CN108117582A - Big ring epoxy ketone peptides and preparation method thereof and medical usage - Google Patents

Big ring epoxy ketone peptides and preparation method thereof and medical usage Download PDF

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Publication number
CN108117582A
CN108117582A CN201711492550.XA CN201711492550A CN108117582A CN 108117582 A CN108117582 A CN 108117582A CN 201711492550 A CN201711492550 A CN 201711492550A CN 108117582 A CN108117582 A CN 108117582A
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alkyl
carbon
methoxy
phe
formoxyls
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刘滔
李佳
胡永洲
周宇波
李大强
高立信
董晓武
胡小蓓
余建均
张小团
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Zhejiang University ZJU
Shanghai Institute of Materia Medica of CAS
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Zhejiang University ZJU
Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a kind of new big ring epoxy ketone peptide derivative and its optical isomer or pharmaceutically acceptable salt or their solvate.By using the compound of carboxy protective as starting material, amino acid condensation with amido protecting is protected through deamination, the protection of alkene cyclization double decomposition and decarboxylize, obtained with epoxy ketone fragment condensation again.The big ring epoxy ketone peptides with brand-new skeleton of the present invention are with good proteasome inhibition activity, there is extremely strong in-vitro multiplication inhibitory action to the Huppert's diseases such as RPMI 8226, MM.1S, NCI H929 and other a variety of solid tumor cell strains, while such compound also has good oral result.It can be in the application in the drug for preparing antitumor and immunity disease.Raw material needed for the synthesis of the compounds of this invention is easy to get.Highway route design is reasonable, and reaction condition is mild, and each yield that walks is high, easy to operate, is suitble to industrialized production.With logical formula (I) structure：

Description

Big ring epoxy ketone peptides and preparation method thereof and medical usage
Technical field
The present invention relates to drug fields, are related to a kind of Macrocyclic peptides class compound, and especially a kind of big ring epoxy ketone peptides are spread out Biology, and in particular to Macrocyclic peptides albuminoid enzyme body inhibitor derivates, the salt of the compound and with the compound or its salt class For the drug of active ingredient, available for the treatment tumor-related illness such as Huppert's disease and lymphoma mantle cell.
Background technology
Malignant tumour is to threaten one of major disease of human health, and there are about 12,700,000 cancers the whole world in 2008 to increase trouble newly Person, 7,600,000 die of cancer, by inference to the year two thousand twenty, global cancer will newly-increased 15,000,000 cancer patients, the death toll of cancer In global swift and violent rising, 13,200,000 may be increased to.With the aging trend being continuously increased with population of the size of population, in addition Various unhealthy life styles including smoking be widely present and the pollution of environment, this trend swell getting worse The prevention of knurl has become the important subject of countries in the world the world of medicine.
Proteasome is one and is prevalent in eucaryote and Archaea cells matter and endonuclear protein is compound Object controls the degradation of intracellular 80%-90% protein, in cell cycle regulating, Apoptosis, cell signalling, DNA Particularly important effect is played in the different physiological roles such as reparation, cell growth, development.Proteasome is thin by regulating and controlling to influence The level of born of the same parents' signal path key protein (such as P53, NF- κ B), and then adjustment effect is played to various vital movements.Pass through inhibition Proteasome activity can influence the degradation of intracellular multiple cyclins, promote Apoptosis.
It is found so far from proteasome, the micromolecular compound of various structures type is found to have protease inhibition body Activity shows good antitumous effect in neoplastic hematologic disorder.At present, the small molecule proteasome inhibitor clinically applied For boric acid peptides Bortezomib, Ixazomib and epoxy ketone peptides Carfilzomib.
Although Bortezomib and Carfilzomib, which is the treatment of Huppert's disease, brings hope, both It is to be administered by being injected intravenously, in order to improve the compliance of patient medication and security, for the two structure of modification Through obtaining success.Ixazomib is transformed through Bortezomib, passes through prodrug design and structural adjustment, substantially improving Absorption and the stability of object are closed, due to its good oral result, which ratified to list, be used in 2015 by FDA Treatment previously at least received a kind of multiple myeloma patients for the treatment of, however the drug can not be still avoided by boric acid base group Caused peripheral neuropathy.Therefore, design with Orally active epoxy ketone compounds Carfilzomib analog into For the emphasis of research, wherein the Oprozomib transformed through Carfilzomib causes extensive concern, the compound Oral administration biaavailability in beasle dog reaches 39%, is currently under clinical second phase research, but according to pertinent literature, The compound can cause serious dose-dependent gastrointestinal side effect, be currently being deployed corresponding dosage form during oral To solve the problems, such as this.
The content of the invention
The present invention first purpose be to provide a kind of new big ring epoxy ketone peptide derivative and its esters or they Solvate.
Specifically, the present invention provides a kind of Macrocyclic peptides analog derivative, there is logical formula (I) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate；
Wherein：
R1、R2It is each independently selected from H ,-C1-10Alkyl-D, C1-10Hydroxy alkyl ,-C2-10Unsaturated alkyl-D ,-halogenated C1-10Alkyl-D ,-C1-3Alkyl-S-C1-5Alkyl, C1-10Alkoxyalkyl, halogenated C1-10Alkoxyalkyl, C3-10Unsaturated alkane Oxygroup, C3-10Cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl.Wherein, D is N(Ra)RbOr missing；RaSelected from H, OH, C1-6Alkyl, halogenated C1-6Alkyl；RbSelected from N-terminal protecting group；
R3、R4It is each independently selected from H, C1-10Alkyl, halogenated C1-10Alkyl, aryl, aralkyl；
R5Selected from H, C1-6Alkyl, C1-6Hydroxy alkyl, halogenated C1-6Alkyl, C1-6Alkoxyalkyl, halogenated C1-6Alcoxyl Base alkyl；
R6Selected from H, C1-10Alkyl, C1-10Alkoxyalkyl, C2-10Unsaturated alkyl, cycloalkyl；
X is O, S, NH, N-C1-6Alkyl；
Y isWithOr missing, wherein R are selected from H, C1-10Alkane Base, halogenated C1-10Alkyl；
Ar is selected from unsubstituted or substitution cycloalkyl, unsubstituted or substitution Heterocyclylalkyl, unsubstituted or substitution cyclenes It is base, unsubstituted or substitution heterocycloalkenyl, unsubstituted or substitution aryl, unsubstituted or substitution aralkyl, unsubstituted or take The heteroaryl in generation, unsubstituted or substitution heteroarylalkyl, arbitrarily condensed aryl；
L is
Wherein B1It is selected from
D1、D2It is identical or different, it is respectively and independently selected from as-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkyl OC1-8Alkyl-,-SC1-8Alkyl-,-C1-8Alkyl S- ,-C1-8Alkyl SC1-8Alkyl-,-N (Rd)-、-N(Rd)C1-8Alkyl-,-C1-8 Alkyl N (Rd)-、-C1-8Alkyl N (Rd)C1-8Alkyl-,-N (Rd)C(O)-、-N(Rd)C(O)C1-8Alkyl-,-C1-8Alkyl N (Rd)C (O)-、-C1-8Alkyl N (Rd)C(O)C1-8Alkyl-,-C (O) N (Rd)-、-C(O)N(Rd)C1-8Alkyl-,-C1-8Alkyl C (O) N (Rd)-、-C1-8Alkyl C (O) N (Rd)C1-8Alkyl-,-C (O) C1-8Alkyl-,-C (O) C1-8Unsaturated alkyl-,-N (Rd)SO2-、- N(Rd)SO2C1-8Alkyl-,-C1-8Alkyl N (Rd)SO2-、-C1-8Alkyl N (Rd)SO2C1-8Alkyl-,-OC (O) C1-8Alkyl-,-C1-8 Alkyl OC (O)-,-C1-8Alkyl OC (O) C1-8Alkyl-,-C (O) OC1-8Alkyl-,-C1-8Alkyl C (O) O- ,-C1-8Alkyl C (O) OC1-8Alkyl-；RdSelected from H, C1-4Alkyl, halogenated C1-4It is alkyl, cycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, miscellaneous Aralkyl.
The substituted substituent group is optionally from halogen, nitro, amino, cyano, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxyalkyl, C1-6Alkylamino radical, halogenated C1-6Alkoxy, halogenated C1-6It is alkoxyalkyl, halogenated C1-6Alkylamino radical, C3-8Cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl.
Preferably, the present invention provides the compounds with formula (II) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvated compounds, wherein：
X is preferably O；
Y is preferred
Ring A is preferably with lower structure：
Wherein, V1、V2、V3、V4、W1、W2And W3It is each independently selected from N, C；
ReSelected from H, halogen, nitro, amino, cyano, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, C1-6 Alkoxyalkyl, C1-6Alkylamino radical, halogenated C1-6Alkoxy, halogenated C1-6Alkoxyalkyl, halogenated C1-6Alkylamino radical, C3-8 Cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl；
Z is selected from O, S ,-N (Rf)-；Wherein, RfIn the presence of or missing, selected from H, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkane Oxygroup, C1-6Alkoxyalkyl, halogenated C1-6Alkoxy, C3-8Cycloalkyl, Heterocyclylalkyl, C3-8Cycloalkenyl group, heterocycloalkenyl, virtue Base, aralkyl, heteroaryl, heteroarylalkyl；
L、R1、R2、R3、R4And R5As general formula (I) structure defines.
More specifically, the present invention provides following compounds or its pharmaceutically acceptable salt with formula (III) structure Or solvated compounds：
Wherein：
V1、V2、V3、V4And RgAs general formula (II) structure defines；
B1、D1、D2、R1And R2As general formula (I) structure defines.
Further, currently preferred compound has general formula (IV) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：
V1And V4Each independent is preferably C, N；
B1Preferably
D1And D2It is identical or different, it is preferably independently-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkane Base OC1-8Alkyl-；
R1Preferably methoxymethyl, isobutyl group, isopropyl, (N- morpholinyls) formyl-methyl, (N- morpholinyls) first Sulfonyl-ethyl；
R2Preferably benzyl, isobutyl group；
RgIt preferably is selected from H, halogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Alkoxyalkyl.
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
More specifically, the preferred compound of general formula (IV) structure of the present invention is：
N- [(8S, 11S) -11- (methoxy) -10,13- dioxos -3,4,5,7,8,9,10,11,12,13- ten 15 carbon -8- formoxyls of hydrogen -2H-1,6,9,12- benzo dioxas diazacyclo]-Phe- epoxy ketone
N- [(9S, 12S) -12- (methoxy) -11,14- dioxo -2,3,4,5,6,8,9,10,11,12,13, Ten dihydro -1,7,10,13- benzo dioxas diazacyclos of 14-, 16 carbon -9- formoxyls]-Phe- epoxy ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -3,4,5,6,7,9,10,11,12,13,14, Ten dihydro -2H-1,8,11,14- benzo dioxas diazacyclos of 15-, 17 carbon -10- formoxyls]-Leu- epoxy ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -3,4,5,6,7,9,10,11,12,13,14, Ten dihydro -1,8,11,14- benzo dioxas diazacyclos of 15-2H-, 17 carbon -10- formoxyls]-Phe- epoxy ketone
N- [(11S, 14S) -14- (methoxy) -13,16- dioxo -2,3,4,5,6,7,8,10,11,12,13, Ten tetrahydrochysene -1,9,12,15- benzo dioxas diazacyclos of 14,15,16-, 18 carbon -11- formoxyls]-Phe- epoxy ketone
N- [(12S, 15S) -15- (methoxy) -14,17- dioxo -3,4,5,6,7,8,9,11,12,13,14, Ten tetrahydrochysene -2H-1,10,13,16- benzo dioxas diazacyclos of 15,16,17-2H-, 19 carbon -12- formoxyls]-Phe- epoxies Ketone
N- [(13S, 16S) -16- (methoxy) -15,18- dioxo -3,4,5,6,7,8,9,10,13,14,15, 20 carbon -13- formoxyls of 16,17,18- ten tetrahydrochysene -2H, 12H- benzo [i] [1,11] dioxa [4,7] diazacyclo]-Phe- Epoxy ketone
N- [(7S, 10S) -7- (methoxy) -5,8- dioxo -6,7,8,9,10,11,13,14,15,16,17, 17 carbon -10- formoxyls of 18- ten dihydro -5H- pyridos [3,2-i] [1,11] dioxa [4,7] diazacyclo]-Phe- epoxies Ketone
N- [(14S, 17S) -17- (methoxy) -16,19- dioxo -6,7,8,9,10,11,14,15,16,17, 18,19- ten dihydro -13H- pyridos [2,3-i] [1,11] dioxa [4,7] 17 carbon-14s of diazacyclo-formoxyl]-Phe- Epoxy ketone
N- [(9S, 12S) -12- (methoxy) -11,14- dioxo -3,4,5,6,7,8,9,10,11,12,13, 16 carbon -9- formoxyls of 14- ten dihydro -2H- benzos [b] [1] oxa- [5,8]-diazacyclo]-Phe- epoxy ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,8,9,10,11,12, Ten tetrahydrochysenes of 13,14,15--benzo [b] [1] oxa- [5,8]-diazacyclo, 17 carbon -10- formoxyls]-Phe- epoxy ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, Ten dihydro -9H-19- methoxyl groups of 15- -17 carbon -10- formoxyls of benzo [i] [1,11] dioxa [4,7]-diazacyclo] - Phe- epoxy ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, 17 carbon -10- formoxyls of 15- ten the fluoro- benzos of dihydro -9H-19- [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- rings Oxygen ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, 17 carbon -10- formoxyls of 15- ten the fluoro- benzos of dihydro -9H-18- [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- rings Oxygen ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, 17 carbon -10- formoxyls of 15- ten the chloro- benzos of dihydro -9H-18- [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- rings Oxygen ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, Ten dihydro -9H-18- methoxyl groups of 15- -17 carbon -10- formoxyls of benzo [i] [1,11] dioxa [4,7]-diazacyclo] - Phe- epoxy ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, Ten dihydro -9H-18- methyl of 15- -17 carbon -10- formoxyls of benzo [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- Epoxy ketone
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, 17 carbon -10- formoxyls of 15- ten the chloro- benzos of dihydro -9H-17- [i] [1,11] dioxa [4,7] diazacyclo]-Phe- epoxies Ketone
N- [(10S, 13S) -13- (2- morpholino -2- oxoethyls) -12,15- dioxo -2,3,4,5,6,7,10,11, 17 carbon -10- formoxyls of 12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- Epoxy ketone
N- [(10S, 13S) -13- (3- morpholino -3- oxopropyls) -12,15- dioxo -2,3,4,5,6,7,10,11, 17 carbon -10- formoxyls of 12,13,14,15- ten dihydro -9H benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- Epoxy ketone
N- [(9S, 12S) -12- (methoxy) -11,14- dioxos -2,3,5,6,9,10,11,12,13,14- ten 16 carbon -9- formoxyls of hydrogen -8H- benzos [o] [1,4,7]-trioxa [10,13]-diazacyclo]-Phe- epoxy ketone
N- [(12S, 15S) -15- (methoxy) -14,17- dioxo -2,3,5,6,8,9,12,13,14,15,16, [1,4,7,10] four oxa- [13,16] of ten dihydro -11H- benzos [r] of 17- -19 carbon -12- formoxyls of diazacyclo]-Phe- rings Oxygen ketone
N- [(10S, 13S) -13- (2- (cyclopropylamino) -2- oxoethyls) -12,15- dioxo -2,3,4,5,6,7, 17 carbon -10- formyls of 10,11,12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7] diazacyclo Base]-Phe- epoxy ketone
N- [(10S, 13S) -13- isobutyl group -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- ten 17 carbon -10- formoxyls of dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- epoxy ketone
N- [(10S, 13S)-isopropyl -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- 12 17 carbon -10- formoxyls of hydrogen -9H-13- benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- epoxy ketone
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
More specifically, the present invention provides following compounds or its pharmaceutically acceptable salt with formula (V) structure Or solvated compounds：
Wherein：
B1Preferably
D1And D2It is identical or different, it is preferably independently-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkyl OC1-8Alkane Base-,-C1-8Alkyl OC1-8Alkyl-；
RhIt preferably is selected from H.
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
More specifically, the preferred compound of general formula (V) structure of the present invention is：
[(13S, 16S) -16- (methoxy) -15,18- dioxo -2,11- dioxa -14,17- diazas are double by N- 13 carbon -1 (23) of ring [17.3.1]-two, 19,21- triolefin -13- formoxyls]-Phe- epoxy ketone
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
Yet further, currently preferred compound has general formula (VI) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：
W1And W2Respectively preferably C, N；
Z is preferably N (C1-6Alkyl)；
B1Preferably
D1And D2It is identical or different, it is preferably independently-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkane Base OC1-8Alkyl-；
RiPreferably H.
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
More specifically, the preferred compound of general formula (VI) structure of the present invention is：
N- [(6S, 9S) -6- (methoxy) -4,7- dioxo -1,4,5,6,7,8,9,10,12,13,14,15,16, Ten dihydro -1- methyl pyrazoles of 17- simultaneously 17 carbon -9- formoxyls of [4,3-i] [1,11] dioxa [4,7] diazacyclo]-Phe- Epoxy ketone
N- [(6S, 9S) -6- (methoxy) -1- methyl -4,7- dioxo -4,5,6,7,8,9,10,12,13,14, 17 carbon -9- formoxyls of 15,16,17,18- ten tetrahydrochysene -1H- pyrazolos [4,3-i] [1] oxa- [4,7]-diazacyclo]-Phe- Epoxy ketone
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
Preferably, the present invention also provides compounds or its pharmaceutically acceptable salt or molten with formula (VII) structure Immunomodulator compounds：
Wherein：
W1And W2Respectively preferably C, N；
Z is preferably S；
B1Preferably
D1And D2It is identical or different, it is preferably independently-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkane Base OC1-8Alkyl-；
RjPreferably H, methyl.
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
More specifically, the preferred compound of general formula (VII) structure of the present invention is：
N- [(13S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10,13,14,15,16, 17 carbon -13- formoxyls of 17,18- ten dihydro -12H- thienos [2,3-i] [1,11] dioxa [4,7] diazacyclo]-Phe- Epoxy ketone
N- [(13S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10,13,14,15,16, Ten dihydro -12H-2- methYl-thiazols of 17,18- simultaneously 17 carbon -13- formyls of [4,5-i] [1,11] dioxa [4,7] diazacyclo Base]-Phe- epoxy ketone
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
Preferably, the present invention also provides compounds or its pharmaceutically acceptable salt or molten with formula (VIII) structure Immunomodulator compounds：
Wherein：
W1、W2And W3Respectively preferably C, N；
Z is preferably N；
B1Preferably
D1And D2It is identical or different, it is preferably independently-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkane Base OC1-8Alkyl-；
RkPreferably H.
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
More specifically, the preferred compound of general formula (VIII) structure of the present invention is：
N- (13S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10,13,14,15,16,17, 16 carbon -13- formoxyls of 18- ten dihydro -12H- imidazos [2,1-i] [1] [4,7,10]-three azacyclo- of oxa-]-Phe- epoxies Ketone
N- (12S, 15S) -15- (methoxy) -14,17- dioxos -6,7,8,9,12,13,14,15,16,17- ten 15 carbon -12- formoxyls of hydrogen -5H, 11H- imidazo [2,1-i] [1] [4,7,10]-three azacyclo- of oxa-]-Phe- epoxy ketone
N- (11S, 14S) -14- (methoxy) -13,16- dioxos -5,6,7,8,11,12,13,14,15,16- ten 14 carbon -11- formoxyls of hydrogen -10H- imidazos [2,1-i] [1] [4,7,10]-three azacyclo- of oxa-]-Phe- epoxy ketone
N- (3S, 6S) -3- (methoxy) -1,4- dioxos -2,3,4,5,6,7,9,10,11,12,13,14- 12 16 carbon -6- formoxyls of hydrogen -1H- pyrrolo-es [2,1-i] [1] [4,7,10]-three azacyclo- of oxa-]-Phe- epoxy ketone
N- (6S, 9S) -6- (methoxy) -4,7- dioxos -5,6,7,8,9,10,12,13,14,15,16,17- ten 16 carbon -9- formoxyls of dihydro -4H- pyrazolos [5,1-i] [1] [4,7,10]-three azacyclo- of oxa-]-Phe- epoxy ketone
N- (6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,13,14,15,16- decahydro -4H, 15 carbon -9- formoxyls of 12H- pyrazolos [5,1-i] [1] [4,7,10] three azacyclo- of oxa-]-Phe- epoxy ketone
N- (6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,12,13,14,15- decahydros -4H- [4,7,10]-three azepine ring carbon -9- formoxyls of pyrazolo [5,1-i] [1] oxa-]-Phe- epoxy ketone
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
Preferably, the present invention also provides compounds or its pharmaceutically acceptable salt or molten with formula (Ⅸ) structure Immunomodulator compounds：
Wherein：
B1Preferably
D2Preferably-C1-8Alkyl-,-C1-8Alkyl OC1-8Alkyl-；
RmPreferably H.
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
More specifically, the preferred compound of general formula (Ⅸ) structure of the present invention is：
N- [- ten hexahydro -1H- pyrrolo-es [2,1-i] of (3S, 6S, 18aS) -3- (methoxy) -1,4,14- trioxy-s [1] 16 carbon -6- formoxyls of [4,7,10] three azacyclo- of oxa-]-Phe- epoxy ketone
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
It is a further object to provide the preparation methods of above-mentioned target compound, are realized by following steps：
(1) compound 5 and the amino acid of amido protecting react to obtain compound 6, the condensation of selection under condensation reagent effect Reagent has dicyclohexylcarbodiimide/4-dimethylaminopyridine, dicyclohexylcarbodiimide/1- hydroxy benzo triazoles, N- (3- Dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride/1- hydroxy benzo triazoles, benzotriazole-N, N, N', N'- tetra- Methylurea hexafluorophosphoric acid ester/1- hydroxy benzo triazoles.0-30 DEG C of reaction temperature, when reaction time 2-8 is small, crude product can be direct For the next step；
(2) compound 6 removes Boc protecting groups under the action of trifluoroacetic acid, and crude product is directly used in the next step；
(3) compound 7 reacts to obtain compound 8 with compound 2 under condensation reagent effect, and the condensation reagent of selection has two rings Hexyl carbodiimide/4-dimethylaminopyridine, dicyclohexylcarbodiimide/1- hydroxy benzo triazoles, N- (3- dimethylaminos third Base)-N '-ethyl-carbodiimide hydrochloride/1- hydroxy benzo triazoles, benzotriazole-N, N, N', N'- tetramethylurea hexafluoro Phosphate/1- hydroxy benzo triazoles.0-30 DEG C of reaction temperature, when reaction time 2-8 is small, it is anti-that crude product can be directly used for lower step It should；
(4) compound 8 cyclization and removes carboxyl-protecting group and obtains chemical combination under the action of metallic catalyst or condensing agent Object 9, the metallic catalyst of selection is Grubbs second generation catalyst, and condensing agent is identical with (1), metal catalysed reaction temperature 30-100 DEG C, when reaction time 0.5-3 is small, 0-30 DEG C of setting-up point, when reaction time 3-8 is small, products obtained therefrom is used for down Step reaction；
(5) compound 9 reacts to obtain product Compound 10 with compound 11 under condensation reagent effect, selects condensation reagent same Step (1), gained crude product obtain sterling through column chromatography for separation.
Reaction equation：
Wherein：
R1-R4、B1、D1、D2The definition of substituent group is identical with general formula I.
The definition of ring A substituent groups is identical with general formula II.
The synthesis of wherein raw materials used compound 11 is referring to document J.Med.Chem.2009,52,3028.
It is a further object to provide the big ring epoxy ketone peptide derivative in antitumor drug is prepared Application.The tumour is selected from neoplastic hematologic disorders and breast cancer, sarcoma, lung cancer, the forefront such as myeloma, lymthoma, leukaemia Gland cancer, colon and rectum carcinoma, kidney, cancer of pancreas, neuroblastoma, glioma, head cancer, neck cancer, thyroid cancer, liver Cancer, oophoroma, carcinoma of vulva, cervix cancer, carcinoma of endometrium, carcinoma of testis, carcinoma of urinary bladder, the cancer of the esophagus, stomach cancer, nasopharyngeal carcinoma, cheek cancer, mouth Chamber cancer, gastrointestinal stromal tumor, cutaneum carcinoma.
The big ring epoxy ketone peptide derivative includes its esters or their solvate.
The drug is made of big ring epoxy ketone peptide derivative and its esters or their solvate and pharmaceutical carrier.
It is also another object of the present invention to provide the big ring epoxy ketone peptide derivatives to prepare the medicine of immunity disease Application in object.The big ring epoxy ketone peptide derivative includes its esters or their solvate.
The pharmaceutical dosage form of the present invention includes injection, freeze drying powder injection, tablet, capsule and granule etc..Drug of the present invention Administration route elect drug administration by injection, oral medication, sucking or drug delivery implant etc. as.
It is demonstrated experimentally that the big ring epoxy ketone peptides with brand-new skeleton of the present invention are with good proteasome Inhibitory activity has the Huppert's diseases such as RPMI 8226, MM.1S, NCI-H929 and other a variety of solid tumor cell strains extremely strong In-vitro multiplication inhibitory action, while such compound also have good oral result.Needed for the synthesis of the compounds of this invention Raw material is easy to get.Highway route design is reasonable, and reaction condition is mild, and each yield that walks is high, easy to operate, is suitble to industrialized production.
Description of the drawings
To proteasome inhibition activity in mouse PBMC after the big ring epoxy ketone peptides oral administrations of Fig. 1.
Specific embodiment
The present invention is further described in conjunction with the embodiments, and following embodiment is illustrative of the invention rather than with any Mode limits the present invention.
Prepare embodiment 1 2- (allyloxy) methyl benzoate (1a)
By gaultherolin (4.2ml, 33mmol), potassium carbonate (13.8g, 99mmol) and 3- bromopropenes (4.0ml, 46mmol) be placed in 100mL three-necked bottles, add in 50mL acetone, the reaction solution react under reflux conditions 18 it is small when.TLC is monitored After reaction, reaction solution is cooled to room temperature, is removed under reduced pressure solvent, add in 100ml ethyl acetate, successively with water (2 × 100ml), saturated salt solution (2 × 100ml) washs, and solvent is removed under reduced pressure after anhydrous sodium sulfate drying, column chromatography for separation obtains colourless Oily liquids 5.9g, yield 93%.1H NMR(500MHz,CDCl3) δ 7.80 (dd, J=8.0,2.0Hz, 1H), 7.44 (ddd, J =8.0,7.5,2.0Hz, 1H), 7.01-6.94 (m, 2H), 6.11-6.02 (m, 1H), 5.54-5.48 (m, 1H), 5.32-5.27 (m, 1H), 4.63 (dt, J=5.0,1.5Hz, 2H), 3.90 (s, 3H) ppm；ESI-MS:M/z=193 [M+H]+.
Prepare embodiment 2 2- (3- butene-1s-base oxygroup) methyl benzoate (1b).
Using the bromo- 1- butylene of 4- as raw material, synthesis and post processing obtain colourless oil liquid 4.0g, yield with embodiment 1 is prepared 88%.1H NMR(500MHz,CDCl3) δ 7.77 (dd, J=7.5,1.5Hz, 1H), 7.47-7.38 (m, 1H), 7.00-6.91 (m, 2H), 6.00-5.88 (m, 1H), 5.22-5.07 (m, 2H), 4.08 (t, J=6.5Hz, 2H), 3.88 (s, 3H), 2.62- 2.54(m,2H)ppm；ESI-MS:M/z=207 [M+H]+。
Prepare embodiment 3 2- (4- amylene -1- bases oxygroup) methyl benzoate (1c)
Using the bromo- 1- amylenes of 5- as raw material, synthesis and post processing obtain colourless oil liquid 5.8g, yield with embodiment 1 is prepared 80%.1H NMR(500MHz,CDCl3) δ 7.78 (dd, J=7.5,1.5Hz, 1H), 7.44 (ddd, J=8.0,7.5,1.5Hz, 1H),6.99–6.94(m,2H),5.92–5.80(m,1H),5.09–5.04(m,1H),5.02–4.98(m,1H),4.05(t,J =6.5Hz, 2H), 3.89 (s, 3H), 2.34-2.25 (m, 2H), 1.98-1.88 (m, 2H) ppm；ESI-MS:M/z=221 [M+ H]+.
Prepare embodiment 4 2- (5- hexene -1- bases oxygroup) methyl benzoate (1d)
Using the bromo- 1- hexenes of 6- as raw material, synthesis and post processing obtain colourless oil liquid 6.3g, yield with embodiment 1 is prepared 81%.1H NMR(500MHz,CDCl3) δ 7.78 (d, J=8.0Hz, 1H), 7.47-7.41 (m, 1H), 6.99-6.93 (m, 2H), 5.88-5.78 (m, 1H), 5.08-4.94 (m, 2H), 4.04 (t, J=6.5Hz, 2H), 3.88 (s, 3H), 2.17-2.10 (m, 2H),1.90–1.81(m,2H),1.65–1.57(m,2H)ppm；ESI-MS:M/z=235 [M+H]+。
Prepare embodiment 5 2- (6- heptene -1- bases oxygroup) methyl benzoate (1e)
Using the bromo- 1- heptene of 7- as raw material, synthesis and post processing obtain colourless oil liquid 6.1g, yield with embodiment 1 is prepared 75%.1H NMR(500MHz,CDCl3) δ 7.78 (d, J=8.0Hz, 1H), 7.46-7.41 (m, 1H), 6.98-6.93 (m, 2H), 5.89-5.76 (m, 1H), 5.04-4.90 (m, 2H), 4.03 (t, J=6.5Hz, 2H), 3.89 (s, 3H), 2.13-2.06 (m, 2H),1.89–1.80(m,2H),1.56–1.42(m,4H)ppm；ESI-MS:M/z=249 [M+H]+。
Prepare embodiment 6,2- (7- octene-1s-base oxygroup) methyl benzoate (1f)
Using the bromo- 1- octenes of 8- as raw material, synthesis and post processing obtain colourless oil liquid 6.1g, yield with embodiment 1 is prepared 70%.1H NMR(500MHz,CDCl3) δ 7.78 (d, J=8.0Hz, 1H), 7.46-7.40 (m, 1H), 6.99-6.92 (m, 2H), 5.87-5.75 (m, 1H), 5.05-4.90 (m, 2H), 4.03 (t, J=6.5Hz, 2H), 3.89 (s, 3H), 2.10-2.01 (m, 2H),1.88–1.79(m,2H),1.55–1.46(m,2H),1.46–1.34(m,4H)ppm；ESI-MS:M/z=263 [M+H]+.
Prepare embodiment 7, the chloro- 2- of 5- (4- amylene -1- bases oxygroup) methyl benzoate (1g)
By 5- chlorine-2-hydroxyls methyl benzoate (6.1g, 33mmol), potassium carbonate (9.1g, 66mmol) and the bromo- 1- amylenes of 5- (4.0ml, 46mmol) is placed in 100mL three-necked bottles, add in 50mL acetone, the reaction solution react under reflux conditions 18 it is small when. Reaction solution is cooled to room temperature, solvent is removed under reduced pressure, 100ml ethyl acetate is added in, successively with water (2 × 100ml), saturated common salt Water (2 × 100ml) washs, and solvent is removed under reduced pressure after anhydrous sodium sulfate drying, and column chromatography for separation obtains colourless oil liquid 6.9g, receives Rate 82%.1H NMR(500MHz,CDCl3) δ 7.75 (d, J=3.0Hz, 1H), 7.38 (dd, J=9.0,3.0Hz, 1H), 6.89 (d, J=9.0Hz, 1H), 5.90-5.79 (m, 1H), 5.09-5.03 (m, 1H), 5.02-4.97 (m, 1H), 4.02 (t, J= 6.5Hz,2H),3.89(s,3H),2.31–2.24(m,2H),1.96–1.87(m,2H)ppm；ESI-MS:M/z=255 [M+H ]+.
Prepare embodiment 8, the chloro- 2- of 4- (4- amylene -1- bases oxygroup) methyl benzoate (1h)
Using 4- chlorine-2-hydroxyls methyl benzoate as raw material, synthesis and post processing obtain colorless oil liquid with embodiment 7 is prepared Body 7.1g, yield 85%.1H NMR(500MHz,CDCl3)δ7.77–7.72(m,1H),6.97–6.93(m,2H),5.90–5.80 (m, 1H), 5.10-4.99 (m, 2H), 4.03 (t, J=6.5Hz, 2H), 3.88 (s, 3H), 2.32-2.25 (m, 2H), 1.98- 1.90(m,2H)ppm；ESI-MS:M/z=255 [M+H]+.
Prepare embodiment 9, the fluoro- 2- of 4- (4- amylene -1- bases oxygroup) methyl benzoate (1i)
Using the fluoro- 2 hydroxybenzoic acid methyl esters of 4- as raw material, synthesis and post processing obtain colorless oil liquid with embodiment 7 is prepared Body 6.4g, yield 82%.1H NMR(500MHz,CDCl3)δ7.86–7.81(m,1H),6.68–6.63(m,2H),5.90–5.80 (m, 1H), 5.10-5.04 (m, 1H), 5.03-4.99 (m, 1H), 4.02 (t, J=6.5Hz, 2H), 3.88 (s, 3H), 2.32- 2.26(m,2H),1.98–1.91(m,2H)ppm；ESI-MS:M/z=239 [M+H]+.
Prepare embodiment 10,4- methyl -2- (4- amylene -1- bases oxygroup) methyl benzoate (1j)
Using 4- methyl -2 hydroxybenzoic acid methyl esters as raw material, synthesis and post processing obtain colorless oil with embodiment 7 is prepared Liquid 6.1g, yield 79%.1H NMR(500MHz,CDCl3) δ 7.71 (d, J=7.5Hz, 1H), 6.80-6.74 (m, 2H), 5.92-5.82 (m, 1H), 5.10-5.04 (m, 1H), 5.02-4.97 (m, 1H), 4.03 (t, J=6.4Hz, 2H), 3.87 (s, 3H),2.36(s,3H),2.32–2.26(m,2H),1.97–1.90(m,2H)ppm；ESI-MS:M/z=235 [M+H]+.
Prepare embodiment 11,4- methoxyl groups -2- (4- amylene -1- bases oxygroup) methyl benzoate (1k)
Using 4- methoxyl groups -2 hydroxybenzoic acid methyl esters as raw material, synthesis and post processing obtain colorless oil with embodiment 7 is prepared Shape liquid 6.9g, yield 84%.1H NMR(500MHz,CDCl3) δ 7.84 (d, J=8.5Hz, 1H), 6.49 (dd, J=8.5, 2.5Hz, 1H), 6.46 (d, J=2.5Hz, 1H), 5.91-5.81 (m, 1H), 5.09-5.03 (m, 1H), 5.02-4.97 (m, 1H), 4.02 (t, J=6.5Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.33-2.26 (m, 2H), 1.98-1.91 (m, 2H) ppm；ESI-MS:M/z=251 [M+H]+.
