, (heteroaryl) carbonylamino or ((assorted araliphatic) carbonylamino), nitro, carboxyl (for example, HOOC-, alkoxy carbonyl or alkyl-carbonyl oxygen base), acyl group (for example, (cyclic aliphatic) carbonyl, (cyclic aliphatic) aliphatic series) carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl or (assorted araliphatic) carbonyl), cyano group, halogen, hydroxyl, sulfydryl, alkylsulfonyl (for example, alkyl-SO 2-or aryl-SO 2-), sulfinyl (for example, alkyl-S (O)-), sulfanyl (for example, alkyl-S-), sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" loop section " used herein comprises cyclic aliphatic, heterocycle aliphatic series, aryl or heteroaryl, and wherein each is as previously defined.
Term used herein " heterocycle aliphatic series " comprises Heterocyclylalkyl and heterocycloalkenyl, and wherein each is as described belowly optionally substituted.
" Heterocyclylalkyl " used herein (for example refers to 3-10 unit monocycle or dicyclo (condense or bridging), 5 yuan to 10 yuan monocycles or dicyclo) saturated rings structure, wherein one or more annular atomses are heteroatoms (for example, N, O, S or their combination).The example of Heterocyclylalkyl comprises piperidyl, piperazinyl, THP trtrahydropyranyl, tetrahydrofuran base, 1, 4-dioxolane base, 1, 4-dithiane base, 1, 3-dioxolane base, oxazolidinyl, isoxazole alkyl, morpholinyl, thio-morpholinyl, octahydro benzofuryl, octahydro chromenyl, octahydro sulfo-chromenyl, octahydro indyl, octahydro pyrindine base, decahydroquinolyl, octahydro benzo [b] thienyl, 2-oxa--dicyclo [2.2.2] octyl group, 1-aza-bicyclo [2.2.2] octyl group, 3-aza-bicyclo [3.2.1] octyl group and 2, 6-dioxa-tri-encircle [3.3.1.0 3,7] nonyl.Monocyclic heterocycles alkyl can condense with phenyl moiety, for example tetrahydroisoquinoline." heterocycloalkenyl " used herein refer to have one or more pairs of keys and wherein one or more annular atomses be heteroatoms (for example, N, O or S) monocycle or the non-aromatic ring structure of dicyclo (for example, 5 yuan to 10 yuan monocycle or dicyclo).Monocycle and dicyclo heterolipid family number according to standard chemical nomenclature.
Heterocyclylalkyl or heterocycloalkenyl can optionally be replaced by one or more substituting groups, and described substituting group is aliphatic series (for example, alkyl for example, alkenyl or alkynyl), cyclic aliphatic, (cyclic aliphatic) aliphatic series, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, aryl, heteroaryl, alkoxyl group, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base, aryloxy, heteroaryloxy, (araliphatic) oxygen base, (assorted araliphatic) oxygen base, aroyl, 4-hetaroylpyrazol, amino, amido (for example, (aliphatic series) carbonylamino, (cyclic aliphatic) carbonylamino, (cyclic aliphatic) aliphatic series) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycle aliphatic series) carbonylamino, ((heterocycle aliphatic series) aliphatic series) carbonylamino, (heteroaryl) carbonylamino or (assorted araliphatic) carbonylamino), nitro, carboxyl (for example, HOOC-, alkoxy carbonyl or alkyl-carbonyl oxygen base), acyl group (for example, (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic series) carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl or (assorted araliphatic) carbonyl), nitro, cyano group, halogen, hydroxyl, sulfydryl, alkylsulfonyl (for example, alkyl sulphonyl or aryl sulfonyl), sulfinyl (for example, alkyl sulphinyl), sulfanyl (for example, alkyl alkylthio base), sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" heteroaryl " used herein refers to monocycle, dicyclo or the three ring member ring systems with 4-15 annular atoms, wherein one or more annular atomses be heteroatoms (for example, N, O, S or their combination) and wherein monocycle ring body be aromatics, or dicyclo or three rings at least one ring in member ring systems are aromatics.Heteroaryl comprises the benzo-fused member ring systems with 2-3 ring.For example, benzo-fused group comprises and one or two 4-8 unit's heterocycle aliphatic series part benzo-fused (for example, indolizine base, indyl, pseudoindoyl, 3H-indyl, indoline base, benzo [b] furyl, benzo [b] thienyl, quinolyl or isoquinolyl).Some examples of heteroaryl be azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrryl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazyl, benzofuryl, isoquinolyl, benzothiazolyl,
Figure 943900DEST_PATH_IMAGE009
ton base, sulfo-
Figure 937264DEST_PATH_IMAGE009
ton base, thiodiphenylamine, indoline, benzo [1,3] dioxole, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl-, benzothiazolyl, purine radicals, cinnolinyl, quinolyl, quinazolyl, phthalazinyl, quinazolyl, quinoxalinyl, isoquinolyl, 4H-quinolizinyl, phendioxin, 2,5-thiadiazolyl group and 1,8-naphthyridinyl.
Bicyclic heteroaryl is not with restriction and is comprised furyl, thienyl, 2H-pyrryl, pyrryl, oxazolyl, thiazolyl (thazolyl), imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl group, 2H-pyranyl, 4-H-pyranyl (4-H-pranyl), pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, pyrazinyl and 1,3,5-triazinyl.Bicyclic heteroaryl is numbered according to standard chemical nomenclature.
Bicyclic heteroaryl is not with restriction and is comprised indolizine base, indyl, pseudoindoyl, 3H-indyl, indoline base, benzo [b] furyl, benzo [b] thienyl, quinolyl, isoquinolyl, indolizine base, pseudoindoyl, indyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl-, benzothiazolyl, purine radicals, 4H-quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolyl, quinoxalinyl, 1,8-naphthyridinyl and pteridyl.Bicyclic heteroaryl is numbered according to standard chemical nomenclature.
Heteroaryl is optionally replaced by one or more substituting groups, and described substituting group is aliphatic series (for example, alkyl for example, alkenyl or alkynyl), cyclic aliphatic, (cyclic aliphatic) aliphatic series, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, aryl, heteroaryl, alkoxyl group, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base, aryloxy, heteroaryloxy, (araliphatic) oxygen base, (assorted araliphatic) oxygen base, aroyl, 4-hetaroylpyrazol, amino, oxo (on the non-aromatic carbocyclic ring or heterocyclic ring of dicyclo or tricyclic heteroaryl), carboxyl, amido, acyl group (for example, aliphatic carbonyl, (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic series) carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl or (assorted araliphatic) carbonyl), alkylsulfonyl (for example, aliphatic alkylsulfonyl or amino-sulfonyl), sulfinyl (for example, aliphatic sulfinyl), sulfanyl (for example, aliphatic sulfanyl), nitro, cyano group, halogen, hydroxyl, sulfydryl, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide and formamyl.Or heteroaryl can not be substituted.
The limiting examples of substituted heteroaryl comprises (halo) heteroaryl (for example, single (halo) heteroaryl and two (halo) heteroaryl), (carboxyl) heteroaryl (for example, (alkoxy carbonyl) heteroaryl), cyanoheteroaryl, aminoheteroaryl (for example, ((alkyl sulphonyl) amino) heteroaryl and ((dialkyl group) amino) heteroaryl), (amido) heteroaryl (for example, aminocarboxyl heteroaryl, ((alkyl-carbonyl) amino) heteroaryl, ((((alkyl) amino) alkyl) aminocarboxyl) heteroaryl, (((heteroaryl) amino) carbonyl) heteroaryl, ((heterocycle aliphatic series) carbonyl) heteroaryl or ((alkyl-carbonyl) amino) heteroaryl), (cyano group alkyl) heteroaryl, (alkoxyl group) heteroaryl, (sulfamyl) heteroaryl (for example, (amino-sulfonyl) heteroaryl), (alkylsulfonyl) heteroaryl ((for example, (alkyl sulphonyl) heteroaryl), (hydroxyalkyl) heteroaryl, (alkoxyalkyl) heteroaryl, (hydroxyl) heteroaryl, ((carboxyl) alkyl) heteroaryl, (((dialkyl group) amino) alkyl) heteroaryl, (heterocycle aliphatic series) heteroaryl, (cyclic aliphatic) heteroaryl, (4-nitro alkyl) heteroaryl, (((alkyl sulphonyl) amino) alkyl) heteroaryl, ((alkyl sulphonyl) alkyl) heteroaryl, (cyano group alkyl) heteroaryl, (acyl group) heteroaryl (for example, (alkyl-carbonyl) heteroaryl), (alkyl) heteroaryl and (haloalkyl) heteroaryl (for example, tri haloalkyl heteroaryl).
