CN108191957A - Tripeptides macrocyclic derivatives and its preparation method and application - Google Patents

Tripeptides macrocyclic derivatives and its preparation method and application Download PDF

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Publication number
CN108191957A
CN108191957A CN201711489219.2A CN201711489219A CN108191957A CN 108191957 A CN108191957 A CN 108191957A CN 201711489219 A CN201711489219 A CN 201711489219A CN 108191957 A CN108191957 A CN 108191957A
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alkyl
compound
halogenated
cancer
dioxa
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CN108191957B (en
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刘滔
李佳
胡永洲
周宇波
李大强
高立信
董晓武
许磊
洪对对
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
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • 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)
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  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention provides a kind of tripeptides macrocyclic derivatives and its optical isomer or its pharmaceutically acceptable salt or solvate.By using the compound of carboxy protective as starting material; with acid condensation, again through alkene cyclization double decomposition and decarboxylize; simultaneously with boc-protected amino acid and epoxy ketone fragment condensation, slough amino protecting group again, obtain target product with the intermediate condensation of above-mentioned decarboxylize.It is demonstrated experimentally that the present invention's there is completely new skeleton to have preferable proteasome inhibition activity, there is good inhibiting effect of rising in value to Huppert's diseases such as RPMI 8226, MM.1S.Raw material needed for the synthesis of the compounds of this invention is easy to get, and highway route design is reasonable, and reaction condition is mild, easy to operate, is suitble to industrialized production.It is with formula (I) structure.

Description

Tripeptides macrocyclic derivatives and its preparation method and application
Technical field
The present invention relates to drug fields, are related to tripeptides macrocyclic derivatives and its preparation method and application, are related to as albumen The tripeptides macrocyclic derivatives of enzyme body inhibitor, the salt containing it and the drug that is prepared using the compound or its salt class as active constituent Application in antitumor.
Background technology
It is in addition various unhealthy including smoking with the aging trend being continuously increased with population of the size of population Life style be widely present and the pollution of environment, the positive serious threat of malignant tumour the life of the mankind, in China's malignant tumour The first big fatal disease is become, prevention has become the important subject of China or even countries in the world the world of medicine.Traditional Cancer treatment method mainly has operative treatment, radiotherapy and chemotherapy etc., wherein mostly important with chemotherapy.In recent years Come, as tumor cells target is gradually illustrated, many anti-tumor drugs targetings oneself enter clinical practice.Although these targeting medicines Object clinically has been achieved for good progress, but patient still has a degree of toxic side effect in medication, easily produces The problems such as raw drug resistance, make its clinical treatment by larger limitation.
Important component of the proteasome as Ubiquitin-proteasome protein degradation access, is distributed widely in eukaryon Multi-subunit giant protein matter compound in cell has a variety of catalysis, controls intracellular 80%-90% protein Degradation maintains Cell Homeostasis, and then regulating cell week by false folding in degradation of cell or the protein being damaged The different physiological roles such as phase, Apoptosis, cell signalling, DNA reparations, cell growth, development.Thus, proteasome work( The inhibition of energy can lead to the imbalance with a plurality of signal path GAP-associated protein GAP level, wither so as to cause cell-cycle arrest and cell It dies.These crucial regulatory proteins include nuclear factor NF- κ B, Tumor suppressor p53 and cell cycle related proteins cyclin and CDK Deng.Therefore, the occurrence and development of proteasome and tumour are closely related, and proteasome inhibitor can be lived by protease inhibition body Property cause Apoptosis and achieve the purpose that treat tumour.
It is found so far from proteasome, the micromolecular compound of various structures type is found to have the work of protease inhibition body Property, good antitumous effect is especially shown in blood tumor.At present, the small molecule proteasome clinically applied inhibits Agent is boric acid peptides Bortezomib, Ixazomib and epoxy ketone peptides Carfilzomib.
Invention content
The object of the present invention is to provide a kind of tripeptides macrocyclic derivatives, with 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 isOr 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：
Or its pharmaceutically acceptable salt or solvated compounds, wherein：
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 Alkylamino radical, halogenated C1-6Alkoxy, halogenated C1-6Alkylamino radical, C3-8Cycloalkyl, 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, C1-6Alcoxyl Base, C1-6Alkoxyalkyl, halogenated C1-6Alkoxy, C3-8Cycloalkyl, Heterocyclylalkyl, C3-8Cycloalkenyl group, heterocycloalkenyl, aryl, 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 V4Respectively 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；
R2Preferably benzyl, isobutyl group；
RgIt preferably is selected from H, halogen, C1-6Alkyl, C1-6Alkoxy, C3-8Cycloalkyl.
Wherein, if not being specifically noted, involved amino acid is L-type amino acid.
More specifically, the preferred compound of general formula (I V) structure of the present invention is：
N- [16 carbon -1 (16) of (S) -11- oxo -2,7- dioxa -10- azabicyclos [10,4,0], 12,14- triolefins - 9- formoxyls]-(O- methyl)-Ser-Phe- epoxy ketone
N- [17 carbon -1 (17) of (S) -12- oxo -2,8- dioxa -11- azabicyclos [11,4,0], 13,15- triolefins - 10- formoxyls]-(O- methyl)-Ser-Phe- epoxy ketone
N- [18 carbon -1 (18) of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0], 14,16- triolefins - 11- formoxyls]-(O- methyl)-Ser-Phe- epoxy ketone
N- [19 carbon -1 (19) of (S) -14- oxo -2,10- dioxa -13- azabicyclics [13,4,0], 15,17- tri- Alkene -12- formoxyls]-(O- methyl)-Ser-Leu- epoxy ketone
N- [(S) -15- oxos -2,11- dioxa -14- azabicyclos [14,4,0] eicosane -1 (20), 16,18- tri- Alkene -13- formoxyls]-(O- methyl)-Ser-Phe- epoxy ketone
N- [(S) -16- oxos -2,12- dioxa -15- azabicyclics [15,4,0] heneicosane -1 (21), 17,19- tri- Alkene -14- formyls
Base]-(O- methyl)-Ser-Phe- epoxy ketone
N- [18 carbon -1 (18) of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0], 14,16- triolefins - 11- formoxyls]-(O- methyl)-Ser-Leu- epoxy ketone
And its optical isomer of above compound or its pharmaceutically acceptable salt or solvate.