Prepare embodiment 12,2- methyl -4- (4- amylene -1- bases oxygroup) thiazole-5-carboxylic acid ethyl ester (1l)
Using 2- methyl -4- Hydroxy-thiazol -5- carboxylic acid, ethyl esters as raw material, synthesis and post processing obtain nothing with embodiment 7 is prepared Color oily liquids 6.6g, yield 78%.1H NMR(500MHz,CDCl3)δ5.92–5.78(m,1H),5.09–5.03(m,1H), 5.01-4.96 (m, 1H), 4.45 (t, J=6.5Hz, 2H), 4.28 (q, J=7.0Hz, 2H), 2.61 (s, 3H), 2.28-2.21 (m, 2H), 1.96-1.87 (m, 2H), 1.33 (t, J=7.0Hz, 3H) ppm；ESI-MS:M/z=256 [M+H]+.
Prepare embodiment 13,2- (4- amylene -1- bases oxygroup) thiophene -3- methyl formates (1m)
Using 2- hydroxy thiophene -3- methyl formates as raw material, synthesis and post processing obtain white solid with embodiment 7 is prepared 6.2g, yield 83%.1H NMR(500MHz,CDCl3) δ 7.39 (d, J=5.5Hz, 1H), 6.83 (d, J=5.5Hz, 1H), 5.91-5.80 (m, 1H), 5.09-5.03 (m, 1H), 5.02-4.98 (m, 1H), 4.14 (t, J=6.5Hz, 2H), 3.84 (s, 3H),2.30–2.24(m,2H),1.97–1.90(m,2H)ppm；ESI-MS:M/z=227 [M+H]+.
Prepare embodiment 14,3- (4- amylene -1- bases oxygroup) pyridine carboxylic acid methyl esters (1n)
By 3- hydroxy-picolinic acids methyl esters (0.31g, 2mmol), potassium carbonate (0.61mg, 4.4mmol) and 5- bromine 1- amylenes (0.28ml, 2.4mmol) is placed in the mono- neck bottles of 25mL, adds in 10ml DMF, reaction solution is when 80 DEG C of reactions 3 are small.By reaction solution It is cooled to room temperature, adds in 20ml ethyl acetate and 20ml water, separate organic layer, then successively with water (20ml × 2), saturated salt solution (20ml × 1) is washed, and solvent is removed under reduced pressure after anhydrous sodium sulfate drying, column chromatography for separation obtains colourless oil liquid 0.39g, yield 89%.1H NMR(500MHz,CDCl3) δ 8.25 (dd, J=4.5,1.5Hz, 1H), 7.38 (dd, J=8.5,4.5Hz, 1H), 7.33 (dd, J=8.5,1.5Hz, 1H), 5.89-5.78 (m, 1H), 5.09-5.03 (m, 1H), 5.02-4.97 (m, 1H), 4.06 (t, J=6.5Hz, 2H), 3.96 (s, 3H), 2.31-2.23 (m, 2H), 1.97-1.89 (m, 2H) ppm；ESI-MS:M/z=222 [M+H]+.
Prepare embodiment 15,4- amylene -1- bases 2- (4- amylene -1- bases oxygroup) nicotinate (1o)
4- amylene-1-ols (1.45ml, 14.0mmol) are added in 24ml THF, -8 DEG C is cooled to, is slowly added dropwise 1.0N double (trimethyl silicon substrate) Sodamides (14.0ml, 14.0mmol) after 25min, add in the 2- chlorine cigarettes being dissolved in 24ml THF Sour methyl esters (0.61ml, 4.7mmol), reaction solution react at room temperature 2 it is small when.It is quenched instead with the saturated aqueous ammonium chloride of 50ml Should, it adds in dichloromethane (30ml × 3) and extracts, merge organic phase, then washed with saturated salt solution (50ml × 1), anhydrous slufuric acid Solvent is removed under reduced pressure after sodium drying, column chromatography for separation obtains colourless oil liquid 0.52g, yield 40%.1H NMR(500MHz, CDCl3) δ 8.28 (dd, J=5.0,2.0Hz, 1H), 8.14 (dd, J=7.5,2.0Hz, 1H), 6.92 (dd, J=7.5, 5.0Hz,1H),5.91–5.78(m,2H),5.09–5.07(m,1H),5.05–5.03(m,1H),5.03–4.96(m,2H), 4.42 (t, J=6.5Hz, 2H), 4.32 (t, J=6.5Hz, 2H), 2.29-2.19 (m, 4H), 1.95-1.82 (m, 4H) ppm； ESI-MS:M/z=276 [M+H]+.
Prepare embodiment 16,1- methyl -5- (4- amylene -1- bases oxygroup) -1H- pyrazoles -4- formic acid mixed esters (1p)
Using the chloro- 1- methyl-1s H- pyrazoles -4- Ethyl formates of 5- as raw material, synthesis and post processing are obtained with embodiment 15 is prepared Colourless oil liquid mixture (methyl esters and 4- amylene -1- carbamates) 0.51, yield 39%.
Prepare embodiment 17,3- (hept- 6- alkene -1- bases oxygroup) methyl benzoate (1q)
By 3- methyl hydroxybenzoates (0.46g, 3mmol), potassium carbonate (0.91mg, 6.6mmol) and the bromo- 1- heptene of 7- (0.55ml, 3.6mmol) is placed in the mono- neck bottles of 25mL, adds in 15ml DMF, reaction solution is when 80 DEG C of reactions 3 are small.By reaction solution It is cooled to room temperature, adds in 30ml ethyl acetate and 30ml water, separate organic layer, then successively with water (30ml × 2), saturated salt solution (30ml × 1) is washed, and solvent is removed under reduced pressure after anhydrous sodium sulfate drying, column chromatography for separation obtains colourless oil liquid 0.61g, yield 82%.1H NMR(500MHz,CDCl3) δ 7.62 (d, J=7.5Hz, 1H), 7.57-7.52 (m, 1H), 7.36-7.30 (m, 1H), 7.09 (dd, J=8.0,2.0Hz, 1H), 5.87-5.76 (m, 1H), 5.04-4.98 (m, 1H), 4.98-4.93 (m, 1H), 4.00 (t, J=6.5Hz, 2H), 3.91 (s, 3H), 2.14-2.06 (m, 2H), 1.83-1.77 (m, 2H), 1.55-1.40 (m, 4H) ppm；ESI-MS:M/z=249 [M+H]+.
Prepare embodiment 18, the fluoro- 2- of 3- (4- amylene -1- bases oxygroup) methyl benzoate (1r)
Using the fluoro- 2 hydroxybenzoic acid methyl esters of 3- as raw material, synthesis and post processing obtain colorless oil liquid with embodiment 7 is prepared Body 6.2g, yield 80%.ppm；ESI-MS:M/z=239 [M+H]+.
Prepare embodiment 19,3- methoxyl groups -2- (amyl- 4- alkene -1- bases oxygroup) methyl benzoate (1s)
Using 3- methoxyl groups -2 hydroxybenzoic acid methyl esters as raw material, synthesis and post processing obtain colorless oil with embodiment 7 is prepared Shape liquid 7.4g, yield 90%.1H NMR(500MHz,CDCl3) δ 7.31 (dd, J=7.5,2.0Hz, 1H), 7.09-7.02 (m, 2H), 5.93-5.84 (m, 1H), 5.09-5.03 (m, 1H), 5.00-4.96 (m, 1H), 4.04 (t, J=6.5Hz, 2H), 3.89 (s,3H),3.86(s,3H),2.29–2.21(m,2H),1.93–1.84(m,2H)ppm；ESI-MS:M/z=251 [M+H]+.
Prepare embodiment 20,5- pi-allyl -1- methyl-1 H- pyrazoles -4- carboxylic acid, ethyl esters (1t)
By the bromo- 1- methyl-1s H- pyrazoles -4- Ethyl formates (1.2g, 5.3mmol) of 5-, allyl tributyltin (1.8ml, 5.8mmol), Pd2(dba)3(0.24g, 0.27mmol), tri-tert-butylphosphine (0.27ml, 1.1mmol) and potassium fluoride (1.5g, It 26mmol) is placed in 50ml three-necked bottles, N2The protection anhydrous THF 25ml of lower injection, when back flow reaction 5 is small.By THF vacuum rotary steams To doing, 40ml ethyl acetate and 30ml water are added in, organic layer is separated, is washed with saturated salt solution (30ml × 2), anhydrous sodium sulfate Solvent is removed under reduced pressure after drying, column chromatography for separation obtains colourless oil liquid 0.82g, yield 80%.1H NMR(500MHz,CDCl3) δ 7.85 (s, 1H), 5.94-5.80 (m, 1H), 5.16-5.06 (m, 1H), 5.02-4.90 (m, 1H), 4.28 (q, J=7.0Hz, 2H), 3.85-3.73 (m, 5H), 1.34 (t, J=7.0Hz, 3H) ppm；ESI-MS:M/z=195 [M+H]+.
Prepare embodiment 21,1- (amyl- 4- alkene -1- bases) -1H- pyrazoles -5- carboxylate methyl esters (1u)
Using 3- pyrazole carboxylic acids methyl esters as raw material, synthesis and post processing obtain colourless oil liquid with embodiment 14 is prepared 0.16g, yield 40%.1H NMR(500MHz,CDCl3) δ 7.48 (d, J=2.0Hz, 1H), 6.83 (d, J=2.0Hz, 1H), 5.86–5.76(m,1H),5.08–5.01(m,1H),5.00–4.96(m,1H),4.62–4.54(m,2H),3.88(s,3H), 2.12–2.04(m,2H),1.99–1.90(m,2H)ppm；ESI-MS:M/z=195 [M+H]+.
Prepare embodiment 22,1- pi-allyl -1H- imidazoles -2- carboxylic acid, ethyl esters (1v)
Using imidazoles -2- Ethyl formates as raw material, synthesis and post processing obtain colourless oil liquid with embodiment 14 is prepared 0.21g, yield 58%.1H NMR(500MHz,CDCl3)δ7.18(s,1H),7.08(s,1H),6.06–5.95(m,1H), 5.28-5.19 (m, 1H), 5.13-5.01 (m, 3H), 4.40 (q, J=7.0Hz, 2H), 1.42 (t, J=7.0Hz, 3H) ppm； ESI-MS:M/z=
181[M+H]+.
Prepare embodiment 23,1- (butyl- 3- alkene -1- bases) -1H- imidazoles -2- carboxylic acid, ethyl esters (1w)
Using imidazoles -2- Ethyl formates as raw material, synthesis and post processing obtain colourless oil liquid with embodiment 14 is prepared 0.25g, yield 69%.1H NMR(500MHz,CDCl3) δ 7.14 (d, J=1.0Hz, 1H), 7.05 (d, J=1.0Hz, 1H), 5.80-5.70 (m, 1H), 5.08-5.01 (m, 2H), 4.47 (t, J=7.0Hz, 2H), 4.41 (q, J=7.0Hz, 2H), 2.59- 2.50 (m, 2H), 1.43 (t, J=7.0Hz, 3H) ppm；ESI-MS:M/z=195 [M+H]+.
Prepare embodiment 24,1- (amyl- 4- alkene -1- bases) -1H- imidazoles -2- carboxylic acid, ethyl esters (1x)
Using imidazoles -2- Ethyl formates as raw material, synthesis and post processing obtain colourless oil liquid with embodiment 14 is prepared 0.34g, yield 81%.1H NMR(500MHz,CDCl3) δ 7.15 (d, J=1.0Hz, 1H), 7.06 (d, J=1.0Hz, 1H), 5.85–5.73(m,1H),5.08–4.99(m,2H),4.44–4.35(m,4H),2.14–2.05(m,2H),1.96–1.86(m, 2H), 1.43 (t, J=7.0Hz, 3H) ppm；ESI-MS:M/z=209 [M+H]+.
Prepare embodiment 25,1- (amyl- 4- alkene -1- bases) -1H- pyrroles -2- carboxylate methyl esters (1y)
By 2- pyrrole methyl formates (1.0g, 8.0mmol), potassium carbonate (2.2g, 16mmol), potassium iodide (0.13g, It 0.8mmol) is placed in the bromo- 1- amylenes (1.1ml, 9.6mmol) of 5- in the mono- neck bottles of 50mL, adds in 10ml DMF, reaction solution is 80 DEG C reaction 3 it is small when.Reaction solution is cooled to room temperature, 30ml ethyl acetate and 20ml water is added in, separates organic layer, then use water successively Solvent is removed under reduced pressure after anhydrous sodium sulfate drying in (20ml × 2), saturated salt solution (20ml × 1) washing, and column chromatography for separation obtains nothing Color oily liquids 0.46g, yield 30%.1H NMR(500MHz,CDCl3) δ 6.95 (dd, J=4.0,2.0Hz, 1H), 6.84- 6.82 (m, 1H), 6.12 (dd, J=4.0,2.5Hz, 1H), 5.86-5.76 (m, 1H), 5.08-4.98 (m, 2H), 4.34-4.28 (m,2H),3.81(s,3H),2.10–2.03(m,2H),1.91–1.83(m,2H)ppm；ESI-MS:M/z=194 [M+H]+.
Prepare embodiment 26, amyl- 4- enoyl-s-L-PROLINE methyl esters (1z)
Raw material 4- penetenoic acids (1.0g, 10mmol) (2.0g, 12mmol) are dissolved in 30mL dichloromethane, add in 1- hydroxy benzos Triazole (1.6g, 12mmol) and N- (3- dimethylamino-propyls)-N '-ethyl-carbodiimide hydrochloride (3.5g, 18mmol), room Temperature reaction 30 minutes.Ice bath is cooled to 0 DEG C, add in L-PROLINE methyl ester hydrochloride (2.0g, 12mmol) and DIPEA (5.0ml, 30mmol), when room temperature reaction 3 is small.The dilution of 50mL saturated sodium bicarbonates is added in, separates organic layer, then with saturated salt solution (10mL × 1) wash, solvent is evaporated off, and column chromatography for separation obtains colourless oil liquid 1.9g, yield 92% in anhydrous sodium sulfate drying.1H NMR (500MHz,CDCl3) δ 5.93-5.80 (m, 1H), 5.09-4.96 (m, 2H), 4.50 (dd, J=8.5,3.5Hz, 1H), 3.73 (s,3H),3.68–3.62(m,1H),3.54–3.46(m,1H),2.47–2.36(m,4H),2.21–2.14(m,1H),2.11– 2.03(m,1H),2.03–1.94(m,2H)ppm；ESI-MS:M/z=212 [M+H]+
Prepare embodiment 27,2 hydroxybenzoic acid allyl ester (1za)
By salicylic acid (4.1g, 30mmol), potassium carbonate (4.1mg, 36mmol) and 3- bromopropenes (3.0ml, 36mmol) are put In the mono- neck bottles of 100mL, add in 40ml DMF, reaction solution react at room temperature 3 it is small when.Add in 80ml ethyl acetate and 60ml Water separates organic layer, then uses water (50ml × 2) successively, and saturated salt solution (50ml × 1) washing subtracts after anhydrous sodium sulfate drying Pressure removes solvent, and column chromatography for separation obtains colourless oil liquid 4.6g, yield 86%.1H NMR(500MHz,CDCl3)δ10.74(s, 1H), 7.89 (dd, J=8.0,1.5Hz, 1H), 7.49-7.43 (m, 1H), 6.99 (dd, J=8.5,1.0Hz, 1H), 6.93- 6.86 (m, 1H), 6.04 (ddt, J=17.0,10.5,5.5Hz, 1H), 5.47-5.40 (m, 1H), 5.36-5.30 (m, 1H), 4.86 (dt, J=5.5,1.5Hz, 2H) ppm；ESI-MS:M/z=179 [M+H]+.
Prepare embodiment 28,2- (allyloxy) benzoic acid (2a)
Raw material 2- (allyloxy) methyl benzoate (6.0g, 31mmol) is dissolved in 20mL methanol and 20ml THF, dropwise Add in 3N KOH aqueous solution 50mL, be heated to 50 DEG C reaction 3 it is small when.Reaction solution removes methanol and THF, water layer 3N HCl under reduced pressure PH to 2-3 is adjusted, ethyl acetate extraction (50mL × 3) merges organic layer, solvent is removed under reduced pressure after anhydrous sodium sulfate drying.Gained Product is directly used in the next step.
Prepare embodiment 29,2- (3- butene-1s-base oxygroup) benzoic acid (2b)
Using 2- (butyl- 3- alkene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, institute It obtains product and is directly used in the next step.
Prepare embodiment 30,2- (4- amylene -1- bases oxygroup) benzoic acid (2c)
Using 2- (amyl- 4- alkene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, institute It obtains product and is directly used in the next step.
Prepare embodiment 31,2- (5- hexene -1- bases oxygroup) benzoic acid (2d)
Using 2- (hex- 5- alkene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, institute It obtains product and is directly used in the next step.
Prepare embodiment 32,2- (6- heptene -1- bases oxygroup) benzoic acid (2e)
Using 2- (hept- 6- alkene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, institute It obtains product and is directly used in the next step.
Prepare embodiment 33,2- (7- octene-1s-base oxygroup) benzoic acid (2f)
Using 2- (octyl- 7- alkene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, institute It obtains product and is directly used in the next step.
Prepare embodiment 34, the chloro- 2- of 5- (4- amylene -1- bases oxygroup) benzoic acid (2g)
Using the chloro- 2- of 5- (4- amylene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 35, the chloro- 2- of 4- (4- amylene -1- bases oxygroup) benzoic acid (2h)
Using the chloro- 2- of 4- (4- amylene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 36, the fluoro- 2- of 4- (4- amylene -1- bases oxygroup) benzoic acid (2i)
Using the fluoro- 2- of 4- (4- amylene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 37,4- methyl -2- (4- amylene -1- bases oxygroup) benzoic acid (2j)
Using 4- methyl -2- (4- amylene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 38,4- methoxyl groups -2- (4- amylene -1- bases oxygroup) benzoic acid (2k)
Using 4- methoxyl groups -2- (4- amylene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are implemented with preparation Example 28, products therefrom is directly used in the next step.
Prepare embodiment 39,2- methyl -4- (4- amylene -1- bases oxygroup) thiazole -5- formic acid (2l)
Using 2- methyl -4- (4- amylene -1- bases oxygroup) thiazole-5-carboxylic acid ethyl ester as raw material, synthesis and post processing are the same as preparation Embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 40,2- (4- amylene -1- bases oxygroup) thiophene -3- formic acid (2m)
Using 2- (4- amylene -1- bases oxygroup) thiophene -3- methyl formates as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 41,3- (4- amylene -1- bases oxygroup) pyridine carboxylic acid (2n)
Using 3- (4- amylene -1- bases oxygroup) pyridine carboxylic acid methyl esters as raw material, synthesis and post processing are the same as preparation embodiment 28, institute It obtains product and is directly used in the next step.
Prepare embodiment 42,4- amylene -1- bases 2- (4- amylene -1- bases oxygroup) niacin (2o)
Using 4- amylene -1- bases 2- (4- amylene -1- bases oxygroup) nicotinate as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 43,1- methyl -5- (4- amylene -1- bases oxygroup) -1H- pyrazoles -4- formic acid (2p)
Using 1- methyl -5- (4- amylene -1- bases oxygroup) -1H- pyrazoles -4- formic acid mixed esters as raw material, synthesis and post processing With embodiment 28 is prepared, products therefrom is directly used in the next step.
Prepare embodiment 44,3- (hept- 6- alkene -1- bases oxygroup) benzoic acid (2q)
Using 3- (hept- 6- alkene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, institute It obtains product and is directly used in the next step.
Prepare embodiment 45, the fluoro- 2- of 3- (4- amylene -1- bases oxygroup) benzoic acid (2r)
Using the fluoro- 2- of 3- (4- amylene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 46,3- methoxyl groups -2- (amyl- 4- alkene -1- bases oxygroup) benzoic acid (2s)
Using 3- methoxyl groups -2- (amyl- 4- alkene -1- bases oxygroup) methyl benzoate as raw material, synthesis and post processing are real with preparing Example 28 is applied, products therefrom is directly used in the next step.
Prepare embodiment 47,5- pi-allyl -1- methyl-1 H- pyrazoles -4- formic acid (2t)
Using 5- pi-allyl -1- methyl-1 H- pyrazoles -4- Ethyl formates as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 48,1- (amyl- 4- alkene -1- bases) -1H- pyrazoles -5- formic acid (2u)
Using 1- (amyl- 4- alkene -1- bases) -1H- pyrazoles -5- methyl formates as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 49,1- pi-allyl -1H- imidazoles -2- formic acid (2v)
Raw material 1- pi-allyl -1H- imidazoles -2- Ethyl formates (0.37g, 2.0mmol) are dissolved in 0.5mL methanol and 0.5ml In THF, 3N KOH aqueous solution 1.0mL are added dropwise, be heated to 50 DEG C reaction 3 it is small when.Reaction solution removes methanol and THF under reduced pressure, Water layer 3N HCl tune pH to 2-3, dichloromethane：Acetone=3:1 (4mL × 3) are extracted, and merge organic layer, and anhydrous sodium sulfate is done It removes solvent after dry under reduced pressure and obtains white gum liquid 0.18g (10% decarboxylate), yield 59%.1H NMR(500MHz, DMSO) δ 8.04 (d, J=4.0Hz, 1H), 7.10 (s, 1H), 6.05-5.93 (m, 1H), 5.20 (dd, J=10.0,1.5Hz, 1H), 5.11 (dd, J=17.0,1.5Hz, 1H), 4.67 (d, J=6.0Hz, 2H) ppm；ESI-MS:M/z=153 [M+H]+.
Prepare embodiment 50,1- (butyl- 3- alkene -1- bases) -1H- imidazoles -2- formic acid (2w)
Using 1- (butyl- 3- alkene -1- bases) -1H- imidazoles -2- Ethyl formates as raw material, synthesis and post processing are the same as preparation embodiment 49, obtain white gum liquid 0.23g (12% decarboxylate), yield 69%.1H NMR(500MHz,DMSO)δ8.26(s,1H), 7.06 (s, 1H), 5.55-5.43 (m, 1H), 4.79-4.72 (m, 2H), 3.92 (t, J=7.0Hz, 2H), 2.31-2.20 (m, 2H)ppm；ESI-MS:M/z=167 [M+H]+.
Prepare embodiment 51,1- (amyl- 4- alkene -1- bases) -1H- imidazoles -2- formic acid (2x)
Using 1- (amyl- 4- alkene -1- bases) -1H- imidazoles -2- Ethyl formates as raw material, synthesis and post processing are the same as preparation embodiment 49, obtain white gum liquid 0.26g (15% decarboxylate), yield 72%.1H NMR(500MHz,DMSO)δ8.87(s,1H), 8.09(s,1H),5.86–5.75(m,1H),5.10–4.95(m,2H),4.44–4.36(m,2H),2.07–2.00(m,2H), 1.93–1.83(m,2H)ppm；ESI-MS:M/z=181 [M+H]+.
Prepare embodiment 52,1- (amyl- 4- alkene -1- bases) -1H- pyrroles -2- formic acid (2y)
Using 1- (amyl- 4- alkene -1- bases) -1H- pyrroles -2- methyl formates as raw material, synthesis and post processing are the same as preparation embodiment 28, products therefrom is directly used in the next step.
Prepare embodiment 53, amyl- 4- enoyl-s-L-PROLINE (2z)
The amyl- 4- enoyl-s of raw material-L-PROLINE methyl esters (0.47g, 2.2mmol) is dissolved in 1.6mL methanol and 1.6ml THF In, 1N LiOH aqueous solution 3.3mL are added dropwise, when room temperature reaction 5 is small.Reaction solution removes methanol and THF, water layer 3N under reduced pressure HCl tune pH to 2-3, ethyl acetate (6mL × 3) extraction merge organic layer, solvent are removed under reduced pressure after anhydrous sodium sulfate drying.Institute It obtains product and is directly used in the next step.
Prepare embodiment 54, Boc-Ser-OBn (3a)
Boc-L- serines (4.0g, 19.5mmol) are dissolved in 500ml DMF, add in potassium carbonate (3.2g, 23mmol), ice Bath is cooled to 0 DEG C, and cylite (2.8ml, 23mmol), which is dissolved in after 100ml DMF, slowly instills above-mentioned reaction solution, room temperature reaction 10 Hour.Ethyl acetate 100ml and water 100ml is added in into reaction solution, separates organic layer, then it is molten with saturated sodium bicarbonate water successively Liquid 100ml, saturated salt solution 100ml are washed, and are removed solvent under reduced pressure after anhydrous sodium sulfate drying, are obtained by column chromatography for separation white Solid 5.2g, yield 90%.m.p.:69-71℃；1H NMR(500MHz,CDCl3)δ7.40–7.31(m,5H),5.45(s, 1H), 5.28-5.16 (m, 2H), 4.48-4.38 (m, 1H), 3.99 (dd, J=11.0,3.5Hz, 1H), 3.92 (dd, J= 11.0,3.0Hz,1H),1.94(br s,1H),1.45(s,9H)ppm；ESI-MS:M/z=296 [M+H]+.
Prepare embodiment 55, Boc-Ser-OMe (3b)
Serine methyl ester hydrochloride (3.6g, 30.0mmol) is dissolved in 50ml methanol, addition triethylamine (8.3ml, 60.0mmol), ice bath is cooled to 0 DEG C, and Boc acid anhydrides (7.9g, 36mmol), which is dissolved in after 20ml methanol, slowly instills above-mentioned reaction solution, React at room temperature 10 it is small when.It removes solvent under reduced pressure, ethyl acetate 100ml and water 100ml is added in into reaction solution, separates organic layer, Again successively with saturated aqueous ammonium chloride 100ml, saturated salt solution 100ml washings, anhydrous sodium sulfate removes under reduced pressure molten after drying Agent obtains pale yellow oily liquid 5.9g, yield 90% by column chromatography for separation.1H NMR(500MHz,CDCl3)δ5.47(s, 1H), 4.43-4.33 (m, 1H), 3.96 (dd, J=11.0,3.5Hz, 1H), 3.90 (dd, J=11.0,3.5Hz, 1H), 3.78 (s,3H),2.27(br s,1H),1.45(s,9H)ppm；ESI-MS:M/z=220 [M+H]+.
Prepare embodiment 56, O- pi-allyl-Boc-Ser- benzyl esters (4a)
Reactant 3a (2.7g, 9.1mmol) and tetra-triphenylphosphine palladium (0.53g, 0.46mmol) are dissolved in 40mL THF, N2It protects Allyl methyl carbonate (1.5ml, 12.7mmol) is slowly injected under shield, be heated to reflux 5 it is small when.Reaction solution removes under reduced pressure molten Agent, adds in ethyl acetate 50ml and saturated sodium bicarbonate aqueous solution (50ml x 1), and organic layer uses saturated salt solution (30ml x again 1) wash, remove solvent under reduced pressure after anhydrous sodium sulfate drying, pale yellow oily liquid 1.9g, yield are obtained by column chromatography for separation 62%.1H NMR(500MHz,CDCl3) δ 7.41-7.30 (m, 5H), 5.86-5.68 (m, 1H), 5.41 (d, J=8.5Hz, 1H), 5.32-5.17 (m, 2H), 5.17-5.10 (m, 2H), 4.51-4.42 (m, 1H), 3.99-3.84 (m, 3H), 3.65 (dd, J= 9.5,3.0Hz,1H),1.45(s,9H)ppm；ESI-MS:M/z=336 [M+H]+.
Prepare embodiment 57, O- pi-allyl-Boc-Ser- methyl esters (4b)
Using 3b as raw material, synthesize and post-process with preparating example 37, obtain pale yellow oily liquid 1.4g, yield 59%.1H NMR(500MHz,CDCl3) δ 5.87-5.78 (m, 1H), 5.38 (d, J=8.0Hz, 1H), 5.27-5.20 (m, 1H), 5.20- 5.15 (m, 1H), 4.42 (dt, J=7.0,3.0Hz, 1H), 4.01-3.92 (m, 2H), 3.85 (dd, J=9.5,3.0Hz, 1H), 3.76 (s, 3H), 3.64 (dd, J=9.5,3.0Hz, 1H), 1.45 (s, 9H) ppm；ESI-MS:M/z=260 [M+H]+。
Prepare embodiment 58, (S) -2- ((tert-butoxycarbonyl) amino) -5- hexenes acid benzyl ester (4c)
Reactant 3a (3.0g, 10mmol) and triphenylphosphine (3.9g, 15mmol) are added in 100ml three-necked bottles, nitrogen THF 30ml are added in after displacement and are cooled to 0 DEG C.Pyridine (1.7ml, 20mmol) is added dropwise at such a temperature, finally by solid Iodine (3.8g, 15mmol) adds in three times, when room temperature reaction 4 is small.Ether (20ml x 3) is added in into reaction solution, uses 1N successively HCl (20ml x 3), 1N Na2S2O3(20ml x 2) and saturated salt solution (20ml x1) wash, and subtract after anhydrous sodium sulfate drying Solvent is evaporated off in pressure, passes through column chromatography (EtOAc：Petroleum ether=1:60to1:30) white solid 3.6g is separated to obtain, is received Rate 89%.1H NMR(500MHz,CDCl3) δ 7.41-7.33 (m, 5H), 5.36 (d, J=7.0Hz, 1H), 5.21 (q, J= 12.0Hz, 2H), 4.59-4.51 (m, 1H), 3.61 (dd, J=10.0,4.0Hz, 1H), 3.56 (dd, J=10.0,4.0Hz, 1H),1.45(s,9H)ppm；ESI-MS:M/z=406 [M+H]+。
Zinc powder (0.33g, 4.9mmol) after activation is placed in 25ml three-necked bottles, is cooled to 0 DEG C, under nitrogen protection dropwise (R) -2- ((tert-butoxycarbonyl) the amino) -3- iodopropionic acids benzyl ester (0.5g, 1.2mmol) for being dissolved in 3ml DMF is added in, room temperature is anti- Answer 3h.Stop stirring, washed after solid sedimentation and take supernatant spare.
Cuprous bromide (0.036g, 0.25mmol) and 3- bromopropenes (0.22g, 1.9mmol) are added in 2ml DMF, cold But to -15 DEG C, supernatant is injected dropwise, room temperature reaction is overnight.Ethyl acetate 10ml is added in into reaction solution, uses H successively2O (10ml x 2), 1N Na2S2O3(20ml x 2) and saturated salt solution (20ml x 1) wash, and are depressurized after anhydrous sodium sulfate drying Solvent is evaporated off, passes through column chromatography (EtOAc：Petroleum ether=1:15) white solid 0.23g, yield 60% are separated to obtain 。1H NMR(500MHz,CDCl3)δ7.41–7.31(m,5H),5.81–5.70(m,1H),5.24–5.10(m,2H),5.10– 4.93(m,3H),4.42–4.32(m,1H),2.15–2.02(m,2H),1.97–1.82(m,1H),1.78–1.67(m,1H), 1.44(s,9H)ppm；ESI-MS:M/z=320 [M+H]+。
Prepare embodiment 59, N- (tert-butoxycarbonyl)-O- (hex- 5- alkene -1- bases)-Serine benzyl ester (4d)
Boc-Ser (2.0g, 10mmol) is dissolved in 25ml DMF, and ice bath is cooled to 0 DEG C, be slowly added to NaH (0.60g, 25mmol), 30min is reacted at this temperature, adds in the bromo- 1- hexenes (1.3ml, 10mmol) of 6-, room temperature reaction is overnight.Delay under ice bath It is slow to add in water 50ml and ethyl acetate 50ml, organic layer is separated, water (50ml x 2) and saturated salt solution (50ml x 2) is added to wash It washs, removing solvent under reduced pressure after anhydrous sodium sulfate drying obtains colourless oil liquid 1.6g, yield 56%.1H NMR(500MHz, CDCl3) δ 5.84-5.72 (m, 1H), 5.42 (d, J=8.0Hz, 1H), 5.06-4.88 (m, 2H), 4.47-4.37 (m, 1H), 3.87 (dd, J=11.0,3.0Hz, 2H), 3.65 (dd, J=9.5,3.5Hz, 1H), 3.45 (t, J=6.5Hz, 2H), 2.08- 2.02(m,2H),1.60–1.52(m,2H),1.49–1.38(m,11H)ppm；ESI-MS:M/z=288 [M+H]+。
Above-mentioned gained raw material is dissolved in 15ml DMF, Anhydrous potassium carbonate (0.92g, 6.7mmol) and bromine are added under ice bath Change benzyl (0.79ml, 6.7mmol), room temperature reaction is overnight.Ethyl acetate 30ml and water 30ml is added in into reaction solution, is separated organic Layer, then washed successively with water (30ml x 2) and saturated salt solution (30ml x 2), it is removed under reduced pressure after anhydrous sodium sulfate drying molten Agent obtains colourless oil liquid 1.1g, yield 52% by column chromatography for separation.1H NMR(500MHz,CDCl3)δ7.41–7.29(m, 5H), 5.85-5.71 (m, 1H), 5.38 (d, J=8.5Hz, 1H), 5.28-5.09 (m, 2H), 5.05-4.89 (m, 2H), 4.52- 4.39 (m, 1H), 3.84 (dd, J=9.5,3.0Hz, 1H), 3.63 (dd, J=9.5,3.0Hz, 1H), 3.45-3.27 (m, 2H), 2.07–1.99(m,2H),1.55–1.33(m,13H)ppm；ESI-MS:M/z=378 [M+H]+。
It is former to prepare embodiment 60, (S) -2- ((tert-butoxycarbonyl) amino) -4- morpholino -4- ketobutyric acids benzyl esters (4e) Material Boc-L- aspartic acid -1- benzyl esters (1.0g, 3.0mmol) are dissolved in 15mL dichloromethane, add in 1- hydroxy benzo triazoles (0.49g, 3.6mmol) and N- (3- dimethylamino-propyls)-N '-ethyl-carbodiimide hydrochloride (1.0g, 5.4mmol), room temperature React half an hour.Ice bath is cooled to 0 DEG C, adds in morpholine (0.31g, 3.6mmol) and DIPEA (0.99ml, 6.0mmol), room temperature React 3 it is small when.The dilution of 20mL saturated sodium bicarbonate solutions is added in, separates organic layer, saturated brine (10mL × 1) washing is anhydrous Solvent is removed under reduced pressure after sodium sulphate drying, and column chromatography for separation obtains pale yellow oily liquid 1.1g, yield 93%.1H NMR (500MHz,CDCl3) δ 7.37-7.29 (m, 5H), 5.80 (d, J=9.0Hz, 1H), 5.22 (d, J=12.5Hz, 1H), 5.13 (d, J=12.5Hz, 1H), 4.65-4.56 (m, 1H), 3.68-3.49 (m, 6H), 3.39 (t, J=4.5Hz, 2H), 3.12 (dd, J=16.5,4.0Hz, 1H), 2.76 (dd, J=16.5,4.0Hz, 1H), 1.41 (s, 9H) ppm；ESI-MS:M/z=393 [M+ H]+.