" assorted araliphatic " (for example heteroaralkyl) used herein refers to aliphatic group (for example, the C being replaced by heteroaryl 1-4alkyl).Aliphatic series, alkyl and heteroaryl as above define.
" heteroaralkyl " used herein refers to alkyl (for example, the C being replaced by heteroaryl 1-4alkyl).Both as above define " alkyl " and " heteroaryl ".Heteroaralkyl is optionally replaced by one or more substituting groups, for example alkyl of described substituting group (comprises carboxyalkyl, such as trifluoromethyl of hydroxyalkyl and haloalkyl), thiazolinyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, Heterocyclylalkyl, (Heterocyclylalkyl) alkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, heterocycle alkoxyl group, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, aroyl, 4-hetaroylpyrazol, nitro, carboxyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, aminocarboxyl, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino, heteroaralkyl carbonylamino, cyano group, halogen, hydroxyl, acyl group, sulfydryl, alkyl alkylthio base, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" acyl group " used herein refers to formyl radical or R x-C (O)-(for example alkyl-C (O)-, also referred to as " alkyl-carbonyl "), wherein R xwith alkyl as previously defined.Ethanoyl and valeryl are the examples of acyl group.
" aroyl " used herein or " 4-hetaroylpyrazol " refer to aryl-C (O)-or heteroaryl-C (O)-.Aryl and the heteroaryl moieties of aroyl or 4-hetaroylpyrazol are optionally substituted as previously defined.
" alkoxyl group " used herein refers to alkyl-O-group, and wherein alkyl as previously defined.
" formamyl " used herein refers to have structure-O-CO-NR xr yor-NR x-CO-O-R zgroup, wherein R xand R yas above definition, and R zcan be aliphatic series, aryl, araliphatic, heterocycle aliphatic series, heteroaryl or assorted araliphatic.
" carboxyl " used herein refer in the time using endways-COOH ,-COOR x,-OC (O) H or-OC (O) R x, refer to-OC (O) in the time using in inside-or-C (O) O-.
" halogenated aliphatic " used herein group refers to the aliphatic group being replaced by 1-3 halogen.For example, term haloalkyl comprises group-CF 3.
" sulfydryl " used herein refer to-SH.
" sulfo group " used herein refer in the time using endways-SO 3h or-SO 3r x, refer to-S (O) in the time using in inside 3-.
" sulphonamide " used herein group refers to structure-NR in the time using endways x-S (O) 2-NR yr z, refer to-NR in the time using in inside x-S (O) 2-NR y-, wherein R x, R yand R zas above definition.
" sulphonamide " used herein group refers to structure-S (O) in the time using endways 2-NR xr yor-NR x-S (O) 2-R z, refer to-S (O) in the time using in inside 2-NR x-or-NR x-S (O) 2-, wherein R x, R yand R zas above definition.
" sulfanyl " used herein refer in the time using endways-S-R x, refer to-S-, wherein R in the time using in inside xas above definition.The example of sulfanyl comprises aliphatic series-S-, cyclic aliphatic-S-and aryl-S-etc.
" sulfinyl " used herein refer in the time using endways-S (O)-R x, refer to-S (O) in the time using in inside-, wherein R xas above definition.The example of sulfinyl comprise aliphatic series-S (O)-, aryl-S (O)-, (cyclic aliphatic (aliphatic series))-S (O)-, cycloalkyl-S (O)-, heterocycle aliphatic series-S (O)-and heteroaryl-S (O)-etc.
" alkylsulfonyl " used herein refer in the time using endways-S (O) 2-R x, refer to-S (O) in the time using in inside 2-, wherein R xas above definition.Exemplary alkylsulfonyl comprises aliphatic series-S (O) 2-, aryl-S (O) 2-, ((cyclic aliphatic (aliphatic series))-S (O) 2-, cyclic aliphatic-S (O) 2-, heterocycle aliphatic series-S (O) 2-, heteroaryl-S (O) 2-and (cyclic aliphatic (amido (aliphatic series)))-S (O) 2-etc.
" sulphur oxygen base " used herein refers to-O-SO-R in the time using endways xor-SO-O-R x, refer to-O-S (O) in the time using in inside-or-S (O)-O-, wherein R xas above definition.
" halogen " used herein or " halo " group refer to fluorine, chlorine, bromine or iodine.
" alkoxy carbonyl " used herein (it is included in " carboxyl ", separately use or with another moiety combinations) refer to for example alkyl-O-C (O)-group.
" alkoxyalkyl " used herein refer to for example alkyl-O-alkyl-alkyl, wherein alkyl as above defines.
" carbonyl " used herein refer to-C (O)-.
Refer to=O of " oxo " used herein group.
" aminoalkyl group " used herein refers to structure (R x) 2n-alkyl-.
" cyano group alkyl " used herein refer to structure (NC)-alkyl-.
" urea " used herein group refers to structure-NR x-CO-NR yr z, and " thiocarbamide " group refers to structure-NR in the time using endways x-CS-NR yr z, refer to-NR in the time using in inside x-CO-NR y-or-NR x-CS-NR y-, wherein R x, R yand R zas above definition.
" guanidine " used herein group refers to structure N=C (N (R xr y)) N (R xr y) or-NR x-C (=NR x) NR xr y, wherein R xand R yas above definition.
" amidino groups " used herein refers to structure-C=(NR x) N (R xr y), wherein R xand R yas above definition.
Term used herein " neighbour " refers on the group that comprises two or more carbon atoms places substituting group, and wherein substituting group is connected with adjacent carbon atom.
Term used herein " together with " refer on the group that comprises two or more carbon atoms and place substituting group, wherein substituting group connects with identical carbon atom.
Term used herein " end " and " inside " refer to the position of group in substituting group.When group is present in substituent end and during not with the other bonding of rest part of chemical structure, this group endways.Carboxyalkyl (, R xo (O) C-alkyl) example of carboxyl that uses for end.When group is not inner endways time.Alkyl carboxyl (for example, alkyl-C (O)-O-or alkyl-O-C (O)-) and alkyl carboxyl aryl (for example, alkyl-C (O)-O-aryl-or alkyl-O-C (O)-aryl-) be the example of the inner carboxyl using.
" ring " used herein group comprises monocycle, dicyclo and three ring member ring systems, for example cyclic aliphatic, heterocycle aliphatic series, aryl and heteroaryl, and wherein each as above defines.
" the dicyclo member ring systems of bridging " used herein refers to and wherein encircles the heterocycle aliphatic series member ring systems of the dicyclo that is bridging or the cyclic aliphatic member ring systems of dicyclo.The example of the dicyclo member ring systems of bridging includes but not limited to adamantyl, norborneol alkyl, dicyclo [3.2.1] octyl group, dicyclo [2.2.2] octyl group, dicyclo [3.3.1] nonyl, dicyclo [3.2.3] nonyl, 2-oxabicyclo [2.2.2] octyl group, 1-azabicyclo [2.2.2] octyl group, 3-azabicyclo [3.2.1] octyl group and 2,6-dioxa-tri-ring [3.3.1.0 3,7] nonyl.The dicyclo member ring systems of bridging can optionally be replaced by one or more substituting groups, and for example alkyl of described substituting group (comprises carboxyalkyl, such as trifluoromethyl of hydroxyalkyl and haloalkyl), thiazolinyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, Heterocyclylalkyl, (Heterocyclylalkyl) alkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, heterocycle alkoxyl group, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, aroyl, 4-hetaroylpyrazol, nitro, carboxyl, alkoxy carbonyl, alkyl carbonyl oxy, aminocarboxyl, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino, heteroaralkyl carbonylamino, cyano group, halogen, hydroxyl, acyl group, sulfydryl, alkyl alkylthio base, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" aliphatic chain " used herein refers to branching or linear aliphatic group (for example, alkyl, alkenyl or alkynyl).Linear aliphatic chain has structure-(CH 2) v-, wherein v is 1-6.The aliphatic chain of branching is the linear aliphatic chain being replaced by one or more aliphatic groups.The aliphatic chain of branching has structure-(CHQ) v-, wherein v is 1-6, and Q is hydrogen or aliphatic group; But Q should be aliphatic group at least one situation.Term aliphatic chain comprises alkyl chain, alkenylene chain and alkynyl chain, and wherein alkyl, thiazolinyl and alkynyl as above define.