Second object of the present invention is to provide the preparation method of above-mentioned Macrocyclic peptides analog derivative, passes through following steps reality It is existing：
(1) compound 2 reacts to obtain compound 6, the condensation of selection with the amino acid of carboxy protective 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.0-30 DEG C of reaction temperature, reaction time 2-5 hours, crude product can be directly used for the next step；
(2) compound 6 cyclization and removes carboxyl-protecting group and obtains chemical combination under the action of metallic catalyst or condensing agent Object 7, 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, in reaction time 0.5-3 hour, 0-30 DEG C of setting-up point, in reaction time 2-8 hour, products obtained therefrom is used for down Step；
(3) amino acid of amido protecting reacts to obtain compound 8, the condensation of selection with compound 11 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, reaction time 2-8 hour, crude product can be direct For the next step；
(4) compound 8 removes Boc protecting groups under the action of trifluoroacetic acid, and crude product is directly used in the next step；
(5) compound 7 reacts to obtain product 10 with compound 9 under condensation reagent effect, selects the same step of condensation reagent (1), gained crude product obtains sterling through column chromatography for separation.
Reaction equation：
Wherein：
R1-R4、B1、D1、D2The definition of substituent group is identical with logical 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.
Third object of the present invention is to provide the Macrocyclic peptides analog derivative in the drug for preparing treatment malignant tumour 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, gastric cancer, nasopharyngeal carcinoma, cheek cancer, mouth Chamber cancer, gastrointestinal stromal tumor, cutaneum carcinoma.
The drug is made of Macrocyclic peptides analog derivative with pharmaceutical carrier.
The pharmaceutical dosage form of the present invention includes injection, freeze drying powder injection, tablet, capsule and granule etc..Administration route is selected For drug administration by injection, oral medication, sucking or drug delivery implant etc..
It is demonstrated experimentally that the present invention with completely new skeleton with preferable proteasome inhibition activity, to RPMI 8226th, the Huppert's diseases such as MM.1S have increment inhibiting effect well.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, easy to operate, is suitble to industrialized production.
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, It 46mmol) is placed in 100mL three-necked bottles, adds in 50mL acetone, which reacts 18 hours under reflux conditions.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 7,2- (allyloxy) benzoic acid (2a)
Raw material 2- (allyloxy) methyl benzoate (6.0g, 31mmol) is dissolved in 20mL methanol and 20ml THF, dropwise 3N KOH aqueous solution 50mL are added in, 50 DEG C is heated to and reacts 3 hours.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 8,2- (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 7, gained Product is directly used in the next step.
Prepare embodiment 9,2- (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 7, gained Product is directly used in the next step.
Prepare embodiment 10,2- (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 7, gained Product is directly used in the next step.
Prepare embodiment 11,2- (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 7, gained Product is directly used in the next step.
Prepare embodiment 12,2- (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 7, gained Product is directly used in the next step.
Prepare embodiment 13, 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 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 14, 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, is heated to reflux 5 hours.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) it washs, removes 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 15, 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) reacts at room temperature 2 hours.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 16, N- (2- (allyloxy) benzoyl)-O- pi-allyls-Serine benzyl ester (6a)
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- pi-allyls-Ser- OBn hydrochlorides (5a, 0.33g, 1.2mmol) and DIPEA (0.50ml, 3.0mmol) are reacted at room temperature 3 hours.Reaction solution adds in 5mL saturated sodium bicarbonate aqueous solutions dilute, and separate organic layer, and saturated common salt washing (5mL x 2) subtracts after anhydrous sodium sulfate drying Pressure removes solvent, and column chromatography for separation obtains colourless oil liquid 0.28g, yield 71%.1H NMR(500MHz,CDCl3)δ8.87(d, J=8.0Hz, 1H), 8.21 (dd, J=8.0,2.0Hz, 1H), 7.46-7.41 (m, 1H), 7.39-7.29 (m, 5H), 7.10- 7.05 (m, 1H), 6.97 (d, J=8.0Hz, 1H), 6.16-6.06 (m, 1H), 5.86-5.73 (m, 1H), 5.46-5.40 (m, 1H), 5.32-5.18 (m, 4H), 5.16-5.11 (m, 1H), 5.05 (dt, J=8.0,3.5Hz, 1H), 4.68 (d, J=5.5Hz, 2H), 4.03-3.90 (m, 3H), 3.79 (dd, J=9.5,3.0Hz, 1H) ppm；ESI-MS:M/z=396 [M+H]+.