Prepare embodiment 61, (S) -2- ((tert-butoxycarbonyl) amino) -5- morpholino -5- oxopentanoic acids benzyl esters (4f)
Using Boc-L- glutamic acid -1- benzyl esters as raw material, synthesize and post-process with preparating example 59, obtain white solid 1.1g, Yield 90%.1H NMR(500MHz,CDCl3) δ 7.39-7.31 (m, 5H), 5.31 (d, J=7.0Hz, 1H), 5.22 (d, J= 12.0Hz, 1H), 5.13 (d, J=12.0Hz, 1H), 4.40-4.28 (m, 1H), 3.68-3.53 (m, 6H), 3.37-3.26 (m, 2H),2.41–2.15(m,3H),2.06–1.97(m,1H),1.43(s,9H)ppm；ESI-MS:M/z=407 [M+H]+.It prepares Embodiment 62, N2- (tert-butoxycarbonyl)-N4- cyclopropyl-altheine acid benzyl ester (4g) using cyclopropylamine as raw material, synthesis and Post processing obtains white solid 1.1g, yield 99% with preparating example 59.1H NMR(500MHz,CDCl3)δ7.38–7.28(m, 6H), 5.24-5.12 (m, 3H), 4.56-4.47 (m, 1H), 2.83 (dd, J=15.5,4.5Hz, 1H), 2.70-2.61 (m, 2H),1.42(s,9H),0.77–0.70(m,1H),0.48–0.42(m,2H)ppm；ESI-MS:M/z=363 [M+H]+。
Prepare embodiment 63, O- pi-allyl-Ser-OBn hydrochlorides (5a)
Reactant 4a (3.4g, 10mmol) is dissolved in 15mL CH2Cl2, ice bath is cooled to 0 DEG C, adds in the second of 2N HCl saturations Acetate solution (20mL), when room temperature reaction 2 is small.Reaction solution removes solvent under reduced pressure and obtains faint yellow solid, and products obtained therefrom is directly used In the next step.
Prepare embodiment 64, O- pi-allyl-Ser-OMe hydrochlorides (5b)
Using 4b as raw material, with preparating example 63, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 65, (S) -2- amino -5- hexene acid benzyl ester hydrochlorides (5c)
Using 4c as raw material, with preparating example 63, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 66, O- (5- hexene -1- bases)-Serine benzyl ester hydrochloride (5d)
Using 4d as raw material, with preparating example 63, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 67, (2- (2- (benzyloxy) ethyoxyl) ethyl)-Serine methyl ester hydrochloride (5e)
2- [2- (benzyloxy) ethyoxyl] ethyl alcohol (5.7g, 29mmol), triethylamine (4.4ml, 32mmol) and DMAP (0.35g, 2.9mmol) is dissolved in 100ml dichloromethane, and 0 DEG C is cooled under ice bath.Be added dropwise paratoluensulfonyl chloride (6.0g, 32mmol), when room temperature reaction 8 is small.50ml dichloromethane and 2N HCl 100ml are added in, organic layer is separated, adds water (100ml x 2) remove solvent under reduced pressure with saturated salt solution (80ml x 2) washing, anhydrous sodium sulfate after drying, obtained by column chromatography for separation light Yellow oily liquid 6.4g, yield 63%.1H NMR(500MHz,CDCl3)δ7.82–7.77(m,2H),7.37–7.27(m, 7H),4.53(s,2H),4.20–4.15(m,2H),3.72–3.68(m,2H),3.64–3.54(m,4H),2.43(s,3H)ppm； ESI-MS:M/z=351 [M+H]+。
Boc-Ser (2.1g, 10mmol) is dissolved in 30ml DMF, and ice bath is cooled to 0 DEG C, be slowly added to NaH (0.6g, 25mmol), react 30min at this temperature, add in 2- [2- (benzyloxy) ethyoxyl) ethyl] -4- toluenesulfonic acid ethyl esters (3.5g, 10mmol), room temperature reaction is overnight.50ml water and 50ml ethyl acetate are slowly added under ice bath, separates organic layer, adds water (50ml x 2) and saturated salt solution (50ml x 2) wash, and removing solvent under reduced pressure after anhydrous sodium sulfate drying obtains colorless oil liquid Body 2.0g, yield 52%.ESI-MS:M/z=384 [M+H]+。
O- (2- (2- (benzyloxy) ethyoxyl) ethyl)-N- (tertbutyloxycarbonyl)-Serine (2.0g, 5.2mmol) is molten In 25ml absolute methanols, thionyl chloride (0.83ml, 11mmol) is slowly added dropwise under ice bath, when back flow reaction 5 is small, removes under reduced pressure Solvent obtains colourless oil liquid, and products obtained therefrom is directly used in the next step.
Prepare embodiment 68, four 14 carbon-14s of oxa- of (S) -13- amino -1- phenyl -2,5,8,11--acid methyl ester hydrochloride salt (5f)
Triethylene glycol list benzyl oxide (1.5g, 6.2mmol), triethylamine (1.7ml, 12mmol) and DMAP (0.076g, It 0.62mmol) is dissolved in 20ml dichloromethane, 0 DEG C is cooled under ice bath.Be added dropwise paratoluensulfonyl chloride (1.8g, 9.4mmol), when room temperature reaction 8 is small.10ml dichloromethane and 2N HCl (20ml) are added in, organic layer is separated, adds water (20ml x 2) remove solvent under reduced pressure with saturated salt solution (20ml x 2) washing, anhydrous sodium sulfate after drying, obtained by column chromatography for separation light Yellow oily liquid 1.5g, yield 61%.1H NMR(500MHz,CDCl3)δ7.81–7.77(m,2H),7.36–7.27(m, 7H),4.56(s,2H),4.18–4.14(m,2H),3.71–3.67(m,2H),3.66–3.56(m,8H),2.43(s,3H)ppm； ESI-MS:M/z=395 [M+H]+。
Boc-Ser (0.68g, 3.3mmol) is dissolved in 10ml DMF, and ice bath is cooled to 0 DEG C, be slowly added to NaH (0.33g, 8.3mmol), 30min is reacted at this temperature, adds in 2- (2- (2- (benzyloxy) ethyoxyl) ethyoxyl) ethyl) -4- methylbenzene sulphurs Acetoacetic ester (1.3g, 3.3mmol), room temperature reaction is overnight.20ml water and 30ml ethyl acetate are slowly added under ice bath, is separated organic Layer adds water (20ml x 2) and saturated salt solution (20ml x 2) to wash, and removing solvent under reduced pressure after anhydrous sodium sulfate drying obtains nothing Color oily liquids 1.0g, yield 71%.1H NMR(500MHz,CDCl3) δ 7.38-7.27 (m, 5H), 5.56 (d, J=8.0Hz, 1H), 4.66-4.56 (m, 2H), 4.45-4.40 (m, 1H), 3.94 (dd, J=9.5,3.0Hz, 1H), 3.76-3.55 (m, 13H),1.45(s,9H)ppm；ESI-MS:M/z=428 [M+H]+。
(S)-13- ((tertbutyloxycarbonyl) amino)-1- phenyl-2,5,8,11- tetra- oxa-, 14 carbon-14-acid (1.0g, It 2.3mmol) is dissolved in 10ml absolute methanols, thionyl chloride (0.37ml, 5.1mmol) is slowly added dropwise under ice bath, back flow reaction 5 is small When, it removes solvent under reduced pressure and obtains colourless oil liquid, products obtained therefrom is directly used in the next step.
Prepare embodiment 69, N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- pi-allyls-Serine Benzyl ester (6a)
Raw material Boc-O- methyl-Ser (2.2g, 10mmol) is dissolved in 30mL dichloromethane, adds in 1- hydroxy benzo triazoles (1.6g, 12mmol) and N- (3- dimethylamino-propyls)-N '-ethyl-carbodiimide hydrochloride (3.5g, 18mmol), room temperature reaction Half an hour.Ice bath is cooled to 0 DEG C, add in O- pi-allyl-Ser-OBn hydrochlorides (5a, 3.3g, 12mmol) and DIPEA (5.0ml, 30mmol), when room temperature reaction 3 is small.The dilution of 50mL saturated sodium bicarbonates is added in, separates organic layer, saturated brine (30mL x 2) It washes, solvent is evaporated off, and column chromatography for separation obtains colourless oil liquid 2.7g, yield 61% in anhydrous sodium sulfate drying.1H NMR (500MHz,CDCl3) δ 7.39 (d, J=6.5Hz, 1H), 7.36-7.29 (m, 5H), 5.80-5.70 (m, 1H), 5.43 (d, J= 5.0Hz, 1H), 5.26-5.21 (m, 1H), 5.21-5.16 (m, 1H), 5.16-5.11 (m, 2H), 4.74 (dt, J=8.0, 3.0Hz, 1H), 4.31-4.24 (m, 1H), 3.94-3.87 (m, 3H), 3.77 (dd, J=9.0,4.0Hz, 1H), 3.65 (dd, J =9.5,3.0Hz, 1H), 3.43 (dd, J=9.0,7.0Hz, 1H), 3.33 (s, 3H), 1.44 (s, 9H) ppm；ESI-MS:m/z =437 [M+H]+.
Prepare embodiment 70, N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- pi-allyls-Serine Methyl esters (6b)
With 5b (2.3g, 12mmol) for raw material, synthesize and post-process with preparating example 69, obtain pale yellow oily liquid 2.6g, yield 72%.1H NMR(500MHz,CDCl3) δ 7.34 (d, J=3.5Hz, 1H), 5.87-5.76 (m, 1H), 5.42 (s, 1H), 5.26-5.15 (m, 2H), 4.70 (dt, J=8.0,3.5Hz, 1H), 4.31-4.24 (m, 1H), 3.99-3.95 (m, 2H), 3.88 (dd, J=9.5,3.0Hz, 1H), 3.81 (dd, J=9.0,3.5Hz, 1H), 3.76 (s, 3H), 3.65 (dd, J=9.5, 3.5Hz, 1H), 3.48 (dd, J=9.0,7.0Hz, 1H), 3.39 (s, 3H), 1.45 (s, 9H) ppm；ESI-MS:M/z=361 [M +H]+.
Prepare embodiment 71, (S) -2- ((S) -2- ((tertbutyloxycarbonyl) amino) -3- methoxypropionamides base) -5- hexenes Acid benzyl ester (6c)
With 5c (3.1g, 12mmol) for raw material, synthesize and post-process with preparating example 69, obtain pale yellow oily liquid 2.4g, yield 57%.1H NMR(500MHz,CDCl3) δ 7.40-7.31 (m, 5H), 7.11 (d, J=5.5Hz, 1H), 5.79- 5.68 (m, 1H), 5.41 (d, J=3.5Hz, 1H), 5.17 (q, J=12.0Hz, 2H), 5.01-4.94 (m, 2H), 4.67 (td, J =7.5,4.5Hz, 1H), 4.25 (s, 1H), 3.79 (dd, J=9.0,4.0Hz, 1H), 3.46-3.40 (m, 1H), 3.35 (s, 3H),2.11–1.92(m,3H),1.84–1.74(m,1H),1.45(s,9H)ppm；ESI-MS:M/z=421 [M+H]+.
Preparation embodiment 72, N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (5- hexene -1- bases) - Serine benzyl ester (6d)
With 5d (3.8g, 12mmol) for raw material, synthesize and post-process with preparating example 69, obtain pale yellow oily liquid 2.8g, yield 59%.1H NMR(500MHz,CDCl3)δ7.41–7.29(m,6H),5.83–5.72(m,1H),5.42(s,1H), 5.26-5.11 (m, 2H), 5.03-4.92 (m, 2H), 4.73 (dt, J=8.0,3.0Hz, 1H), 4.28 (s, 1H), 3.88 (dd, J =9.5,3.0Hz, 1H), 3.77 (dd, J=9.0,4.0Hz, 1H), 3.64 (dd, J=9.5,3.0Hz, 1H), 3.46-3.32 (m,6H),2.07–1.99(m,2H),1.56–1.48(m,2H),1.45(s,9H),1.41–1.33(m,2H)ppm；ESI-MS: M/z=479 [M+H]+.
Prepare embodiment 73, N- (N- (tertbutyloxycarbonyl)-O- methyl-L- seryl-s)-O- (2- (2- (benzyloxy) second Oxygroup) ethyl)-Serine methyl esters (6e)
With 5e (4.0g, 12mmol) for raw material, synthesize and post-process with preparating example 69, obtain pale yellow oily liquid 2.5g, yield 51%.1H NMR(500MHz,CDCl3) δ 7.39-7.27 (m, 6H), 5.50 (d, J=4.5Hz, 1H), 4.74- 4.66 (m, 1H), 4.57 (s, 2H), 4.34-4.25 (m, 1H), 3.96 (dd, J=10.0,3.5Hz, 1H), 3.79 (dd, J= 9.0,4.0Hz, 1H), 3.75-3.70 (m, 4H), 3.67-3.59 (m, 8H), 3.48 (dd, J=9.0,6.5Hz, 1H), 3.37 (s,3H),1.46(s,9H)ppm；ESI-MS:M/z=499 [M+H]+.
Prepare embodiment 74, (S) -13- ((S) -2- ((tertbutyloxycarbonyl) amino) -3- methoxy propyls acylamino-) -1- benzene The four oxa- tetradecane -14- acid methyl esters (6f) of base -2,5,8,11-
With 5f (4.5g, 12mmol) for raw material, synthesize and post-process with preparating example 69, obtain pale yellow oily liquid 2.3g, yield 43%.1H NMR(500MHz,CDCl3) δ 7.40-7.31 (m, 5H), 7.31-7.27 (m, 1H), 5.48 (d, J= 4.0Hz, 1H), 4.70 (dt, J=7.0,3.0Hz, 1H), 4.57 (s, 2H), 4.33-4.25 (m, 1H), 3.94 (dd, J= 10.0,3.5Hz, 1H), 3.80 (dd, J=9.5,3.5Hz, 1H), 3.74 (s, 3H), 3.71 (dd, J=9.5,3.0Hz, 1H), 3.69-3.58 (m, 12H), 3.49 (dd, J=9.2,6.6Hz, 1H), 3.38 (s, 3H), 1.46 (s, 9H) ppm；ESI-MS:m/z =543 [M+H]+.
Prepare embodiment 75, N- ((S) -2- ((tert-butoxycarbonyl) amino) -4- morpholino -4- oxobutanoyls)-O- Pi-allyl-Serine benzyl ester (6g)
Reactant 4e (0.80g, 2.0mmol) is dissolved in 4ml methanol, adds in Pd/C (0.08g), room temperature is anti-after hydrogen displacement Answer 3h.It filters and removes Pd/C, remove solvent under reduced pressure, products obtained therefrom is directly used in the next step.
Upper step raw material (S) -2- ((tert-butoxycarbonyl) amino) -4- morpholino -4- ketobutyric acids (0.19g, 5mL dichloromethane 0.63mmol) is dissolved in, adds in 1- hydroxy benzo triazoles (0.1g, 0.76mmol) and N- (3- dimethylaminos third Base)-N '-ethyl-carbodiimide hydrochloride (0.22g, 1.1mmol), react at room temperature half an hour.Ice bath is cooled to 0 DEG C, adds in O- Pi-allyl-Ser-OBn hydrochlorides (5a, 0.21g, 0.76mmol) and DIPEA (0.31ml, 1.9mmol), when room temperature reaction 3 is small. The dilution of 5mL saturated sodium bicarbonates is added in, separates organic layer, saturated brine (5mL x2) is washed, and anhydrous sodium sulfate drying is evaporated off molten Agent, column chromatography for separation obtain colourless oil liquid 0.22g, yield 67%.1H NMR(500MHz,CDCl3) δ 7.65 (d, J= 8.0Hz, 1H), 7.38-7.29 (m, 5H), 6.02 (d, J=8.0Hz, 1H), 5.84-5.74 (m, 1H), 5.28-5.10 (m, 4H), 4.71 (dt, J=8.5,3.5Hz, 1H), 4.68-4.62 (m, 1H), 4.01-3.95 (m, 1H), 3.95-3.88 (m, 2H), 3.71-3.60 (m, 5H), 3.60-3.53 (m, 2H), 3.49-3.36 (m, 2H), 3.13 (dd, J=16.5,2.0Hz, 1H), 2.57 (dd, J=16.5,6.0Hz, 1H), 1.45 (s, 9H) ppm；ESI-MS:M/z=520 [M+H]+.
Prepare embodiment 76, N- ((S) -2- ((tert-butoxycarbonyl) amino) -5- morpholino -5- Oxopentanoyls)-O- Pi-allyl-Serine benzyl ester (6h)
Reactant 4f (0.80g, 2.0mmol) is dissolved in 4ml methanol, adds in Pd/C (0.08g), room temperature is anti-after hydrogen displacement Answer 3h.It filters and removes Pd/C, remove solvent under reduced pressure, products obtained therefrom is directly used in the next step.
Upper step raw material (S) -2- ((tert-butoxycarbonyl) amino) -5- morpholino -5- oxopentanoic acids (0.20g, 5mL dichloromethane 0.63mmol) is dissolved in, adds in 1- hydroxy benzo triazoles (0.10g, 0.76mmol) and N- (3- dimethylaminos Propyl)-N '-ethyl-carbodiimide hydrochloride (0.22g, 1.1mmol), react at room temperature half an hour.Ice bath is cooled to 0 DEG C, adds in O- pi-allyl-Ser-OBn hydrochlorides (5a, 0.21g, 0.76mmol) and DIPEA (0.31ml, 1.9mmol), room temperature reaction 3 are small When.The dilution of 5mL saturated sodium bicarbonates is added in, separates organic layer, saturated brine (5mL x2) is washed, and anhydrous sodium sulfate drying is evaporated off Solvent, column chromatography for separation obtain colourless oil liquid 0.33g, yield 98%.1H NMR(500MHz,CDCl3) δ 7.56 (d, J= 7.0Hz, 1H), 7.40-7.29 (m, 5H), 5.85-5.73 (m, 1H), 5.56 (d, J=6.3Hz, 1H), 5.28-5.09 (m, 4H),4.79–4.73(m,1H),4.27–4.18(m,1H),4.01–3.88(m,3H),3.78–3.55(m,7H),3.49–3.38 (m,2H),2.61–2.51(m,1H),2.50–2.41(m,1H),2.19–2.10(m,1H),1.98–1.89(m,1H),1.43 (s,9H)ppm；ESI-MS:M/z=534 [M+H]+.
Prepare embodiment 77, N- (N2- (tert-butoxycarbonyl)-N4- cyclopropyl-altheine acyl group)-O- pi-allyls- Serine benzyl ester (6i)
Reactant 4g (0.72g, 2.0mmol) is dissolved in 4ml methanol, adds in Pd/C (0.08g), room temperature is anti-after hydrogen displacement Answer 3h.It filters and removes Pd/C, remove solvent under reduced pressure, products obtained therefrom is directly used in the next step.
Upper step raw material N2- (tert-butoxycarbonyl)-N4- cyclopropyl-altheine (0.27g, 1.0mmol) is dissolved in 5mL bis- It is sub- to add in 1- hydroxy benzo triazoles (0.16g, 1.2mmol) and N- (3- dimethylamino-propyls)-N '-ethyl carbon two for chloromethanes Amine hydrochlorate (0.35g, 1.8mmol) reacts at room temperature half an hour.Ice bath is cooled to 0 DEG C, adds in O- pi-allyl-Ser-OBn hydrochloric acid Salt (5a, 0.30g, 1.1mmol) and DIPEA (0.50ml, 3.0mmol), when room temperature reaction 3 is small.Add in 5mL saturated sodium bicarbonates Dilution, separates organic layer, and saturated brine (5mL x 2) is washed, and anhydrous sodium sulfate drying removes solvent under reduced pressure, column chromatography for separation obtains White solid 0.35g, yield 71%.1H NMR(500MHz,CDCl3) δ 7.60 (d, J=7.0Hz, 1H), 7.40-7.29 (m, 6H), 6.15 (d, J=5.5Hz, 1H), 5.83-5.72 (m, 1H), 5.27-5.09 (m, 4H), 4.75-4.66 (m, 1H), 4.56- 4.44 (m, 1H), 4.01-3.86 (m, 3H), 3.63 (dd, J=9.5,3.5Hz, 1H), 2.80-2.61 (m, 2H), 2.49 (dd, J =15.0,6.0Hz, 1H), 1.44 (s, 9H), 0.77-0.68 (m, 2H), 0.53-0.44 (m, 2H) ppm；ESI-MS:M/z= 499[M+H]+.
Prepare embodiment 78, N- ((tert-butoxycarbonyl)-L- leucyls)-O- pi-allyls-Serine benzyl ester (6j)
Raw material Boc- leucines (0.28g, 1.2mmol) are dissolved in 5mL dichloromethane, add in 1- hydroxy benzo triazoles (0.19g, 1.4mmol) and N- (3- dimethylamino-propyls)-N '-ethyl-carbodiimide hydrochloride (0.42g, 2.2mmol), room temperature React half an hour.Ice bath is cooled to 0 DEG C, adds in O- pi-allyl-Ser-OBn hydrochlorides (5a, 0.39g, 1.4mmol) and DIPEA (0.59ml, 3.6mmol), when room temperature reaction 3 is small.The dilution of 5mL saturated sodium bicarbonates is added in, separates organic layer, saturated brine (5mL x 2) is washed, and anhydrous sodium sulfate drying removes solvent under reduced pressure, column chromatography for separation obtains colourless oil liquid 0.45g, yield 83%.1H NMR(500MHz,CDCl3) δ 7.39-7.30 (m, 5H), 6.73 (d, J=8.0Hz, 1H), 5.82-5.71 (m, 1H), 5.31-5.11 (m, 4H), 4.91 (d, J=7.0Hz, 1H), 4.77 (dt, J=8.5,3.0Hz, 1H), 4.20-4.13 (m, 1H), 3.99-3.86 (m, 3H), 3.64 (dd, J=9.5,3.0Hz, 1H), 1.68-1.59 (m, 2H), 1.51-1.39 (m, 10H), 0.96–0.89(m,6H)ppm；ESI-MS:M/z=449 [M+H]+.
Prepare embodiment 79, N- ((tert-butoxycarbonyl)-L- valyls)-O- pi-allyls-Serine benzyl ester (6k)
With Boc- valines (0.29g, 1.2mmol) for raw material, synthesize and post-process with preparating example 78, it obtains faint yellow Oily liquids 0.48g, yield 92%.1H NMR(500MHz,CDCl3) δ 7.40-7.30 (m, 5H), 6.59 (d, J=7.0Hz, 1H), 5.81-5.71 (m, 1H), 5.30-5.07 (m, 5H), 4.79 (dt, J=8.0,3.0Hz, 1H), 4.04-3.86 (m, 4H), 3.64 (dd, J=9.5,3.0Hz, 1H), 2.18-2.07 (m, 1H), 1.44 (s, 9H), 0.97 (d, J=6.5Hz, 3H), 0.91 (d, J=6.5Hz, 3H) ppm；ESI-MS:M/z=435 [M+H]+.
Prepare embodiment 80, N- (O- methyl-L- seryl-s)-O- pi-allyls-Serine benzyl ester hydrochloride (7a)
Reactant 6a (2.2g, 5.0mmol) is dissolved in 5mL CH2Cl2, ice bath is cooled to 0 DEG C, adds in the second of 2N HCl saturations Acetate solution (10mL), when room temperature reaction 2 is small.Reaction solution removes solvent under reduced pressure and obtains pale yellow oily liquid, and products obtained therefrom is straight It connects for the next step.
Prepare embodiment 81, N- (O- methyl-L- seryl-s)-O- pi-allyls-Serine benzyl ester hydrochloride (7b)
Using 6b as raw material, with preparating example 80, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 82, (S) -2- ((S) -2- amino -3- methoxypropionamides base) -5- hexene acid benzyl ester hydrochlorides (7c)
Using 6c as raw material, with preparating example 80, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 83, N- (O- methyl-L- seryl-s)-O- (hex- 5- alkene -1- bases)-Serine benzyl ester hydrochloric acid Salt (7d)
Using 6d as raw material, with preparating example 80, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 84, N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (2- (2- '-hydroxyethoxies Base) ethyl)-Serine methyl esters (7e)
Reactant 6e (0.72g, 1.4mmol) is dissolved in 4ml methanol and 2ml ethyl acetate, adds in Pd/C (0.12g), hydrogen 50 DEG C of reaction 3h after gas displacement.It filters and removes Pd/C, remove solvent under reduced pressure and obtain pale yellow oily liquid 0.59g, yield 100%.1H NMR(500MHz,CDCl3) δ 7.43 (d, J=8.0Hz, 1H), 5.64 (d, J=4.0Hz, 1H), 4.73 (dt, J=8.0, 3.0Hz, 1H), 4.35-4.28 (m, 1H), 3.98 (dd, J=10.0,3.0Hz, 1H), 3.81 (dd, J=9.0,4.0Hz, 1H), 3.78-3.70 (m, 6H), 3.66-3.57 (m, 6H), 3.50 (dd, J=9.5,6.0Hz, 1H), 3.38 (s, 3H), 1.45 (s, 9H)ppm；ESI-MS:M/z=409 [M+H]+.
Prepare embodiment 85, N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (2- (2- (2- hydroxyl second Oxygroup) ethyoxyl) ethyl)-Serine methyl esters (7f)
With 6f (0.78g, 1.4mmol) for raw material, synthesize and post-process with preparating example 84, obtain pale yellow oily liquid 0.60g, yield 95%.1H NMR(500MHz,CDCl3) δ 7.83 (d, J=7.0Hz, 1H), 5.68 (d, J=6.0Hz, 1H), 4.79-4.70 (m, 1H), 4.42-4.32 (m, 1H), 3.96 (dd, J=9.5,3.0Hz, 1H), 3.80-3.54 (m, 18H), 3.38(s,3H),2.45(br s,1H),1.45(s,9H)ppm；ESI-MS:M/z=453 [M+H]+.
Prepare embodiment 86, N- ((S) -2- amino -4- morpholino -4- oxobutanoyls)-O- pi-allyls-Serine benzyl Ester hydrochloride (7g)
Using 6g as raw material, with preparating example 80, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 87, N- ((S) -2- amino -5- morpholino -5- Oxopentanoyls)-O- pi-allyls-Serine benzyl Ester hydrochloride (7h)
Using 6h as raw material, with preparating example 80, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 88, N- (N4- cyclopropyl-altheine acyl group)-O- pi-allyls-Serine benzyl ester hydrochloride (7i)
Using 6i as raw material, with preparating example 80, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 89, N- (L- leucyls)-O- pi-allyls-Serine benzyl ester hydrochloride (7j)
Using 6j as raw material, with preparating example 80, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 90, N- (L- valyls)-O- pi-allyls-Serine benzyl ester hydrochloride (7k)
Using 6k as raw material, with preparating example 80, products obtained therefrom is directly used in the next step for synthesis and post processing.
Preparation embodiment 91, N- (N- (2- (allyloxy) benzoyl)-O- methyl-L- seryl-s)-O- pi-allyls- Serine benzyl ester (8a)
Raw material 2- (allyloxy) benzoic acid (2a, 0.18g, 1.0mmol) is placed in 10ml reaction bulbs, and it is anhydrous to add in 4mL CH2Cl2Dissolving adds in 1- hydroxy benzo triazoles (0.16g, 1.2mmol) and N- (3- dimethylamino-propyls)-N '-ethyl immediately Carbodiimide hydrochloride (0.35g, 1.8mmol) reacts at room temperature half an hour.Then, 0 DEG C is cooled to, adds in O- methyl-Ser-O- Pi-allyl-Ser-OBn hydrochlorides (7a, 52.0mg, 1.2mmol) and DIPEA (0.50ml, 3.0mmol), when room temperature reaction 3 is small. Reaction solution adds in the dilution of 5mL saturated sodium bicarbonate aqueous solutions, separates organic layer, saturated common salt washing (5mL × 2), anhydrous slufuric acid Solvent is removed under reduced pressure after sodium drying, column chromatography for separation obtains colourless oil liquid 0.39g, yield 78%.
1H NMR(500MHz,CDCl3) δ 8.80 (d, J=6.5Hz, 1H), 8.19 (d, J=8.0Hz, 1H), 7.48-7.40 (m, 2H), 7.39-7.29 (m, 5H), 7.11-7.04 (m, 1H), 6.97 (d, J=8.3Hz, 1H), 6.24-6.11 (m, 1H), 5.80–5.70(m,1H),5.48–5.30(m,2H),5.27–5.08(m,4H),4.87–4.77(m,2H),4.75–4.67(m, 2H),3.97–3.87(m,4H),3.71–3.65(m,1H),3.56–3.49(m,1H),3.38(s,3H)ppm；ESI-MS:m/z =497 [M+H]+.
Prepare embodiment 92, N- (N- (2- (3- butene-1s-base oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- Pi-allyl-Serine benzyl ester (8b)
Using 2- (3- butene-1s-base oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 91 is prepared Shape liquid 0.38g, yield 77%.1H NMR(500MHz,CDCl3) δ 8.79 (d, J=6.5Hz, 1H), 8.20 (d, J=7.5Hz, 1H), 7.49-7.39 (m, 2H), 7.37-7.28 (m, 5H), 7.11-7.04 (m, 1H), 6.97 (d, J=8.5Hz, 1H), 5.96- 5.85(m,1H),5.80–5.68(m,1H),5.27–5.07(m,6H),4.90–4.82(m,1H),4.82–4.77(m,1H), 4.18 (t, J=6.5Hz, 2H), 3.95-3.87 (m, 4H), 3.72-3.66 (m, 1H), 3.57-3.50 (m, 1H), 3.39 (s, 3H),2.77–2.63(m,2H)ppm；ESI-MS:M/z=511 [M+H]+.
Prepare embodiment 93, N- (N- (2- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- Pi-allyl-Serine benzyl ester (8c)
Using 2- (4- amylene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 91 is prepared Shape liquid 0.32g, yield 61%.1H NMR(500MHz,CDCl3) δ 8.85 (d, J=6.5Hz, 1H), 8.21 (d, J=8.0Hz, 1H), 7.48-7.42 (m, 1H), 7.40 (d, J=8.0Hz, 1H), 7.36-7.29 (m, 5H), 7.09-7.03 (m, 1H), 6.96 (d, J=8.0Hz, 1H), 5.89-5.79 (m, 1H), 5.79-5.69 (m, 1H), 5.27-4.98 (m, 6H), 4.88-4.82 (m, 1H),4.81–4.77(m,1H),4.16–4.09(m,2H),3.97–3.87(m,4H),3.70–3.65(m,1H),3.55–3.49 (m,1H),3.38(s,3H),2.30–2.22(m,2H),2.11–1.97(m,2H)ppm；ESI-MS:M/z=525 [M+H]+.
Prepare embodiment 94, N- (N- (2- (5- hexene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- Pi-allyl-Serine benzyl ester (8d)
Using 2- (5- hexene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 91 is prepared Shape liquid 0.35g, yield 65%.1H NMR(500MHz,CDCl3) δ 8.85 (d, J=6.5Hz, 1H), 8.20 (dd, J=8.0, 2.0Hz, 1H), 7.44 (ddd, J=8.5,7.5,2.0Hz, 1H), 7.40 (d, J=8.0Hz, 1H), 7.37-7.28 (m, 5H), 7.09-7.03 (m, 1H), 6.96 (d, J=8.0Hz, 1H), 5.88-5.70 (m, 2H), 5.26-5.13 (m, 3H), 5.12-5.09 (m, 1H), 5.05-4.99 (m, 1H), 4.99-4.93 (m, 1H), 4.84 (td, J=7.0,4.0Hz, 1H), 4.79 (dt, J= 8.0,3.0Hz, 1H), 4.17-4.08 (m, 2H), 3.97-3.87 (m, 4H), 3.67 (dd, J=9.5,3.0Hz, 1H), 3.53 (dd, J=9.0,6.5Hz, 1H), 3.39 (s, 3H), 2.16-2.10 (m, 2H), 2.00-1.90 (m, 2H), 1.63-1.54 (m, 2H)ppm；ESI-MS:M/z=539 [M+H]+.
Prepare embodiment 95, N- (N- (2- (6- heptene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- Pi-allyl-Serine benzyl ester (8e)
Using 2- (6- heptene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 91 is prepared Shape liquid 0.33g, yield 60%.1H NMR(500MHz,CDCl3) δ 8.86 (d, J=6.5Hz, 1H), 8.20 (dd, J=8.0, 2.0Hz, 1H), 7.47-7.42 (m, 1H), 7.40 (d, J=8.0Hz, 1H), 7.38-7.28 (m, 5H), 7.09-7.02 (m, 1H), 6.96 (d, J=8.0Hz, 1H), 5.85-5.69 (m, 2H), 5.27-5.13 (m, 3H), 5.13-5.08 (m, 1H), 5.03- 4.97 (m, 1H), 4.97-4.92 (m, 1H), 4.84 (td, J=7.0,4.0Hz, 1H), 4.79 (dt, J=8.0,3.0Hz, 1H), 4.15-4.09 (m, 2H), 3.96-3.87 (m, 4H), 3.67 (dd, J=9.5,3.5Hz, 1H), 3.53 (dd, J=9.0, 7.0Hz,1H),3.39(s,3H),2.11-2.05(m,2H),1.99–1.91(m,2H),1.53–1.43(m,4H)ppm；ESI- MS:M/z=553 [M+H]+.
Prepare embodiment 96, N- (N- (2- (7- octene-1s-base oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- Pi-allyl-Serine benzyl ester (8f)
Using 2- (7- octene-1s-base oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 91 is prepared Shape liquid 0.31g, yield 55%.1H NMR(500MHz,CDCl3) δ 8.85 (d, J=7.0Hz, 1H), 8.20 (dd, J=8.0, 2.0Hz, 1H), 7.44 (ddd, J=8.0,7.5,2.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.36-7.30 (m, 6H), 7.08-7.03 (m, 1H), 6.96 (d, J=8.0Hz, 1H), 5.84-5.69 (m, 2H), 5.26-5.13 (m, 4H), 5.12-5.08 (m, 1H), 5.02-4.96 (m, 1H), 4.95-4.91 (m, 1H), 4.84 (td, J=7.0,4.0Hz, 1H), 4.79 (dt, J= 8.0,3.0Hz, 1H), 3.95-3.88 (m, 4H), 3.67 (dd, J=9.5,3.5Hz, 1H), 3.53 (dd, J=9.0,7.0Hz, 1H),3.38(s,3H),2.07–2.02(m,2H),1.98–1.90(m,2H),1.51–1.44(m,2H),1.44–1.35(m, 4H)ppm；ESI-MS:M/z=567 [M+H]+.
Prepare embodiment 97, N- (N- (the chloro- 2- of 5- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8g)
Using the chloro- 2- of 5- (4- amylene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.41g, yield 73%.1H NMR(500MHz,CDCl3) δ 8.80 (d, J=6.5Hz, 1H), 8.17 (d, J= 3.0Hz, 1H), 7.40-7.30 (m, 7H), 6.90 (d, J=9.0Hz, 1H), 5.89-5.69 (m, 2H), 5.26-5.22 (m, 1H),5.21–5.09(m,3H),5.09–5.03(m,1H),5.03–4.98(m,1H),4.84–4.76(m,2H),4.13–4.09 (m, 2H), 3.95-3.87 (m, 4H), 3.67 (dd, J=9.5,3.5Hz, 1H), 3.52 (dd, J=9.0,7.0Hz, 1H), 3.37 (s,3H),2.28–2.22(m,2H),2.07–2.00(m,2H)ppm；ESI-MS:M/z=559 [M+H]+.