Phrase used herein " is optionally substituted " " to be substituted or not to be substituted " with phrase and is used interchangeably.Compound of the present invention described herein can optionally be replaced by one or more substituting groups, for example summary description above of described substituting group, or specific category of the present invention, subclass and thing class are illustrated.Variable R described herein 1, R 2, R 3and R 4and other variable comprises specific group, for example alkyl and aryl.Unless otherwise indicated, otherwise for variable R 1, R 2, R 3and R 4other variable wherein comprising, each specific group can optionally be replaced by one or more substituting groups described herein.Each substituting group of special groups is further optionally replaced by 1-3 halogen, cyano group, oxo, alkoxyl group, hydroxyl, amino, nitro, aryl, cyclic aliphatic, heterocycle aliphatic series, heteroaryl, haloalkyl and alkyl.For example, alkyl can be replaced by alkyl alkylthio base, and alkyl alkylthio base can optionally be replaced by 1-3 halogen, cyano group, oxo, alkoxyl group, hydroxyl, amino, nitro, aryl, haloalkyl and alkyl.As other example, the cycloalkyl moiety of (cycloalkyl) carbonylamino can optionally be replaced by 1-3 halogen, cyano group, alkoxyl group, hydroxyl, nitro, haloalkyl and alkyl.When two alkoxyl groups and identical atom or adjacent atom in conjunction with time, the atom that two alkoxyl groups can be attached to them forms ring jointly.
Term used herein " is substituted ", no matter whether has term " optionally " above, refers in given structure with the substituent group displacement hydrogen group of specifying.Concrete substituting group is described in above definition and following compound is described and embodiment in.Unless otherwise indicated, otherwise optional substituted group can have substituting group in the each commutable position of group, and in the time that more than one position in any given structure can be replaced by the substituting group of the more than one group that is selected from appointment, can be identical or different at each position substituting group.Ring substituents (for example Heterocyclylalkyl) can encircle with another (for example cycloalkyl) combination, and to form spiral shell-dicyclo member ring systems, that is, two rings are shared a shared atom.The present invention expection substituent be combined as cause forming stable or in those combinations of chemically feasible compound.
Phrase used herein " stable or chemically feasible " refer to when stand certain condition with allow their production, detection and preferably they recovery, purifying and during for the purposes of one or more objects disclosed herein, substantially indeclinable compound.In some embodiments, stable compound or be when remaining at 40 ℃ or lower temperature at chemically feasible compound, moisture or other chemical reactivity condition not in the presence of, it does not substantially change within least one week.
Phrase used herein " enantioselectivity ground preparation " refers to that asymmetric synthesis preparation is rich in enantiotopic compound.This is further defined as one or more technology that use, the compound of expecting with high enantiomerism excessive (, 60% or more) preparation.The technology comprising can comprise use chiral raw material (for example, chirality pond is synthetic), uses chiral auxiliary(reagent) and chiral catalyst, and applies asymmetric induction.
" enantiomerism is excessive " used herein or " e.e. " refer to the optical purity of compound.
" interior type: external form " used herein refers to the ratio of endo isomer and exo isomer.
" enantiomerism ratio " used herein or " e.r. " are the ratio of a kind of per-cent of enantiomer and the per-cent of another kind of enantiomer in mixture.
" protecting group " used herein is defined as to be incorporated in molecule and in chemical reaction subsequently, reacts to prevent it to change the functional group being present in molecule, therefore obtains the group of chemo-selective.In step below in synthetic, it is removed from molecule.For example, the hydrogen on the replaceable amine of carbobenzoxy-(Cbz) (Cbz) group, to prevent that it from reacting with electrophilic reagent, Cbz group can be removed by hydrolysis in the step below subsequently.
Acid used herein and amine protecting group be known in the art (referring to; for example; T.W. Greene and P.G.M Wutz; " Protective Groups in Organic Synthesis (protecting group in organic synthesis) "; the 3rd edition; John Wiley & Sons, Inc. (1999)).Example for sour suitable protecting group comprises tert.-butoxy, benzyloxy, allyloxy and methoxymethoxy.The example that is used for the suitable protecting group of amine comprises 9-fluorenyl methyl carbamate, tertiary butyl carbamate, benzylamino manthanoate, trifluoroacetamide and para toluene sulfonamide.
" significant quantity " used herein is defined as giving result for the treatment of required amount through the patient for the treatment of, and the age based on patient, surface-area, weight and situation are determined conventionally.The mutual relationship (based on milli gram/m body surface) of animal and human's dosage is described in the people such as Freireich, Cancer Chemother. Rep., 50:219 (1966).Body surface area can roughly be determined by patient's height and weight.Referring to, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970)." patient " used herein refers to and comprises people by Mammals.
Unless otherwise indicated, otherwise structure described herein is also intended to comprise all isomeric form (for example, enantiomerism, diastereo-isomerism and how much (or conformation) isomeries) of structure; For example,, for the R of each asymmetric center and S configuration, (Z) and (E) double bond isomer and (Z) and (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention and enantiomerism, diastereo-isomerism and how much (or conformation) heterogeneous mixtures are within the scope of the invention.Unless otherwise indicated, otherwise all tautomeric forms of compound of the present invention within the scope of the invention.
In addition, unless otherwise indicated, otherwise being also intended to comprise difference, structure described herein is only to exist one or more compounds that are rich in isotopic atom.For example,, except being replaced hydrogen or be rich in by deuterium or tritium 13c or 14the carbon displacement carbon of C, has the compound of structure of the present invention within the scope of the invention.Such compound for example can be used as analysis tool or probe in biology is measured.
" EDC " used herein is 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, " HOBt " is I-hydroxybenzotriazole, and " THF " is tetrahydrofuran (THF), and " Cbz " is carbobenzoxy-(Cbz), " DCM " is methylene dichloride, and " Boc " is tert-butoxycarbonyl.
Used herein " 1h NMR " represent proton magnetic resonance (PMR), " TLC " represents thin layer chromatography.
embodiment
On the one hand, the invention provides method and the intermediate for the production of the bicyclic derivatives of formula Ia or Ib:
Figure 691593DEST_PATH_IMAGE010
Wherein:
Ring A is C 3-12cyclic aliphatic ring;
Ring B is C 3-12heterocycle aliphatic series ring, it contains other 0-2 heteroatoms that is selected from independently of one another O, N and S, and it can optionally be replaced by 1-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group, aryl and hydroxyl;
R 1for H or protecting group; With
R 2for H or C 1-12aliphatic series.
In one embodiment, ring A is C 3-6cyclic aliphatic ring.
More especially, ring A is cyclopentyl.
More especially, ring A is
Figure 694184DEST_PATH_IMAGE011
.
In another embodiment, ring A is cyclopropyl.
More especially, ring A is 1,1-dimethyl cyclopropyl.
More especially, ring A is
Figure 217569DEST_PATH_IMAGE012
.
In one embodiment, ring B is aryl.
More especially, ring B is phenyl.
More especially, ring B is:
Figure 335829DEST_PATH_IMAGE013
.
In one embodiment, ring B is the ring of 5 yuan of heterocycles.