Prepare embodiment 17, N- (2- (butyl- 3- alkene -1- bases oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester (6b)
Using 2- (3- butene-1s-base oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 16 is prepared Shape liquid 0.34g, yield 83%.1H NMR(500MHz,CDCl3) δ 8.89 (d, J=7.5Hz, 1H), 8.22 (dd, J=7.5, 2.0Hz, 1H), 7.48-7.40 (m, 1H), 7.39-7.29 (m, 5H), 7.11-7.03 (m, 1H), 6.97 (d, J=8.0Hz, 1H), 5.99-5.85 (m, 1H), 5.84-5.72 (m, 1H), 5.33-5.01 (m, 7H), 4.16 (t, J=7.0Hz, 2H), 4.02- 3.90 (m, 3H), 3.79 (dd, J=9.5,3.0Hz, 1H), 2.70-2.60 (m, 2H) ppm；ESI-MS:M/z=410 [M+H]+.
Prepare embodiment 18, N- (2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester (6c)
Using 2- (4- amylene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 16 is prepared Shape liquid 0.33g, yield 78%.1H NMR(500MHz,CDCl3) δ 8.95 (d, J=8.0Hz, 1H), 8.22 (dd, J=8.0, 2.0Hz, 1H), 7.46-7.40 (m, 1H), 7.38-7.29 (m, 5H), 7.10-7.03 (m, 1H), 6.97 (d, J=8.0Hz, 1H),5.88–5.72(m,2H),5.33–5.26(m,1H),5.23–5.16(m,2H),5.15–5.10(m,1H),5.09–5.03 (m, 2H), 5.02-4.98 (m, 1H), 4.15-4.09 (m, 2H), 4.02-3.88 (m, 3H), 3.79 (dd, J=9.5,3.0Hz, 1H),2.30–2.22(m,2H),2.03–1.95(m,2H)ppm；ESI-MS:M/z=424 [M+H]+.
Prepare embodiment 19, N- (2- (hex- 5- alkene -1- bases oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester (6d)
Using 2- (5- hexene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 16 is prepared Shape liquid 0.39g, yield 89%.1H NMR(500MHz,CDCl3) δ 8.97 (d, J=8.0Hz, 1H), 8.22 (dd, J=8.0, 2.0Hz, 1H), 7.44 (ddd, J=8.0,7.5,2.0Hz, 1H), 7.39-7.29 (m, 5H), 7.09-7.02 (m, 1H), 6.97 (d, J=8.0Hz, 1H), 5.86-5.71 (m, 2H), 5.33-5.28 (m, 1H), 5.23-5.16 (m, 2H), 5.15-5.10 (m, 1H), 5.07 (dt, J=8.0,3.0Hz, 1H), 5.05-4.99 (m, 1H), 4.98-4.94 (m, 1H), 4.12 (t, J=6.5Hz, 2H), 4.01-3.96 (m, 2H), 3.95-3.89 (m, 1H), 3.78 (dd, J=9.5,3.5Hz, 1H), 2.14-2.08 (m, 2H), 1.96–1.88(m,2H),1.63–1.56(m,2H)ppm；ESI-MS:M/z=438 [M+H]+.
Prepare embodiment 20, N- (2- (6- heptene -1- bases oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester (6e)
Using 2- (6- heptene -1- bases oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 16 is prepared Shape liquid 0.40g, yield 89%.1H NMR(500MHz,CDCl3) δ 8.98 (d, J=8.0Hz, 1H), 8.22 (dd, J=8.0, 2.0Hz, 1H), 7.44 (ddd, J=8.0,7.5,2.0Hz, 1H), 7.38-7.28 (m, 5H), 7.09-7.02 (m, 1H), 7.00- 6.92(m,1H),5.87–5.71(m,2H),5.31–5.29(m,1H),5.23–5.17(m,2H),5.15–5.11(m,1H), 5.07 (dt, J=8.0,3.0Hz, 1H), 5.03-4.98 (m, 1H), 4.97-4.93 (m, 1H), 4.14-4.08 (m, 2H), 4.01-3.96 (m, 2H), 3.95-3.90 (m, 1H), 3.78 (dd, J=9.5,3.0Hz, 1H), 2.10-2.05 (m, 2H), 1.96–1.86(m,2H),1.54–1.41(m,4H)ppm；ESI-MS:M/z=452 [M+H]+.
Prepare embodiment 21, N- (2- (7- octene-1s-base oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester (6f)
Using 2- (7- octene-1s-base oxygroup) benzoic acid as raw material, synthesis and post processing obtain colorless oil with embodiment 16 is prepared Shape liquid 0.42g, yield 90%.1H NMR(500MHz,CDCl3) δ 8.98 (d, J=7.5Hz, 1H), 8.22 (dd, J=8.0, 2.0Hz, 1H), 7.44 (ddd, J=8.5,7.5,2.0Hz, 1H), 7.39-7.29 (m, 5H), 7.09-7.02 (m, 1H), 6.97 (d, J=8.0Hz, 1H), 5.87-5.71 (m, 2H), 5.31-5.30 (m, 1H), 5.23-5.17 (m, 2H), 5.15-5.10 (m, 1H), 5.07 (dt, J=8.0,3.0Hz, 1H), 5.03-4.97 (m, 1H), 4.96-4.91 (m, 1H), 4.11 (t, J=6.5Hz, 2H), 4.02-3.96 (m, 2H), 3.95-3.89 (m, 1H), 3.78 (dd, J=9.5,3.0Hz, 1H), 2.08-2.02 (m, 2H), 1.96–1.85(m,2H),1.53–1.45(m,2H),1.44–1.32(m,4H)ppm；ESI-MS:M/z=466 [M+H]+.