Prepare embodiment 98, N- (N- (the chloro- 2- of 4- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8h)
Using the chloro- 2- of 4- (4- amylene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.39g, yield 70%.1H NMR(500MHz,CDCl3) δ 8.70 (d, J=7.0Hz, 1H), 8.21 (dd, J =8.5,7.0Hz, 1H), 7.37 (d, J=9.0Hz, 1H), 7.35-7.31 (m, 5H), 6.76 (ddd, J=9.0,7.5, 2.5Hz, 1H), 6.67 (dd, J=10.5,2.5Hz, 1H), 5.88-5.70 (m, 2H), 5.26-5.05 (m, 5H), 5.04-5.00 (m, 1H), 4.84-4.76 (m, 2H), 4.12-4.08 (m, 2H), 3.96-3.87 (m, 4H), 3.67 (dd, J=9.5,3.5Hz, 1H), 3.52 (dd, J=9.0,7.0Hz, 1H), 3.38 (s, 3H), 2.29-2.23 (m, 2H), 2.10-2.01 (m, 2H) ppm； ESI-MS:M/z=559 [M+H]+.
Prepare embodiment 99, N- (N- (the fluoro- 2- of 4- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8i)
Using the fluoro- 2- of 4- (4- amylene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.40g, yield 74%.1H NMR(500MHz,CDCl3) δ 8.72 (d, J=6.5Hz, 1H), 8.13 (d, J= 8.5Hz, 1H), 7.37 (d, J=8.5Hz, 1H), 7.35-7.31 (m, 5H), 7.04 (dd, J=8.5,2.0Hz, 1H), 6.95 (d, J=2.0Hz, 1H), 5.88-5.70 (m, 2H), 5.26-5.05 (m, 5H), 5.04-5.00 (m, 1H), 4.84-4.76 (m, 2H), 4.11 (t, J=6.5Hz, 2H), 3.97-3.87 (m, 4H), 3.67 (dd, J=9.5,3.0Hz, 1H), 3.52 (dd, J= 9.0,7.0Hz,1H),3.38(s,3H),2.29–2.23(m,2H),2.09–2.01(m,2H)ppm；ESI-MS:M/z=543 [M +H]+.
Prepare embodiment 100, N- (N- (4- methyl -2- (4- amylene -1- bases oxygroup) benzoyl)-L- ammonia of-O- methyl Acyl group)-O- pi-allyls-Serine benzyl ester (8j)
Using 4- methyl -2- (4- amylene -1- bases oxygroup) benzoic acid as raw material, synthesis and the same preparation embodiment 91 of post processing, Obtain colourless oil liquid 0.44g, yield 82%.1H NMR(500MHz,CDCl3) δ 8.80 (d, J=7.0Hz, 1H), 8.08 (d, J =8.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.36-7.29 (m, 5H), 6.87 (d, J=8.0Hz, 1H), 6.76 (s, 1H),5.90–5.79(m,1H),5.79–5.69(m,1H),5.26–5.04(m,5H),5.03–4.98(m,1H),4.84(td,J =7.0,4.0Hz, 1H), 4.79 (dt, J=8.0,3.0Hz, 1H), 4.15-4.09 (m, 2H), 3.96-3.87 (m, 4H), 3.67 (dd, J=9.5,3.0Hz, 1H), 3.52 (dd, J=9.0,6.5Hz, 1H), 3.37 (s, 3H), 2.38 (s, 3H), 2.29-2.23 (m,2H),2.06–2.02(m,2H)ppm；ESI-MS:M/z=539 [M+H]+.
Prepare embodiment 101, N- (N- (4- methoxyl groups -2- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- Aminoacyl)-O- pi-allyls-Serine benzyl ester (8k)
Using 4- methoxyl groups -2- (4- amylene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing are the same as preparation embodiment 91, obtain colourless oil liquid 0.41g, yield 76%.1H NMR(500MHz,CDCl3) δ 8.71 (d, J=6.5Hz, 1H), 8.16 (d, J=8.5Hz, 1H), 7.40 (d, J=8.0Hz, 1H), 7.37-7.28 (m, 5H), 6.58 (dd, J=9.0,2.0Hz, 1H), 6.46 (d, J=2.5Hz, 1H), 5.88-5.69 (m, 2H), 5.26-5.03 (m, 5H), 5.02-4.98 (m, 1H), 4.83 (td, J =7.0,4.0Hz, 1H), 4.78 (dt, J=8.0,3.0Hz, 1H), 4.09 (t, J=6.5Hz, 2H), 3.96-3.87 (m, 4H), 3.84 (s, 3H), 3.67 (dd, J=9.5,3.0Hz, 1H), 3.52 (dd, J=9.5,6.5Hz, 1H), 3.37 (s, 3H), 2.30- 2.20(m,2H),2.09–1.98(m,2H)ppm；ESI-MS:M/z=555 [M+H]+.
Prepare embodiment 102, N- (N- (2- methyl -4- (4- amylene -1- bases oxygroup) thiazole -5- formoxyls)-O- methyl - L- seryl-s)-O- pi-allyls-Serine methyl esters (8l)
Raw material 2- methyl -4- (4- amylene -1- bases oxygroup) thiazole -5- formic acid (2l, 0.16g, 0.70mmol) is placed in 10ml In reaction bulb, the anhydrous CH of 3mL are added in2Cl2Dissolving adds in 1- hydroxy benzo triazoles (0.11g, 0.84mmol) and N- (3- immediately Dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (0.24g, 1.3mmol), react at room temperature half an hour.Then, it is cooled to 0 DEG C, add in O- methyl-Ser-O- pi-allyl-Ser-OMe hydrochlorides (7b, 0.25mg, 0.84mmol) and DIPEA (0.35ml, 2.1mmol), when room temperature reaction 3 is small.Reaction solution adds in the dilution of 5mL saturated sodium bicarbonate aqueous solutions, separates organic layer, saturation food Salt washes (5mL × 2), and solvent is removed under reduced pressure after anhydrous sodium sulfate drying, and column chromatography for separation obtains colourless oil liquid 0.25g, receives Rate 76%.1H NMR(500MHz,CDCl3) δ 7.93 (d, J=7.0Hz, 1H), 7.34 (d, J=8.0Hz, 1H), 5.89-5.76 (m,2H),5.25–5.17(m,1H),5.17–5.12(m,1H),5.10–5.04(m,1H),5.02–4.97(m,1H),4.76– 4.68 (m, 2H), 4.53-4.44 (m, 2H), 3.99-3.95 (m, 2H), 3.93 (dd, J=9.0,4.0Hz, 1H), 3.89 (dd, J =9.5,3.0Hz, 1H), 3.76 (s, 3H), 3.66 (dd, J=9.5,3.0Hz, 1H), 3.54 (dd, J=9.0,7.0Hz, 1H), 3.43(s,3H),2.61(s,3H),2.28–2.21(m,2H),1.97–1.90(m,2H)ppm；ESI-MS:M/z=470 [M+H ]+.
Prepare embodiment 103, N- (O- methyl-N- (2- (4- amylene -1- bases oxygroup) thiophene -3- formoxyls)-L- seryls Base)-O- pi-allyls-Serine methyl esters (8m)
Using 2- (4- amylene -1- bases oxygroup) thiophene -3- formic acid as raw material, synthesis and post processing are obtained with embodiment 102 is prepared Colourless oil liquid 0.27g, yield 84%.1H NMR(500MHz,CDCl3) δ 8.13 (d, J=7.0Hz, 1H), 7.39 (d, J= 5.5Hz, 1H), 7.36 (d, J=8.5Hz, 1H), 6.83 (d, J=5.5Hz, 1H), 5.88-5.76 (m, 2H), 5.24-5.18 (m,1H),5.16–5.12(m,1H),5.10–5.04(m,1H),5.03–4.98(m,1H),4.79–4.71(m,2H),4.18 (td, J=6.5,2.0Hz, 2H), 3.98-3.94 (m, 3H), 3.89 (dd, J=9.5,3.0Hz, 1H), 3.75 (s, 3H), 3.66 (dd, J=9.5,3.5Hz, 1H), 3.55 (dd, J=9.0,7.0Hz, 1H), 3.43 (s, 3H), 2.30-2.24 (m, 2H), 2.01–1.93(m,2H)ppm；ESI-MS:M/z=455 [M+H]+.
Prepare embodiment 104, N- (O- methyl-N- (3- (4- amylene -1- bases oxygroup) picolinoyl)-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8n)
Using 3- (4- amylene -1- bases oxygroup) pyridine carboxylic acid as raw material, synthesis and post processing obtain colourless with embodiment 91 is prepared Oily liquids 0.50g, yield 95%.1H NMR(500MHz,CDCl3) δ 8.58 (d, J=7.0Hz, 1H), 8.29 (dd, J= 4.0,1.5Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.40-7.28 (m, 7H), 5.88-5.71 (m, 2H), 5.26-5.10 (m, 4H), 5.10-4.97 (m, 2H), 4.83 (td, J=7.0,4.0Hz, 1H), 4.78 (dt, J=8.0,3.5Hz, 1H), 4.10 (t, J=6.5Hz, 2H), 3.95-3.89 (m, 4H), 3.68 (dd, J=9.5,3.5Hz, 1H), 3.52 (dd, J=9.0, 7.5Hz,1H),3.37(s,3H),2.31–2.24(m,2H),2.06–1.99(m,2H)ppm；ESI-MS:M/z=526 [M+H ]+.
Prepare embodiment 105, N- (O- methyl-N- (2- (4- amylene -1- bases oxygroup) niacin formoxyl)-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8o)
Using 4- amylene -1- bases 2- (4- amylene -1- bases oxygroup) niacin as raw material, synthesis and post processing are the same as preparation embodiment 91, obtain colourless oil liquid 0.31g, yield 59%.1H NMR(500MHz,CDCl3) δ 8.87 (d, J=6.5Hz, 1H), 8.50 (dd, J=7.5,2.0Hz, 1H), 8.27 (dd, J=5.0,2.0Hz, 1H), 7.39-7.31 (m, 6H), 7.04 (dd, J=7.5, 5.0Hz,1H),5.91–5.81(m,1H),5.79–5.70(m,1H),5.27–5.04(m,5H),5.01–4.97(m,1H), 4.84-4.78 (m, 2H), 4.58-4.46 (m, 2H), 3.96-3.87 (m, 4H), 3.68 (dd, J=9.5,3.5Hz, 1H), 3.53 (dd, J=9.0,7.0Hz, 1H), 3.39 (s, 3H), 2.29-2.22 (m, 2H), 2.05-1.98 (m, 2H) ppm；ESI-MS:m/z =526 [M+H]+.
Prepare embodiment 106, N- (O- methyl-N- (1- methyl -5- (4- amylene -1- bases oxygroup) -1H- pyrazoles -4- formyls Base)-L- seryl-s)-O- pi-allyls-Serine benzyl ester (8p)
Using 1- methyl -5- (4- amylene -1- bases oxygroup) -1H- pyrazoles -4- formic acid as raw material, synthesis and post processing are the same as preparation Embodiment 91 obtains colourless oil liquid 0.36g, yield 68%.1H NMR(500MHz,CDCl3)δ7.74(s,1H),7.42(d,J =8.0Hz, 1H), 7.36-7.32 (m, 5H), 7.02 (d, J=6.5Hz, 1H), 5.87-5.70 (m, 2H), 5.28-5.12 (m, 4H),5.09–5.00(m,2H),4.78–4.69(m,2H),4.27–4.18(m,2H),3.94–3.85(m,5H),3.70(s, 3H), 3.67 (dd, J=9.5,3.0Hz, 1H), 3.47 (dd, J=9.5,7.5Hz, 1H), 3.37 (s, 2H), 2.28-2.21 (m, 2H),1.99–1.91(m,2H)ppm；ESI-MS:M/z=529 [M+H]+.
Preparation embodiment 107, N- (N- (3- (hept- 6- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s) - O- pi-allyls-Serine benzyl ester (8q)
Using 3- (hept- 6- alkene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing obtain colourless with embodiment 91 is prepared Oily liquids 0.50g, yield 90%.1H NMR(500MHz,CDCl3) δ 7.51 (d, J=8.0Hz, 1H), 7.39-7.30 (m, 8H), 7.12 (d, J=6.0Hz, 1H), 7.06-7.02 (m, 1H), 5.87-5.72 (m, 2H), 5.29-5.12 (m, 4H), 5.05- 4.99 (m, 1H), 4.97-4.93 (m, 1H), 4.80-4.72 (m, 2H), 4.00 (t, J=6.5Hz, 2H), 3.96-3.88 (m, 4H), 3.68 (dd, J=9.5,3.0Hz, 1H), 3.49 (t, J=8.5Hz, 1H), 3.39 (s, 3H), 2.12-2.06 (m, 2H), 1.83–1.76(m,2H),1.52–1.43(m,4H)ppm；ESI-MS:M/z=553 [M+H]+.
Prepare embodiment 108, N- (N- (the fluoro- 2- of 3- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-L- ammonia of-O- methyl Acyl group)-O- pi-allyls-Serine benzyl ester (8r)
Using the fluoro- 2- of 3- (4- amylene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.33g, yield 61%.1H NMR(500MHz,CDCl3) δ 8.78 (d, J=6.5Hz, 1H), 7.90 (dt, J =8.0,1.5Hz, 1H), 7.37-7.29 (m, 6H), 7.25-7.19 (m, 1H), 7.10 (td, J=8.0,4.5Hz, 1H), 5.88–5.70(m,2H),5.27–5.10(m,4H),5.08–5.02(m,1H),5.01–4.97(m,1H),4.84–4.76(m, 2H), 4.28-4.16 (m, 2H), 3.97-3.88 (m, 4H), 3.68 (dd, J=9.5,3.0Hz, 1H), 3.54 (dd, J=9.0, 7.0Hz,1H),3.38(s,3H),2.26–2.20(m,2H),2.01–1.94(m,2H)ppm；ESI-MS:M/z=543 [M+H ]+.
Prepare embodiment 109, N- (N- (3- methoxyl groups -2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- Seryl-)-O- pi-allyls-Serine benzyl ester (8s)
Using 3- methoxyl groups -2- (amyl- 4- alkene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing are the same as preparation embodiment 91, obtain colourless oil liquid 0.36g, yield 65%.1H NMR(500MHz,CDCl3) δ 8.93 (d, J=7.0Hz, 1H), 7.70 (dd, J=8.0,1.5Hz, 1H), 7.39-7.28 (m, 6H), 7.13 (t, J=8.0Hz, 1H), 7.05 (dd, J=8.0, 1.5Hz,1H),5.90–5.80(m,1H),5.78–5.69(m,1H),5.26–5.13(m,3H),5.13–5.08(m,1H), 5.08–5.02(m,1H),5.00–4.96(m,1H),4.85–4.76(m,2H),4.11–4.04(m,2H),3.97–3.86(m, 7H), 3.67 (dd, J=9.5,3.5Hz, 1H), 3.54 (dd, J=9.0,6.5Hz, 1H), 3.37 (s, 3H), 2.26-2.20 (m, 2H),1.99–1.91(m,2H)ppm；ESI-MS:M/z=555 [M+H]+.
Prepare embodiment 110, N- (N- (5- pi-allyl -1- methyl-1 H- pyrazoles -4- carbonyls)-O- methyl-L- seryls Base)-O- (5- hexene -1- bases)-Serine benzyl ester (8t)
Using 5- pi-allyl -1- methyl-1 H- pyrazoles -4- formic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.36g, yield 68%.1H NMR(500MHz,CDCl3) δ 7.72 (s, 1H), 7.47 (d, J=8.0Hz, 1H), 7.38-7.29 (m, 5H), 6.72 (d, J=6.0Hz, 1H), 5.89 (ddt, J=17.0,10.0,6.0Hz, 1H), 5.81- 5.72 (m, 1H), 5.26-5.21 (m, 1H), 5.18-5.09 (m, 2H), 5.02-4.92 (m, 3H), 4.74 (dt, J=8.0, 3.0Hz, 1H), 4.69 (ddd, J=8.0,6.5,4.0Hz, 1H), 3.89 (dd, J=9.5,3.0Hz, 1H), 3.85 (dd, J= 9.0,4.0Hz, 1H), 3.81-3.77 (m, 5H), 3.65 (dd, J=9.5,3.5Hz, 1H), 3.48-3.43 (m, 1H), 3.42- 3.34(m,5H),2.06–1.97(m,2H),1.54–1.45(m,2H),1.42–1.31(m,2H)ppm；ESI-MS:M/z=527 [M+H]+.
Prepare embodiment 111, N- (N- (1- (amyl- 4- alkene -1- bases) -1H- pyrazoles -5- carbonyls)-O- methyl-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8u)
Using 1- (amyl- 4- alkene -1- bases) -1H- pyrazoles -5- formic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.33g, yield 66%.1H NMR(500MHz,CDCl3)δ7.50–7.45(m,2H),7.39–7.31(m, 5H), 6.96 (d, J=6.5Hz, 1H), 6.59 (d, J=2.0Hz, 1H), 5.85-5.72 (m, 2H), 5.29-5.12 (m, 4H), 5.06-4.94 (m, 2H), 4.76 (dt, J=8.5,3.0Hz, 1H), 4.67 (ddd, J=8.0,6.0,4.0Hz, 1H), 4.60- 4.52 (m, 2H), 3.99-3.90 (m, 3H), 3.86 (dd, J=9.0,4.0Hz, 1H), 3.68 (dd, J=9.5,3.5Hz, 1H), 3.47 (t, J=8.5Hz, 1H), 3.39 (s, 3H), 2.10-2.05 (m, 2H), 1.99-1.92 (m, 2H) ppm；ESI-MS:m/z =499 [M+H]+.
Prepare embodiment 112, N- (N- (1- pi-allyl -1H- imidazoles -2- carbonyls)-O- methyl-L- seryl-s)-O- alkene Propyl-Serine benzyl ester (8v)
Using 1- pi-allyl -1H- imidazoles -2- formic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 91 is prepared Liquid 0.28g, yield 60%.1H NMR(500MHz,CDCl3) δ 8.08 (d, J=7.5Hz, 1H), 7.42-7.29 (m, 6H), 7.10-7.01 (m, 2H), 6.07-5.94 (m, 1H), 5.79-5.69 (m, 1H), 5.28-5.07 (m, 8H), 4.78 (dt, J= 8.0,3.0Hz, 1H), 4.73-4.65 (m, 1H), 3.95-3.83 (m, 4H), 3.66 (dd, J=9.5,3.5Hz, 1H), 3.55 (dd, J=9.5,6.5Hz, 1H), 3.37 (s, 3H) ppm；ESI-MS:M/z=471 [M+H]+.
Prepare embodiment 113, N- (N- (1- (butyl- 3- alkene -1- bases) -1H- imidazoles -2- carbonyls)-O- methyl-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8w)
Using 1- (butyl- 3- alkene -1- bases) -1H- imidazoles -2- formic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.31g, yield 64%.1H NMR(500MHz,CDCl3) δ 8.09 (d, J=6.5Hz, 1H), 7.32-7.22 (m, 6H), 7.00-6.92 (m, 2H), 5.75-5.61 (m, 2H), 5.20-4.93 (m, 6H), 4.72 (dt, J=8.0,3.0Hz, 1H), 4.62 (td, J=7.0,4.0Hz, 1H), 4.51-4.37 (m, 2H), 3.90-3.78 (m, 4H), 3.60 (dd, J=9.5, 3.0Hz, 1H), 3.50 (dd, J=9.0,6.5Hz, 1H), 3.31 (s, 3H), 2.53-2.45 (m, 2H) ppm；ESI-MS:M/z= 485[M+H]+.
Prepare embodiment 114, N- (N- (1- (amyl- 4- alkene -1- bases) -1H- imidazoles -2- carbonyls)-O- methyl-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8x)
Using 1- (amyl- 4- alkene -1- bases) -1H- imidazoles -2- formic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.35g, yield 70%.1H NMR(500MHz,CDCl3) δ 8.19 (d, J=4.0Hz, 1H), 7.38-7.29 (m, 6H), 7.07 (d, J=1.0Hz, 1H), 7.03 (d, J=1.0Hz, 1H), 5.85-5.70 (m, 2H), 5.26-5.22 (m, 1H), 5.21-5.10 (m, 3H), 5.08-4.99 (m, 2H), 4.79 (dt, J=8.0,3.0Hz, 1H), 4.69 (td, J=7.0, 4.5Hz, 1H), 4.48-4.42 (m, 2H), 3.98-3.85 (m, 4H), 3.67 (dd, J=9.5,3.0Hz, 1H), 3.57 (dd, J =9.0,6.5Hz, 1H), 3.38 (s, 3H), 2.81 (s, 3H), 2.12-2.06 (m, 2H), 1.97-1.88 (m, 2H) ppm；ESI- MS:M/z=499 [M+H]+.
Prepare embodiment 115, N- (N- (1- (amyl- 4- alkene -1- bases) -1H- pyrroles -2- carbonyls)-O- methyl-L- seryls Base)-O- pi-allyls-Serine benzyl ester (8y)
Using 1- (amyl- 4- alkene -1- bases) -1H- pyrroles -2- formic acid as raw material, synthesis and post processing are obtained with embodiment 91 is prepared Colourless oil liquid 0.25g, yield 50%.1H NMR(500MHz,CDCl3) δ 7.48 (d, J=8.0Hz, 1H), 7.39-7.30 (m, 5H), 6.80-6.75 (m, 2H), 6.67 (dd, J=4.0,2.0Hz, 1H), 6.10 (dd, J=4.0,2.5Hz, 1H), 5.84-5.71 (m, 2H), 5.28-5.24 (m, 1H), 5.22-5.12 (m, 3H), 5.06-4.95 (m, 2H), 4.77 (dt, J= 8.0,3.0Hz, 1H), 4.70-4.65 (m, 1H), 4.40-4.26 (m, 2H), 3.97-3.90 (m, 3H), 3.87 (dd, J=9.0, 4.0Hz, 1H), 3.68 (dd, J=9.5,3.0Hz, 1H), 3.46 (dd, J=9.0,8.0Hz, 1H), 3.38 (s, 3H), 2.08- 2.02(m,2H),1.91–1.83(m,2H)ppm；ESI-MS:M/z=498 [M+H]+.
Prepare embodiment 116, N- (N- (4- pentenoyl-L- prolyls)-O- methyl-L- seryl-s)-O- allyls Base-Serine benzyl ester (8z)
Using amyl- 4- enoyl-s-L-PROLINE as raw material, synthesis and post processing obtain colorless oil liquid with embodiment 91 is prepared Body 0.36g, yield 70%.1H NMR(500MHz,CDCl3)δ7.40–7.29(m,6H),7.26–7.24(m,1H),5.92– 5.72(m,2H),5.29–5.11(m,4H),5.09–4.95(m,2H),4.78–4.70(m,1H),4.60–4.48(m,2H), 3.98-3.91 (m, 2H), 3.89 (dd, J=9.5,3.5Hz, 1H), 3.79 (dd, J=9.5,4.0Hz, 1H), 3.67 (dd, J= 9.5,3.5Hz, 1H), 3.62-3.56 (m, 1H), 3.46 (dd, J=9.0,7.0Hz, 2H), 3.33 (s, 3H), 2.50-2.35 (m,4H),2.32–2.23(m,1H),2.15–2.04(m,1H),2.02–1.93(m,2H)ppm；ESI-MS:M/z=516 [M+ H]+.
Prepare embodiment 117, N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (2- ((2- pi-allyls Oxygen carbonyl) phenoxy group) ethyl)-Serine methyl esters (8za)
Reactant N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (2- (2- (2- hydroxyl-oxethyls) second Oxygroup) ethyl)-Serine methyl esters (7f, 0.61g, 1.5mmol), 2 hydroxybenzoic acid allyl ester (0.25g, 1.4mmol) and Triphenylphosphine (0.39g, 1.5mmol) is placed in 10ml three-necked bottles, N2Protection is lower to add in the anhydrous THF dissolvings of 3mL, then, cooling To 0 DEG C, DIAD (0.35g, 1.7mmol) is slowly added dropwise, room temperature reaction is overnight.Reaction solution adds in 1ml ethyl acetate and 5ml oil Ether, be stirred at room temperature 1 it is small when, filter, filtrate decompression removes solvent, and column chromatography for separation obtains colourless oil liquid 0.52g, yield 64%.1H NMR(500MHz,CDCl3) δ 7.81 (dd, J=8.0,1.5Hz, 1H), 7.57-7.51 (m, 1H), 7.35 (d, J= 5.5Hz,1H),7.03–6.97(m,2H),6.08–5.97(m,1H),5.49–5.38(m,2H),5.30–5.24(m,1H), 4.82-4.77 (m, 2H), 4.74-4.66 (m, 1H), 4.31-4.25 (m, 1H), 4.22-4.16 (m, 2H), 3.95 (dd, J= 10.0,3.0Hz, 1H), 3.91-3.84 (m, 2H), 3.79 (dd, J=9.5,4.0Hz, 1H), 3.76-3.67 (m, 6H), 3.66- 3.60 (m, 2H), 3.48 (dd, J=9.5,6.5Hz, 1H), 3.37 (s, 3H), 1.45 (s, 9H) ppm；ESI-MS:M/z=569 [M+H]+.
Prepare embodiment 118, N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (2- (2- ((2- allyls Epoxide carbonyl) phenoxy group) ethyoxyl) ethyl)-Serine methyl esters (8zb)
With N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (2- (2- (2- hydroxyl-oxethyls) ethoxies Base) ethyl)-Serine methyl esters be raw material, synthesis and post processing with prepare embodiment 117, obtain colourless oil liquid 0.55g, Yield 60%.1H NMR(500MHz,CDCl3) δ 7.80 (dd, J=8.0,2.0Hz, 1H), 7.49-7.42 (m, 1H), 7.37 (d, J=5.5Hz, 1H), 7.02-6.96 (m, 2H), 6.07-5.97 (m, 1H), 5.49 (d, J=2.5Hz, 1H), 5.45-5.38 (m, 1H), 5.29-5.23 (m, 1H), 4.79 (dt, J=5.5,1.5Hz, 2H), 4.69 (dt, J=8.0,3.5Hz, 1H), 4.33- 4.25 (m, 1H), 4.23-4.18 (m, 2H), 3.94 (dd, J=10.0,3.5Hz, 1H), 3.92-3.87 (m, 2H), 3.79 (dd, J=9.0,4.0Hz, 1H), 3.76-3.68 (m, 6H), 3.66-3.57 (m, 6H), 3.48 (dd, J=9.0,6.5Hz, 1H), 3.37(s,3H),1.45(s,9H)ppm；ESI-MS:M/z=613 [M+H]+.
Prepare embodiment 119, N- ((S) -4- morpholino -4- oxos -2- (2- (4- amylene -1- bases oxygroup) benzene carbon amides Base) bytyry)-O- pi-allyls-Serine benzyl ester (8zc)
Raw material 2- (4- amylene -1- bases oxygroup) benzoic acid (2c, 0.068g, 0.33mmol) is placed in 5ml reaction bulbs, is added in The anhydrous CH of 2mL2Cl2Dissolving adds in 1- hydroxy benzo triazoles (0.053g, 0.40mmol) and N- (3- dimethylaminos third immediately Base)-N '-ethyl-carbodiimide hydrochloride (0.11g, 0.59mmol), react at room temperature half an hour.Then, 0 DEG C is cooled to, is added in N- ((S) -2- amino -4- morpholino -4- oxobutanoyls)-O- pi-allyls-Serine benzyl ester hydrochloride (7g, 0.18g, 0.40mmol) and DIPEA (0.16ml, 0.99mmol), when room temperature reaction 3 is small.It is molten that reaction solution adds in 2mL saturated sodium bicarbonate waters Liquid dilutes, and separates organic layer, and solvent, column chromatography point is removed under reduced pressure in saturated common salt washing (2mL × 2) after anhydrous sodium sulfate drying From white solid 0.13g, yield 65%.1H NMR(500MHz,CDCl3) δ 9.17 (d, J=7.5Hz, 1H), 8.18 (dd, J =7.5,1.5Hz, 1H), 7.93 (d, J=8.0Hz, 1H), 7.46-7.41 (m, 1H), 7.37-7.28 (m, 5H), 7.05 (t, J =7.5Hz, 1H), 6.96 (d, J=8.0Hz, 1H), 5.90-5.80 (m, 1H), 5.80-5.70 (m, 1H), 5.27-5.03 (m, 6H), 5.03-4.96 (m, 1H), 4.75 (dt, J=8.0,3.0Hz, 1H), 4.17-4.08 (m, 2H), 3.98-3.88 (m, 3H), 3.71-3.53 (m, 7H), 3.47-3.33 (m, 2H), 3.21 (dd, J=16.5,3.0Hz, 1H), 2.65 (dd, J=16.5, 7.0Hz,1H),2.29–2.21(m,2H),2.12–2.05(m,2H)ppm；ESI-MS:M/z=608 [M+H]+.
Prepare embodiment 120, N- ((S) -5- morpholino -5- oxos -2- (2- (4- amylene -1- bases oxygroup) benzene carbon amides Base) valeryl)-O- pi-allyls-Serine benzyl ester (8zd)
Using N- ((S) -2- amino -5- morpholino -5- Oxopentanoyls)-O- pi-allyls-Serine benzyl ester hydrochlorides as Raw material, synthesis and post processing obtain colourless oil liquid 0.21g, yield 76% with embodiment 119 is prepared.1H NMR(500MHz, CDCl3) δ 8.83 (d, J=7.0Hz, 1H), 8.15 (dd, J=8.0,2.0Hz, 1H), 7.89 (d, J=8.5Hz, 1H), 7.42 (ddd, J=8.5,7.5,2.0Hz, 1H), 7.37-7.29 (m, 5H), 7.07-7.01 (m, 1H), 6.95 (d, J=8.0Hz, 1H),5.90–5.72(m,2H),5.29–5.18(m,2H),5.15–5.04(m,3H),5.03–4.97(m,1H),4.83–4.73 (m,2H),4.17–4.09(m,2H),4.00–3.88(m,3H),3.74–3.61(m,6H),3.60–3.53(m,1H),3.53– 3.40(m,2H),2.79–2.69(m,1H),2.58–2.49(m,1H),2.32–2.23(m,3H),2.12–1.99(m,3H) ppm；ESI-MS:M/z=622 [M+H]+.
Prepare embodiment 121, N- (N4- cyclopropyl-N2- (2- (4- amylene -1- bases oxygroup) benzoyl)-altheine Acyl group)-O- pi-allyls-Serine benzyl ester (8ze)
With N- (N4- cyclopropyl-altheine acyl group)-O- pi-allyls-Serine benzyl ester hydrochloride be raw material, synthesis And post processing obtains white solid 0.11g, yield 58% with embodiment 119 is prepared.1H NMR(500MHz,CDCl3)δ9.19(d,J =6.5Hz, 1H), 8.14 (dd, J=8.0,2.0Hz, 1H), 8.01 (d, J=8.0Hz, 1H), 7.43 (ddd, J=8.5,7.5, 2.0Hz, 1H), 7.38-7.29 (m, 5H), 7.07-7.01 (m, 1H), 6.96 (d, J=8.0Hz, 1H), 6.20 (d, J= 3.5Hz, 1H), 5.90-5.70 (m, 2H), 5.28-4.96 (m, 7H), 4.78-4.72 (m, 1H), 4.15 (t, J=6.5Hz, 2H), 3.99-3.87 (m, 3H), 3.66 (dd, J=9.5,3.5Hz, 1H), 2.82 (dd, J=15.0,3.5Hz, 1H), 2.73- 2.66 (m, 1H), 2.61 (dd, J=15.0,7.0Hz, 1H), 2.29-2.18 (m, 2H), 2.12-2.01 (m, 2H), 0.78- 0.69(m,2H),0.57–0.44(m,2H)ppm；ESI-MS:M/z=578 [M+H]+.
Preparation embodiment 122, N- ((2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-L- leucyl-s)-O- pi-allyls - Serine benzyl ester (8zf)
Using N- (L- leucyl-s)-O- pi-allyls-Serine benzyl ester hydrochloride as raw material, synthesis and post processing are the same as preparation Embodiment 119 obtains colourless oil liquid 0.12g, yield 68%.1H NMR(500MHz,CDCl3) δ 8.42 (d, J=8.0Hz, 1H),8.23–8.17(m,1H),7.46–7.40(m,1H),7.38–7.30(m,5H),7.09–7.03(m,1H),6.95(d,J =8.5Hz, 1H), 6.90 (d, J=8.0Hz, 1H), 5.90-5.80 (m, 1H), 5.79-5.70 (m, 1H), 5.29-5.23 (m, 1H),5.20–5.01(m,5H),4.81–4.73(m,2H),4.18–4.10(m,2H),3.97–3.85(m,3H),3.62(dd,J =9.5,3.5Hz, 1H), 2.29 (q, J=7.5Hz, 2H), 2.07-1.98 (m, 2H), 1.82-1.73 (m, 2H), 1.68-1.59 (m, 1H), 0.95 (d, J=6.0Hz, 6H) ppm；ESI-MS:M/z=537 [M+H]+.
Preparation embodiment 123, N- ((2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-L- valyls base)-O- pi-allyls - Serine benzyl ester (8zg)
Using N- (L- valyls base)-O- pi-allyls-Serine benzyl ester hydrochloride as raw material, synthesis and post processing are the same as preparation Embodiment 119 obtains colourless oil liquid 0.088g, yield 51%.1H NMR(500MHz,CDCl3) δ 8.56 (d, J=8.5Hz, 1H), 8.20 (dd, J=8.0,2.0Hz, 1H), 7.46-7.40 (m, 1H), 7.39-7.29 (m, 5H), 7.09-7.02 (m, 1H), 6.97 (d, J=8.5Hz, 1H), 6.68 (d, J=8.0Hz, 1H), 5.90-5.69 (m, 2H), 5.30-5.23 (m, 1H), 5.20- 4.99 (m, 5H), 4.81 (dt, J=8.0,3.0Hz, 1H), 4.62 (dd, J=8.5,6.0Hz, 1H), 4.20-4.09 (m, 2H), 3.97-3.84 (m, 3H), 3.62 (dd, J=9.5,3.0Hz, 1H), 2.36-2.16 (m, 3H), 2.09-2.01 (m, 2H), 1.06–0.99(m,6H)ppm；ESI-MS:M/z=523 [M+H]+.