In one embodiment, ring B is:
Figure 577455DEST_PATH_IMAGE014
.
In another embodiment, ring B is replaced by aryl rings, and described aryl rings is optionally replaced by 1-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group and hydroxyl.
More especially, ring B is:
Figure 852578DEST_PATH_IMAGE015
。
In one embodiment, R 1for H.
In another embodiment, R 1for protecting group.
More especially, R 1for tertiary butyl carbamate (Boc).
In one embodiment, R 2for H.
In another embodiment, R 2for C 1-12aliphatic series.
More especially, R 2for C 1-6alkyl.
In one embodiment, R 2for methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, the tertiary butyl, n-pentyl or isopentyl.
More especially, R 2for isobutyl-.
In another embodiment, R 2for the tertiary butyl.
In another embodiment, R 2for cyclic aliphatic ring.
Relate on the other hand a kind of for the compound via formula Ic to Ih, the method for the compound of enantioselectivity ground preparation formula Ia or Ib:
。
Under existing, the compound that described method is included in formula III makes the step of the compound carboxylation of formula IIa or IIb:
，
Wherein R a1for protecting group,
Figure 450152DEST_PATH_IMAGE018
；
Wherein R 3for protecting group or C 1-12aliphatic series, and R 4for H or C 1-4the aliphatic series of non-branching.
In one embodiment, R 1afor tertiary butyl carbamate (Boc).
In one embodiment, make the step of the compound carboxylation of formula II have the compound of formula III a:
Figure 528966DEST_PATH_IMAGE019
。
In another embodiment, make the step of the compound carboxylation of formula II have the compound of formula III b:
Figure 26944DEST_PATH_IMAGE020
。
In one embodiment, R 3for C 1-12aliphatic series.
More especially, R 3for C 1-6alkyl.
In one embodiment, R 3be selected from methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, the tertiary butyl, normal-butyl, n-pentyl and isopentyl.
More especially, R 3for the tertiary butyl.
In another embodiment, R 3for protecting group.
In one embodiment, R 4for H.
In another embodiment, R 4for C 1-4non-branching aliphatic series.
More especially, R 4for methyl.
In one embodiment, carboxylation step comprises the compound of processing formula IIa or IIb with carbonic acid gas and lithium alkali under aprotic solvent exists.
In one embodiment, aprotic solvent is selected from toluene, ethyl acetate, benzene and methyl tertiary butyl ether (MTBE).
More especially, aprotic solvent is MTBE.
In one embodiment, lithium alkali is s-butyl lithium.
In one embodiment, method of the present invention obtains the mixture of the product that comprises I-1a (external form), I-3 (external form), I-2 (interior type) and I-4 (interior type).
In one embodiment, after carboxylation, in the mixture of the compound (exo isomer) of contained Ia and Id and the compound (endo isomer) of formula Ic and Ie, the weight percent of combination is 100 % by weight.
In one embodiment, the ratio of the combination weight per-cent of the combination weight per-cent of Ia and Id (exo isomer) and Ic and Ie (endo isomer) is 60:40 at least.
More especially, external form/interior type ratio is 80:20 at least.
More especially, external form/interior type ratio is 90:10 at least.
More especially, external form/interior type ratio is 95:5 at least.
More especially, external form/interior type ratio is 97:3 at least.
In one embodiment, described method also comprises the step of removing the compound of a part of formula Ic and/or Ie from product mixtures.
More especially, by making the compound crystal of formula Ia or Ib, remove the compound of formula Ic and/or Ie.
In another embodiment, by making the compound recrystallization of formula Ia or Ib, remove the compound of formula Ic and/or Ie.
In one embodiment, the ratio of the weight percent of Ia and Id is 60:40 at least.
More especially, the ratio of the weight percent of Ia and Id is 80:20 at least.
More especially, the ratio of the weight percent of Ia and Id is 90:10 at least.
More especially, the ratio of the weight percent of Ia and Id is 95:5 at least.
More especially, the ratio of the weight percent of Ia and Id is 99:1 at least.
More especially, the ratio of the weight percent of Ia and Id is 99.6:0.4 at least.
More especially, the ratio of the weight percent of Ia and Id is 100:0 at least.
Relate on the other hand a kind of method of the compound for the preparation of formula 10:
Figure 798591DEST_PATH_IMAGE021
，
Wherein R 2for H, C 1-12aliphatic series or protecting group, and Z 2for H or protecting group, said method comprising the steps of:
A. under existing, the compound of formula III forms the 2-negatively charged ion of the compound of formula IIa:
Figure 811546DEST_PATH_IMAGE022
，
Wherein R 1aa as above defines with ring,
Figure 694051DEST_PATH_IMAGE023
Wherein R 3and R 4as above definition;
B. use the 2-negatively charged ion of carbon dioxide treatment step a, with the compound of enantioselectivity ground production Ia; With
C. make the compound of formula Ia react with the compound of formula 26:
，
Wherein Z 3for protecting group.
In one embodiment, the compound of formula III is the compound of formula III a.
In another embodiment, the compound of formula III is the compound of formula III b.
In one embodiment, the compound of formula 26 is the compound of formula 26-a:
Figure 598870DEST_PATH_IMAGE025
。
In another embodiment, the compound of formula 26 is the compound of formula 26-b:
Figure 36805DEST_PATH_IMAGE026
。
Relate in one aspect to the compound of the formula Ia-1 preparing by method disclosed herein:
Figure 457422DEST_PATH_IMAGE027
。
Relate on the other hand the compound of the formula Ia-2 preparing by method disclosed herein:
Figure 929992DEST_PATH_IMAGE028
。
Relate on the other hand the compound of the formula Ia-3 preparing by method disclosed herein:
Figure 309020DEST_PATH_IMAGE029
。
Relate on the other hand the compound of the formula Ia-4 preparing by method disclosed herein:
Figure 234251DEST_PATH_IMAGE030
。
Relate in one aspect to the compound of the formula 10-a preparing by method disclosed herein:
Figure 68346DEST_PATH_IMAGE031
。
In one embodiment, the compound of formula 10 is the compound of formula 10-a, wherein Z 2for H, and R 2for the tertiary butyl.
Relate on the other hand the compound of the formula 10-b preparing by method disclosed herein:
Figure 129843DEST_PATH_IMAGE032
。
Relate on the other hand the compound of the formula 10-c preparing by method disclosed herein:
。
In one embodiment, the compound of formula 10 is the compound of formula 10-b, wherein Z 2for H, and R 2for the tertiary butyl.
Relate on the other hand the compound of the formula 10-d preparing by method disclosed herein:
Figure 92300DEST_PATH_IMAGE034
。
method and intermediate
On the one hand, the invention provides a kind of method and intermediate of the compound for the preparation of formula Ia, as scheme I general introduction, wherein R 1, R 2, R 3, R 4with ring A as previously defined.
Scheme I
Figure 120299DEST_PATH_IMAGE035
By first form the 2-negatively charged ion of formula IIa under the compound existence of formula III, realize the carboxylation of the compound of formula IIa.In order to form similar negatively charged ion, referring to, for example, the people such as Daniel. J. Pippel, J. Org. Chem., 1998,63,2; The people such as Donald J. Gallagher, J. Org. Chem., 1995,60 (22), 7092-7093; The people such as Shawn T. Kerrick, J. Am. Chem. Soc., 1991,113 (25), 9708-9710; The people such as Donald J. Gallagher, J. Org. Chem., 1995,60 (25), 8148-8154; With the people such as Peter Beak, J. Am. Chem. Soc., 1994,116 (8), 3231-3239.Under existing by the compound at formula III, with strong lithium alkali (for example, s-butyl lithium or isopropyl lithium) at suitable aprotic solvent (for example, MTBE, Anaesthetie Ether or toluene) in the compound of processing formula IIa, the 2-negatively charged ion (not showing in scheme I) of preparation formula IIa.