Embodiment 22,16 carbon -1 (16) of (S) -11- oxo -2,7- dioxa -10- azabicyclos [10,4,0] are prepared, 12,14- triolefin -9- carboxylic acids (7a)
Raw material N- (2- (allyloxy) benzoyl)-O- pi-allyls-Serine benzyl ester (5a, 0.079g, It 0.20mmol) is placed in two neck bottles of 250ml, the dissolving of 60mL toluene is added in, in N2100 DEG C are heated under protection.Then will Grubbs second generation catalyst is dissolved in 7ml toluene and is slowly injected into reaction system, reacts 1 hour at such a temperature.Decompression removes Solvent is removed, column chromatography for separation obtains grey oily liquids 52mg (containing atropisomer), and yield 71%, products obtained therefrom is directly used in down Step reaction.
Above-mentioned raw materials are dissolved in 3ml methanol, add in 10%Pd/C (6mg), H23h is reacted under protection in room temperature, uses silicon Diatomaceous earth filtering removal catalyst, removes solvent under reduced pressure and obtains canescence foaming solid 37mg, yield 94%.ESI-MS:M/z= 280[M+H]+.
Prepare embodiment 23, N- [17 carbon -1 of (S) -12- oxo -2,8- dioxa -11- azabicyclos [11,4,0] (17), 13,15- triolefins -10- carboxylic acids (7b)
Using N- (2- (butyl- 3- alkene -1- bases oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester as raw material, synthesis and Post processing obtains white foam solid 42mg, two step yields 72% with embodiment 22 is prepared.1H NMR(500MHz,DMSO)δ 8.89 (d, J=7.5Hz, 1H), 7.98 (dd, J=8.0,2.0Hz, 1H), 7.51 (ddd, J=8.0,7.0,2.0Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 7.09-7.02 (m, 1H), 4.52-4.41 (m, 1H), 4.18-4.08 (m, 2H), 4.05 (dd, J =9.5,2.5Hz, 1H), 3.70-3.64 (m, 1H), 3.59 (dd, J=9.5,3.8Hz, 1H), 3.44 (td, J=9.7, 3.4Hz,1H),1.89–1.74(m,3H),1.73–1.64(m,1H),1.63–1.55(m,1H),1.54–1.45(m,1H)ppm； ESI-MS:M/z=294 [M+H]+.
Prepare embodiment 24, N- [18 carbon -1 of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0] (18), 14,16- triolefins -11- carboxylic acids (7c)
Using N- (2- (amyl- 4- alkene -1- bases oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester as raw material, synthesis and Post processing obtains white foam solid 49mg, two step yields 80% with embodiment 22 is prepared.1H NMR(500MHz,DMSO)δ 8.84 (d, J=8.5Hz, 1H), 8.01 (dd, J=7.5,2.0Hz, 1H), 7.51 (ddd, J=8.5,7.5,2.0Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 7.11-7.02 (m, 1H), 4.61-4.54 (m, 1H), 4.28-4.19 (m, 1H), 4.13 (td, J =9.0,1.5Hz, 1H), 3.89 (dd, J=9.5,2.0Hz, 1H), 3.70-3.59 (m, 2H), 3.37-3.28 (m, 1H), 1.96–1.84(m,1H),1.82–1.73(m,1H),1.73–1.64(m,1H),1.64–1.45(m,5H)ppm；ESI-MS:m/z =308 [M+H]+.
Prepare embodiment 25, N- [19 carbon -1 of (S) -14- oxo -2,10- dioxa -13- azabicyclics [13,4,0] (19), 15,17- triolefins -12- carboxylic acids (7d)
Using N- (2- (hex- 5- alkene -1- bases oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester as raw material, synthesis and Post processing obtains white foam solid 53mg, two step yields 82% with embodiment 22 is prepared.1H NMR(500MHz,CDCl3)δ 8.97 (d, J=7.5Hz, 1H), 8.22 (d, J=7.5Hz, 1H), 7.48-7.39 (m, 1H), 7.08-7.01 (m, 1H), 6.95 (d, J=8.0Hz, 1H), 5.05-4.96 (m, 1H), 4.27-4.18 (m, 1H), 4.11 (t, J=8.5Hz, 1H), 4.00 (dd, J =9.5,2.5Hz, 1H), 3.82-3.73 (m, 1H), 3.64-3.55 (m, 1H), 3.53-3.45 (m, 1H), 1.98-1.75 (m, 3H),1.69–1.31(m,7H)ppm；ESI-MS:M/z=322 [M+H]+.
Prepare embodiment 26, N- [(S) -15- oxos -2,11- dioxa -14- azabicyclos [14,4,0] eicosanes -1 (20), 16,18- triolefins -13- carboxylic acids (7e)
Using N- (2- (6- heptene -1- bases oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester as raw material, synthesis and Post processing obtains white foam solid 51mg, two step yields 76% with embodiment 22 is prepared.1H NMR(500MHz,CDCl3)δ 8.96 (d, J=8.0Hz, 1H), 8.24 (d, J=6.5Hz, 1H), 7.48-7.40 (m, 1H), 7.10-7.02 (m, 1H), 6.99 (d, J=8.5Hz, 1H), 5.11-5.03 (m, 1H), 4.27-4.07 (m, 2H), 3.96 (dd, J=9.5,2.5Hz, 1H), 3.90–3.83(m,1H),3.58–3.49(m,1H),3.48–3.41(m,1H),2.05–1.89(m,1H),1.85–1.66(m, 2H),1.62–1.21(m,9H)ppm；ESI-MS:M/z=336 [M+H]+.