Prepare embodiment 124, (S) -2- (N- (2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- seryls Base) amino hex- 5- olefin(e) acids benzyl ester (8zh)
Using (S) -2- ((S) -2- amino -3- methoxypropionamides base) -5- hexene acid benzyl ester hydrochlorides as raw material, synthesis and Post processing obtains colourless oil liquid 0.15g, yield 88% with embodiment 119 is prepared.1H NMR(500MHz,CDCl3)δ8.83 (d, J=7.0Hz, 1H), 8.21 (dd, J=8.0,1.5Hz, 1H), 7.50-7.42 (m, 1H), 7.39-7.29 (m, 5H), 7.14 (d, J=8.0Hz, 1H), 7.07 (t, J=7.5Hz, 1H), 6.97 (d, J=8.5Hz, 1H), 5.88-5.67 (m, 2H), 5.21- 5.10 (m, 2H), 5.09-4.90 (m, 4H), 4.81 (td, J=6.5,4.0Hz, 1H), 4.69 (td, J=7.5,4.5Hz, 1H), 4.16-4.12 (m, 2H), 3.96 (dd, J=9.0,3.5Hz, 1H), 3.51 (dd, J=9.0,6.0Hz, 1H), 3.39 (s, 3H), 2.29–2.22(m,2H),2.11–1.93(m,5H),1.84–1.73(m,1H)ppm；ESI-MS:M/z=509 [M+H]+.
Prepare embodiment 125, (S) -2- (N- (2- (hex- 5- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- seryls Base) amino hex- 5- olefin(e) acids benzyl ester (8zi)
Raw material 2- (5- hexene -1- bases oxygroup) benzoic acid (2d, 0.15g, 0.69mmol) is placed in 5ml reaction bulbs, is added in The anhydrous THF dissolvings of 3mL, add in 1- hydroxy benzo triazoles (0.11g, 0.80mmol), benzotriazole-N, N, N', N'- immediately Tetramethylurea hexafluorophosphoric acid ester (0.30g, 0.80mmol) and (S) -2- ((S) -2- amino -3- methoxypropionamides base) -5- oneself Olefin(e) acid benzyl ester hydrochloride (0.29g, 0.80mmol).Then, 0 DEG C is cooled to, adds in DIPEA (0.23ml, 1.4mmol), room temperature React 3 it is small when.It removes solvent under reduced pressure, adds in 5mL ethyl acetate and 4ml water, separate organic layer, use saturated sodium bicarbonate water successively Solution (4mL × 2) and saturated salt solution (4mL × 2) washing, solvent, column chromatography for separation are removed under reduced pressure after anhydrous sodium sulfate drying Obtain colourless oil liquid 0.31g, yield 86%.1H NMR(500MHz,CDCl3) δ 8.83 (d, J=6.5Hz, 1H), 8.21 (dd, J=8.0,1.5Hz, 1H), 7.45 (ddd, J=8.5,7.0,2.0Hz, 1H), 7.38-7.29 (m, 5H), 7.15 (d, J= 8.0Hz, 1H), 7.10-7.04 (m, 1H), 6.97 (d, J=8.0Hz, 1H), 5.86-5.67 (m, 2H), 5.21-5.10 (m, 2H), 5.06-4.90 (m, 4H), 4.81 (td, J=6.5,3.5Hz, 1H), 4.68 (td, J=7.5,4.5Hz, 1H), 4.16- 4.11 (m, 2H), 3.94 (dd, J=9.0,3.5Hz, 1H), 3.51 (dd, J=9.0,6.5Hz, 1H), 3.40 (s, 3H), 2.17- 2.10(m,2H),2.09–1.90(m,5H),1.84–1.75(m,1H),1.63–1.54(m,2H)ppm；ESI-MS:M/z=523 [M+H]+.
Embodiment 126, (8S, 11S) -11- (methoxy) -10,13- dioxo -3,4,5,7,8,9,10 are prepared, 15 carbon -8- carboxylic acids (9a) of 11,12,13- decahydro -2H-1,6,9,12- benzo dioxas diazacyclo
Raw material N- (N- (2- (allyloxy) benzoyl)-O- methyl-L- seryl-s)-O- pi-allyls-Serine Benzyl ester (8a, 0.10g, 0.20mmol) is placed in two neck bottles of 100ml, the dissolving of 60mL toluene is added in, in N2100 are heated under protection ℃.Then Grubbs second generation catalyst is dissolved in 7ml toluene and is slowly injected into reaction system, it is small to react 1 at such a temperature When.Solvent is removed under reduced pressure, column chromatography for separation obtains grey oily liquids 80mg (containing cis-trans-isomer), yield 85%, products obtained therefrom It is directly used in the next step.
Above-mentioned raw materials are dissolved in 3ml methanol, add in 10%Pd/C (8mg), H23h is reacted under protection in room temperature, uses silicon Diatomaceous earth filtering removal catalyst, removes solvent under reduced pressure and obtains white foam solid 58mg, yield 89%.1H NMR(500MHz, CDCl3) δ 8.48 (d, J=9.0Hz, 1H), 8.09 (d, J=7.0Hz, 1H), 7.50-7.43 (m, 1H), 7.35 (d, J= 7.0Hz, 1H), 7.12-7.06 (m, 1H), 6.99 (d, J=8.5Hz, 1H), 5.04-4.97 (m, 1H), 4.74-4.68 (m, 1H), 4.23-4.03 (m, 4H), 3.74-3.66 (m, 2H), 3.51 (dd, J=9.0,3.5Hz, 1H), 3.45-3.40 (m, 1H), 3.35(s,3H),2.06–1.97(m,1H),1.87–1.75(m,2H),1.69–1.60(m,1H)ppm；ESI-MS:M/z=381 [M+H]+.
Embodiment 127, (9S, 12S) -12- (methoxy) -11,14- dioxo -2,3,4,5,6,8,9,10 are prepared, Ten dihydro -1,7,10,13- benzo dioxas diazacyclos of 11,12,13,14-, 16 carbon -9- carboxylic acids (9b)
With N- (N- (2- (3- butene-1s-base oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- pi-allyls-L- Propylhomoserin benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains white foam solid 66mg, two step yields 84% 。1H NMR(500MHz,CDCl3) δ 8.93 (d, J=9.0Hz, 1H), 8.19 (d, J=7.0Hz, 1H), 7.50-7.41 (m, 1H), 7.28 (d, J=9.0Hz, 1H), 7.11-7.03 (m, 1H), 6.98 (d, J=8.5Hz, 1H), 5.00-4.91 (m, 1H), 4.80- 4.71(m,1H),4.27–4.20(m,1H),4.17–4.08(m,2H),4.06–3.96(m,1H),3.79–3.73(m,1H), 3.67-3.61 (m, 1H), 3.59-3.53 (m, 1H), 3.50 (dd, J=9.0,3.5Hz, 1H), 3.37 (s, 3H), 1.93-1.73 (m,3H),1.60–1.48(m,3H)ppm；ESI-MS:M/z=395 [M+H]+.
Embodiment 128, (10S, 13S) -13- (methoxy) -12,15- dioxo -3,4,5,6,7,9,10 are prepared, Ten dihydro -1,8,11,14- benzo dioxas diazacyclos of 11,12,13,14,15-2H-, 17 carbon -10- carboxylic acids (9c)
With N- (N- (2- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- pi-allyls-L- Propylhomoserin benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains white foam solid 62mg, two step yields 76% 。1H NMR(500MHz,CDCl3) δ 9.00 (d, J=8.0Hz, 1H), 8.18 (d, J=7.0Hz, 1H), 7.47-7.38 (m, 1H), 7.23 (d, J=6.5Hz, 1H), 7.06-6.99 (m, 1H), 6.94 (d, J=8.5Hz, 1H), 4.92-4.82 (m, 1H), 4.65- 4.55(m,1H),4.23–4.16(m,1H),4.14–4.05(m,2H),3.80–3.67(m,2H),3.56–3.47(m,2H), 3.45–3.40(m,1H),3.36(s,3H),1.98–1.88(m,1H),1.82–1.69(m,2H),1.63–1.36(m,5H) ppm；ESI-MS:M/z=409 [M+H]+.
Embodiment 129, (11S, 14S) -14- (methoxy) -13,16- dioxo -2,3,4,5,6,7,8 are prepared, Ten tetrahydrochysene -1,9,12,15- benzo dioxas diazacyclos of 10,11,12,13,14,15,16-, 18 carbon -11- carboxylic acids (9d)
With N- (N- (2- (5- hexene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- pi-allyls-L- Propylhomoserin benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains white foam solid 68mg, two step yields 80% 。1H NMR(500MHz,CDCl3) δ 9.00 (d, J=7.5Hz, 1H), 8.18 (d, J=7.5Hz, 1H), 7.50-7.40 (m, 1H), 7.23 (d, J=6.5Hz, 1H), 7.10-7.01 (m, 1H), 6.98 (d, J=8.5Hz, 1H), 4.87-4.81 (m, 1H), 4.75- 4.69 (m, 1H), 4.28-4.21 (m, 1H), 4.15-4.03 (m, 2H), 3.86 (dd, J=10.5,4.5Hz, 1H), 3.76 (dd, J=10.5,2.5Hz, 1H), 3.56 (dd, J=9.0,4.5Hz, 1H), 3.53-3.47 (m, 1H), 3.45-3.35 (m, 4H), 2.03–1.94(m,1H),1.88–1.77(m,1H),1.64–1.32(m,8H)ppm；ESI-MS:M/z=423 [M+H]+.
Embodiment 130, (12S, 15S) -15- (methoxy) -14,17- dioxo -3,4,5,6,7,8,9 are prepared, 19 carbon -12- carboxylic acids (9e) of 11,12,13,14,15,16,17- tetrahydrochysene -2H-1,10,13,16- benzos dioxane
With N- (N- (2- (6- heptene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- pi-allyls-L- Propylhomoserin benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains white foam solid 67mg, two step yields 77% 。1H NMR(500MHz,CDCl3) δ 9.03 (d, J=6.0Hz, 1H), 8.20 (d, J=7.5Hz, 1H), 7.49-7.39 (m, 1H), 7.28 (d, J=7.5Hz, 1H), 7.07-7.00 (m, 1H), 6.97 (d, J=8.5Hz, 1H), 4.80-4.75 (m, 1H), 4.74- 4.68 (m, 1H), 4.22-4.12 (m, 2H), 3.97 (dd, J=9.5,4.0Hz, 1H), 3.80-3.70 (m, 2H), 3.66 (dd, J =9.5,5.0Hz, 1H), 3.54-3.48 (m, 1H), 3.46-3.36 (m, 4H), 2.03-1.96 (m, 1H), 1.91-1.82 (m, 1H),1.60–1.28(m,10H)ppm；ESI-MS:M/z=437 [M+H]+.
Embodiment 131, (13S, 16S) -16- (methoxy) -15,18- dioxo -3,4,5,6,7,8,9 are prepared, 20 carbon -13- carboxylics of 10,13,14,15,16,17,18- tetrahydrochysenes -2H, 12H- benzo [i] [1,11] dioxa [4,7] diazacyclo Sour (9f)
With N- (N- (2- (7- octene-1s-base oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- pi-allyls-L- Propylhomoserin benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains white foam solid 67mg, two step yields 77% 。1H NMR(500MHz,CDCl3) δ 8.97 (d, J=6.5Hz, 1H), 8.21 (d, J=7.5Hz, 1H), 7.49-7.41 (m, 1H), 7.22 (d, J=6.0Hz, 1H), 7.07-7.01 (m, 1H), 6.97 (d, J=8.5Hz, 1H), 4.82-4.75 (m, 1H), 4.68- 4.61 (m, 1H), 4.23-4.18 (m, 1H), 4.17-4.12 (m, 1H), 4.01 (dd, J=9.5,3.0Hz, 1H), 3.80-3.72 (m, 2H), 3.63 (dd, J=9.5,3.5Hz, 1H), 3.55-3.48 (m, 1H), 3.41-3.29 (m, 4H), 2.01-1.89 (m, 1H),1.83–1.72(m,1H),1.67–1.29(m,12H)ppm；ESI-MS:M/z=451 [M+H]+.
Embodiment 132, (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10 are prepared, Ten dihydro -9H-17- chlorobenzenes of 11,12,13,14,15- simultaneously 17 carbon -10- carboxylic acids of [i] [1,11] dioxa [4,7] diazacyclo (9g)
With N- (N- (the chloro- 2- of 5- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- allyls Base-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains white foam solid 61mg, two steps are received Rate 69%.1H NMR(500MHz,CDCl3) δ 8.95 (d, J=8.5Hz, 1H), 8.18 (d, J=3.0Hz, 1H), 7.39 (dd, J =8.5,3.0Hz, 1H), 7.13 (d, J=7.0Hz, 1H), 6.91 (d, J=8.5Hz, 1H), 4.93-4.86 (m, 1H), 4.75- 4.66 (m, 1H), 4.27-4.18 (m, 1H), 4.14-4.07 (m, 2H), 3.81 (dd, J=10.0,4.5Hz, 1H), 3.75 (dd, J=10.0,3.5Hz, 1H), 3.58-3.52 (m, 2H), 3.42-3.34 (m, 4H), 2.00-1.90 (m, 1H), 1.85-1.72 (m,2H),1.68–1.38(m,5H)ppm；ESI-MS:M/z=443 [M+H]+.
Embodiment 133, (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10 are prepared, Ten dihydro -9H-18- chlorobenzenes of 11,12,13,14,15- simultaneously 17 carbon -10- carboxylic acids of [i] [1,11] dioxa [4,7] diazacyclo (9h)
With N- (N- (the chloro- 2- of 4- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- allyls Base-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 66mg, two steps Yield 75%.1H NMR(500MHz,CDCl3) δ 8.86 (d, J=8.0Hz, 1H), 8.26-8.18 (m, 1H), 7.15 (d, J= 6.5Hz, 1H), 6.79-6.72 (m, 1H), 6.69 (d, J=10.5Hz, 1H), 4.93-4.86 (m, 1H), 4.72-4.64 (m, 1H),4.23–4.16(m,1H),4.14–4.04(m,2H),3.82–3.69(m,2H),3.57–3.49(m,2H),3.41–3.32 (m,4H),1.99–1.89(m,1H),1.82–1.73(m,2H),1.66–1.36(m,5H)ppm；ESI-MS:M/z=443 [M+ H]+.
Embodiment 134, (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10 are prepared, Ten dihydro -9H-18- fluorobenzene of 11,12,13,14,15- simultaneously 17 carbon -10- carboxylic acids of [i] [1,11] dioxa [4,7] diazacyclo (9i)
With N- (N- (the fluoro- 2- of 4- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- allyls Base-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 59mg, two steps Yield 69%.1H NMR(500MHz,CDCl3) δ 8.87 (d, J=8.5Hz, 1H), 8.15 (d, J=8.5Hz, 1H), 7.15 (d, J =7.0Hz, 1H), 7.05 (d, J=8.5Hz, 1H), 6.98 (s, 1H), 4.93-4.86 (m, 1H), 4.72-4.64 (m, 1H), 4.24–4.18(m,1H),4.13–4.08(m,2H),3.82–3.70(m,2H),3.56–3.49(m,2H),3.41–3.32(m, 5H),2.00–1.89(m,1H),1.83–1.72(m,2H),1.67–1.35(m,5H)ppm；ESI-MS:M/z=427 [M+H]+.
Embodiment 135, (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10 are prepared, 17 carbon -10- carboxylics of 11,12,13,14,15- ten dihydro -9H-18- methyl benzo [i] [1,11] dioxa [4,7] diazacyclo Sour (9j)
With N- (N- (4- methyl -2- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- allyls Base-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 63mg, two steps Yield 75%.1H NMR(500MHz,CDCl3) δ 8.98 (d, J=8.5Hz, 1H), 8.09 (d, J=8.0Hz, 1H), 7.16 (d, J =7.0Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.77 (s, 1H), 4.96-4.89 (m, 1H), 4.72-4.64 (m, 1H), 4.23-4.15 (m, 1H), 4.15-4.08 (m, 2H), 3.78 (dd, J=10.0,4.5Hz, 1H), 3.73 (dd, J=10.0, 3.5Hz,1H),3.56–3.47(m,2H),3.43–3.33(m,4H),2.38(s,3H),1.99–1.89(m,1H),1.82– 1.72(m,2H),1.66–1.36(m,5H)ppm；ESI-MS:M/z=423 [M+H]+.
Embodiment 136, (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10 are prepared, 17 carbon -10- of 11,12,13,14,15- ten dihydro -9H-18- methoxyl groups benzo [i] [1,11] dioxa [4,7] diazacyclo Carboxylic acid (9k)
With N- (N- (4- methoxyl groups -2- (4- amylene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- alkene Propyl-Serine benzyl ester be raw material, synthesis and post processing with embodiment 126 is prepared, obtain canescence foaming solid 59mg, two Walk yield 69%.1H NMR(500MHz,CDCl3) δ 8.87 (d, J=8.0Hz, 1H), 8.16 (d, J=8.5Hz, 1H), 7.18 (d, J=6.5Hz, 1H), 6.58 (d, J=8.5Hz, 1H), 6.47 (s, 1H), 4.93-4.84 (m, 1H), 4.69-4.59 (m, 1H), 4.22-4.16 (m, 1H), 4.14-4.05 (m, 2H), 3.85 (s, 3H), 3.79 (dd, J=9.5,4.5Hz, 1H), 3.73 (dd, J=9.5,3.0Hz, 1H), 3.57-3.48 (m, 2H), 3.43-3.31 (m, 4H), 2.00-1.88 (m, 1H), 1.84- 1.71(m,2H),1.69–1.36(m,5H)ppm；ESI-MS:M/z=439 [M+H]+.
Embodiment 137, (3S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10,13 are prepared, Ten dihydro -12H-2- methylthiazols of 14,15,16,17,18- simultaneously 17 carbon of [5,4-i] [1,11] dioxa [4,7] diazacyclo - 13- carboxylic acids (9l)
Raw material N- (N- (2- methyl -4- (4- amylene -1- bases oxygroup) thiazole -5- formoxyls)-O- methyl-L- seryls Base)-O- pi-allyls-Serine methyl esters (8l, 0.12g, 0.26mmol) is placed in two neck bottles of 250ml, it is molten to add in 65mL toluene Solution, is heated to 100 DEG C under nitrogen protection.Then Grubbs second generation catalyst is dissolved in 8ml toluene and is slowly injected into anti- System is answered, when reaction 1 is small at such a temperature.Solvent is removed under reduced pressure, column chromatography for separation obtains colourless oil liquid 0.10g and (contains along anti- Isomers), yield 88%, products obtained therefrom is directly used in the next step.
Above-mentioned raw materials are dissolved in 3ml methanol, add in 10%Pd/C (30mg), H23h is reacted under protection in room temperature, is used Diatomite filtering removal catalyst, removes solvent under reduced pressure, column chromatography for separation obtains colourless oil liquid 86mg, yield 85%.1H NMR(500MHz,CDCl3) δ 7.95 (d, J=9.5Hz, 1H), 7.21 (d, J=7.0Hz, 1H), 4.89-4.83 (m, 1H), 4.69-4.63 (m, 1H), 4.59 (td, J=10.0,2.5Hz, 1H), 4.51-4.45 (m, 1H), 4.16-4.09 (m, 2H), 3.84 (dd, J=10.0,3.0Hz, 1H), 3.72 (s, 3H), 3.68 (dd, J=10.0,3.0Hz, 1H), 3.56-3.49 (m, 2H),3.38(s,3H),2.64(s,3H),1.89–1.73(m,2H),1.69–1.50(m,5H),1.48–1.38(m,1H)ppm； ESI-MS:M/z=444 [M+H]+。
Reactant (3S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10,13,14,15,16, Ten dihydro -12H-2- methylthiazols of 17,18- simultaneously 17 carbon -13- carboxylic acid first of [5,4-i] [1,11] dioxa [4,7] diazacyclo Ester (60mg, 0.14mmol) is dissolved in 0.68mL acetone, and 0 DEG C is cooled under ice bath, and 0.3N LiOH aqueous solutions are added dropwise 0.67mL, when reaction 2 is small at this temperature.Acetone, water layer 3N HCl tune pH to 2-3, ethyl acetate extraction (2mL is removed under reduced pressure × 3), merge organic layer, solvent is removed under reduced pressure after anhydrous sodium sulfate drying.Products therefrom is directly used in the next step.
Embodiment 138, (6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,12,13 are prepared, 17 carbon -9- carboxylic acids (9m) of 14,15,16,17- ten dihydro -4H- thienos [3,2-i] [1,11] dioxa [4,7] diazacyclo
With N- (O- methyl-N- (2- (4- amylene -1- bases oxygroup) thiophene -3- formoxyls)-L- seryl-s)-O- allyls Base-Serine methyl esters is raw material, synthesis and the same preparation embodiment 135 of post processing, obtains colourless oil liquid 76mg, two step yields 68%.1H NMR(500MHz,CDCl3) δ 8.14 (d, J=9.0Hz, 1H), 7.44 (d, J=5.5Hz, 1H), 7.24 (d, J= 7.0Hz, 1H), 6.87 (d, J=5.5Hz, 1H), 4.96-4.91 (m, 1H), 4.71-4.66 (m, 1H), 4.33-4.27 (m, 1H), 4.21-4.13 (m, 2H), 3.82 (dd, J=10.0,3.5Hz, 1H), 3.73-3.68 (m, 4H), 3.57-3.50 (m, 2H),3.42–3.36(m,4H),1.95–1.85(m,1H),1.80–1.69(m,2H),1.63–1.54(m,4H),1.48–1.40 (m,1H)ppm；ESI-MS:M/z=429 [M+H]+.
Reactant (6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,12,13,14,15,16, 17 carbon -9- methyl formates of 17- ten dihydro -4H- thienos [3,2-i] [1,11] dioxa [4,7] diazacyclo (60mg, 0.70mL acetone 0.14mmol) is dissolved in, 0 DEG C is cooled under ice bath, 0.3N LiOH aqueous solution 0.70mL, the temperature is added dropwise It is lower reaction 2 it is small when.Acetone, water layer 3N HCl tune pH to 2-3 is removed under reduced pressure, ethyl acetate extraction (2mL x 3) merges organic Layer removes solvent under reduced pressure after anhydrous sodium sulfate drying.Products therefrom is directly used in the next step.
Embodiment 139, (14S, 17S) -17- (methoxy) -16,19- dioxo -6,7,8,9,10,11 are prepared, 14,15,16,17,18,19- ten dihydro -13H- pyridos [3-i] [1,11] dioxa [4,7] 17 carbon-14s of diazacyclo-carboxylic Sour (9n)
With N- (O- methyl-N- (3- (4- amylene -1- bases oxygroup) picolinoyl)-L- seryl-s)-O- pi-allyls-L- Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains light red foaming solid 45mg, two step yields 55%.ESI-MS:M/z=410 [M+H]+.
Embodiment 140, (7S, 10S) -7- (methoxy) -5,8- dioxo -6,7,8,9,10,11,13,14 are prepared, 17 carbon -10- carboxylic acids of 15,16,17,18- ten dihydro -5H- pyridos [3,2-i] [1,11] dioxa [1,11] diazacyclo (9o)
With N- (O- methyl-N- (2- (4- amylene -1- bases oxygroup) niacin formoxyl)-L- seryl-s)-O- pi-allyls-L- Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains light red foaming solid 50mg, two step yields 61%.ESI-MS:M/z=410 [M+H]+.
Embodiment 141, (6S, 9S) -6- (methoxy) -4,7- dioxo -1,4,5,6,7,8,9,10,12 are prepared, Ten tetrahydrochysene -1- methyl pyrazoles of 13,14,15,16,17- simultaneously 17 carbon -9- of [4,3-i] [1,11] dioxa [4,7] diazacyclo Formic acid (9p)
With N- (O- methyl-N- (1- methyl -5- (4- amylene -1- bases oxygroup) -1H- pyrazoles -4- formoxyls)-L- seryls Base)-O- pi-allyls-Serine benzyl ester be raw material, synthesis and post processing with prepare embodiment 126, obtain canescence foam-like and consolidate Body 68mg, two step yields 82%.ESI-MS:M/z=413 [M+H]+.
Embodiment 142, (13S, 16S) -16- (methoxy) -15,18- dioxo -2,11- dioxa -14 are prepared, 13 carbon -1 (23) of 17- diazabicyclos [17.3.1]-two, 19,21- triolefin -13- carboxylic acids (9q)
With N- (N- (3- (hept- 6- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- pi-allyls-L- Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 61mg, two step yields 70%.1H NMR(500MHz,CDCl3) δ 7.42 (d, J=8.0Hz, 1H), 7.39-7.31 (m, 3H), 7.09-7.00 (m, 2H), 4.92-4.84 (m, 1H), 4.74-4.68 (m, 1H), 4.19-4.09 (m, 2H), 4.07 (dd, J=10.0,3.5Hz, 1H), 4.03-3.93 (m, 1H), 3.88 (dd, J=10.0,3.5Hz, 1H), 3.67 (dd, J=10.0,3.5Hz, 1H), 3.62 (dd, J =9.5,4.0Hz, 1H), 3.44-3.36 (m, 4H), 1.86-1.69 (m, 3H), 1.55-1.40 (m, 5H), 1.40-1.29 (m, 4H)ppm；ESI-MS:M/z=437 [M+H]+.
Embodiment 143, (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10 are prepared, 17 carbon -10- carboxylics of 11,12,13,14,15- ten the fluoro- benzos of dihydro -9H-19- [i] [1,11] dioxa [4,7]-diazacyclo Sour (9r)
With N- (N- (the fluoro- 2- of 3- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- allyls Base-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 70mg, two steps Yield 82%.1H NMR(500MHz,CDCl3) δ 8.96 (d, J=8.0Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.25- 7.20(m,2H),7.13–7.02(m,1H),4.88–4.79(m,1H),4.68–4.60(m,1H),4.42–4.34(m,1H), 4.32-4.24 (m, 1H), 4.13-4.06 (m, 1H), 3.80 (dd, J=9.5,3.5Hz, 1H), 3.75 (dd, J=9.5, 2.5Hz,1H),3.57–3.49(m,2H),3.39–3.34(m,4H),2.01–1.91(m,1H),1.77–1.68(m,1H), 1.64–1.36(m,6H)ppm；ESI-MS:M/z=427 [M+H]+.
Embodiment 144, (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10 are prepared, Ten dihydro -9H-19- methoxyl groups of 11,12,13,14,15--benzo [i] [1,11] dioxa [4,7] -17 carbon of diazacyclo - 10- carboxylic acids (9s)
With N- (N- (3- methoxyl groups -2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s)-O- Pi-allyl-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 60mg, Two step yields 68%.1H NMR(500MHz,CDCl3) δ 9.14 (d, J=7.5Hz, 1H), 7.72 (d, J=7.5Hz, 1H), 7.23 (d, J=7.0Hz, 1H), 7.15-7.10 (m, 1H), 7.10-7.04 (m, 1H), 4.85-4.78 (m, 1H), 4.69-4.61 (m, 1H), 4.11-4.01 (m, 2H), 3.91-3.81 (m, 5H), 3.75 (dd, J=9.5,2.5Hz, 1H), 3.54 (dd, J=9.0, 3.5Hz,2H),3.42–3.32(m,4H),1.78–1.67(m,1H),1.64–1.55(m,1H),1.53–1.18(m,6H)ppm； ESI-MS:M/z=439 [M+H]+.
Embodiment 145, (6S, 9S) -6- (methoxy) -4,7- dioxo -4,5,6,7,8,9,10,12,13 are prepared, Ten tetrahydrochysene -1H-1- methyl pyrazoles of 14,15,16,17,18- simultaneously 17 carbon -9- carboxylics of [4,3-i] [1] oxa- [4,7]-diazacyclo Sour (9t)
With N- (N- (5- pi-allyl -1- methyl-1 H- pyrazoles -4- carbonyls)-O- methyl-L- seryl-s)-O- (5- hexenes - 1- yls)-Serine benzyl ester be raw material, synthesis and post processing with prepare embodiment 126, obtain canescence foaming solid 71mg, Two step yields 87%.1H NMR(500MHz,CDCl3) δ 9.14 (d, J=7.5Hz, 1H), 7.72 (d, J=7.5Hz, 1H), 7.23 (d, J=7.0Hz, 1H), 7.15-7.10 (m, 1H), 7.10-7.04 (m, 1H), 4.85-4.78 (m, 1H), 4.69-4.61 (m, 1H), 4.11-4.01 (m, 2H), 3.91-3.81 (m, 5H), 3.75 (dd, J=9.5,2.5Hz, 1H), 3.54 (dd, J=9.0, 3.5Hz,2H),3.42–3.32(m,4H),1.78–1.67(m,1H),1.64–1.55(m,1H),1.53–1.18(m,6H)ppm； ESI-MS:M/z=411 [M+H]+.
Embodiment 146, (6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,12,13 are prepared, 16 carbon -9- carboxylic acids (9u) of 14,15,16,17- ten dihydro -4H- pyrazolos [5,1-i] [1] [4,7,10]-three azacyclo- of oxa-
With N- (N- (1- (amyl- 4- alkene -1- bases) -1H- pyrazoles -5- carbonyls)-O- methyl-L- seryl-s)-O- pi-allyls - Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 57mg, two steps are received Rate 75%.1H NMR(500MHz,CDCl3) δ 7.47 (d, J=2.0Hz, 1H), 6.60 (d, J=2.0Hz, 1H), 5.15-5.06 (m, 1H), 4.75-4.69 (m, 1H), 4.58-4.52 (m, 1H), 4.19 (dt, J=13.5,5.0Hz, 1H), 3.90 (dd, J= 10.0,5.5Hz, 1H), 3.75 (dd, J=10.0,4.0Hz, 1H), 3.70-3.62 (m, 2H), 3.48-3.28 (m, 5H), 2.01–1.90(m,1H),1.76–1.66(m,1H),1.51–1.29(m,3H),1.28–0.99(m,3H)ppm；ESI-MS:m/z =383 [M+H]+.
Embodiment 147, (11S, 14S) -14- (methoxy) -13,16- dioxo -5,6,7,8,11,12 are prepared, 14 carbon -11- carboxylic acids (9v) of 13,14,15,16- decahydro -10H- imidazos [2,1-i] [1] [4,7,10]-three azacyclo- of oxa-
With N- (N- (1- pi-allyl -1H- imidazoles -2- carbonyls)-O- methyl-L- seryl-s)-O- pi-allyls-Serine Benzyl ester is raw material, and synthesis and post processing obtain pale red solid 47mg, two step yields 66% with embodiment 126 is prepared.1H NMR (500MHz,CDCl3) δ 8.27 (d, J=5.5Hz, 1H), 7.61 (d, J=6.5Hz, 1H), 7.09-6.94 (m, 2H), 4.69- 4.47 (m, 3H), 4.34-4.24 (m, 1H), 3.98 (dd, J=10.0,6.5Hz, 1H), 3.93-3.80 (m, 2H), 3.69 (dd, J=9.0,2.5Hz, 1H), 3.62-3.56 (m, 1H), 3.44-3.28 (m, 4H), 1.90-1.80 (m, 1H), 1.76-1.67 (m, 1H),1.54–1.39(m,2H)ppm；ESI-MS:M/z=355 [M+H]+.
Embodiment 148, (12S, 15S) -15- (methoxy) -14,17- dioxo -6,7,8,9,12,13 are prepared, 15 carbon -12- carboxylic acids of 14,15,16,17- decahydros -5H, 11H- imidazo [2,1-i] [1] [4,7,10]-three azacyclo- of oxa- (9w)
With N- (N- (1- (butyl- 3- alkene -1- bases) -1H- imidazoles -2- carbonyls)-O- methyl-L- seryl-s)-O- pi-allyls - Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains pale red solid 44mg, two step yields 60% 。1H NMR(500MHz,CDCl3) δ 8.13 (d, J=7.5Hz, 1H), 7.34 (d, J=7.5Hz, 1H), 7.10-6.97 (m, 2H), 4.76-4.69 (m, 1H), 4.56-4.47 (m, 1H), 4.08-3.95 (m, 3H), 3.73 (dd, J=9.5,4.0Hz, 1H), 3.61–3.52(m,2H),3.49(s,1H),3.42(s,3H),3.26–3.18(m,1H),1.86–1.75(m,1H),1.68– 1.55(m,2H),1.43–1.26(m,3H)ppm；ESI-MS:M/z=369 [M+H]+.
Embodiment 149, (13S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10,13 are prepared, 16 carbon -13- carboxylic acids of 14,15,16,17,18- ten dihydro -12H- imidazos [2,1-i] [1] [4,7,10]-three azacyclo- of oxa- (9x)
With N- (N- (1- (amyl- 4- alkene -1- bases) -1H- imidazoles -2- carbonyls)-O- methyl-L- seryl-s)-O- pi-allyls - Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains pale red solid 45mg, two step yields 59% 。1H NMR(500MHz,CDCl3) δ 8.13 (d, J=6.7Hz, 1H), 7.46 (d, J=7.9Hz, 1H), 7.10-7.04 (m, 2H), 4.68-4.62 (m, 1H), 4.56-4.50 (m, 1H), 4.03-3.94 (m, 2H), 3.80 (dd, J=9.5,3.0Hz, 1H), 3.74 (dd, J=10.0,4.5Hz, 1H), 3.63 (dd, J=9.5,3.0Hz, 1H), 3.49-3.31 (m, 6H), 1.87-1.75 (m, 2H),1.61–1.45(m,2H),1.43–1.32(m,2H),1.30–1.21(m,2H)ppm；ESI-MS:M/z=383 [M+H]+.
Embodiment 150, (3S, 6S) -3- (methoxy) -1,4- dioxo -2,3,4,5,6,7,9,10,11 are prepared, 16 carbon -6- carboxylic acids (9y) of 12,13,14- ten dihydro -1H- pyrrolo-es [2,1-i] [1] [4,7,10]-three azacyclo- of oxa-
With N- (N- (1- (amyl- 4- alkene -1- bases) -1H- pyrroles -2- carbonyls)-O- methyl-L- seryl-s)-O- pi-allyls - Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 58mg, two steps are received Rate 76%.1H NMR(500MHz,CDCl3) δ 7.40 (d, J=8.0Hz, 1H), 6.91-6.76 (m, 2H), 6.66 (d, J= 2.5Hz, 1H), 6.17 (dd, J=3.5,2.5Hz, 1H), 5.22-5.09 (m, 1H), 4.62 (dt, J=8.0,2.5Hz, 1H), 4.59-4.52 (m, 1H), 3.99 (dd, J=10.0,5.0Hz, 1H), 3.93 (dd, J=9.5,2.0Hz, 2H), 3.76-3.65 (m,2H),3.51–3.36(m,5H),1.78–1.59(m,2H),1.60–1.49(m,1H),1.47–1.36(m,2H),1.33– 1.19(m,3H)ppm；ESI-MS:M/z=382 [M+H]+.
Prepare embodiment 151,-ten hexahydro -1H- pyrroles of (3S, 6S, 18aS) -3- (methoxy) -1,4,14- trioxy-s Cough up simultaneously 16 carbon -6- carboxylic acids (9z) of [2,1-i] [1] [4,7,10] three azacyclo- of oxa-
With N- (N- (4- pentenoyl-L- prolyls)-O- methyl-L- seryl-s)-O- pi-allyls-Serine benzyl Ester is raw material, and synthesis and post processing obtain canescence oily liquids 68mg, two step yields 85% with embodiment 126 is prepared.1H NMR (500MHz,CDCl3) δ 7.68 (d, J=7.0Hz, 1H), 6.65 (d, J=8.0Hz, 1H), 4.79-4.69 (m, 1H), 4.59- 4.44 (m, 2H), 3.98 (dd, J=10.0,2.5Hz, 1H), 3.90-3.77 (m, 2H), 3.76-3.67 (m, 1H), 3.65- 3.49(m,4H),3.32(s,3H),2.47–2.39(m,2H),2.36–2.30(m,1H),2.10–1.94(m,4H),1.72– 1.63(m,1H),1.55–1.39(m,3H),1.35–1.28(m,1H)ppm；ESI-MS:M/z=400 [M+H]+.