The optically active compound of formula III can be induced enantioselectivity carboxylation, with obtain the enantiomerism excessive (e.e.) with about 10%-approximately 95% product (referring to, for example, the people such as Beak, J. Org. Chem., 1995,60,8148-8154).Under formula III exists, the compound of formula IIa can be used carbon dioxide treatment, and to obtain the mixture of external form/interior type compound, wherein external form/interior type ratio is 60:40,80:20,90:10,95:5 or is greater than 98:2.
Reference scheme I, uses the compound of known method preparation formula IIa, wherein R 1afor for example tert-butoxycarbonyl (Boc).Referring to, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (protecting group in organic synthesis), the 3rd edition, John Wiley and Sons, Inc. (1999).
The compound of formula III can be prepared as shown in scheme II.Referring to, for example, the people such as D. Stead, Org. Letters, 2008,10,1409-1412.
Scheme II
Figure 301881DEST_PATH_IMAGE036
In scheme II, (±)-trans-hexanaphthene-1,2-diamines decomposes with tartrate, so that the diamines of the stereochemistry character with expectation to be provided.The diamines obtaining is converted into the compound of the expectation of formula III subsequently via the known reaction of professional and technical personnel.
The compound that scheme III describes formula 26 reacts with the compound of formula Ia, to form the compound of formula 28, wherein R 2as above definition.
Scheme III
Figure 304603DEST_PATH_IMAGE037
In scheme III, under coupling reagent exists, bicyclic amino group ester (the wherein R of formula Ia 2for the tertiary butyl) react (wherein Z with the shielded amino acid of formula 26 3for amine protecting group, and can under acidity, alkalescence or hydrogenation conditions, remove, described condition is different from for removing R 2those of protecting group), to obtain the amide-ester of formula 10.Remove protecting group Z from the amide-ester of formula 10 2, to obtain the amine-ester compound of formula 28.
In another embodiment, the compound of formula 28 is the intermediate in synthesizing according to the proteinase inhibitor of scheme IV.
Scheme IV
Figure 204426DEST_PATH_IMAGE038
Scheme IV is disclosed in U.S. Patent number 7,776,887, and its all content is incorporated herein by reference.
In scheme IV, under coupling reagent exists, (it can as described hereinly prepare the bicyclic amino group ester of formula Ia, wherein R 2for the tertiary butyl) react (wherein Z with the shielded amino acid of formula 26 2for amine protecting group, and can under acidity, alkalescence or hydrogenation conditions, remove, described condition is different from for removing R 2those of protecting group), to obtain the amide-ester of formula 10.Remove protecting group Z from the amide-ester of formula 10 2, to obtain the amine-ester compound of formula 28.Under coupling reagent exists, reacting with shielded amino acid 29 containing aminocompound of formula 28, obtains the tripeptides of formula 30.Remove the protecting group Z in the tripeptides of formula 30, the free amino-tripeptides of formula 31 is provided.Under coupling reagent exists, the amino-tripeptides of formula 31 reacts with pyrazine-2-formic acid of formula 32, obtains the acid amides-tripeptide ester of formula 33.Make the ester hydrolysis of the acid amides-tripeptide ester of formula 33, the amido-tripeptide acid of formula 34 is provided.Under coupling reagent exists, the amido-tripeptide acid of formula 34 reacts with the amino-oxyamide of formula 18, obtains the hydroxyl-peptide of formula 35.In last step, make the hydroxyl oxidize of the compound of formula 35, the compound of formula 4 is provided.
In another embodiment, the method for scheme III can be amplified in proportion for scale operation, for example, and in manufactory.Scale operation can for example be amplified in proportion and be greater than 1000 kilograms.
Although in the some parts of scheme I-IV, for some compounds, individual isomer is only described, the present invention is intended to comprise all steric isomers of compound.
Describe following non-limiting example, make to more fully understand the present invention.These embodiment are only for illustration purpose, and should not regard as by any way and limit the scope of the invention.
Embodiment
Embodiment 1:N-tert-butoxycarbonyl-3-azabicyclo [3.3.0] octane (6).
Figure 770537DEST_PATH_IMAGE039
Method 1
Under nitrogen, band stirs, in the 2L tri-neck round-bottomed flasks of outfit mechanical stirrer, 500 mL feed hoppers and thermometer, pack 3-azabicyclo [3.3.0] nonane hydrochloride (100 g into, 0.677 mol), salt of wormwood (187 g, 1.35 mol), MTBE (220 mL) and water (160 mL).Mixture is cooled to 14-16 ℃.In 500 mL Erlenmeyer flasks, pack Boc into 2o (di-tert-butyl dicarbonic acid ester) (145 g, 0.644 mol) and MTBE (190 mL).Stir the mixture, until complete dissolving.Solution poured in feed hopper and join in reaction mixture, keeping temperature of reaction lower than 25 ℃.Add water (290 mL), with dissolved solids, and mixture is stirred to 10-15 minute.Remove after water 5% water-based NaHSO for organic phase 4washing (twice, each 145 mL), then water (145 mL) washing.Organic phase is concentrated, add MTBE (1.3 L), to obtain the MTBE solution of title compound.Referring to, for example, R.Griot, Helv. Chim. Acta., 42,67 (1959).
Method 2
By salt of wormwood (187 g, 1.35 mol) water (160 mL) solution join 3-azabicyclo [3.3.0] octane hydrochloride (100 g, 0.677 mol) and the mixture of MTBE (220 mL) in, obtained is cooled to 14-16 ℃ by mixture.Add Boc 2mTBE (190 mL) solution of O (145 g, 0.644 mol) keeps temperature lower than 35 ℃ simultaneously.After adding, mixture is stirred 1 hour to subsequent filtration.MTBE for solid (50 mL) washing.Separation of phases subsequently, 5% water-based NaHSO for organic phase 4the washing of (twice, each 145 mL) and water (145 mL).Under vacuum, be concentrated into subsequently 300 mL.Add MTBE (300 mL), mixture is concentrated, to reduce water concentration to being less than 550 ppm.With MTBE (400 mL) dilution enriched material, so that the MTBE solution of title compound to be provided.
Embodiment 2:(1S, 3aR, 6aS)-tertiary butyl 2-((S)-2-(benzyl oxygen base carbonylamino)-3,3-dimethyl butyrate acyl group) also [c] pyrroles-1-manthanoate (27) of octahydro pentamethylene.
Figure 931260DEST_PATH_IMAGE040
Method 1
Be equipped with the 3L tri-neck round-bottomed flask nitrogen purging several minutes of overhead, condenser, thermopair and nitrogen outlet.In independent flask, the water dilution of 442 mL for sulfuric acid (46.2 mL, 0.867 mol).Make solution slightly cooling.In reaction flask, pack Cbz-L-Terleu dicyclohexyl amine salt (330.0 g, 0.739 mol) into.MTBE (1620 mL) is joined in reactor, stir the mixture, so that salt suspension.The sulphuric acid soln of as above preparation was joined in reactor through approximately 10 minutes, maintain the temperature at 20 ± 5 ℃.At room temperature, by mixture stir about 1 hour, water (455 mL) slowly dilutes subsequently.Stop stirring, make each layer of sedimentation.Take out water, so that the colourless solution of pH 1 of 1100mL to be provided.In remaining organic phase in flask, pack other water (200 mL) into.At room temperature by mixture stir about 1 hour.Stop stirring, make each layer of sedimentation.Take out water, so that the colourless solution of pH 2 of 500mL to be provided.Organic phase is heated to approximately 35 ℃, with DMF (300 mL) dilution, under decompression, is concentrated into the point that distillation is significantly slowed down, leave the enriched material of approximately 500 mL.Without rinsing, enriched material is transferred to the Xiao Te bottle of 1L.Enriched material (colourless solution of clarification) weighs 511.6 g.Based on measured in solution analysis and solution weight, solution contains 187.2 g (0.706 mol) carboxyl benzyl-S-Leucines (Cbz-L-Terleu).