Prepare embodiment 27, N- [(S) -16- oxos -2,12- dioxa -15- azabicyclics [15,4,0] heneicosanes -1 (21), 17,19- triolefins -14- carboxylic acids (7f)
Using N- (2- (7- octene-1s-base oxygroup) benzoyl)-O- pi-allyls-Serine benzyl ester as raw material, synthesis and Post processing obtains white foam solid 52mg, two step yields 74% with embodiment 22 is prepared.1H NMR(500MHz,CDCl3)δ 9.08 (d, J=7.5Hz, 1H), 8.25 (dd, J=8.0,1.5Hz, 1H), 7.50-7.41 (m, 1H), 7.12-7.03 (m, 1H), 6.98 (d, J=8.5Hz, 1H), 5.14-5.05 (m, 1H), 4.28-4.10 (m, 2H), 3.96 (dd, J=9.5,2.5Hz, 1H), 3.90 (dd, J=9.5,2.0Hz, 1H), 3.58-3.51 (m, 1H), 3.47-3.40 (m, 1H), 2.11-1.99 (m, 1H), 1.87–1.76(m,1H),1.75–1.66(m,1H),1.62–1.30(m,11H)ppm；ESI-MS:M/z=350 [M+H]+.
Prepare embodiment 28, N- (Boc-O- methyl-seryl-)-L-Leu- epoxies ketone (8a)
Raw material Boc-O- methyl-serine (0.44g, 2.0mmol) is dissolved in the anhydrous THF of 8ml, adds in three nitrogen of 1- hydroxy benzos Azoles (0.32g, 2.4mmol), benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (0.91g, 2.4mmol) and Leu- epoxy ketone trifluoroacetates (0.68g, 2.4mmol) are cooled to 0 DEG C under ice bath.Then, add in DIPEA (0.66mL, 4.0mmol), it reacts at room temperature 3 hours.Solvent is removed under reduced pressure, adds in 15mL ethyl acetate and 12ml water, separates organic layer, successively It is washed with saturated sodium bicarbonate solution (12mL x 2) and saturated salt solution (12mL x 2), anhydrous sodium sulfate drying, decompression removes Solvent is removed, column chromatography for separation obtains colourless oil liquid 0.50g, yield 67%.1H NMR(500MHz,CDCl3) δ 6.90 (d, J= 3.5Hz, 1H), 5.34 (d, J=3.0Hz, 1H), 4.66-4.58 (m, 1H), 4.27-4.15 (m, 1H), 3.76 (dd, J=9.0, 3.5Hz, 1H), 3.46-3.36 (m, 4H), 3.28 (d, J=5.0Hz, 1H), 2.88 (d, J=5.0Hz, 1H), 1.71-1.59 (m,1H),1.58–1.49(m,4H),1.45(s,9H),1.32–1.23(m,1H),0.98–0.89(m,6H)ppm；ESI-MS: M/z=373 [M+H]+.
Prepare embodiment 29, N- (Boc-O- methyl-seryl-)-L-Phe- epoxies ketone (8b)
Using Phe- epoxy ketone trifluoroacetates as raw material, synthesis and post processing obtain colorless oil liquid with embodiment 28 is prepared Body 0.49mg, two step yields 60%.1H NMR(500MHz,CDCl3)δ7.32–7.27(m,2H),7.26–7.22(m,1H), 7.16-7.11 (m, 2H), 7.02 (d, J=6.0Hz, 1H), 5.27 (d, J=3.0Hz, 1H), 4.83 (td, J=7.5,5.0Hz, 1H), 4.21-4.09 (m, 1H), 3.72 (d, J=6.5Hz, 1H), 3.38 (dd, J=9.0,7.0Hz, 1H), 3.35-3.25 (m, 4H), 3.13 (dd, J=14.0,5.0Hz, 1H), 2.90 (d, J=4.9Hz, 1H), 2.86 (dd, J=14.0,7.3Hz, 1H), 1.50(s,3H),1.43(s,9H)ppm；ESI-MS:M/z=407 [M+H]+.
Prepare embodiment 30, O- methyl-seryl--L-Leu- epoxy ketone trifluoroacetates (9a)
Reactant B oc-Leu- epoxies ketone (0.50g, 1.3mmol) is dissolved in 2.6mL CH2Cl2, ice bath is cooled to 0 DEG C, adds in 1.3mL trifluoroacetic acids react 5 hours at this temperature.Reaction solution is removed under reduced pressure solvent and obtains pale yellow oily liquid, and products obtained therefrom is straight It connects for the next step
Prepare embodiment 31, O- methyl-seryl--L-Phe- epoxy ketone trifluoroacetates (9b)
Using 8b as raw material, with preparating example 30, products obtained therefrom is directly used in the next step for synthesis and post processing.