Embodiment 152, (9S, 12S) -12- (methoxy) -11,14- dioxo -2,3,5,6,9,10,11 are prepared, 16 carbon -9- carboxylic acids (9za) of 12,13,14- decahydro -8H- benzos [o] [1,4,7]-trioxa [10,13]-diazacyclo
Raw material N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (2- ((2- allyloxycarbonyls) benzene oxygen Base oxethyl) ethyl)-Serine methyl esters (8za, 0.68g, 1.2mmol) is placed in 25ml round-bottomed flasks, add in four triphenyls Phosphine palladium (0.069g, 0.06mmol) and 1,3- dimethyl barbituric acid (0.19g, 1.2mmol), in N2The lower injection 8ml bis- of protection Chloromethanes, room temperature reaction is overnight.Add in 8ml saturated sodium bicarbonate solutions, stirring 1 it is small when after separate organic layer, water layer 3N HCl tune PH to 2-3, ethyl acetate (10ml x 2) extraction, saturated salt solution (8ml x 2) washing, anhydrous sodium sulfate drying subtract Pressure removes solvent and obtains colourless oil liquid 0.37g, yield 58%.1H NMR(500MHz,CDCl3) δ 8.14 (d, J=7.5Hz, 1H), 7.57-7.51 (m, 1H), 7.40 (d, J=4.0Hz, 1H), 7.17-7.10 (m, 1H), 7.04 (d, J=8.0Hz, 1H), 5.55 (d, J=6.5Hz, 1H), 4.76-4.70 (m, 1H), 4.39-4.30 (m, 3H), 3.94 (dd, J=9.5,2.5Hz, 1H), 3.91-3.86 (m, 2H), 3.81 (dd, J=9.5,4.0Hz, 1H), 3.77-3.71 (m, 4H), 3.70-3.63 (m, 4H), 3.55–3.48(m,1H),3.38(s,3H),1.44(s,9H)ppm；ESI-MS:M/z=529 [M+H]+.
Reactant 2- (((6S, 9S) -9- (methoxycarbonyl) -6- (methoxy) -2,2- dimethyl -4,7- dioxos 3,11,14 trioxa -5,8- diaza, 16 carbon -16- oxygroups) benzoic acid (0.37g, 0.69mmol) is dissolved in 2.0mL CH2Cl2, Ice bath is cooled to 0 DEG C, 1.0mL trifluoroacetic acids is added in, when room temperature reaction 2 is small.Reaction solution removes solvent under reduced pressure and obtains faint yellow solid, Products obtained therefrom is directly used in the next step.
2- (((4S, 7S) -4- amino -7- (methoxycarbonyl) -5- oxo -2,9,12- trioxa -6- azepines tetradecane - 14- yls) oxygroup) benzoic acid trifluoroacetate (0.69mmol), 1- hydroxy benzo triazoles (0.11g, 0.83mmol) and benzo Triazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (0.31g, 0.83mmol) is dissolved in the anhydrous THF of 138ml, is cooled to 0 DEG C, DIPEA (0.27mL, 1.7mmol) is added dropwise, when room temperature reaction 5 is small.Solvent is removed under reduced pressure, adds in 10ml ethyl acetate With 8ml water, organic layer is separated.Then, successively with saturated sodium bicarbonate solution (10mL x 2) and saturated salt solution (8mL x2) Solvent is removed under reduced pressure after anhydrous sodium sulfate drying in washing, and column chromatography for separation obtains colourless oil liquid 0.15g, two step yields 53% 。1H NMR(500MHz,CDCl3) δ 8.90 (d, J=9.5Hz, 1H), 8.25 (dd, J=8.0,2.0Hz, 1H), 7.51-7.45 (m, 1H), 7.38 (d, J=8.5Hz, 1H), 7.14-7.08 (m, 1H), 6.97 (d, J=8.0Hz, 1H), 5.13-5.07 (m, 1H), 4.84 (dt, J=8.5,3.0Hz, 1H), 4.42-4.35 (m, 1H), 4.31-4.24 (m, 1H), 4.16 (dd, J=9.0, 2.0Hz, 1H), 4.07 (dd, J=10.0,2.0Hz, 1H), 3.96-3.89 (m, 2H), 3.86-3.79 (m, 1H), 3.75-3.66 (m, 4H), 3.62 (dd, J=10.0,3.0Hz, 1H), 3.59-3.51 (m, 2H), 3.50-3.45 (m, 1H), 3.39 (s, 3H) ppm；ESI-MS:M/z=411 [M+H]+.
Above-mentioned raw materials (9S, 12S) -12- (methoxy) -11,14- dioxo -2,3,5,6,9,10,11,12,13, 16 carbon -9- carboxylate methyl esters of 14- decahydro -8H- benzos [o] [Isosorbide-5-Nitrae, 7]-trioxa [10,13]-diazacyclo (0.14g, 1.3mL acetone 0.34mmol) is dissolved in, 0 DEG C is cooled under ice bath, 0.3N lithium hydroxide aqueous solution 1.7ml, the temperature is added dropwise Lower reaction 30 minutes.3N HCl tune PH to 2-3 are slowly added to, acetone, ethyl acetate (3mL x 2) extraction, saturation is removed under reduced pressure Saline solution (2mL x2) washs, and solvent, which is removed under reduced pressure, after anhydrous sodium sulfate drying obtains colourless oil liquid 0.11mg, yield 82%. Products obtained therefrom is directly used in the next step.
Prepare embodiment 153, N- [(12S, 15S) -15- (methoxy) -14,17- dioxo -2,3,5,6,8,9, Ten dihydro -11H- benzos [r] of 12,13,14,15,16,17- [1,4,7,10] four oxa- [13,16] -19 carbon of diazacyclo - 12- carboxylic acids (9zb)
Raw material N- (N- (tert-butoxycarbonyl)-O- methyl-L- seryl-s)-O- (2- (2-((2- allyloxy carbonyls) Phenoxy group) ethyoxyl) ethyl)-Serine methyl esters (8zb, 0.12g, 0.20mmol) is placed in 10ml round-bottomed flasks, Tetra-triphenylphosphine palladium (0.011g, 0.01mmol) and 1,3- dimethyl barbituric acid (0.03g, 0.20mmol) are added in, in N2It protects The lower injection 4ml dichloromethane of shield, room temperature reaction is overnight.Add in 5ml saturated sodium bicarbonate solutions, stirring 1 it is small when after separate it is organic Layer, water layer 3N HCl tune PH to 2-3, ethyl acetate (5ml x 2) extraction, saturated salt solution (4ml x 2) washing, anhydrous sulphur Sour sodium drying, is removed under reduced pressure solvent and obtains colourless oil liquid 0.098g, yield 86%.1H NMR(500MHz,CDCl3)δ8.15 (d, J=7.5Hz, 1H), 7.57-7.51 (m, 1H), 7.37 (d, J=5.5Hz, 1H), 7.17-7.11 (m, 1H), 7.05 (d, J =8.0Hz, 1H), 5.48 (d, J=5.0Hz, 1H), 4.72-4.66 (m, 1H), 4.41-4.36 (m, 2H), 4.33-4.25 (m, 1H), 3.96-3.90 (m, 3H), 3.79 (dd, J=9.0,4.0Hz, 1H), 3.76-3.64 (m, 9H), 3.62-3.58 (m, 4H), 3.49 (dd, J=8.5,7.0Hz, 1H), 3.38 (s, 3H), 1.45 (s, 9H) ppm；ESI-MS:M/z=573 [M+H]+.
Reactant 2- (((6S, 9S) -9- (methoxycarbonyl) -6- (methoxy) -2,2- dimethyl -4,7- dioxies Generation -3,11,14,17- tetra- oxa- -5,8- diaza 19 carbon -19- bases) oxygroup) benzoic acid (0.16g, 0.28mmol) is dissolved in 0.6mL CH2Cl2, ice bath is cooled to 0 DEG C, 0.3mL trifluoroacetic acids added in, when room temperature reaction 2 is small.Reaction solution removes solvent under reduced pressure Faint yellow solid is obtained, products obtained therefrom is directly used in the next step.
2-((four oxa--6- azepines 17 of (4S, 7S)-4- amino-7- (methoxycarbonyl)-5- oxos-2,9,12,15- Alkane -17- bases) oxygroup) benzoic acid trifluoroacetate (0.16g, 0.28mmol), 1- hydroxy benzo triazoles (0.045g, 0.34mmol) and benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (0.13g, 0.34mmol) be dissolved in 93ml without Water THF is cooled to 0 DEG C, DIPEA (92 μ L, 0.56mmol) is added dropwise, when room temperature reaction 5 is small.Solvent is removed under reduced pressure, adds in 5ml ethyl acetate and 4ml water, separate organic layer.Then, successively with saturated sodium bicarbonate solution (5mL x 2) and saturated common salt Water (4mL x 2) washs, and solvent is removed under reduced pressure after anhydrous sodium sulfate drying, and column chromatography for separation obtains colourless oil liquid 59mg, and two Walk yield 46%.1H NMR(500MHz,CDCl3) δ 8.77 (d, J=7.5Hz, 1H), 8.23 (d, J=8.0Hz, 1H), 7.49- 7.42 (m, 1H), 7.30 (d, J=7.0Hz, 1H), 7.13-7.05 (m, 1H), 6.97 (d, J=8.5Hz, 1H), 4.95-4.88 (m,1H),4.77–4.70(m,1H),4.42–4.35(m,1H),4.28–4.20(m,1H),4.11–4.01(m,2H),3.91– 3.82(m,3H),3.73–3.64(m,8H),3.64–3.58(m,2H),3.57–3.47(m,2H),3.41(s,3H)ppm；ESI- MS:M/z=455 [M+H]+.
Above-mentioned raw materials (12S, 15S) -15- (methoxy) -14,17- dioxo -2,3,5,6,8,9,12,13,14, [1,4,7,10] four oxa- [13,16] of ten dihydro -11H- benzos [r] of 15,16,17- -19 carbon -12- carboxylate methyl esters of diazacyclo (65mg, 0.14mmol) is dissolved in 0.5mL acetone, and 0 DEG C is cooled under ice bath, and 0.3N LiOH aqueous solution 0.7ml are added dropwise, should At a temperature of react 30 minutes.3N HCl tune PH to 2-3 are slowly added to, acetone is removed under reduced pressure, ethyl acetate (1mL x 2) extracts, Saturated salt solution (1mL x 2) washs, and solvent, which is removed under reduced pressure, after anhydrous sodium sulfate drying obtains colourless oil liquid 53mg, yield 86%.Products obtained therefrom is directly used in the next step.
Embodiment 154, (10S, 13S) -13- (2- morpholino -2- oxoethyls) -12,15- dioxo -2,3,4 are prepared, 17 carbon -10- of 5,6,7,10,11,12,13,14,15- ten dihydro -9H benzos [i] [1,11] dioxa [4,7]-diazacyclo Carboxylic acid (9zc)
With N- ((S) -4- morpholino -4- oxos -2- (2- (4- amylene -1- bases oxygroup) benzamido) bytyry)-O- Pi-allyl-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence foaming solid 62mg, Two step yields 63%.1H NMR(500MHz,CDCl3) δ 9.40 (d, J=9.5Hz, 1H), 8.24 (dd, J=8.0,2.0Hz, 1H), 7.49-7.41 (m, 1H), 7.20 (d, J=7.0Hz, 1H), 7.09-7.02 (m, 1H), 6.97 (d, J=8.0Hz, 1H), 5.36–5.28(m,1H),4.78–4.71(m,1H),4.25–4.12(m,2H),3.83–3.73(m,2H),3.69–3.61(m, 5H), 3.55-3.46 (m, 4H), 3.43-3.37 (m, 2H), 2.56 (dd, J=16.5,4.5Hz, 1H), 2.19-2.09 (m, 1H),1.89–1.79(m,1H),1.75–1.61(m,2H),1.58–1.44(m,4H)ppm；ESI-MS:M/z=492 [M+H]+.
Embodiment 155, (10S, 13S) -13- (3- morpholino -3- oxopropyls) -12,15- dioxo -2,3,4 are prepared, 17 carbon -10- of 5,6,7,10,11,12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo Carboxylic acid (9zd)
With N- ((S) -5- morpholino -5- oxos -2- (2- (4- amylene -1- bases oxygroup) benzamido) valeryl)-O- Pi-allyl-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains pale solid 70mg, two steps are received Rate 69%.1H NMR(500MHz,CDCl3) δ 8.67 (d, J=7.5Hz, 1H), 8.16-8.11 (m, 1H), 7.48-7.42 (m, 1H), 7.29 (d, J=8.0Hz, 1H), 7.09-7.03 (m, 1H), 6.96 (d, J=8.5Hz, 1H), 4.87-4.80 (m, 1H), 4.29-4.23 (m, 1H), 4.17-4.08 (m, 2H), 3.81 (dd, J=10.0,4.0Hz, 1H), 3.71 (dd, J=10.0, 6.5Hz,1H),3.68–3.39(m,10H),2.56–2.48(m,1H),2.47–2.40(m,1H),2.38–2.29(m,1H), 2.23–2.14(m,1H),2.06–1.95(m,2H),1.86–1.78(m,1H),1.69–1.59(m,2H),1.55–1.42(m, 3H)ppm；ESI-MS:M/z=506 [M+H]+.
Preparation embodiment 156, (10S, 13S) -13- (2- (cyclopropylamino) -2- oxoethyls) -12,15- dioxos - 2,3,4,5,6,7,10,11,12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7] diazacyclo 17 Carbon -10- carboxylic acids (9ze)
With N- (N4- cyclopropyl-N2- (2- (4- amylene -1- bases oxygroup) benzoyl)-altheine acyl group)-O- allyls Base-Serine benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains canescence oily liquids 70mg, two steps are received Rate 76%.ESI-MS:M/z=462 [M+H]+.
Embodiment 157, (10S, 13S) -13- isobutyl group -12,15- dioxo -2,3,4,5,6,7,10,11,12 are prepared, 17 carbon -10- carboxylic acids (9zf) of 13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo
With N- ((2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-L- leucyl-s)-O- pi-allyls-Serine benzyl ester For raw material, synthesis and post processing obtain pale solid 79mg, two step yields 94% with embodiment 126 is prepared.1H NMR (500MHz,CDCl3) δ 8.47 (d, J=8.5Hz, 1H), 8.25 (dd, J=8.0,1.5Hz, 1H), 7.51-7.44 (m, 1H), 7.16-7.06 (m, 2H), 7.01 (d, J=8.0Hz, 1H), 4.84 (dd, J=9.0,4.0Hz, 1H), 4.76-4.70 (m, 1H), 4.33-4.26 (m, 1H), 4.19-4.09 (m, 1H), 3.76 (d, J=4.0Hz, 2H), 3.57-3.50 (m, 1H), 3.42-3.35 (m,1H),1.98–1.88(m,1H),1.85–1.76(m,2H),1.69–1.32(m,6H),1.30–1.23(m,2H),0.98 (d, J=7.0Hz, 3H), 0.95 (d, J=7.0Hz, 3H) ppm；ESI-MS:M/z=421 [M+H]+.
Embodiment 158, (10S, 13S) -13- isopropyl -12,15- dioxo -2,3,4,5,6,7,10,11,12 are prepared, 17 carbon -10- carboxylic acids (9zg) of 13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo
With N- ((2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-L- valyls base)-O- pi-allyls-Serine benzyl ester For raw material, synthesis and post processing obtain pale solid 67mg, two step yields 82% with embodiment 126 is prepared.1H NMR (500MHz,CDCl3) δ 8.50 (d, J=8.5Hz, 1H), 8.22 (dd, J=8.0,1.0Hz, 1H), 7.51-7.44 (m, 1H), 7.17 (d, J=7.0Hz, 1H), 7.11-7.06 (m, 1H), 6.98 (d, J=8.5Hz, 1H), 4.88 (td, J=9.6,4.5Hz, 1H),4.79–4.73(m,1H),4.30–4.24(m,1H),4.19–4.10(m,1H),3.78–3.69(m,2H),3.52–3.41 (m,2H),2.01–1.93(m,1H),1.90–1.82(m,2H),1.75–1.66(m,2H),1.65–1.43(m,4H),1.00– 0.91(m,6H)ppm；ESI-MS:M/z=407 [M+H]+.
Embodiment 159, (9S, 12S) -12- (methoxy) -11,14- dioxo -3,4,5,6,7,8,9,10 are prepared, 16 carbon -9- carboxylic acids (9zh) of 11,12,13,14- ten dihydro -2H- benzos [b] [1] oxa- [5,8]-diazacyclo
With (S) -2- (N- (2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s) amino hex- 5- Olefin(e) acid benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains pale solid 62mg, two step yields 79%.1H NMR(500MHz,CDCl3) δ 9.02 (d, J=8.5Hz, 1H), 8.24 (dd, J=8.0,1.5Hz, 1H), 7.51-7.44 (m, 1H),7.11–7.05(m,1H),7.00–6.92(m,2H),4.97–4.91(m,1H),4.66–4.59(m,1H),4.25–4.19 (m, 1H), 4.18-4.08 (m, 2H), 3.52 (dd, J=9.0,4.0Hz, 1H), 3.41 (s, 3H), 2.11-1.89 (m, 3H), 1.83–1.74(m,1H),1.69–1.62(m,1H),1.60–1.52(m,1H),1.50–1.29(m,6H)ppm；ESI-MS:m/z =393 [M+H]+.
Embodiment 160, (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,8,9 are prepared, Ten tetrahydrochysenes of 10,11,12,13,14,15--benzo [b] [1] oxa- [5,8]-diazacyclo, 17 carbon -10- carboxylic acids (9zi)
With (S) -2- (N- (2- (hex- 5- alkene -1- bases oxygroup) benzoyl)-O- methyl-L- seryl-s) amino hex- 5- Olefin(e) acid benzyl ester is raw material, synthesis and the same preparation embodiment 126 of post processing, obtains pale solid 66mg, two step yields 81%.1H NMR(500MHz,CDCl3) δ 8.70 (d, J=8.0Hz, 1H), 8.13 (dd, J=8.0,1.5Hz, 1H), 7.45-7.38 (m, 1H), 7.06-7.00 (m, 1H), 6.94 (d, J=8.0Hz, 1H), 6.89 (d, J=8.0Hz, 1H), 4.94-4.85 (m, 1H), 4.64 (td, J=8.5,3.5Hz, 1H), 4.25-4.18 (m, 1H), 4.06-3.98 (m, 2H), 3.46 (dd, J=9.0, 5.5Hz,1H),3.35(s,3H),2.02–1.91(m,2H),1.71–1.44(m,4H),1.41–1.11(m,8H)ppm；ESI- MS:M/z=407 [M+H]+.
Prepare embodiment 161, N- [(8S, 11S) -11- (methoxy) -10,13- dioxo -3,4,5,7,8,9, 15 carbon -8- formoxyls of 10,11,12,13- decahydro -2H-1,6,9,12- benzo dioxas diazacyclo]-Phe- epoxy ketone (10a)
Raw material (8S, 11S) -11- (methoxy) -10,13- dioxos -3,4,5,7,8,9,10,11,12,13- ten Hydrogen -2H-1, it is anhydrous that 6,9,12- benzo dioxa diazacyclo, 15 carbon -8- carboxylic acids (9a, 38mg, 0.10mmol) are dissolved in 2mL THF adds in 1- hydroxy benzo triazoles (16mg, 0.12mmol), benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid Ester (45mg, 0.12mmol) and Phe- epoxy ketone trifluoroacetates (38mg, 0.12mmol) are cooled to 0 DEG C under ice bath.Then, DIPEA (0.033mL, 0.20mmol) is added in, when room temperature reaction 3 is small.Solvent is removed under reduced pressure, adds in 5mL ethyl acetate and 4ml Water separates organic layer, is washed successively with saturated sodium bicarbonate solution (3mL x 2) and saturated salt solution (3mL x 2), anhydrous sulphur Sour sodium drying, removes solvent under reduced pressure, column chromatography for separation obtains white solid 42mg, yield 74%.1H NMR(500MHz,CDCl3)δ 8.03-7.97 (m, 2H), 7.49 (ddd, J=8.5,7.5,2.0Hz, 1H), 7.15-7.10 (m, 2H), 7.07-6.94 (m, 7H),4.84–4.78(m,1H),4.78–4.72(m,1H),4.56–4.51(m,1H),4.20–4.15(m,1H),4.12–4.06 (m, 1H), 4.04 (dd, J=9.0,2.5Hz, 1H), 3.76 (dd, J=9.5,4.5Hz, 1H), 3.56 (dd, J=9.5, 3.5Hz, 1H), 3.53-3.44 (m, 2H), 3.37-3.30 (m, 5H), 3.06 (dd, J=14.0,4.0Hz, 1H), 2.87 (d, J =5.0Hz, 1H), 2.70 (dd, J=14.0,9.5Hz, 1H), 1.99-1.81 (m, 2H), 1.71-1.60 (m, 1H), 1.51- 1.41(m,4H)ppm；ESI-MS:M/z=568 [M+H]+.
Prepare embodiment 162, N- [(9S, 12S) -12- (methoxy) -11,14- dioxo -2,3,4,5,6,8,9, Ten dihydro -1,7,10,13- benzo dioxas diazacyclos of 10,11,12,13,14-, 16 carbon -9- formoxyls]-Phe- epoxy ketone (10b)
With (9S, 12S) -12- (methoxy) -11,14- dioxos -2,3,4,5,6,8,9,10,11,12,13,14- Ten dihydros -1,7,10,13- benzo dioxa diazacyclo, 16 carbon -9- carboxylic acids are raw material, and synthesis and post processing are implemented with preparation Example 161 obtains white solid 45mg, yield 79%.1H NMR(500MHz,CDCl3) δ 8.78 (d, J=5.0Hz, 1H), 8.19 (d, J=7.5Hz, 1H), 7.54-7.44 (m, 1H), 7.10-6.92 (m, 9H), 4.80-4.67 (m, 2H), 4.66-4.58 (m, 1H), 4.39–4.20(m,2H),4.07–3.96(m,2H),3.68–3.58(m,1H),3.56–3.50(m,1H),3.40(s,3H), 3.34 (d, J=5.0Hz, 1H), 3.31-3.27 (m, 1H), 3.22-3.15 (m, 1H), 3.04 (dd, J=13.5,4.5Hz, 1H), 2.82 (d, J=4.0Hz, 1H), 2.73 (dd, J=13.5,9.0Hz, 1H), 1.93-1.87 (m, 1H), 1.83-1.76 (m,1H),1.65–1.54(m,2H),1.48–1.39(m,5H)ppm；ESI-MS:M/z=582 [M+H]+.
Prepare embodiment 163, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -3,4,5,6,7,9, Ten dihydro -1,8,11,14- benzo dioxas diazacyclos of 10,11,12,13,14,15-2H-, 17 carbon -10- formoxyls] - Phe- epoxies ketone (10c)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -3,4,5,6,7,9,10,11,12,13,14, Ten dihydros -1,8 of 15-2H-, 11,14- benzo dioxa diazacyclo, 17 carbon -10- carboxylic acids are raw material, and synthesis and post processing are same Embodiment 161 is prepared, obtains white solid 42mg, yield 71%.1H NMR(500MHz,CDCl3) δ 8.90 (d, J=6.5Hz, 1H), 8.23 (dd, J=8.0,2.0Hz, 1H), 7.52-7.46 (m, 1H), 7.13-6.96 (m, 8H), 6.87 (d, J=8.0Hz, 1H), 4.78-4.72 (m, 1H), 4.70-4.65 (m, 1H), 4.58 (dt, J=7.5,4.5Hz, 1H), 4.31-4.27 (m, 1H), 4.15-4.12 (m, 1H), 4.04 (dd, J=9.5,2.0Hz, 1H), 3.64 (dd, J=9.5,4.0Hz, 1H), 3.60 (dd, J= 9.5,5.0Hz, 1H), 3.50 (dd, J=10.0,4.0Hz, 1H), 3.41 (s, 3H), 3.35-3.28 (m, 3H), 3.04 (dd, J =14.0,4.5Hz, 1H), 2.83 (d, J=5.0Hz, 1H), 2.70 (dd, J=14.0,9.0Hz, 1H), 1.99-1.91 (m, 1),1.88–1.80(m,1H),1.64–1.56(m,2H),1.51–1.45(m,2H),1.44–1.40(m,5H)ppm；ESI-MS: M/z=596 [M+H]+.
Prepare embodiment 164, N- [(11S, 14S) -14- (methoxy) -13,16- dioxo -2,3,4,5,6,7, Ten tetrahydrochysene -1,9,12,15- benzo dioxas diazacyclos of 8,10,11,12,13,14,15,16-, 18 carbon -11- formoxyls] - Phe- epoxies ketone (10d)
With (11S, 14S) -14- (methoxy) -13,16- dioxo -2,3,4,5,6,7,8,10,11,12,13, 14,15,16- ten tetrahydrochysenes -1,9,12,15- benzo dioxa diazacyclo, 18 carbon -11- carboxylic acids are raw material, synthesis and post processing With embodiment 161 is prepared, white solid 46mg, yield 71% are obtained.1H NMR(500MHz,CDCl3) δ 8.89 (d, J=5.5Hz, 1H), 8.19 (dd, J=8.0,1.5Hz, 1H), 7.49-7.43 (m, 1H), 7.21 (d, J=8.0Hz, 1H), 7.15-6.98 (m, 7H), 6.78 (d, J=8.0Hz, 1H), 4.82 (td, J=8.5,5.5Hz, 1H), 4.72-4.66 (m, 2H), 4.35-4.27 (m, 1H), 4.11-4.05 (m, 1H), 3.98 (dd, J=9.5,3.5Hz, 1H), 3.72-3.61 (m, 2H), 3.52 (dd, J=10.0, 4.0Hz, 1H), 3.47-3.39 (m, 4H), 3.36-3.31 (m, 2H), 3.08 (dd, J=14.0,5.5Hz, 1H), 2.83 (d, J =5.0Hz, 1H), 2.78 (dd, J=14.0,9.0Hz, 1H), 2.02-1.96 (m, 1H), 1.88-1.79 (m, 1H), 1.61- 1.52(m,1H),1.50–1.31(m,10H)ppm；ESI-MS:M/z=610 [M+H]+.
Prepare embodiment 165, N- [(12S, 15S) -15- (methoxy) -14,17- dioxo -3,4,5,6,7,8, Ten tetrahydrochysene -2H-1,10,13,16- benzo dioxas diazacyclos of 9,11,12,13,14,15,16,17-2H-, 19 carbon -12- first Acyl group]-Phe- epoxies ketone (10e)
With (12S, 15S) -15- (methoxy) -14,17- dioxo -3,4,5,6,7,8,9,11,12,13,14, 15,16,17-2H- ten tetrahydrochysene -2H-1,10,13,16- benzo dioxa diazacyclo, 19 carbon -12- carboxylic acids are raw material, are synthesized And post processing obtains white solid 46mg, yield 71% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ9.00(d,J =4.0Hz, 1H), 8.27 (dd, J=8.0,2.0Hz, 1H), 7.52-7.45 (m, 1H), 7.42 (d, J=8.0Hz, 1H), 7.18-6.99 (m, 7H), 6.80 (d, J=8.0Hz, 1H), 4.82 (td, J=8.5,5.5Hz, 1H), 4.67-4.60 (m, 2H), 4.28-4.17 (m, 2H), 3.95 (dd, J=9.5,4.5Hz, 1H), 3.70 (dd, J=9.5,4.5Hz, 1H), 3.63 (dd, J= 9.5,5.0Hz, 1H), 3.51 (dd, J=9.5,4.5Hz, 1H), 3.46-3.28 (m, 6H), 3.11 (dd, J=14.0,5.5Hz, 1H), 2.88 (dd, J=14.0,8.5Hz, 1H), 2.83 (d, J=5.0Hz, 1H), 2.03-1.97 (m, 1H), 1.95-1.77 (m,2H),1.66–1.53(m,2H),1.49–1.29(m,10H)ppm；ESI-MS:M/z=624 [M+H]+.
Prepare embodiment 166, N- [(13S, 16S) -16- (methoxy) -15,18- dioxo -3,4,5,6,7,8, 20 carbon -13- of 9,10,13,14,15,16,17,18- tetrahydrochysenes -2H, 12H- benzo [i] [1,11] dioxa [4,7] diazacyclo Formoxyl]-Phe- epoxies ketone (10f)
With (13S, 16S) -16- (methoxy) -15,18- dioxo -3,4,5,6,7,8,9,10,13,14,15, 16,17,18- tetrahydrochysene -2H, 12H- benzo [i] [1,11] dioxa [4,7] diazacyclo, 20 carbon -13- carboxylic acids are raw material, are closed Into and post processing with prepare embodiment 161, obtain white solid 42mg, yield 66%.1H NMR(500MHz,CDCl3)δ9.02(d, J=4.5Hz, 1H), 8.22 (dd, J=8.0,2.0Hz, 1H), 7.49-7.41 (m, 2H), 7.25-7.11 (m, 5H), 7.06- 6.97 (m, 3H), 4.83 (td, J=8.0,5.5Hz, 1H), 4.70-4.64 (m, 1H), 4.58-4.50 (m, 1H), 4.24-4.06 (m, 2H), 3.89 (dd, J=9.5,4.5Hz, 1H), 3.71 (dd, J=9.5,5.0Hz, 1H), 3.59 (dd, J=9.5, 6.5Hz, 1H), 3.50-3.34 (m, 7H), 3.13 (dd, J=14.0,5.0Hz, 1H), 2.91-2.82 (m, 2H), 2.12-2.02 (m,1H),1.95–1.85(m,1H),1.64–1.23(m,15H)ppm；ESI-MS:M/z=638 [M+H]+.
Prepare embodiment 167, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7, Ten dihydro -9H-17- chlorobenzenes of 10,11,12,13,14,15- simultaneously 17 carbon -10- first of [i] [1,11] dioxa [4,7] diazacyclo Acyl group]-Phe- epoxies ketone (10g)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, Ten dihydro -9H-17- chlorobenzenes of 15- simultaneously 17 carbon -10- carboxylic acids of [i] [1,11] dioxa [4,7] diazacyclo be raw material, synthesis and Post processing obtains white solid 49mg, yield 78% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3) δ 8.82 (d, J= 6.5Hz, 1H), 8.19 (d, J=3.0Hz, 1H), 7.41 (dd, J=9.0,2.5Hz, 1H), 7.14-7.02 (m, 6H), 6.93 (d, J=9.0Hz, 1H), 6.78 (d, J=8.0Hz, 1H), 4.76 (td, J=8.5,5.0Hz, 1H), 4.73-4.69 (m, 1H), 4.59 (dt, J=7.5,5.0Hz, 1H), 4.29-4.22 (m, 1H), 4.13-4.03 (m, 2H), 3.63-3.57 (m, 2H), 3.52 (dd, J=10.0,4.0Hz, 1H), 3.42-3.29 (m, 6H), 3.06 (dd, J=14.0,4.5Hz, 1H), 2.83 (d, J= 5.0Hz,1H),2.79–2.74(m,1H),2.01–1.90(m,1H),1.88–1.80(m,1H),1.66–1.56(m,2H), 1.55–1.39(m,7H)ppm；ESI-MS:M/z=631 [M+H]+.
Prepare embodiment 168, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7, Ten dihydro -9H-18- chlorobenzenes of 10,11,12,13,14,15- simultaneously 17 carbon -10- first of [i] [1,11] dioxa [4,7] diazacyclo Acyl group]-Phe- epoxies ketone (10h)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, Ten dihydro -9H-18- chlorobenzenes of 15- simultaneously 17 carbon -10- carboxylic acids of [i] [1,11] dioxa [4,7] diazacyclo be raw material, synthesis and Post processing obtains white solid 44mg, yield 70% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3) δ 8.73 (d, J= 7.0Hz, 1H), 8.16 (d, J=8.5Hz, 1H), 7.12-7.07 (m, 4H), 7.06-7.02 (m, 3H), 6.99 (d, J= 1.5Hz, 1H), 6.80 (d, J=8.0Hz, 1H), 4.78-4.68 (m, 2H), 4.58 (dt, J=7.5,5.5Hz, 1H), 4.30- 4.24 (m, 1H), 4.15-4.08 (m, 1H), 4.05 (dd, J=9.0,2.0Hz, 1H), 3.64-3.57 (m, 2H), 3.51 (dd, J =9.5,4.0Hz, 1H), 3.39 (s, 3H), 3.38-3.29 (m, 3H), 3.04 (dd, J=14.0,5.0Hz, 1H), 2.82 (d, J =5.0Hz, 1H), 2.75 (dd, J=14.0,8.5Hz, 1H), 2.00-1.91 (m, 1H), 1.89-1.81 (m, 1H), 1.67- 1.57(m,2H),1.54–1.40(m,7H)ppm；ESI-MS:M/z=631 [M+H]+.
Prepare embodiment 169, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7, Ten dihydro -9H-18- fluorobenzene of 10,11,12,13,14,15- simultaneously 17 carbon -10- first of [i] [1,11] dioxa [4,7] diazacyclo Acyl group]-Phe- epoxies ketone (10i)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, Ten dihydro -9H-18- fluorobenzene of 15- simultaneously 17 carbon -10- carboxylic acids of [i] [1,11] dioxa [4,7] diazacyclo be raw material, synthesis and Post processing obtains white solid 42mg, yield 68% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3) δ 8.72 (d, J= 6.5Hz, 1H), 8.28-8.21 (m, 1H), 7.12-7.02 (m, 6H), 6.84-6.74 (m, 2H), 6.71 (dd, J=10.5, 2.5Hz, 1H), 4.79-4.70 (m, 2H), 4.59 (dt, J=8.0,5.5Hz, 1H), 4.30-4.22 (m, 1H), 4.13-4.03 (m, 2H), 3.64-3.56 (m, 2H), 3.51 (dd, J=9.9,4.0Hz, 1H), 3.40 (s, 3H), 3.37-3.31 (m, 3H), 3.05 (dd, J=14.0,5.0Hz, 1H), 2.83 (d, J=5.0Hz, 1H), 2.75 (dd, J=14.0,9.0Hz, 1H), 2.02- 1.93(m,1H),1.90–1.81(m,1H),1.69–1.58(m,2H),1.57–1.40(m,7H)ppm；ESI-MS:M/z=614 [M+H]+.