Pack HOBTH into being equipped with in the four neck round-bottomed flasks of 5L of overhead, thermopair, feed hopper and nitrogen inlet 2o (103.73 g, 0.678 mol, 1.20 molar equivalents), EDCHCl (129.48 g, 0.675 mol, 1.20 molar equivalents) and DMF (480 mL).Slurry is cooled to 0-5 ℃.The sour DMF of the Cbz-L-Terleu of 36.6 % by weight (491.3 g, 0.745 mol, 1.32 molar equivalents) solution was joined in reaction mixture through 47 minutes, maintain the temperature at 0-5 ℃ simultaneously.Reaction mixture is stirred 1 hour 27 minutes.The isopropyl acetate of 3-azabicyclo (3.3.0) octane-2-formic acid-tertiary butyl ester (28.8 % by weight, 414.3 g, 0.564 mol) solution was added through 53 minutes, keep temperature of reaction at 0-5.1 ℃ simultaneously.Reaction mixture was warmed to 20 ± 5 ℃ through approximately 1 hour.4-methylmorpholine (34.29 g, 0.339 mol, 0.60 molar equivalent) was added through 5 minutes.Reaction mixture is stirred 16 hours, subsequently isopropyl acetate (980 mL) is joined in reaction soln.In 4 minutes by histamine 2 HCl (41.58 g, 0.226 mol, 0.40 molar equivalent) water (53.02 g) solution join in reaction mixture, then add 4-methylmorpholine (45.69 g, 0.45 mol, 0.80 molar equivalent).After 3.5 hours, to reaction mixture sampling.Add water (758 mL), by mixture stir about 20 minutes, sedimentation subsequently 11 minutes.Separation of phases.Isopropyl acetate for water (716 mL) extraction, merges organic phase.By add 37 % by weight hydrochloric acid (128.3 mL) in water (1435 ml), preparation 1 N water-based hydrochloric acid.Organic phase is used 1N salt acid elution approximately 20 minutes.By dissolving salt of wormwood (171 g, 1.23 mol, 2.19 molar equivalents) in water (1540 mL), preparation 10 % by weight water-based solution of potassium carbonate.Organic phase is washed approximately 20 minutes with 10 % by weight water-based solution of potassium carbonate.(1862.1 g), stands measured in solution to sample the light yellow organic solution of final clarification.Based on the weight of measured in solution and solution, the product of the title compound that solution contains 238.3 g (0.520 mol).
1H?NMR?(DMSO-d 6，500?MHz)：δ?7.37?ppm?(5?H，s)，7.25-7.33?ppm?(1?H，m)，5.03?ppm?(2?H，s)，4.17?ppm?(1?H，d)，3.98?ppm?(1?H，d)，3.67-3.75?ppm?(2?H，m)，2.62-2.74?ppm?(1?H，m)，2.48-2.56?ppm?(1?H，m)，1.72-1.89?ppm?(2?H，m)，1.60-1.69?ppm?(1?H，m)，1.45-1.58?ppm?(2?H，m)，1.38?ppm?(9?H，s)，1.36-1.42?ppm?(1?H，m)，0.97?ppm?(9?H，s)。
Method 2
By salt of wormwood, (73.3 water (220 mL) solution g) join (1S, 2S, 5R) (in 80.0 isopropyl acetate (400 mL) suspension g), keep temperature is approximately 20 ℃ to 3-azabicyclo [3.3.0] octane-2-carboxyl-tertiary butyl ester-barkite simultaneously.Mixture is stirred 0.5 hour, separation of phases, organic phase is washed with 25 % by weight water-based salt of wormwood (80 mL), to obtain the solution of free alkali.In independent flask, sulfuric acid (400 mL, 0.863 M) is joined in t-butyl methyl ether (640 mL) suspension of Cbz-Terleu dicyclohexyl amine salt (118.4g), keep temperature is approximately 20 ℃ simultaneously.Mixture is stirred 0.5 hour to separation of phases, organic phase water (200 mL) washing.Separation of phases, joins N-methylmorpholine (80 mL) in organic phase, it is evaporated at 40 ℃ to 80 mL, to obtain the solution of free acid in N-methylmorpholine.At 0-10 ℃, this solution is joined to EDC HCl, and (50.8 g) and HOBt hydrate (in 40.6 mixture/N-methylmorpholines (280 mL) g).At approximately 5 ℃, mixture is stirred 1 hour.At 0-20 ℃, add from above 3-azabicyclo [3.3.0] octane-2-carboxyl, the solution of tertiary butyl ester, then adds N-methylmorpholine (32 mL).Mixture being stirred 6 hours, use subsequently isopropyl acetate (600 mL) dilution, is then 1 N hydrochloric acid (400 mL) dilution.Stir after 0.5 hour separation of phases, 25 % by weight water-based salt of wormwood (400 mL) and water (80 mL) washing for organic phase.By mixture stir about 1 hour, separation of phases, to obtain the isopropyl acetate solution of title compound.
Method 3
By (1S, 2S, 5R) 3-azabicyclo [3.3.0] octane-2-carboxyl-tertiary butyl ester-barkite (1.0 equivalent) is suspended in isopropyl acetate (6 volume), at 20-25 ℃, add water (3.5 volume) solution of salt of wormwood (3.0 equivalent).Mixture is stirred 3 hours to separation of phases subsequently.Organic phase water (2 volume) washing.
Cbz-Terleu dicyclohexyl amine salt (1.05 equivalent) is suspended in isopropyl acetate (6 volume), at 20-25 ℃, adds sulfuric acid (1.3 equivalent)/water (5 volume).Mixture is stirred 30 minutes to separation of phases, organic phase water (2 times, 2.5 volumes) washing.
By two kinds of solution combinations from above, be cooled to subsequently 0-5 ℃.HOBt hydrate (1.1 equivalent) and EDC (1.1 equivalent) are suspended in mixture, mixture is stirred 6 hours.Mixture water (5 volume) washing, at 20-25 ℃, the 1B for organic phase (1 equivalent) obtaining and N-methylmorpholine (2 equivalent) are processed, to destroy excessive Acibenzolar.Mixture is used 5% salt of wormwood (5 volume), 1 N hydrochloric acid (5 volume), 5% salt of wormwood (5 volume) and water (twice, 5 volume) washing subsequently, to obtain the isopropyl acetate solution of title compound.
Embodiment 3:(1S, 3aR, 6aS) also [c] pyrroles-1-manthanoate (28) of-tertiary butyl 2-((S)-2-amino-3,3-dimethyl butyrate acyl group)-octahydro pentamethylene.
Figure 291834DEST_PATH_IMAGE041
Method 1
Nitrogen purging three times of the Buchi hydrogenator of 1L.To (the 1S that packs 12.8 % by weight of 307.8 g deals in reactor into; 3aR; 6aS)-tertiary butyl 2-((S)-2-(benzyl oxygen base carbonylamino)-3; 3-dimethyl butyrate acyl group) octahydro pentamethylene also [c] pyrroles-1-manthanoate (as embodiment 6; the method preparation of method 1) isopropyl acetate (39.39 g, 0.086 mol) solution.Isopropyl acetate (100 mL) is joined in reactor.Prepare 50% water and wet 20% Pd (OH) 2/ carbon (3.97 g) slurries in isopropyl acetate (168 mL), and pack in reactor, start to stir.Reactor is forced into 30 psig with nitrogen, ventilates and be down to normal atmosphere.Repeat twice.Then, reactor is forced into reactor with hydrogen, ventilates and be down to normal atmosphere.Repeat twice.Reactor is forced into 30 psig with hydrogen, and stirs at ambient temperature 1 hour.The Büchner funnel filtering mixt that use contains Whatman #1 filter paper, to remove catalyzer.Isopropyl acetate for filter cake (80 mL) washing.This program repeats twice again, uses the initial compounds solution of 12.8 % by weight of 617 g and 290.6 g.By the combination of materials from three hydrogenations, decompression (28 holder) distillation.To obtained solution (468.68 g) measure title compound.
1H?NMR?(DMSO-d 6，500?MHz)：δ?3.96?ppm?(1?H，d)，3.67?ppm?(1?H，dd)，3.53?ppm?(1?H，dd)，3.19?ppm?(1?H，s)，2.66-2.75?ppm?(1?H，m)，2.49-2.53?ppm?(1?H，m)，1.75-1.92?ppm?(2?H，m)，1.66-1.74?ppm?(1?H，m)，1.48-1.60?ppm?(4?H，m)，1.38?ppm?(9?H，s)，1.36-1.42?ppm?(1?H，m)，0.91?ppm?(9?H，s)。
Method 2
In hydrogenation equipment, will be from embodiment 6, the solution of the Cbz derivative 27 of method 2 joins 20% Pd (OH) 2/ water (50%, 12.2 g) in.Use hydrogen that equipment is forced into 30 psi, at approximately 20 ℃, stir 2 hours subsequently.Filtering mixt, to remove catalyzer, isopropyl acetate for filter cake (160 mL) washing.At 40 ℃, the filtrate of combination is evaporated 2-3 time with the heptane of approximately 4 volumes, to remove isopropyl acetate.Obtained is cooled to slurry to 0 ℃, filters, by product drying under reduced pressure, to obtain title compound.
Method 3
Will be from embodiment 6; (the 1S of method 3; 3aR, 6aS)-tertiary butyl 2-((S)-2-amino-3,3-dimethyl butyrate acyl group)-octahydro pentamethylene also the isopropyl acetate solution of [c] pyrroles-1-manthanoate join 20% Pd (OH) 2in (2 % by weight loads, 50% wet), by mixture hydrogenation 2 hours at 2 bar and 20-25 ℃.By removing by filter catalyzer, and wash with isopropyl acetate (2 volume).At 40 ℃, concentrate filtrate to 10 volumes, to obtain the isopropyl acetate solution of title compound.
Although we have presented multiple embodiment of the present invention, it is evident that, can change our foundation structure, so that other embodiment of utilizing Compounds and methods for of the present invention to be provided.Therefore, it should be understood that scope of the present invention is defined by the following claims, rather than limited by the specific embodiments presenting as an example.