Prepare embodiment 32, N- [16 carbon -1 of (S) -11- oxo -2,7- dioxa -10- azabicyclos [10,4,0] (16), 12,14- triolefins -9- formoxyls]-(O- methyl)-Ser-Phe- epoxies ketone (10a)
16 carbon -1 (16) of raw material (S) -11- oxo -2,7- dioxa -10- azabicyclos [10,4,0], 12,14- tri- Alkene -9- carboxylic acids (7a, 28mg, 0.10mmol) are dissolved in the anhydrous THF of 2mL, add in 1- hydroxy benzo triazoles (18mg, 0.13mmol), benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (49mg, 0.13mmol) and Phe- epoxy ketone Trifluoroacetate (55mg, 0.13mmol) is cooled to 0 DEG C under ice bath.Then, DIPEA (0.043mL, 0.26mmol), room are added in Temperature reaction 3 hours.Solvent is removed under reduced pressure, adds in 5mL ethyl acetate and 4ml water, separates organic layer, use saturated sodium bicarbonate successively Solvent, column chromatography for separation is removed under reduced pressure in solution (3mL x 2) and saturated salt solution (3mL x 2) washing, anhydrous sodium sulfate drying Obtain white solid 33mg, yield 58%.1H NMR(500MHz,CDCl3) δ 8.86 (d, J=6.5Hz, 1H), 8.76 (d, J= 6.5Hz, 1H), 8.21 (dd, J=8.0,1.5Hz, 1H), 8.13 (dd, J=8.0,1.5Hz, 1H), 7.50-7.43 (m, 1H), 7.41-7.36 (m, 1H), 7.33-7.23 (m, 2H), 7.22-6.98 (m, 14H), 6.95 (d, J=7.0Hz, 1H), 6.89 (d, J =8.5Hz, 1H), 4.87-4.68 (m, 4H), 4.51-4.39 (m, 2H), 4.25-4.16 (m, 2H), 4.02-3.94 (m, 2H), 3.79 (dd, J=10.2,3.5Hz, 1H), 3.74-3.68 (m, 2H), 3.65 (dd, J=9.5,3.5Hz, 1H), 3.62-3.53 (m,2H),3.50–3.40(m,2H),3.39–3.21(m,6H),3.19–3.05(m,8H),2.87–2.82(m,2H),2.80 (s,2H),2.18–2.08(m,2H),2.00–1.91(m,2H),1.86–1.70(m,2H),1.67–1.55(m,2H),1.49– 1.42(m,6H)ppm；ESI-MS:M/z=568 [M+H]+.
Prepare embodiment 33, N- [17 carbon -1 of (S) -12- oxo -2,8- dioxa -11- azabicyclos [11,4,0] (17), 13,15- triolefins -10- formoxyls]-(O- methyl)-Ser-Phe- epoxies ketone (10b)
With N- [17 carbon -1 (17) of (S) -12- oxo -2,8- dioxa -11- azabicyclos [11,4,0], 13,15- tri- Alkene -10- carboxylic acids are raw material, synthesis and the same preparation embodiment 32 of post processing, obtain white solid 36mg, yield 62%.1H NMR (500MHz,CDCl3) δ 9.26 (d, J=5.0Hz, 1H), 8.20 (dd, J=8.0,2.0Hz, 1H), 7.47 (ddd, J=8.0, 7.5,2.0Hz, 1H), 7.35 (d, J=8.0Hz, 1H), 7.22-7.11 (m, 5H), 7.08-7.01 (m, 2H), 6.95 (d, J= 8.2Hz,1H),4.85–4.76(m,1H),4.68–4.63(m,1H),4.50–4.43(m,1H),4.18–4.11(m,3H), 3.77-3.68 (m, 2H), 3.64 (dd, J=9.0,4.0Hz, 1H), 3.51 (td, J=9.5,4.0Hz, 1H), 3.37 (dd, J= 9.5,5.5Hz, 1H), 3.33 (d, J=5.0Hz, 1H), 3.14 (s, 3H), 3.11 (dd, J=14.0,5.0Hz, 1H), 2.88 (dd, J=13.5,8.5Hz, 1H), 2.84 (d, J=5.0Hz, 1H), 1.94-1.85 (m, 3H), 1.81-1.75 (m, 1H), 1.74–1.68(m,1H),1.67–1.60(m,1H),1.44(s,3H)ppm；ESI-MS:M/z=582 [M+H]+.
Prepare embodiment 34, N- [18 carbon -1 of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0] (18), 14,16- triolefins -11- formoxyls]-(O- methyl)-Ser-Phe- epoxies ketone (10c)
With N- [18 carbon -1 (18) of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0], 14,16- tri- Alkene -11- carboxylic acids are raw material, synthesis and the same preparation embodiment 32 of post processing, obtain white solid 39mg, yield 65%.11H NMR (500MHz,CDCl3) δ 9.00 (d, J=6.5Hz, 1H), 8.20 (dd, J=8.0,2.0Hz, 1H), 7.48 (ddd, J=8.5, 7.5,2.0Hz, 1H), 7.22 (d, J=7.5Hz, 1H), 7.15-7.03 (m, 6H), 7.02-6.97 (m, 2H), 4.77 (td, J= 8.0,5.0Hz, 1H), 4.73-4.68 (m, 1H), 4.49-4.43 (m, 1H), 4.23-4.14 (m, 2H), 3.99 (dd, J=9.5, 2.5Hz, 1H), 3.74-3.68 (m, 3H), 3.44-3.39 (m, 1H), 3.37 (dd, J=9.5,5.5Hz, 1H), 3.32 (d, J= 5.0Hz, 1H), 3.13 (s, 3H), 3.08 (dd, J=13.5,5.0Hz, 1H), 2.85-2.78 (m, 2H), 1.91-1.82 (m, 1H),1.80–1.69(m,2H),1.68–1.58(m,5H),1.45(s,3H)ppm；ESI-MS:M/z=596 [M+H]+.