Prepare embodiment 170, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7, 17 carbon -10- of 10,11,12,13,14,15- ten dihydro -9H-18- methyl benzo [i] [1,11] dioxa [4,7] diazacyclo Formoxyl]-Phe- epoxies ketone (10j)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, 17 carbon -10- carboxylic acids of 15- ten dihydro -9H-18- methyl benzo [i] [1,11] dioxa [4,7] diazacyclo are raw material, are synthesized And post processing obtains white solid 48mg, yield 79% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ8.84(d,J =6.5Hz, 1H), 8.12 (d, J=8.0Hz, 1H), 7.18 (d, J=8.1Hz, 1H), 7.11-7.01 (m, 5H), 6.87 (d, J =8.0Hz, 1H), 6.83-6.76 (m, 2H), 4.79-4.69 (m, 2H), 4.58 (dt, J=8.0,5.5Hz, 1H), 4.31- 4.22 (m, 1H), 4.17-4.09 (m, 1H), 4.06 (dd, J=9.5,2.0Hz, 1H), 3.61 (dd, J=9.0,3.5Hz, 1H), 3.57 (dd, J=9.5,5.5Hz, 1H), 3.49 (dd, J=9.5,4.0Hz, 1H), 3.39 (s, 3H), 3.36-3.28 (m, 3H), 3.04 (dd, J=14.0,5.0Hz, 1H), 2.82 (d, J=5.0Hz, 1H), 2.75 (dd, J=14.0,9.0Hz, 1H), 2.39 (s,3H),2.00–1.91(m,1H),1.88–1.79(m,1H),1.67–1.56(m,2H),1.53–1.40(m,7H)ppm； ESI-MS:M/z=610 [M+H]+.
Prepare embodiment 171, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7, 17 carbon of 10,11,12,13,14,15- ten dihydro -9H-18- methoxyl groups benzo [i] [1,11] dioxa [4,7] diazacyclo - 10- formoxyls]-Phe- epoxies ketone (10k)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, 17 carbon -10- carboxylic acids of 15- ten dihydro -9H-18- methoxyl groups benzo [i] [1,11] dioxa [4,7] diazacyclo are raw material, are closed Into and post processing with prepare embodiment 161, obtain white solid 50mg, yield 80%.1H NMR(500MHz,CDCl3)δ8.74(d, J=6.5Hz, 1H), 8.19 (d, J=9.0Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.11-7.03 (m, 5H), 6.82 (d, J =8.0Hz, 1H), 6.57 (dd, J=8.8,2.5Hz, 1H), 6.50 (d, J=2.5Hz, 1H), 4.78-4.70 (m, 2H), 4.58 (dt, J=8.0,5.5Hz, 1H), 4.28-4.21 (m, 1H), 4.13-4.02 (m, 2H), 3.85 (s, 3H), 3.63-3.55 (m, 2H), 3.49 (dd, J=10.0,4.0Hz, 1H), 3.39 (s, 3H), 3.36-3.30 (m, 3H), 3.04 (dd, J=14.0, 5.0Hz, 1H), 2.82 (d, J=5.0Hz, 1H), 2.76 (dd, J=14.0,9.0Hz, 1H), 2.00-1.91 (m, 1H), 1.88- 1.79(m,1H),1.65–1.37(m,9H)ppm；ESI-MS:M/z=626 [M+H]+.
Prepare embodiment 172, N- [(3S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10, Ten dihydro -12H-2- methylthiazols of 13,14,15,16,17,18- simultaneously [5,4-i] [1,11] dioxa [4,7] diazacyclo 17 Carbon -13- formoxyls]-Phe- epoxies ketone (10l)
With (3S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10,13,14,15,16,17, Simultaneously 17 carbon -13- carboxylic acids of [5,4-i] [1,11] dioxa [4,7] diazacyclo are original to ten dihydro -12H-2- methylthiazols of 18- Material, synthesis and post processing obtain white solid 46mg, yield 75% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ 7.96 (d, J=7.5Hz, 1H), 7.21-7.13 (m, 3H), 7.11-7.07 (m, 2H), 7.04 (d, J=8.0Hz, 1H), 6.86 (d, J=7.5Hz, 1H), 4.78-4.69 (m, 2H), 4.66-4.60 (m, 1H), 4.54 (dt, J=9.0,5.0Hz, 1H), 4.45 (dt, J=10.5,4.0Hz, 1H), 4.06 (dd, J=9.0,2.0Hz, 1H), 3.71 (dd, J=10.0,5.0Hz, 1H), 3.56 (dd, J=9.0,3.5Hz, 1H), 3.47 (dd, J=10.0,4.0Hz, 1H), 3.44-3.37 (m, 4H), 3.34-3.27 (m, 2H), 3.05 (dd, J=14.0,5.0Hz, 1H), 2.83 (d, J=5.0Hz, 1H), 2.81-2.75 (m, 1H), 2.61 (s, 3H), 1.88–1.80(m,2H),1.58–1.45(m,6H),1.42(s,3H)ppm；ESI-MS:M/z=617 [M+H]+.
Prepare embodiment 173, N- [(6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,12, 17 carbon -9- formyls of 13,14,15,16,17- ten dihydro -4H- thienos [3,2-i] [1,11] dioxa [4,7] diazacyclo Base]-Phe- epoxies ketone (10m)
With (6S, 9S) -6- (methoxy) -4,7- dioxos -5,6,7,8,9,10,12,13,14,15,16,17- ten 17 carbon -9- carboxylic acids of dihydro -4H- thienos [3,2-i] [1,11] dioxa [4,7] diazacyclo are raw material, synthesis and rear place Reason obtains white solid 40mg, yield 66% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3) δ 8.15 (d, J= 7.5Hz, 1H), 7.44 (d, J=5.5Hz, 1H), 7.20-7.08 (m, 5H), 7.05 (d, J=8.0Hz, 1H), 6.89-6.83 (m,2H),4.81–4.70(m,2H),4.60–4.51(m,1H),4.39–4.31(m,1H),4.20–4.13(m,1H),4.11– 4.04 (m, 1H), 3.67 (dd, J=10.0,6.0Hz, 1H), 3.57 (dd, J=9.0,3.0Hz, 1H), 3.48 (dd, J= 10.0,3.5Hz, 1H), 3.42-3.27 (m, 6H), 3.06 (dd, J=14.0,5.0Hz, 1H), 2.82 (d, J=5.0Hz, 1H), 2.77 (dd, J=13.5,8.5Hz, 1H), 1.94-1.78 (m, 2H), 1.63-1.44 (m, 6H), 1.42 (s, 3H) ppm；ESI- MS:M/z=602 [M+H]+.
Prepare embodiment 174, N- [(14S, 17S) -17- (methoxy) -16,19- dioxo -6,7,8,9,10, 17 carbon of 11,14,15,16,17,18,19- ten dihydro -13H- pyridos [3-i] [1,11] dioxa [4,7] diazacyclo - 14- formoxyls]-Phe- epoxies ketone (10n)
With (14S, 17S) -17- (methoxy) -16,19- dioxo -6,7,8,9,10,11,14,15,16,17, 18,19- ten dihydro -13H- pyridos [3-i] [1,11] dioxa [4,7] 17 carbon-14s of diazacyclo-carboxylic acids are raw material, are closed Into and post processing with prepare embodiment 161, obtain white solid 39mg, yield 65%.ESI-MS:M/z=597 [M+H]+.
Prepare embodiment 175, N- [(7S, 10S) -7- (methoxy) -5,8- dioxo -6,7,8,9,10,11,13, 17 carbon -10- first of 14,15,16,17,18- ten dihydro -5H- pyridos [3,2-i] [1,11] dioxa [1,11] diazacyclo Acyl group]-Phe- epoxies ketone (10o)
(7S, 10S) -7- (methoxy) -5,8- dioxos -6,7,8,9,10,11,13,14,15,16,17,18- ten 17 carbon -10- carboxylic acids of dihydro -5H- pyridos [3,2-i] [1,11] dioxa [1,11] diazacyclo be raw material, synthesis and after Processing obtains white solid 40mg, yield 67% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3) δ 8.90 (d, J= 7.0Hz, 1H), 8.50 (dd, J=7.6,2.0Hz, 1H), 8.29 (dd, J=4.8,2.0Hz, 1H), 7.12-6.98 (m, 7H), 6.81 (d, J=7.8Hz, 1H), 4.78-4.69 (m, 3H), 4.60-4.53 (m, 1H), 4.41-4.35 (m, 1H), 4.07 (dd, J =9.3,2.1Hz, 1H), 3.65-3.58 (m, 2H), 3.50 (dd, J=9.8,4.0Hz, 1H), 3.41 (s, 3H), 3.37-3.27 (m, 3H), 3.04 (dd, J=13.9,4.9Hz, 1H), 2.82 (d, J=5.0Hz, 1H), 2.75 (dd, J=13.9,8.6Hz, 1H),1.93–1.86(m,2H),1.63–1.39(m,9H)ppm；ESI-MS:M/z=597 [M+H]+.
Prepare embodiment 176, N- [(6S, 9S) -6- (methoxy) -4,7- dioxo -1,4,5,6,7,8,9,10, Ten tetrahydrochysene -1- methyl pyrazoles of 12,13,14,15,16,17- simultaneously 17 carbon of [4,3-i] [1,11] dioxa [4,7] diazacyclo - 9- formoxyls]-Phe- epoxies ketone (10p)
With (6S, 9S) -6- (methoxy) -4,7- dioxo -1,4,5,6,7,8,9,10,12,13,14,15,16, Simultaneously 17 carbon -9- carboxylic acids of [4,3-i] [1,11] dioxa [4,7] diazacyclo are raw material to ten tetrahydrochysene -1- methyl pyrazoles of 17-, are closed Into and post processing with prepare embodiment 161, obtain white solid 50mg, yield 83%.1H NMR(500MHz,CDCl3)δ7.75(s, 1H), 7.23-7.09 (m, 6H), 7.06 (d, J=8.0Hz, 1H), 6.90 (d, J=6.0Hz, 1H), 4.87 (td, J=8.0, 5.5Hz, 1H), 4.69-4.61 (m, 1H), 4.55-4.50 (m, 1H), 4.38-4.0 (m, 1H), 4.18 (ddd, J=10.0, 8.0,5.5Hz, 1H), 4.00 (dd, J=9.5,3.5Hz, 1H), 3.76-3.69 (m, 4H), 3.61 (dd, J=9.5,4.5Hz, 1H), 3.54 (dd, J=9.5,3.5Hz, 1H), 3.45-3.27 (m, 6H), 3.10 (dd, J=14.0,5.5Hz, 1H), 2.90- 2.81(m,2H),1.90–1.81(m,1H),1.79–1.71(m,1H),1.49–1.34(m,9H)ppm；ESI-MS:M/z=600 [M+H]+.
Prepare embodiment 177, N- [(13S, 16S) -16- (methoxy) -15,18- dioxo -2,11- dioxas - 13 carbon -1 (23) of 14,17- diazabicyclos [17.3.1]-two, 19,21- triolefin -13- formoxyls]-Phe- epoxies ketone (10q)
With (13S, 16S) -16- (methoxy) -15,18- dioxo -2,11- dioxa -14,17- diazabicyclos [17.3.1]-two 13 carbon -1 (23), 19,21- triolefin -13- carboxylic acids are raw material, are synthesized and post-process with preparation embodiment 161, Obtain white solid 50mg, yield 83%.1H NMR(500MHz,CDCl3)δ7.44–7.38(m,2H),7.32–7.29(m,1H), 7.25 (d, J=8.0Hz, 1H), 7.16-7.12 (m, 2H), 7.11-7.03 (m, 5H), 6.97 (d, J=5.5Hz, 1H), 4.82 (td, J=8.5,4.5Hz, 1H), 4.73-4.68 (m, 1H), 4.46-4.41 (m, 1H), 4.22-4.10 (m, 2H), 4.03 (dd, J=10.0,4.0Hz, 1H), 3.81 (dd, J=9.5,2.5Hz, 1H), 3.69 (dd, J=9.5,4.0Hz, 1H), 3.45 (dd, J =9.5,4.0Hz, 1H), 3.40 (s, 3H), 3.37 (d, J=5.0Hz, 1H), 3.20-3.15 (m, 2H), 3.11 (dd, J= 14.0,4.5Hz,1H),2.88–2.81(m,2H),1.91–1.76(m,3H),1.62–1.53(m,1H),1.52–1.40(m, 5H),1.39–1.22(m,6H)ppm；ESI-MS:M/z=624 [M+H]+.
Prepare embodiment 178, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7, 17 carbon -10- of 10,11,12,13,14,15- ten the fluoro- benzos of dihydro -9H-19- [i] [1,11] dioxa [4,7]-diazacyclo Formoxyl]-Phe- epoxies ketone (10r)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11,12,13,14, 17 carbon -10- carboxylic acids of 15- ten the fluoro- benzos of dihydro -9H-19- [i] [1,11] dioxa [4,7]-diazacyclo are raw material, are synthesized And post processing obtains white solid 43mg, yield 70% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ8.84(d,J =6.0Hz, 1H), 8.01-7.95 (m, 1H), 7.32-7.20 (m, 3H), 7.12-7.01 (m, 6H), 6.85 (d, J=8.5Hz, 1H), 4.80 (td, J=9.0,5.0Hz, 1H), 4.67-4.57 (m, 2H), 4.56-4.49 (m, 1H), 4.41-4.33 (m, 1H), 4.03 (dd, J=9.5,2.5Hz, 1H), 3.70-3.61 (m, 2H), 3.52 (dd, J=9.5,4.0Hz, 1H), 3.44-3.38 (m, 4H), 3.35 (d, J=5.0Hz, 1H), 3.33-3.26 (m, 1H), 3.08 (dd, J=14.0,5.0Hz, 1H), 2.87- 2.77(m,2H),2.03–1.92(m,1H),1.91–1.82(m,1H),1.82–1.72(m,1H),1.63–1.48(m,2H), 1.47–1.37(m,6H)ppm；ESI-MS:M/z=614 [M+H]+.
Prepare embodiment 179, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7, 17 carbon -10- of 10,11,12,13,14,15- ten the fluoro- benzos of dihydro -9H-19- [i] [1,11] dioxa [4,7]-diazacyclo Formoxyl]-Phe- epoxies ketone (10s)
With (10S, 13S) -19- methoxyl groups -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,10,11, 12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo, 17 carbon -10- carboxylic acids are raw material, Synthesis and post processing obtain white solid 45mg, yield 72% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ8.99 (d, J=5.5Hz, 1H), 7.78 (dd, J=7.5,2.0Hz, 1H), 7.30-7.27 (m, 1H), 7.13-7.04 (m, 7H), 6.86 (d, J=8.5Hz, 1H), 4.81 (td, J=8.5,5.0Hz, 1H), 4.65-4.58 (m, 2H), 4.30 (dt, J=10.0, 6.5Hz, 1H), 4.13 (dt, J=10.0,6.5Hz, 1H), 4.00 (dd, J=9.5,3.0Hz, 1H), 3.91 (s, 3H), 3.72 (dd, J=9.5,3.5Hz, 1H), 3.63 (dd, J=9.5,4.0Hz, 1H), 3.49 (dd, J=9.5,4.0Hz, 1H), 3.44- 3.35 (m, 5H), 3.28-3.22 (m, 1H), 3.08 (dd, J=14.0,5.0Hz, 1H), 2.86-2.80 (m, 2H), 1.86- 1.73(m,2H),1.57–1.50(m,1H),1.44(s,3H),1.41–1.30(m,5H)ppm；ESI-MS:M/z=626 [M+H ]+.
Prepare embodiment 180, N- [(6S, 9S) -6- (methoxy) -4,7- dioxo -4,5,6,7,8,9,10,12, Ten tetrahydrochysene -1H-1- methyl pyrazoles of 13,14,15,16,17,18- simultaneously [4,3-i] [1] oxa- [4,7] -17 carbon of diazacyclo - 9- formoxyls]-Phe- epoxies ketone (10t)
With (6S, 9S) -6- (methoxy) -1- methyl -4,7- dioxo -4,5,6,7,8,9,10,12,13,14, 15,16,17,18- ten tetrahydrochysene -1H- pyrazolos [4,3-i] [1] oxa- [4,7]-diazacyclo, 17 carbon -9- carboxylic acids are raw material, Synthesis and post processing obtain white solid 40mg, yield 67% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ7.70 (s, 1H), 7.46 (d, J=8.0Hz, 1H), 7.30-7.14 (m, 6H), 6.66 (d, J=6.0Hz, 1H), 5.00-4.93 (m, 1H), 4.62-4.56 (m, 1H), 4.42 (dt, J=7.5,3.0Hz, 1H), 3.97 (dd, J=10.0,5.0Hz, 1H), 3.83- 3.76 (m, 4H), 3.68 (dd, J=10.0,5.0Hz, 1H), 3.51 (dd, J=9.0,3.5Hz, 1H), 3.47-3.37 (m ), Hu8219Hu8219,4H 3.35-3.24 (m, 3H), 3.10 (dd, J=13.5,7.5Hz, 1H), 2.94 (dd, J=14.0, 6.5Hz, 1H), 2.74 (d, J=5.0Hz, 1H), 2.60-2.50 (m, 1H), 1.82-1.70 (m, 1H), 1.48-1.18 (m, 11H),1.17–1.07(m,1H)ppm；ESI-MS:M/z=598 [M+H]+.
Prepare embodiment 181, N- [(6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,12, 16 carbon -9- formyls of 13,14,15,16,17- ten dihydro -4H- pyrazolos [5,1-i] [1] [4,7,10]-three azacyclo- of oxa- Base]-Phe- epoxies ketone (10u)
With (6S, 9S) -6- (methoxy) -4,7- dioxos -5,6,7,8,9,10,12,13,14,15,16,17- ten 16 carbon -9- carboxylic acids of dihydro -4H- pyrazolos [5,1-i] [1] oxa- [4,7,10]-three azacyclo- are raw material, synthesis and post processing With embodiment 161 is prepared, white solid 42mg, yield 74% are obtained.1H NMR(500MHz,CDCl3) δ 7.52 (d, J=2.0Hz, 1H), 7.47 (d, J=8.5Hz, 1H), 7.32-7.27 (m, 2H), 7.25-7.20 (m, 3H), 7.14 (d, J=8.0Hz, 1H), 6.93 (d, J=5.5Hz, 1H), 6.59 (d, J=2.0Hz, 1H), 5.10 (ddd, J=14.0,12.0,4.5Hz, 1H), 5.03 (td, J=8.0,6.0Hz, 1H), 4.59 (dd, J=10.0,4.5Hz, 1H), 4.43 (ddd, J=6.0,3.5,2.5Hz, 1H), 4.14 (ddd, J=13.5,5.0,3.5Hz, 1H), 4.03 (dd, J=10.0,4.5Hz, 1H), 3.82 (dd, J=9.5, 2.5Hz, 1H), 3.72 (dd, J=10.0,4.5Hz, 1H), 3.53 (dd, J=9.5,4.0Hz, 1H), 3.45-3.38 (m, 4H), 3.37-3.27 (m, 2H), 3.15 (dd, J=14.0,6.0Hz, 1H), 2.95 (dd, J=14.0,8.0Hz, 1H), 2.82 (d, J =4.9Hz, 1H), 2.02-1.90 (m, 1H), 1.61-1.50 (m, 1H), 1.50-1.41 (m, 1H), 1.39-1.27 (m, 5H), 1.20–1.06(m,2H),1.03–0.90(m,1H)ppm；ESI-MS:M/z=626 [M+H]+.
Prepare embodiment 182, N- [(11S, 14S) -14- (methoxy) -13,16- dioxo -5,6,7,8,11, 14 carbon -11- formyls of 12,13,14,15,16- decahydro -10H- imidazos [2,1-i] [1] [4,7,10]-three azacyclo- of oxa- Base]-Phe- epoxies ketone (10v)
With (11S, 14S) -14- (methoxy) -13,16- dioxos -5,6,7,8,11,12,13,14,15,16- ten 14 carbon -11- carboxylic acids of hydrogen -10H- imidazos [2,1-i] [1] oxa- [4,7,10]-three azacyclo- are raw material, synthesis and post processing With embodiment 161 is prepared, white solid 39mg, yield 72% are obtained.1H NMR(500MHz,CDCl3)δ9.38(s,1H),7.33 (d, J=7.0Hz, 1H), 7.30-7.25 (m, 3H), 7.24-7.17 (m, 4H), 7.13 (s, 1H), 4.91 (td, J=8.0, 5.0Hz,1H),4.84–4.75(m,1H),4.56–4.49(m,1H),4.42–4.33(m,1H),4.01–3.90(m,2H), 3.77-3.68 (m, 2H), 3.58 (dd, J=9.5,3.5Hz, 1H), 3.53-3.46 (m, 1H), 3.38 (s, 3H), 3.34-3.26 (m, 2H), 3.16 (dd, J=14.0,4.5Hz, 1H), 2.88 (d, J=5.0Hz, 1H), 2.84 (dd, J=14.4,8.6Hz, 1H),1.90–1.77(m,1H),1.77–1.66(m,1H),1.55–1.35(m,5H)ppm；ESI-MS:M/z=542 [M+H]+.
Prepare embodiment 183, N- [(12S, 15S) -15- (methoxy) -14,17- dioxo -6,7,8,9,12, 15 carbon -12- first of 13,14,15,16,17- decahydros -5H, 11H- imidazo [2,1-i] [1] [4,7,10]-three azacyclo- of oxa- Acyl group]-Phe- epoxies ketone (10w)
With (12S, 15S) -15- (methoxy) -14,17- dioxos -6,7,8,9,12,13,14,15,16,17- ten 15 carbon -12- carboxylic acids of hydrogen -5H, 11H- imidazo [2,1-i] [1] oxa- [4,7,10]-three azacyclo- be raw material, synthesis and after Processing obtains white solid 37mg, yield 67% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3) δ 8.10 (d, J= 6.5Hz, 1H), 7.34 (d, J=8.5Hz, 1H), 7.30-7.18 (m, 5H), 7.13 (d, J=7.5Hz, 1H), 7.06 (d, J= 1.0Hz, 1H), 6.99 (d, J=1.0Hz, 1H), 5.16-5.08 (m, 1H), 5.01 (td, J=8.5,6.0Hz, 1H), 4.64- 4.58 (m, 1H), 4.31 (ddd, J=7.5,3.5,2.0Hz, 1H), 4.14-4.09 (m, 1H), 3.95-3.88 (m, 2H), 3.71 (dd, J=9.5,4.0Hz, 1H), 3.43 (dd, J=10.0,4.0Hz, 1H), 3.40 (s, 3H), 3.37-3.33 (m, 1H), 3.31 (d, J=4.5Hz, 1H), 3.20-3.12 (m, 2H), 2.92 (dd, J=14.0,8.0Hz, 1H), 2.83 (d, J= 4.5Hz,1H),1.82–1.71(m,1H),1.54–1.44(m,1H),1.43–1.34(m,4H),1.30–1.21(m,1H), 1.20–1.09(m,2H)ppm；ESI-MS:M/z=556 [M+H]+Embodiment 184, N- [(13S, 16S) -16- (methoxies are prepared Ylmethyl) ten dihydro -12H- imidazos [2,1-i] of -15,18- dioxos -5,6,7,8,9,10,13,14,15,16,17,18- [1] 16 carbon -13- formoxyls of [4,7,10]-three azacyclo- of oxa-]-Phe- epoxies ketone (10x)
With (13S, 16S) -16- (methoxy) -15,18- dioxo -5,6,7,8,9,10,13,14,15,16,17, 16 carbon -13- carboxylic acids of 18- ten dihydro -12H- imidazos [2,1-i] [1] oxa- [4,7,10]-three azacyclo- are raw material, are synthesized And post processing obtains white solid 41mg, yield 72% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ8.13(d,J =5.0Hz, 1H), 7.62 (d, J=8.0Hz, 1H), 7.31-7.15 (m, 6H), 7.10 (s, 1H), 7.07 (s, 1H), 5.40 (td, J=13.0,3.5Hz, 1H), 5.08-5.01 (m, 1H), 4.53 (dd, J=9.0,4.5Hz, 1H), 4.41-4.34 (m, 1H), 4.02 (dd, J=9.5,4.5Hz, 1H), 3.94 (dt, J=13.5,3.5Hz, 1H), 3.79 (dd, J=9.5,2.0Hz, 1H), 3.74 (dd, J=9.5,4.0Hz, 1H), 3.56 (dd, J=9.5,3.5Hz, 1H), 3.40 (s, 3H), 3.38-3.32 (m, 2H), 3.29 (d, J=5.0Hz, 1H), 3.14 (dd, J=14.0,6.0Hz, 1H), 2.96 (dd, J=14.0,7.5Hz, 1H), 2.80 (d, J=5.0Hz, 1H), 1.76-1.66 (m, 1H), 1.66-1.56 (m, 1H), 1.48-1.38 (m, 2H), 1.36 (s, 3H),1.33–1.26(m,1H),1.17–1.09(m,1H),1.08–1.00(m,1H),0.98–0.89(m,1H)ppm；ESI- MS:M/z=570 [M+H]+.
Prepare embodiment 185, N- [(3S, 6S) -3- (methoxy) -1,4- dioxo -2,3,4,5,6,7,9,10, 16 carbon -6- formoxyls of 11,12,13,14- ten dihydro -1H- pyrrolo-es [2,1-i] [1] [4,7,10]-three azacyclo- of oxa-] - Phe- epoxies ketone (10y)
With (3S, 6S) -2,3,4,5,6,7,9,10,11,12,13,14- ten dihydro -1H-3- (methoxy) -1,4- 16 carbon -6- carboxylic acids of dioxo-pyrrolo- [2,1-i] [1] oxa- [4,7,10]-three azacyclo- are raw material, synthesis and post processing With embodiment 161 is prepared, white solid 41mg, yield 72% are obtained.1H NMR(500MHz,CDCl3) δ 7.85 (d, J=8.5Hz, 1H), 7.31-7.18 (m, 6H), 6.86-6.81 (m, 1H), 6.74 (d, J=5.0Hz, 1H), 6.62 (dd, J=3.9,1.4Hz, 1H), 6.17-6.12 (m, 1H), 5.12-5.03 (m, 2H), 4.51 (q, J=4.5Hz, 1H), 4.45-4.40 (m, 1H), 4.03 (dd, J=9.5,4.5Hz, 1H), 3.87-3.77 (m, 2H), 3.72 (dd, J=9.5,4.5Hz, 1H), 3.54 (dd, J=9.5, 3.5Hz, 1H), 3.44-3.38 (m, 4H), 3.37-3.29 (m, 2H), 3.15 (dd, J=14.0,6.5Hz, 1H), 2.98 (dd, J =14.2,7.8Hz, 1H), 2.78 (d, J=5.0Hz, 1H), 1.66-1.57 (m, 1H), 1.55-1.41 (m, 3H), 1.37- 1.29(m,5H),1.24–1.11(m,2H)ppm；ESI-MS:M/z=569 [M+H]+.
Prepare embodiment 186, N- [- ten hexahydro -1H- of (3S, 6S, 18aS) -3- (methoxy) -1,4,14- trioxy-s 16 carbon -6- formoxyls of pyrrolo- [2,1-i] [1] [4,7,10] three azacyclo- of oxa-]-Phe- epoxies ketone (10z)
With-ten hexahydro -1H- pyrrolo-es [2,1-i] of (3S, 6S, 18aS) -3- (methoxy) -1,4,14- trioxy-s [1] 16 carbon -6- carboxylic acids of oxa- [4,7,10] three azacyclo- are raw material, synthesis and the same preparation embodiment 161 of post processing, are obtained white Solid 45mg, yield 77%.1H NMR(500MHz,CDCl3) δ 7.66 (d, J=7.0Hz, 1H), 7.33-7.13 (m, 6H), 6.56 (d, J=7.0Hz, 1H), 4.77 (td, J=9.0,5.0Hz, 1H), 4.61-4.53 (m, 1H), 4.44-4.37 (m, 1H), 4.37-4.32 (m, 1H), 3.90 (dd, J=10.5,2.5Hz, 1H), 3.75-3.69 (m, 1H), 3.67 (dd, J=9.0, 4.0Hz, 1H), 3.62 (dd, J=10.0,4.0Hz, 1H), 3.60-3.55 (m, 1H), 3.55-3.48 (m, 2H), 3.45-3.39 (m, 1H), 3.32-3.26 (m, 4H), 3.04 (dd, J=14.0,5.0Hz, 1H), 2.86-2.78 (m, 2H), 2.41-2.32 (m, 1H),2.12–1.87(m,5H),1.71–1.61(m,1H),1.57–1.45(m,1H),1.44–1.31(m,5H),1.31–1.24 (m,2H)ppm；ESI-MS:M/z=587 [M+H]+.
Prepare embodiment 187, N- [(9S, 12S) -12- (methoxy) -11,14- dioxo -2,3,5,6,9,10, 16 carbon -9- formoxyls of 11,12,13,14- decahydro -8H- benzos [o] [1,4,7]-trioxa [10,13]-diazacyclo] - Phe- epoxies ketone (10za)
With (9S, 12S) -12- (methoxy) -11,14- dioxos -2,3,5,6,9,10,11,12,13,14- ten 16 carbon -9- carboxylic acids of hydrogen -8H- benzos [o] [Isosorbide-5-Nitrae, 7]-trioxa [10,13]-diazacyclo are raw material, and synthesis and post processing are same Embodiment 161 is prepared, obtains white solid 43mg, yield 77%.1H NMR(500MHz,CDCl3) δ 8.82 (d, J=7.0Hz, 1H), 8.18 (dd, J=7.5,2.5Hz, 1H), 7.47 (ddd, J=8.5,7.5,1.5Hz, 1H), 7.12-6.95 (m, 9H), 4.78 (ddd, J=7.0,3.0,2.5Hz, 1H), 4.70 (td, J=8.5,5.5Hz, 1H), 4.64 (dt, J=8.5,3.5Hz, 1H), 4.43-4.32 (m, 2H), 4.03 (dd, J=9.5,2.5Hz, 1H), 3.99 (dd, J=9.0,3.5Hz, 1H), 3.95- 3.89 (m, 1H), 3.78-3.72 (m, 1H), 3.67-3.61 (m, 2H), 3.55 (t, J=8.0Hz, 1H), 3.43-3.38 (m, 6H), 3.33 (d, J=5.0Hz, 1H), 3.00 (dd, J=13.5,5.0Hz, 1H), 2.79 (d, J=5.0Hz, 1H), 2.75 (dd, J=13.5,8.5Hz, 1H), 1.40 (s, 3H) ppm；ESI-MS:M/z=584 [M+H]+.
Prepare embodiment 188, N- [(12S, 15S) -15- (methoxy) -14,17- dioxo -2,3,5,6,8,9, Ten dihydro -11H- benzos [r] of 12,13,14,15,16,17- [1,4,7,10] four oxa- [13,16] -19 carbon of diazacyclo - 12- formoxyls]-Phe- epoxies ketone (10zb)
With (12S, 15S) -15- (methoxy) -14,17- dioxo -2,3,5,6,8,9,12,13,14,15,16, 19 carbon -12- carboxylic acids of 17- ten dihydro -11H- benzos [r] [Isosorbide-5-Nitrae, 7,10] four oxa-s [13,16]-diazacyclo are raw material, are closed Into and post processing with prepare embodiment 161, obtain white solid 42mg, yield 67%.1H NMR(500MHz,CDCl3)δ8.96(d, J=4.5Hz, 1H), 8.26 (dd, J=7.5,1.5Hz, 1H), 7.56-7.50 (m, 1H), 7.49-7.42 (m, 2H), 7.24- 7.08 (m, 5H), 7.07-7.02 (m, 1H), 6.97 (d, J=8.5Hz, 1H), 4.77 (td, J=8.5,5.5Hz, 1H), 4.71- 4.61 (m, 2H), 4.41 (td, J=10.0,2.0Hz, 1H), 4.30-4.24 (m, 1H), 4.09-4.02 (m, 1H), 3.97 (dd, J=10.0,6.5Hz, 1H), 3.85-3.79 (m, 1H), 3.75 (dd, J=10.5,4.0Hz, 1H), 3.73-3.68 (m, 1H), 3.68-3.51 (m, 6H), 3.50-3.43 (m, 3H), 3.42 (s, 3H), 3.35 (d, J=5.0Hz, 1H), 3.06 (dd, J= 14.0,5.5Hz,1H),2.88–2.78(m,2H),1.40(s,3H)ppm；ESI-MS:M/z=628 [M+H]+.
Prepare embodiment 189, N- [(10S, 13S) -13- (2- morpholino -2- oxoethyls) -12,15- dioxo -2,3, 4,5,6,7,10,11,12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7] -17 carbon of diazacyclo - 10- formoxyls]-Phe- epoxies ketone (10zc)
With (10S, 13S) -13- (2- morpholino -2- oxoethyls) -12,15- dioxo -2,3,4,5,6,7,10,11, 12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo, 17 carbon -10- carboxylic acids are raw material, Synthesis and post processing obtain white solid 37mg, yield 55% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ9.24 (d, J=8.5Hz, 1H), 8.24 (dd, J=8.0,1.5Hz, 1H), 7.50-7.41 (m, 1H), 7.20-7.08 (m, 6H), 7.08-7.02 (m, 1H), 6.98 (d, J=8.5Hz, 1H), 6.91 (d, J=7.5Hz, 1H), 5.16-5.10 (m, 1H), 4.75 (td, J=8.5,4.5Hz, 1H), 4.64-4.57 (m, 1H), 4.30-4.15 (m, 2H), 3.68-3.62 (m, 4H), 3.61- 3.56 (m, 1H), 3.55-3.30 (m, 9H), 3.07 (dd, J=13.5,4.5Hz, 1H), 2.84 (d, J=5.0Hz, 1H), 2.77 (dd, J=14.0,9.0Hz, 1H), 2.62 (dd, J=16.5,5.0Hz, 1H), 2.12-2.04 (m, 1H), 1.81-1.73 (m, 1H),1.72–1.58(m,2H),1.52–1.37(m,7H)ppm；ESI-MS:M/z=679 [M+H]+.
Prepare embodiment 190, N- [(10S, 13S) -13- (3- morpholino -3- oxopropyls) -12,15- dioxo -2,3, 4,5,6,7,10,11,12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7] -17 carbon of diazacyclo - 10- formoxyls]-Phe- epoxies ketone (10zd)
With (10S, 13S) -13- (3- morpholino -3- oxopropyls) -12,15- dioxo -2,3,4,5,6,7,10,11, 12,13,14,15- ten dihydro -9H benzos [i] [1,11] dioxas [4,7]-diazacyclo heptadecyl -10- carboxylic acids are raw material, Synthesis and post processing obtain white solid 40mg, yield 58% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ8.72 (d, J=5.5Hz, 1H), 8.10 (dd, J=7.5,2.0Hz, 1H), 7.48-7.41 (m, 1H), 7.34 (d, J=8.5Hz, 1H), 7.11-6.91 (m, 7H), 4.76 (td, J=9.0,4.5Hz, 1H), 4.62-4.46 (m, 2H), 4.37-4.28 (m, 1H), 4.18 (td, J=9.0,2.0Hz, 1H), 3.66-3.39 (m, 9H), 3.37-3.29 (m, 2H), 3.04 (dd, J=13.5,4.5Hz, 1H), 2.83 (d, J=5.0Hz, 1H), 2.73 (dd, J=13.5,9.0Hz, 1H), 2.63-2.42 (m, 2H), 2.30-2.20 (m,2H),2.02–1.96(m,1H),1.90–1.84(m,1H),1.59–1.35(m,8H),1.31–1.21(m,3H)ppm； ESI-MS:M/z=693 [M+H]+.