Claims (65)

1. the method for the compound of enantioselectivity ground preparation formula Ia or Ib:
Figure 2012800346189100001DEST_PATH_IMAGE002
，
The method is via the compound of formula Ic to Ih:
Figure 2012800346189100001DEST_PATH_IMAGE004
，
Under existing, the compound that described method is included in formula III makes the step of the compound carboxylation of formula IIa or IIb:
Figure 2012800346189100001DEST_PATH_IMAGE006
，
Figure DEST_PATH_IMAGE008
，
Wherein:
Ring A is C 3-12cyclic aliphatic ring;
Ring B is C 3-12heterocycle aliphatic series ring, it contains other 0-2 heteroatoms that is selected from independently of one another O, N and S, wherein encircles B and is optionally replaced by 0-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group, aryl and hydroxyl;
R 1for H or protecting group;
R 1afor protecting group;
R 2for H, protecting group or C 1-12aliphatic series;
R 3for protecting group or C 1-12aliphatic series; With
R 4for H or C 1-3non-branching aliphatic series.
2. the process of claim 1 wherein that ring A is C 3-6cyclic aliphatic ring.
3. the method for claim 2, wherein encircling A is cyclopentyl.
4. the method for claim 3, wherein encircles A and is
Figure DEST_PATH_IMAGE010
.
5. the method for claim 2, wherein encircling A is cyclopropyl.
6. the method for claim 5, wherein encircling A is 1,1-dimethyl cyclopropyl.
7. the method for claim 6, wherein encircles A and is
Figure DEST_PATH_IMAGE012
.
8. the process of claim 1 wherein that ring B is aryl.
9. the method for claim 8, wherein encircling B is phenyl.
10. the method for claim 9, wherein encircles B and is .
11. the process of claim 1 wherein that ring B is the ring of 5 yuan of heterocycles.
The method of 12. claims 11, wherein encircles B and is
Figure DEST_PATH_IMAGE016
.
13. the process of claim 1 wherein that ring B is replaced by aryl rings, and described aryl rings is optionally replaced by 0-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group and hydroxyl.
The method of 14. claims 13, wherein encircle B and be:
Figure DEST_PATH_IMAGE018
。
15. the process of claim 1 wherein R 1for H.
16. the process of claim 1 wherein R 1for protecting group.
The method of 17. claims 16, wherein R 1for tertiary butyl carbamate (Boc).
18. the process of claim 1 wherein R 1afor protecting group.
The method of 19. claims 18, wherein R 1afor tertiary butyl carbamate (Boc).
20. the process of claim 1 wherein R 2for H.
21. the process of claim 1 wherein R 2for C 1-12aliphatic series.
The method of 22. claims 21, wherein R 2for C 1-6alkyl.
The method of 23. claims 22, wherein R 2be selected from methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, the tertiary butyl, normal-butyl, n-pentyl and isopentyl.
The method of 24. claims 23, wherein R 2for the tertiary butyl.
The method of 25. claims 21, wherein R 2for cyclic aliphatic ring.
26. the process of claim 1 wherein that the step of the compound carboxylation that makes formula IIa or IIb exists the compound of formula III a:
Figure DEST_PATH_IMAGE020
。
27. the process of claim 1 wherein that the step of the compound carboxylation that makes formula IIa or IIb exists the compound of formula III b:
Figure DEST_PATH_IMAGE022
。
28. the process of claim 1 wherein R 3for C 1-12aliphatic series.
The method of 29. claims 28, wherein R 3for C 1-6alkyl.
The method of 30. claims 29, wherein R 3be selected from methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, the tertiary butyl, normal-butyl, n-pentyl and isopentyl.
The method of 31. claims 30, wherein R 3for the tertiary butyl.
32. the process of claim 1 wherein R 4for H.
33. the process of claim 1 wherein R 4for C 1-4non-branching alkyl.
The method of 34. claims 33, wherein R 4for methyl.
35. the process of claim 1 wherein that described carboxylation step comprises the compound of processing formula II with carbonic acid gas and lithium alkali in aprotic solvent.
The method of 36. claims 35, wherein said aprotic solvent is selected from toluene, ethyl acetate, benzene and methyl tertiary butyl ether MTBE.
The method of 37. claims 36, wherein said aprotic solvent is MTBE.
The method of 38. claims 35, wherein said lithium alkali is s-butyl lithium.
39. the process of claim 1 wherein that the weight percent of combination is 100 % by weight in the mixture of the compound (exo isomer) of contained Ia and Id and the compound (endo isomer) of formula Ic and Ie.
The method of 40. claims 39, wherein said external form/interior type ratio is 60:40 at least.
The method of 41. claims 1, described method also comprises the compound of removing a part of formula Ic and Ie from described mixture.
The method of 42. claims 41, wherein by making the compound crystal of formula Ia remove the compound of formula Ic and Ie.
The method of 43. claims 41, wherein by making the compound recrystallization of formula Ia remove the compound of formula Ic and Ie.
44. the process of claim 1 wherein that the ratio of weight percent of Ia and Id is 60:40 at least.
45. 1 kinds of methods for the preparation of the compound of formula 10:
Figure DEST_PATH_IMAGE024
，
Said method comprising the steps of:
A. under existing, the compound of formula III forms the 2-negatively charged ion of the compound of formula IIa:
Figure DEST_PATH_IMAGE026
，
Figure DEST_PATH_IMAGE028
；
B. use the negatively charged ion of carbon dioxide treatment step a, with the compound of enantioselectivity ground production Ia; With
C. under coupling reagent exists, the compound of formula Ia is reacted with the compound of formula 26,
Figure DEST_PATH_IMAGE030
；
Wherein:
Ring A is C 3-12cyclic aliphatic ring;
R 1for H or protecting group;
R 2for H, protecting group or C 1-12aliphatic series;
R 3for protecting group or C 1-12aliphatic series;
R 4for H or C 1-3non-branching aliphatic series;
Z 2for H or protecting group; With
Z 3for protecting group.
The method of 46. claims 45, the compound of wherein said formula III is formula III a:
。
The method of 47. claims 45, the compound of wherein said formula III is formula III b:
。
The method of 48. claims 45, the compound of wherein said formula 26 is formula 26-a:
。
The method of 49. claims 45, the compound of wherein said formula 26 is formula 26-b:
Figure DEST_PATH_IMAGE038
。
The method of 50. claims 45, the compound of wherein said formula 10 is formula 10-a:
。
The method of 51. claims 50, wherein Z 2for H, and R 2for the tertiary butyl.
The method of 52. claims 45, the compound of wherein said formula 10 is formula 10-b:
。
The method of 53. claims 45, the compound of wherein said formula 10 is formula 10-c:
。
The method of 54. claims 53, wherein Z 2for H, and R 2for the tertiary butyl.
The method of 55. claims 45, the compound of wherein said formula 10 is formula 10-d:
Figure DEST_PATH_IMAGE046
。
56. 1 kinds of methods for the preparation of the compound of formula 4:
，
Said method comprising the steps of:
A. under the compound of formula III exists, make compound and alkali and the CO of formula II-a 2reaction, with the compound of preparation formula I-1a;
B. under coupling reagent exists, the compound of formula Ia is reacted, to form the compound of formula 10 with the compound of formula 26;
C. remove Z from the compound of formula 10 2, to obtain the compound of formula 28:
Figure DEST_PATH_IMAGE050
；
D. under coupling reagent exists, the compound of formula 28 is reacted with the compound of formula 29:
Figure DEST_PATH_IMAGE052
To obtain the compound of formula 30:
Figure DEST_PATH_IMAGE054
Wherein Z is amine protecting group;
E. remove the protecting group Z in the compound of formula 30, to obtain the compound of formula 31:
；
F. under coupling reagent exists, the compound of formula 31 is reacted with the compound of formula 32:
Figure DEST_PATH_IMAGE058
To obtain the compound of formula 33:
Figure DEST_PATH_IMAGE060
；
G. make the ester hydrolysis of the compound of formula 33, to obtain the compound of formula 34:
Figure DEST_PATH_IMAGE062
；
H. under coupling reagent exists, the compound of formula 34 is reacted with the compound of formula 18:
Figure DEST_PATH_IMAGE064
To obtain the compound of formula 35:
; With
I. make the compound oxidation of formula 35, to obtain the compound of formula 4.
The method of 57. claims 56, wherein said method is amplified in proportion for scale operation.
The compound of the 58. formula Ia-1 that prepare by the method for claim 1:
Figure DEST_PATH_IMAGE068
。
The compound of the 59. formula Ia-2 that prepare by the method for claim 1:
。
The compound of the 60. formula Ia-3 that prepare by the method for claim 1:
Figure DEST_PATH_IMAGE072
。
The compound of the 61. formula Ia-4 that prepare by the method for claim 1:
。
The compound of 62. its formula 10-a that prepare by the method for claim 45:
Figure DEST_PATH_IMAGE076
。
The compound of the 63. formula 10-b that prepare by the method for claim 45:
Figure DEST_PATH_IMAGE078
。
The compound of the 64. formula 10-c that prepare by the method for claim 45:
Figure DEST_PATH_IMAGE080
。
The compound of the 65. formula 10-d that prepare by the method for claim 45:
。
CN201280034618.9A 2011-05-13 2012-05-11 Processes and intermediates Pending CN103814001A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201161486125P 2011-05-13 2011-05-13
US61/486,125 2011-05-13
PCT/US2012/037509 WO2012158513A1 (en) 2011-05-13 2012-05-11 Processes and intermediates