Prepare embodiment 35, N- [19 carbon -1 of (S) -14- oxo -2,10- dioxa -13- azabicyclics [13,4,0] (19), 15,17- triolefins -12- formoxyls]-(O- methyl)-Ser-Leu- epoxies ketone (10d)
With N- [19 carbon -1 (19) of (S) -14- oxo -2,10- dioxa -13- azabicyclics [13,4,0], 15,17- tri- Alkene -12- carboxylic acids are raw material, synthesis and the same preparation embodiment 32 of post processing, obtain white solid 36mg, yield 59%.1H NMR (500MHz,CDCl3) δ 8.56 (d, J=7.0Hz, 1H), 8.13 (d, J=8.0Hz, 1H), 7.48-7.43 (m, 1H), 7.25- 7.17(m,2H),7.16–6.95(m,7H),4.80–4.72(m,2H),4.50–4.45(m,1H),4.21–4.12(m,2H), 3.99 (dd, J=10.0,2.5Hz, 1H), 3.75-3.67 (m, 2H), 3.56-3.51 (m, 1H), 3.50-3.44 (m, 1H), 3.36 (dd, J=9.5,5.5Hz, 1H), 3.31 (d, J=5.5Hz, 1H), 3.12 (s, 3H), 3.06 (dd, J=14.0, 5.0Hz, 1H), 2.83 (d, J=4.5Hz, 1H), 2.81-2.77 (m, 1H), 1.76-1.68 (m, 1H), 1.65-1.45 (m, 9H),1.43(s,3H)ppm；ESI-MS:M/z=610 [M+H]+.
Prepare embodiment 36, N- [(S) -15- oxos -2,11- dioxa -14- azabicyclos [14,4,0] eicosanes -1 (20), 16,18- triolefins -13- formoxyls]-(O- methyl)-Ser-Phe- epoxies ketone (10e)
With N- [(S) -15- oxos -2,11- dioxa -14- azabicyclos [14,4,0] eicosane -1 (20), 16,18- tri- Alkene -13- carboxylic acids are raw material, synthesis and the same preparation embodiment 32 of post processing, obtain white solid 35mg, yield 56%.1H NMR (500MHz,CDCl3) δ 8.51 (d, J=6.5Hz, 1H), 8.13 (dd, J=8.0,1.5Hz, 1H), 7.49-7.43 (m, 1H), 7.25–7.20(m,1H),7.18–7.10(m,3H),7.10–6.97(m,5H),4.82–4.72(m,2H),4.51–4.44(m, 1H), 4.25-4.14 (m, 2H), 3.97 (dd, J=9.5,3.0Hz, 1H), 3.78-3.68 (m, 2H), 3.51-3.45 (m, 2H), 3.36 (dd, J=9.5,5.5Hz, 1H), 3.33-3.29 (m, 1H), 3.14 (s, 3H), 3.08 (dd, J=13.5,5.0Hz, 1H),2.86–2.81(m,2H),2.79(s,1H),1.91–1.77(m,2H),1.61–1.35(m,13H)ppm；ESI-MS:m/z =624 [M+H]+.
Prepare embodiment 37, N- [(S) -16- oxos -2,12- dioxa -15- azabicyclics [15,4,0] heneicosanes -1 (21), 17,19- triolefins -14- formoxyls]-(O- methyl)-Ser-Phe- epoxies ketone (10f)
With N- [(S) -16- oxos -2,12- dioxa -15- azabicyclics [15,4,0] heneicosane -1 (21), 17,19- Triolefin -14- carboxylic acids are raw material, synthesis and the same preparation embodiment 32 of post processing, obtain white solid 35mg, yield 55%.1H NMR (500MHz,CDCl3) δ 8.55 (d, J=7.0Hz, 1H), 8.11 (dd, J=8.0,2.0Hz, 1H), 7.48-7.39 (m, 1H), 7.26–7.19(m,2H),7.18–6.95(m,7H),4.83–4.71(m,2H),4.51–4.44(m,1H),4.21–4.10(m, 2H), 3.94 (dd, J=9.5,3.5Hz, 1H), 3.54-3.41 (m, 2H), 3.35 (dd, J=9.5,6.0Hz, 1H), 3.32- 3.22 (m, 2H), 3.16 (s, 3H), 3.07 (dd, J=14.0,5.0Hz, 1H), 2.85-2.76 (m, 3H), 1.97-1.88 (m, 1H),1.86–1.78(m,1H),1.59–1.29(m,15H)ppm；ESI-MS:M/z=638 [M+H]+.
Prepare embodiment 38, N- [18 carbon -1 of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0] (18), 14,16- triolefins -11- formoxyls]-(O- methyl)-Ser-Leu- epoxies ketone (10g)
With N- [18 carbon -1 (18) of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0], 14,16- tri- Alkene -11- carboxylic acids are raw material, synthesis and the same preparation embodiment 32 of post processing, obtain white solid 33mg, yield 59%.1H NMR (500MHz,CDCl3) δ 9.01 (d, J=6.0Hz, 1H), 8.16 (dd, J=8.0,2.0Hz, 1H), 7.50-7.43 (m, 1H), 7.08-7.03 (m, 2H), 7.01 (d, J=8.0Hz, 1H), 6.97 (d, J=8.0Hz, 1H), 4.69-4.64 (m, 1H), 4.56- 4.46 (m, 2H), 4.21-4.09 (m, 2H), 3.98 (dd, J=9.5,2.5Hz, 1H), 3.86 (dd, J=9.5,3.0Hz, 1H), 3.74-3.67 (m, 2H), 3.46-3.37 (m, 2H), 3.31 (d, J=5.0Hz, 1H), 3.28 (s, 3H), 2.83 (d, J= 5.0Hz,1H),2.07–2.00(m,1H),1.91–1.82(m,1H),1.80–1.70(m,2H),1.69–1.65(m,1H), 1.64–1.59(m,3H),1.54–1.45(m,4H),1.43–1.37(m,1H),1.31–1.21(m,1H),0.83–0.79(m, 6H)ppm；ESI-MS:M/z=562 [M+H]+.