Prepare embodiment 191, N- [(10S, 13S) -13- (2- (cyclopropylamino) -2- oxoethyls) -12,15- dioxies Generation -2,3,4,5,6,7,10,11,12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7] diazacyclo ten Seven carbon -10- formoxyls]-Phe- epoxies ketone (10ze)
With (10S, 13S) -13- (2- (cyclopropylamino) -2- oxoethyls) -12,15- dioxo -2,3,4,5,6,7, 17 carbon -10- carboxylic acids of 10,11,12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7] diazacyclo are Raw material, synthesis and post processing obtain white solid 41mg, yield 63% with embodiment 161 is prepared.1H NMR(500MHz,CDCl3)δ 9.43 (d, J=6.5Hz, 1H), 8.17 (dd, J=7.5,1.5Hz, 1H), 7.51-7.42 (m, 1H), 7.38 (d, J=8.0Hz, 1H), 7.16-6.99 (m, 8H), 6.88 (d, J=3.0Hz, 1H), 4.97-4.87 (m, 1H), 4.77 (td, J=9.0,4.5Hz, 1H),4.62–4.54(m,1H),4.49–4.40(m,1H),4.31–4.18(m,1H),3.64–3.54(m,1H),3.50(dd,J =9.5,3.5Hz, 1H), 3.42-3.27 (m, 2H), 3.07 (dd, J=14.0,4.5Hz, 1H), 2.90 (dd, J=15.0, 5.5Hz, 1H), 2.87-2.77 (m, 2H), 2.75-2.67 (m, 1H), 2.63 (dd, J=15.0,5.0Hz, 2H), 2.24-2.12 (m,1H),1.91–1.80(m,1H),1.71–1.54(m,2H),1.53–1.33(m,7H),0.75–0.63(m,2H),0.57– 0.45(m,2H)ppm；ESI-MS:M/z=649 [M+H]+.
Prepare embodiment 192, N- [(10S, 13S) -13- isobutyl group -12,15- dioxo -2,3,4,5,6,7,10,11, 17 carbon -10- formoxyls of 12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- Epoxy ketone (10zf)
With (10S, 13S) -13- isobutyl group -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- 12 17 carbon -10- carboxylic acids of hydrogen -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo are raw material, and synthesis and post processing are the same as system Standby embodiment 161, obtains white solid 45mg, yield 74%.1H NMR(500MHz,CDCl3) δ 8.29 (d, J=6.0Hz, 1H), 8.23 (dd, J=8.0,1.5Hz, 1H), 7.52-7.45 (m, 1H), 7.21 (d, J=8.0Hz, 1H), 7.11-6.99 (m, 7H), 6.81 (d, J=8.0Hz, 1H), 4.76 (td, J=8.5,5.0Hz, 1H), 4.63-4.52 (m, 2H), 4.35-4.30 (m, 1H), 4.19 (td, J=10.0,2.0Hz, 1H), 3.60 (dd, J=10.0,5.5Hz, 1H), 3.48 (dd, J=10.0,4.5Hz, 1H), 3.36-3.27 (m, 3H), 3.05 (dd, J=14.0,5.0Hz, 1H), 2.82 (d, J=5.0Hz, 1H), 2.76 (dd, J= 13.5,9.0Hz,1H),1.98–1.88(m,2H),1.87–1.70(m,2H),1.63–1.49(m,4H),1.47–1.40(m, 6H), 0.99 (d, J=6.5Hz, 3H), 0.95 (d, J=6.5Hz, 3H) ppm；ESI-MS:M/z=608 [M+H]+.
Prepare embodiment 193, N- [(10S, 13S) -13- isopropyl -12,15- dioxo -2,3,4,5,6,7,10,11, 17 carbon -10- formoxyls of 12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- Epoxy ketone (10zg)
With (10S, 13S) -13- isopropyl -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- 12 17 carbon -10- carboxylic acids of hydrogen -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo are raw material, and synthesis and post processing are the same as system Standby embodiment 161, obtains white solid 46mg, yield 77%.1H NMR(500MHz,CDCl3)δ8.26–8.19(m,2H),7.52– 7.46 (m, 1H), 7.21 (d, J=8.0Hz, 1H), 7.11-6.99 (m, 7H), 6.78 (d, J=8.5Hz, 1H), 4.77 (td, J =9.0,5.0Hz, 1H), 4.62-4.55 (m, 2H), 4.37-4.31 (m, 1H), 4.22 (td, J=9.5,3.5Hz, 1H), 3.62 (dd, J=9.5,5.0Hz, 1H), 3.47 (dd, J=9.5,4.0Hz, 1H), 3.37-3.26 (m, 3H), 3.05 (dd, J= 14.0,4.5Hz, 1H), 2.82 (d, J=5.0Hz, 1H), 2.76 (dd, J=14.0,9.0Hz, 1H), 1.96-1.81 (m, 2H), 1.67–1.53(m,2H),1.49–1.36(m,7H),1.30–1.23(m,1H),1.06–0.97(m,6H)ppm；ESI-MS:m/z =594 [M+H]+.
Prepare embodiment 194, N- [(9S, 12S) -12- (methoxy) -11,14- dioxo -3,4,5,6,7,8,9, 16 carbon -9- formoxyls of 10,11,12,13,14- ten dihydro -2H- benzos [b] [1] oxa- [5,8]-diazacyclo]-Phe- rings Oxygen ketone (10zh)
With (9S, 12S) -12- (methoxy) -11,14- dioxos -3,4,5,6,7,8,9,10,11,12,13,14- Ten dihydro -2H- benzos [b] [1] oxa- [5,8]-diazacyclos, 16 carbon -9- carboxylic acids are raw material, and synthesis and post processing are the same as preparation Embodiment 161 obtains white solid 35mg, yield 60%.1H NMR(500MHz,CDCl3) δ 8.87 (d, J=7.5Hz, 1H), 8.27 (dd, J=8.0,2.0Hz, 1H), 7.52-7.45 (m, 1H), 7.23-7.15 (m, 3H), 7.14-7.08 (m, 3H), 7.00 (d, J=8.5Hz, 1H), 6.73 (d, J=7.5Hz, 1H), 6.58 (d, J=8.0Hz, 1H), 4.85-4.73 (m, 2H), 4.46- 4.38 (m, 1H), 4.26-4.19 (m, 1H), 4.18-4.08 (m, 2H), 3.53 (dd, J=9.0,4.0Hz, 1H), 3.41 (s, 3H), 3.32 (d, J=5.0Hz, 1H), 3.10 (dd, J=14.0,5.0Hz, 1H), 2.86 (d, J=5.0Hz, 1H), 2.75 (dd, J=14.0,9.0Hz, 1H), 2.03-1.75 (m, 4H), 1.56-1.26 (m, 11H) ppm；ESI-MS:M/z=580 [M+ H]+.
Prepare embodiment 195, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7, Ten tetrahydrochysenes of 8,9,10,11,12,13,14,15--benzo [b] [1] oxa- [5,8]-diazacyclo, 17 carbon -10- formoxyls] - Phe- epoxies ketone (10zi)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,8,9,10,11,12,13, 14,15- ten tetrahydrochysenes-benzo [b] [1] oxa- [5,8]-diazacyclo, 17 carbon -10- carboxylic acids are raw material, and synthesis and post processing are same Embodiment 161 is prepared, obtains white solid 34mg, yield 57%.1H NMR(500MHz,CDCl3) δ 8.86 (d, J=8.0Hz, 1H), 8.17 (dd, J=8.0,1.5Hz, 1H), 7.48-7.40 (m, 1H), 7.19-7.00 (m, 7H), 6.95 (d, J=8.5Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 4.80-4.74 (m, 1H), 4.73-4.67 (m, 1H), 4.39-4.33 (m, 1H), 4.20- 4.14 (m, 1H), 4.11-4.01 (m, 2H), 3.48 (dd, J=9.0,4.0Hz, 1H), 3.34 (s, 3H), 3.25 (d, J= 5.0Hz, 1H), 3.02 (dd, J=14.0,4.5Hz, 1H), 2.80 (d, J=5.0Hz, 1H), 2.69 (dd, J=14.0, 9.0Hz,1H),1.93–1.83(m,1H),1.82–1.70(m,3H),1.52–1.19(m,13H)ppm；ESI-MS:M/z=594 [M+H]+.
Prepare embodiment 196, N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -3,4,5,6,7,9, Ten dihydro -2H-1,8- diaza -11,14- benzo dioxas diazacyclos of 10,11,12,13,14,15-, 17 carbon -10- formyls Base]-Leu- epoxies ketone (10zj)
With (10S, 13S) -13- (methoxy) -12,15- dioxo -3,4,5,6,7,9,10,11,12,13,14, Ten dihydro -2H-1,8- diaza -11,14- benzo dioxas diazacyclos of 15-, 17 carbon -10- carboxylic acids and Leu- epoxies ketone three Fluoroacetate is raw material, and synthesis and post processing obtain white solid 42mg, yield 75% with embodiment 161 is prepared.1H NMR (500MHz,CDCl3) δ 8.81 (d, J=6.5Hz, 1H), 8.15 (d, J=8.0Hz, 1H), 7.49-7.40 (m, 1H), 7.07- 7.01 (m, 1H), 7.00-6.94 (m, 2H), 6.86 (d, J=8.0Hz, 1H), 4.67-4.62 (m, 2H), 4.48-4.42 (m, 1H), 4.28-4.24 (m, 1H), 4.12-4.07 (m, 1H), 4.03-3.99 (m, 1H), 3.81 (dd, J=9.5,5.0Hz, 1H), 3.61 (dd, J=9.5,3.5Hz, 1H), 3.54-3.44 (m, 2H), 3.39 (s, 3H), 3.30 (d, J=5.0Hz, 1H), 2.81- 2.76(m,2H),1.99–1.90(m,1H),1.86–1.77(m,1H),1.71–1.57(m,2H),1.55–1.37(m,10H), 0.74 (d, J=6.0Hz, 3H), 0.67 (d, J=6.0Hz, 3H)1ppm；ESI-MS:M/z=562 [M+H]+.
The proteasome inhibition activity test of test example 1, big ring epoxy ketone peptides
Experimental method：Activity is detected using fluorogenic substrate Suc-Leu-Leu-Val-Tyr-AMC, observes different compounds pair The activity suppression of enzyme, with the inhibition of preliminary assessment compound.Human proteasome chymotrypsin- Tyr-AMC sequences in likeprotease hydrolysis substrates, release AMC, in the condition of exciting light 355nm transmitting light 460nm The fluorescent absorption value of product AMC after hydrolyzing can be detected down, to observe inhibition situation of the compound to enzymatic activity.As a result referring to Table 1.
1 compound for protein enzyme body CT-L of table and the increment inhibitory activity (English in table to multiple myeloma cells It is changed to Chinese)
Note：NT- is not tested
The multiple myeloma cells proliferation inhibition activity test of test example 2, big ring epoxy ketone peptides
Experimental method：Cell survival rate is detected with mtt assay, the cell of exponential phase will be grown in, through 0.01% Pancreatin digestion, count, with 2.0 × 103The cell density of/well is seeded in 100ml in 96 orifice plates, is placed in 5%CO2Incubator Interior 37 DEG C of overnight incubations.Each compound sets six concentration gradients, and each concentration sets three multiple holes, and each concentration is added separately to In corresponding aperture, 5%CO2When culture 72 is small in 37 DEG C of incubators, the 5mg/ml MTT of 20ml are added in.37 DEG C are after being incubated for 3 hours, Supernatant is abandoned in suction, adds in the DMSO dissolvings of 100ml, 550nm (L1) absorbance value, reference wavelength are surveyed using SpectraMAX 340 (L1-L2) value maps to inhibitor various concentration, IC is obtained through formula fitting by 690nm (L2)50.As a result referring to table 1.
Test example 3, big ring epoxy ketone peptides are to the proliferation inhibition activity test experiments of kinds of tumor cells Method changes corresponding tumour cell into referring to test example 2, simply RPMI8226 and MM.1S cell lines.As a result referring to table 2.
Table 2, compound are to the proliferation inhibition activity of kinds of tumor cells
Proteasome in mouse PBMC is inhibited after test example 4, big ring epoxy ketone peptides oral administration Active testing
Experimental method：Compound 10a, 10b and 10c are chosen, male BABL/C mouse are divided into 4 groups, one of which is the moon Property control, every group of 3 mouse, often only according to group be administered orally 30mg/kg, 100mg/kg, respectively administration sample afterwards for 24 hours, Compound is investigated after BABL/C mouse single administrations, the variation of proteasome activity in PBMC.
The compound of the present invention is all the highly efficient depressor of proteasome, active testing the results show (referring to Fig. 1), big portion Divide compound that there is apparent inhibitory activity to proteasome, the proteasome inhibition activity and positive control for there are 19 compounds Oprozzomib is suitable, and part of compounds is better than Oprozzomib, suitable with listing compound Carfilzomib.Meanwhile we It is also seen that majority of compounds waits until by force in being shown to multiple myeloma cells and other 9 kinds of tumor cell lines In-vitro multiplication inhibitory activity；Mouse through gastric infusion for 24 hours after, compound 10a, 10b and 10c are to proteasome in mouse PBMC There is different degrees of inhibition.In short, such compound has potent anti tumor activity in vitro and good Orally active, It is horizontal as the external and activity in vivo of drug candidate compound to have been equipped with optimization.Therefore, it is according to the present invention to can be used as The big ring epoxy ketone peptide derivative of proteasome inhibitor has wide antitumor application thereof prospect.

Claims (18)

1. a kind of big ring epoxy ketone peptide derivative and its salt, which is characterized in that there is logical formula (I) structure：
And its optical isomer or its solvate,
Wherein：
R1、R2It is each independently selected from H ,-C1-10Alkyl-D, C1-10Hydroxy alkyl ,-C2-10Unsaturated alkyl-D ,-halogenated C1-10Alkane Base-D ,-C1-3Alkyl-S-C1-5Alkyl, C1-10Alkoxyalkyl, halogenated C1-10Alkoxyalkyl, C3-10Unsaturated alkoxy, C3-10Cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl；Wherein, D is N (Ra) RbOr missing；RaSelected from H, OH, C1-6Alkyl, halogenated C1-6Alkyl；RbSelected from N-terminal protecting group；
R3、R4It is each independently selected from H, C1-10Alkyl, halogenated C1-10Alkyl, aryl, aralkyl；
R5Selected from H, C1-6Alkyl, C1-6Hydroxy alkyl, halogenated C1-6Alkyl, C1-6Alkoxyalkyl, halogenated C1-6Alkoxy alkane Base；
R6Selected from H, C1-10Alkyl, C1-10Alkoxyalkyl, C2-10Unsaturated alkyl, cycloalkyl；
X is O, S, NH, N-C1-6Alkyl；
Y isOr missing, wherein R are selected from H, C1-10Alkyl, halogen The C in generation1-10Alkyl；
Ar is selected from unsubstituted or substitution cycloalkyl, unsubstituted or substitution Heterocyclylalkyl, unsubstituted or substitution cycloalkenyl group, nothing Substitution or substitution heterocycloalkenyl, it is unsubstituted or substitution aryl, it is unsubstituted or substitution aralkyl, it is unsubstituted or substitution it is miscellaneous Aryl, unsubstituted or substitution heteroarylalkyl, arbitrarily condensed aryl；
L is
Wherein B1It is selected from
D1、D2It is identical or different, it is respectively and independently selected from-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkyl OC1-8Alkane Base-,-SC1-8Alkyl-,-C1-8Alkyl S- ,-C1-8Alkyl SC1-8Alkyl-,-N (Rd)-、-N(Rd)C1-8Alkyl-,-C1-8Alkyl N (Rd)-、-C1-8Alkyl N (Rd)C1-8Alkyl-,-N (Rd)C(O)-、-N(Rd)C(O)C1-8Alkyl-,-C1-8Alkyl N (Rd)C(O)-、- C1-8Alkyl N (Rd)C(O)C1-8Alkyl-,-C (O) N (Rd)-、-C(O)N(Rd)C1-8Alkyl-,-C1-8Alkyl C (O) N (Rd)-、- C1-8Alkyl C (O) N (Rd)C1-8Alkyl-,-C (O) C1-8Alkyl-,-C (O) C1-8Unsaturated alkyl-,-N (Rd)SO2-、-N(Rd) SO2C1-8Alkyl-,-C1-8Alkyl N (Rd)SO2-、-C1-8Alkyl N (Rd)SO2C1-8Alkyl-,-OC (O) C1-8Alkyl-,-C1-8Alkyl OC(O)-、-C1-8Alkyl OC (O) C1-8Alkyl-,-C (O) OC1-8Alkyl-,-C1-8Alkyl C (O) O- ,-C1-8Alkyl C (O) OC1-8Alkane Base-；RdSelected from H, C1-4Alkyl, halogenated C1-4Alkyl, cycloalkyl, heterocycloalkenyl, aryl, aralkyl, heteroaryl, heteroaryl alkane Base；
The substituted substituent group is selected from halogen, nitro, amino, cyano, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkane Oxygroup, C1-6Alkoxyalkyl, C1-6Alkylamino radical, halogenated C1-6Alkoxy, halogenated C1-6Alkoxyalkyl, halogenated C1-6Alkane Amido, C3-8Cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl.
2. compound according to claim 1, which is characterized in that the compound has general formula (II) structure：
And its optical isomer or pharmaceutically acceptable salt or solvate, wherein：
X elects O as；
Y is selected
Ring A is selected from lower structure：
Wherein, V1、V2、V3、V4、W1、W2And W3It is each independently selected from N, C；
ReSelected from H, halogen, nitro, amino, cyano, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, C1-6Alcoxyl Base alkyl, C1-6Alkylamino radical, halogenated C1-6Alkoxy, halogenated C1-6Alkoxyalkyl, halogenated C1-6Alkylamino radical, C3-8Cycloalkanes Base, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl；
Z is selected from O, S ,-N (Rf)-；Wherein, RfIn the presence of or missing, selected from H, C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxyalkyl, halogenated C1-6Alkoxy, C3-8Cycloalkyl, Heterocyclylalkyl, C3-8Cycloalkenyl group, heterocycloalkenyl, aryl, aralkyl Base, heteroaryl, heteroarylalkyl；
L、R1、R2、R3、R4And R5As claim 1 general formula (I) structure defines.
3. compound according to claim 2, which is characterized in that the compound has general formula (III) structure：
And its optical isomer or pharmaceutically acceptable salt or solvate, wherein：
V1、V2、V3、V4And RgAs general formula (II) structure defines；
B1、D1、D2、R1And R2As claim 1 general formula (I) structure defines.
4. compound according to claim 3, which is characterized in that the compound has general formula (IV) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：
V1And V4It is each independently selected from C, N；
B1It elects as
D1And D2It is identical or different, it is respectively and independently selected from-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkyl OC1-8 Alkyl；
R1Selected from methoxymethyl, isobutyl group, isopropyl, (N- morpholinyls) formyl-methyl, (N- morpholinyls) formoxyl-second Base；
R2Selected from benzyl, isobutyl group；
RgSelected from H, halogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Alkoxyalkyl；
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
5. compound according to claim 4, which is characterized in that the compound is selected from：
N- [(8S, 11S) -11- (methoxy) -10,13- dioxo -3,4,5,7,8,9,10,11,12,13- decahydros -2H- 1,6,9,12- benzo dioxa diazacyclo, 15 carbon -8- formoxyls]-Phe- epoxy ketone,
N- [(9S, 12S) -12- (methoxy) -11,14- dioxos -2,3,4,5,6,8,9,10,11,12,13,14- ten Dihydro -1,7,10,13- benzo dioxa diazacyclo, 16 carbon -9- formoxyls]-Phe- epoxy ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -3,4,5,6,7,9,10,11,12,13,14,15- Ten dihydro -2H-1,8,11,14- benzo dioxa diazacyclo, 17 carbon -10- formoxyls]-Leu- epoxy ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -3,4,5,6,7,9,10,11,12,13,14,15- Ten dihydros -1,8 of 2H-, 11,14- benzo dioxa diazacyclo, 17 carbon -10- formoxyls]-Phe- epoxy ketone,
N- [(11S, 14S) -14- (methoxy) -13,16- dioxo -2,3,4,5,6,7,8,10,11,12,13,14, 15,16- ten tetrahydrochysenes -1,9,12,15- benzo dioxa diazacyclo, 18 carbon -11- formoxyls]-Phe- epoxy ketone,
N- [(12S, 15S) -15- (methoxy) -14,17- dioxo -3,4,5,6,7,8,9,11,12,13,14,15, 16,17-2H- ten tetrahydrochysene -2H-1,10,13,16- benzo dioxa diazacyclo, 19 carbon -12- formoxyls]-Phe- epoxy ketone,
N- [(13S, 16S) -16- (methoxy) -15,18- dioxo -3,4,5,6,7,8,9,10,13,14,15,16, 20 carbon -13- formoxyls of 17,18- ten tetrahydrochysene -2H, 12H- benzo [i] [1,11] dioxa [4,7] diazacyclo]-Phe- rings Oxygen ketone,
N- [(7S, 10S) -7- (methoxy) -5,8- dioxos -6,7,8,9,10,11,13,14,15,16,17,18- ten 17 carbon -10- formoxyls of dihydro -5H- pyridos [3,2-i] [1,11] dioxa [4,7] diazacyclo]-Phe- epoxy ketone,
N- [(14S, 17S) -17- (methoxy) -16,19- dioxo -6,7,8,9,10,11,14,15,16,17,18, 19- ten dihydro -13H- pyridos [2,3-i] [1,11] dioxa [4,7] 17 carbon-14s of diazacyclo-formoxyl]-Phe- rings Oxygen ketone,
N- [(9S, 12S) -12- (methoxy) -11,14- dioxos -3,4,5,6,7,8,9,10,11,12,13,14- ten 16 carbon -9- formoxyls of dihydro -2H- benzos [b] [1] oxa- [5,8]-diazacyclo]-Phe- epoxy ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxo -2,3,4,5,6,7,8,9,10,11,12,13,14, Ten tetrahydrochysenes of 15--benzo [b] [1] oxa- [5,8]-diazacyclo, 17 carbon -10- formoxyls]-Phe- epoxy ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- Ten dihydro -9H-19- methoxyl groups -17 carbon -10- formoxyls of benzo [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- rings Oxygen ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- The ten fluoro- benzos of dihydro -9H-19- [i] [1,11] dioxa [4,7]-diazacyclos, 17 carbon -10- formoxyls]-Phe- epoxies Ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- The ten fluoro- benzos of dihydro -9H-18- [i] [1,11] dioxa [4,7]-diazacyclos, 17 carbon -10- formoxyls]-Phe- epoxies Ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- The ten chloro- benzos of dihydro -9H-18- [i] [1,11] dioxa [4,7]-diazacyclos, 17 carbon -10- formoxyls]-Phe- epoxies Ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- Ten dihydro -9H-18- methoxyl groups -17 carbon -10- formoxyls of benzo [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- rings Oxygen ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- Ten dihydro -9H-18- methyl -17 carbon -10- formoxyls of benzo [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- epoxies Ketone,
N- [(10S, 13S) -13- (methoxy) -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- The ten chloro- benzos of dihydro -9H-17- [i] [1,11] dioxa [4,7] diazacyclos, 17 carbon -10- formoxyls]-Phe- epoxy ketone,
N- [(10S, 13S) -13- (2- morpholino -2- oxoethyls) -12,15- dioxo -2,3,4,5,6,7,10,11,12, 17 carbon -10- formoxyls of 13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- rings Oxygen ketone,
N- [(10S, 13S) -13- (3- morpholino -3- oxopropyls) -12,15- dioxo -2,3,4,5,6,7,10,11,12, 17 carbon -10- formoxyls of 13,14,15- ten dihydro -9H benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- epoxies Ketone,
N- [(9S, 12S) -12- (methoxy) -11,14- dioxo -2,3,5,6,9,10,11,12,13,14- decahydros - 16 carbon -9- formoxyls of 8H- benzos [o] [Isosorbide-5-Nitrae, 7]-trioxa [10,13]-diazacyclo]-Phe- epoxy ketone,
N- [(12S, 15S) -15- (methoxy) -14,17- dioxos -2,3,5,6,8,9,12,13,14,15,16,17- [1,4,7,10] four oxa- [13,16] of ten dihydro -11H- benzos [r] -19 carbon -12- formoxyls of diazacyclo]-Phe- epoxies Ketone,
N- [(10S, 13S) -13- (2- (cyclopropylamino) -2- oxoethyls) -12,15- dioxo -2,3,4,5,6,7,10, 17 carbon -10- formoxyls of 11,12,13,14,15- ten dihydro -9H- benzos [i] [1,11] dioxa [4,7] diazacyclo] - Phe- epoxy ketone,
N- [ten dihydros of (10S, 13S) -13- isobutyl group -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- - 17 carbon -10- formoxyls of 9H- benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- epoxy ketone,
N- [ten dihydro -9H- of (10S, 13S)-isopropyl -12,15- dioxos -2,3,4,5,6,7,10,11,12,13,14,15- 17 carbon -10- formoxyls of 13- benzos [i] [1,11] dioxa [4,7]-diazacyclo]-Phe- epoxy ketone,
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
6. compound according to claim 2, which is characterized in that the compound has general formula (V) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：
B1It elects as
D1And D2It is identical or different, it is respectively and independently selected from-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkyl OC1-8 Alkyl-；
RhSelected from H；
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
7. compound according to claim 6, which is characterized in that the compound is selected from：
N- [(13S, 16S) -16- (methoxy) -15,18- dioxo -2,11- dioxa -14,17- diazabicyclos [17.3.1]-two 13 carbon -1 (23), 19,21- triolefin -13- formoxyls]-Phe- epoxy ketone,
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
8. compound according to claim 2, it is characterised in that the compound has general formula (VI) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：
W1And W2Each elect C, N as；
Z elects N (C as1-6Alkyl)；
B1It elects as
D1And D2It is identical or different, it is respectively and independently selected from-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkyl OC1-8 Alkyl-；
RiElect H as；
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
9. compound according to claim 8, which is characterized in that the compound is selected from：
N- [(6S, 9S) -6- (methoxy) -4,7- dioxos -1,4,5,6,7,8,9,10,12,13,14,15,16,17- Ten dihydro -1- methyl pyrazoles simultaneously 17 carbon -9- formoxyls of [4,3-i] [1,11] dioxa [4,7] diazacyclo]-Phe- epoxies Ketone
N- [(6S, 9S) -6- (methoxy) -1- methyl -4,7- dioxo -4,5,6,7,8,9,10,12,13,14,15, 17 carbon -9- formoxyls of 16,17,18- ten tetrahydrochysene -1H- pyrazolos [4,3-i] [1] oxa- [4,7]-diazacyclo]-Phe- rings Oxygen ketone,
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
10. compound according to claim 2, which is characterized in that the compound has general formula (VI I) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：
W1And W2Each elect C, N as；
Z elects S as；
B1It elects as
D1And D2It is identical or different, it is respectively and independently selected from-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O-；
RjSelected from H, methyl；
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
11. compound according to claim 10, which is characterized in that the compound is selected from：
N- [(13S, 16S) -16- (methoxy) -15,18- dioxos -5,6,7,8,9,10,13,14,15,16,17,18- Ten dihydro -12H- thienos [2,3-i] [1,11] dioxa [4,7] diazacyclos, 17 carbon -13- formoxyls]-Phe- epoxies Ketone,
N- [(13S, 16S) -16- (methoxy) -15,18- dioxos -5,6,7,8,9,10,13,14,15,16,17,18- Ten dihydro -12H-2- methYl-thiazols simultaneously 17 carbon -13- formoxyls of [4,5-i] [1,11] dioxa [4,7] diazacyclo] - Phe- epoxy ketone,
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
12. compound according to claim 2, which is characterized in that the compound has general formula (VIII) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：
W1、W2And W3Each elect C, N as；
Z elects N as；
B1It elects as
D1And D2It is identical or different, it is respectively and independently selected from-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkyl OC1-8 Alkyl-；
RkElect H as；
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
13. compound according to claim 12, it is characterised in that the compound is selected from：
NN- (13S, 16S) -16- (methoxy) -15,18- dioxos -5,6,7,8,9,10,13,14,15,16,17,18- Ten dihydro -12H- imidazos [2,1-i] [1] oxa- [4,7,10]-three azacyclo-s, 16 carbon -13- formoxyls]-Phe- epoxy ketone,
N- (12S, 15S) -15- (methoxy) -14,17- dioxo -6,7,8,9,12,13,14,15,16,17- decahydros - 15 carbon -12- formoxyls of 5H, 11H- imidazo [2,1-i] [1] oxa- [4,7,10]-three azacyclo-]-Phe- epoxy ketone,
N- (11S, 14S) -14- (methoxy) -13,16- dioxo -5,6,7,8,11,12,13,14,15,16- decahydros - 14 carbon -11- formoxyls of 10H- imidazos [2,1-i] [1] oxa- [4,7,10]-three azacyclo-]-Phe- epoxy ketone,
Ten dihydros of N- (3S, 6S) -3- (methoxy) -1,4- dioxos -2,3,4,5,6,7,9,10,11,12,13,14- - 16 carbon -6- formoxyls of 1H- pyrrolo-es [2,1-i] [1] oxa- [4,7,10]-three azacyclo-]-Phe- epoxy ketone,
N- (6S, 9S) -6- (methoxy) -4,7- dioxos -5,6,7,8,9,10,12,13,14,15,16,17- 12 16 carbon -9- formoxyls of hydrogen -4H- pyrazolos [5,1-i] [1] oxa- [4,7,10]-three azacyclo-]-Phe- epoxy ketone,
N- (6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,13,14,15,16- decahydros -4H, 12H- 15 carbon -9- formoxyls of pyrazolo [5,1-i] [1] oxa- [4,7,10] three azacyclo-]-Phe- epoxy ketone,
N- (6S, 9S) -6- (methoxy) -4,7- dioxo -5,6,7,8,9,10,12,13,14,15- decahydro -4H- pyrazoles And-three azepine ring carbon -9- formoxyls of [5,1-i] [1] oxa- [4,7,10]]-Phe- epoxy ketone,
And its optical isomer of above-claimed cpd or its pharmaceutically acceptable salt or solvate.
14. compound according to claim 2, which is characterized in that the compound has general formula (Ⅸ) structure：
And its optical isomer or its pharmaceutically acceptable salt or solvate, wherein：
B1It elects as
D2Selected from-C1-8Alkyl-,-C1-8Alkyl OC1-8Alkyl-,
RmElect H as；
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
15. compound according to claim 14, which is characterized in that the compound is selected from：
N- [(3S, 6S, 18aS) -3- (methoxy) -1,4,14- trioxy-s-ten hexahydro -1H- pyrrolo-es [2,1-i] [1] oxygen Miscellaneous 16 carbon -6- formoxyls of [4,7,10] three azacyclo-]-Phe- epoxies ketone and its above-claimed cpd optical isomer or its Pharmaceutically acceptable salt or solvate.
16. a kind of preparation method of Macrocyclic peptides class compound, which is characterized in that realized by following steps：
(1) compound 5 and the amino acid of amido protecting react to obtain compound 6, the condensation reagent of selection under condensation reagent effect There are dicyclohexylcarbodiimide/4-dimethylaminopyridine, dicyclohexylcarbodiimide/1- hydroxy benzo triazoles, N- (3- diformazans Aminopropyl)-N '-ethyl-carbodiimide hydrochloride/1- hydroxy benzo triazoles, benzotriazole-N, N, N', N'- tetramethyl Urea hexafluorophosphoric acid ester/1- hydroxy benzo triazoles, 0-30 DEG C of reaction temperature, when reaction time 2-8 is small, crude product can be directly used for The next step；
(2) compound 6 removes Boc protecting groups under the action of trifluoroacetic acid, and crude product is directly used in the next step；
(3) compound 7 reacts to obtain compound 8 with compound 2 under condensation reagent effect, and the condensation reagent of selection has dicyclohexyl Carbodiimide/4-dimethylaminopyridine, dicyclohexylcarbodiimide/1- hydroxy benzo triazoles, N- (3- dimethylamino-propyls)- N '-ethyl-carbodiimide hydrochloride/1- hydroxy benzo triazoles, benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid Ester/1- hydroxy benzo triazoles, 0-30 DEG C of reaction temperature, when reaction time 2-8 is small, crude product can be directly used for the next step；
(4) compound 8 cyclization and removes carboxyl-protecting group and obtains compound 9 under the action of metallic catalyst or condensing agent, The metallic catalyst of selection is Grubbs second generation catalyst, and condensing agent is identical with step (1), metal catalysed reaction temperature 0- 100 DEG C, when reaction time 0.5-3 is small, 0-30 DEG C of setting-up point, when reaction time 3-8 is small, products obtained therefrom is anti-for lower step It should；
(5) compound 9 reacts to obtain product 10 with compound 11 under condensation reagent effect, selects the same step of condensation reagent (1), institute It obtains crude product and obtains sterling through column chromatography for separation；
Reaction equation：
Wherein：
R1-R4、B1、D1、D2The definition of substituent group is identical with the logical formula (I) of claim 1；
The definition of ring A substituent groups is identical with the general formula (II) of claim 2.
17. big ring epoxy ketone peptide derivative according to claim 1 is preparing antitumor and anti-immune disease medicament In application, which is characterized in that the big ring epoxy ketone peptide derivative includes its optical isomer class or and pharmaceutically may be used The salt of receiving or their solvate.
18. application according to claim 17, which is characterized in that the tumour is selected from myeloma, lymthoma, leukaemia Wait neoplastic hematologic disorders and breast cancer, sarcoma, lung cancer, prostate cancer, colon and rectum carcinoma, kidney, cancer of pancreas, neuroblast Knurl, glioma, head cancer, neck cancer, thyroid cancer, liver cancer, oophoroma, carcinoma of vulva, cervix cancer, carcinoma of endometrium, testis Cancer, carcinoma of urinary bladder, the cancer of the esophagus, stomach cancer, nasopharyngeal carcinoma, cheek cancer, carcinoma of mouth, gastrointestinal stromal tumor, cutaneum carcinoma.
CN201711492550.XA 2017-12-30 2017-12-30 Big ring epoxy ketone peptides and preparation method thereof and medical usage Pending CN108117582A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111943870A (en) * 2020-09-11 2020-11-17 上海吉奉生物科技有限公司 Synthesis method of L-2- (9H-fluorene-9-methoxycarbonylamino) -3-iodopropionic acid methyl ester
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds
US11578101B2 (en) * 2018-08-06 2023-02-14 University Of Kentucky Research Foundation Proteasome inhibitors

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds
US11578101B2 (en) * 2018-08-06 2023-02-14 University Of Kentucky Research Foundation Proteasome inhibitors
US11999803B2 (en) 2018-08-06 2024-06-04 University Of Kentucky Research Foundation Proteasome inhibitors
CN111943870A (en) * 2020-09-11 2020-11-17 上海吉奉生物科技有限公司 Synthesis method of L-2- (9H-fluorene-9-methoxycarbonylamino) -3-iodopropionic acid methyl ester

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Application publication date: 20180605