Publications (1)

Publication Number Publication Date
CN103814001A true CN103814001A (en) 2014-05-21

Family

ID=47177277

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201280034618.9A Pending CN103814001A (en) 2011-05-13 2012-05-11 Processes and intermediates

Country Status (4)

Country Link
EP (1) EP2707347A1 (en)
CN (1) CN103814001A (en)
IL (1) IL229426A0 (en)
WO (1) WO2012158513A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103435532B (en) * 2013-09-02 2015-07-08 苏州永健生物医药有限公司 Synthetic method of boceprevir intermediate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1946692A (en) * 2004-02-27 2007-04-11 先灵公司 3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis C virus NS3 serine protease
CN101291909A (en) * 2005-08-19 2008-10-22 弗特克斯药品有限公司 Processes and intermediates

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SV2003000617A (en) 2000-08-31 2003-01-13 Lilly Co Eli INHIBITORS OF PROTEASA PEPTIDOMIMETICA REF. X-14912M
CA2672701A1 (en) * 2006-12-20 2008-07-10 Schering Corporation Process for the preparation of 6,6-dimethyl-3-azabicyclo- [3.1.0]- hexane compounds utilizing bisulfite intermediate
AU2011261349A1 (en) * 2010-06-03 2012-12-06 Vertex Pharmaceuticals Incorporated Processes and intermediates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1946692A (en) * 2004-02-27 2007-04-11 先灵公司 3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis C virus NS3 serine protease
CN101291909A (en) * 2005-08-19 2008-10-22 弗特克斯药品有限公司 Processes and intermediates

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
RUI ZHANG，ET AL.: "Design, Synthesis and Evaluationof Poly-L-Proline Type-II Peptide Mimics Based on the 3-Azabicyclo[3.1.0]hexane System", 《J.ORG.CHEM.》 *
SISKA HENDRATA，ET AL.: "Syntheses of dipeptides containing (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxylic acid (4),(1R,5S)-spiro[3-azabicyclo[3.1.0].....(1S,5R)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxylic acid（6）", 《TETRAHEDRON LETTERS》 *
VALENTIN KÖHLER，ET AL.: "Enantioselective Biocatalytic Oxidative Desymmetrization of Substituted Pyrrolidines", 《ANGEW. CHEM. INT. ED.》 *

Also Published As

Publication number Publication date
EP2707347A1 (en) 2014-03-19
IL229426A0 (en) 2014-01-30
WO2012158513A1 (en) 2012-11-22

Similar Documents

Publication Publication Date Title
CN101291909B (en) Processes and intermediates
CN103108865A (en) Processes and intermediates
CN102639499A (en) Processes and intermediates
CN110291065A (en) A kind of new isoindoline derivative, its pharmaceutical composition and application
CA2220407A1 (en) Diazepino-indoles as phosphodiesterase iv inhibitors
EP3331889B1 (en) Cyclic compounds useful as modulators of tnf alpha
CN114057702A (en) Novel inhibitor of coronavirus main protease and preparation method and application thereof
TW538043B (en) Alatrofloxacin parenteral compositions
CN103814001A (en) Processes and intermediates
CN103748059A (en) Process for the preparation of protease inhibitors
CN1374947A (en) Synthetic reoutes for the preparation of rhionvirus protease inhibitor and key intermediates
CA2230303C (en) Polymorphs of the prodrug 6-n-(l-ala-l-ala)-trovafloxacin
CN116396356A (en) Functionalized polypeptide derivative as inhibiting virus main protease, preparation method and application thereof
CN116355044A (en) Amide compound, preparation method and application thereof
BLOG Uncategorized Comments Off on MIRABEGRON
MX2008002322A (en) Processes and intermediates
AU2012216599A1 (en) Processes and intermediates

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1198029

Country of ref document: HK

C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20140521

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1198029

Country of ref document: HK