The proteasome inhibition activity test of test example 1, tripeptides macrocyclic compound
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-like Tyr-AMC sequences in protease hydrolysis substrates, release AMC, can under conditions of exciting light 355nm transmitting light 460nm With detect hydrolysis after product AMC fluorescent absorption value, 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 to multiple myeloma cells
Note：NA- is without activity；NT- is not tested
The multiple myeloma cells proliferation inhibition activity test of test example 2, tripeptides macrocyclic compound
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%CO2Culture 72 hours in 37 DEG C of incubators add in the 5mg/ml MTT of 20ml.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.
As can be seen from the table, until strong inhibitory activity during majority of compounds has proteasome, there are 4 The proteasome inhibition activity of compound is below 1 μM.We are it is also seen that majority of compounds is thin to Huppert's disease Born of the same parents wait until strong in-vitro multiplication inhibitory activity in showing.Therefore, it is according to the present invention to can be used as proteasome inhibitor Big ring epoxy ketones derivant have wide antitumor application thereof prospect.

Claims (9)

1. a kind of tripeptides macrocyclic derivatives, which is characterized in that 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 C1-10Alkane 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, Halogenated C1-10Alkyl；
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 as-C1-8Alkyl-,-OC1-8Alkyl-,-C1-8Alkyl O- ,-C1-8Alkyl OC1-8 Alkyl-,-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 optionally from halogen, nitro, amino, cyano, hydroxyl, C1-6Alkyl, halogenated C1-6Alkyl, C1-6 Alkoxy, C1-6Alkoxyalkyl, C1-6Alkylamino radical, halogenated C1-6Alkoxy, halogenated C1-6Alkoxyalkyl, halogenated C1-6 Alkylamino radical, 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 its pharmaceutically acceptable salt or solvate, wherein：
Y is selected from
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, C1-6Alkanamine Base, halogenated C1-6Alkoxy, halogenated C1-6Alkylamino radical, C3-8Cycloalkyl, 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 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 its 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 V4Respectively independently it is selected as C, N；
B1It is selected 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；
R1It is selected as methoxymethyl；
R2It is selected as benzyl, isobutyl group；
RgSelected from H, halogen, C1-6Alkyl, C1-6Alkoxy, C3-8Cycloalkyl；
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：
N- [16 carbon -1 (16) of (S) -11- oxo -2,7- dioxa -10- azabicyclos [10,4,0], 12,14- triolefin -9- first Acyl group]-(O- methyl)-Ser-Phe- epoxy ketone,
N- [17 carbon -1 (17) of (S) -12- oxo -2,8- dioxa -11- azabicyclos [11,4,0], 13,15- triolefins -10- Formoxyl]-(O- methyl)-Ser-Phe- epoxy ketone,
N- [18 carbon -1 (18) of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0], 14,16- triolefins -11- Formoxyl]-(O- methyl)-Ser-Phe- epoxy ketone,
N- [19 carbon -1 (19) of (S) -14- oxo -2,10- dioxa -13- azabicyclics [13,4,0], 15,17- triolefins -12- Formoxyl]-(O- methyl)-Ser-Leu- epoxy ketone,
N- [(S) -15- oxos -2,11- dioxa -14- azabicyclos [14,4,0] eicosane -1 (20), 16,18- triolefins -13- Formoxyl]-(O- methyl)-Ser-Phe- epoxy ketone,
N- [(S) -16- oxos -2,12- dioxa -15- azabicyclics [15,4,0] heneicosane -1 (21), 17,19- triolefins - 14- formoxyls]-(O- methyl)-Ser-Phe- epoxy ketone,
N- [18 carbon -1 (18) of (S) -13- oxo -2,9- dioxa -12- azabicyclics [12,4,0], 14,16- triolefins -11- Formoxyl]-(O- methyl)-Ser-Leu- epoxy ketone,
And its optical isomer of above compound or its pharmaceutically acceptable salt or solvate.
6. a kind of preparation method of tripeptides macrocyclic compound, is realized by following steps：
(1) compound 2 reacts to obtain compound 6, the condensation reagent of selection with the amino acid of carboxy protective 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, 0-30 DEG C of reaction temperature, the reaction time, 2-5 was small When, crude product can be directly used for the next step；
(2) compound 6 cyclization and removes carboxyl-protecting group and obtains compound 7 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 (1), metal catalysed reaction temperature 0-100 DEG C, in reaction time 0.5-3 hour, 0-30 DEG C of setting-up point, in reaction time 2-8 hour, products obtained therefrom is used for lower step；
(3) amino acid of amido protecting reacts to obtain compound 8, the condensation reagent of selection with compound 11 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, in reaction time 2-8 hour, crude product can be directly used for The next step；
(4) compound 8 removes Boc protecting groups under the action of trifluoroacetic acid, and crude product is directly used in the next step；
(5) compound 7 reacts to obtain product 10 with compound 9 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、D2It is identical that the definition of substituent group with claim 1 leads to formula (I)；
The definition of ring A substituent groups is identical with claim 2 general formula (II).
7. compound application in preparation of anti-tumor drugs described in claim 1.
8. application according to claim 7, which is characterized in that the drug is by Macrocyclic peptides analog derivative and its optical siomerism Body or its pharmaceutically acceptable salt or solvate are made with pharmaceutical carrier.
9. application according to claim 7, which is characterized in that the tumour is selected from myeloma, lymthoma, leukaemia etc. Neoplastic hematologic disorder 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, gastric cancer, nasopharyngeal carcinoma, cheek cancer, carcinoma of mouth, gastrointestinal stromal tumor, cutaneum carcinoma.
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