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【结 构 式】 
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【分子编号】23505 【品名】(3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid 【CA登记号】 |
【 分 子 式 】C22H43N3O5 【 分 子 量 】429.60064 【元素组成】C 61.51% H 10.09% N 9.78% O 18.62% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)The condensation of N-(benzyloxycarbonyl)-L-valine (XXIII) with intermediate heptanoate (VII) by means of NMM and Piv-Cl gives the dipeptide (XXIV), which is N-deprotected by means of H2 over Pd/C to yield the dipeptide (XXV). The condensation of (XXV) with N,N-dimethyl-L-valine (XXVI) (obtained by reductomethylation of L-valine (XXVII) with formaldehyde and H2 over Pd/C) by means of pentafluorophenyl trifluoroacetate and TFAA in pyridine affords the tripeptide (XXVIII), which is treated with TFA to cleave the tert-butyl group, yielding the tripeptide (XXIX). The condensation of (XXIX) with intermediate dipeptide (XXX) by means of DEPC provides the target pentapeptide dolastatin 10. The intermediate dipeptide (XXX) is obtained by condensation of intermediate (XV) with intermediate (XXII) by means of DEPC to give the dipeptide (XXXI), which is N-deprotected by treatment with TFA to afford the desired dipeptide (XXX).
| 【1】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463. |
| 【2】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63. |
| 【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 23514 | tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate | C14H29NO3 | 详情 | 详情 | |
| (XV) | 23520 | (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid | C14H25NO5 | 详情 | 详情 | |
| (XXII) | 54607 | (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine | C11H12N2S | 详情 | 详情 | |
| (XXIII) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (XXIV) | 23516 | tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate | C27H44N2O6 | 详情 | 详情 | |
| (XXV) | 23517 | tert-butyl (3R,4S,5S)-4-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate | C19H38N2O4 | 详情 | 详情 | |
| (XXVI) | 23518 | (2S)-2-(dimethylamino)-3-methylbutyric acid | C7H15NO2 | 详情 | 详情 | |
| (XXVII) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (XXVIII) | 23519 | tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate | C26H51N3O5 | 详情 | 详情 | |
| (XXIX) | 23505 | (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C22H43N3O5 | 详情 | 详情 | |
| (XXX) | 54609 | (2R,3R)-3-methoxy-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]-3-[(2S)pyrrolidinyl]propanamide | C20H27N3O2S | 详情 | 详情 | |
| (XXXI) | 54608 | tert-butyl (2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)-1-pyrrolidinecarboxylate | C25H35N3O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with benzyl propionate (II) by means of lithium diisopropylamide (LDA) in THF gives a mixture of isomers that is separated by flash chromatography, yielding the (2R,3R)-isomer (III). The methylation of (III) with diazomethane and boron trifluoride ethearate or NaH and methyl iodide affords the methoxy derivative (IV), which is deprotected with HCl in dioxane, giving (V). The condensation of (V) with tripeptide (VI) by means of diethyl phosphorocyanidate (DEPC) in DMF yields the tetrapeptide benzyl ester (VII), which is finally debenzylated by hydrogenolysis over Pd/C in tert-butanol and amidated with 2-phenylethylamine (VIII) and DEPC and triethylamine in DMF.
| 【1】 Tsukagoshi, S.; Sakakibara, K.; Gondo, M.; Natsume, T.; Mikami, T.; Kobayashi, M.; Miyazaki, K.; Synthesis and antitumor activity of novel dolastat. Chem Pharm Bull 1995, 43, 10, 1706. |
| 【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404. |
| 【3】 Sakakibara, K.; Gondo, M.; Miyazaki, K. (Teikoku Hormone Manufacturing Co., Ltd.); Novel tetrapeptide derivs.. EP 0598129; JP 1993503479; US 5654399; WO 9303054 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 16724 | tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal | 69610-41-9 | C10H17NO3 | 详情 | 详情 |
| (II) | 23501 | benzyl propionate | 122-63-4 | C10H12O2 | 详情 | 详情 |
| (III) | 23502 | tert-butyl (2S)-2-[(1R,2R)-3-(benzyloxy)-1-hydroxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate | C20H29NO5 | 详情 | 详情 | |
| (IV) | 23503 | tert-butyl (2S)-2-[(1R,2R)-3-(benzyloxy)-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate | C21H31NO5 | 详情 | 详情 | |
| (V) | 23504 | benzyl (2R,3R)-3-methoxy-2-methyl-3-[(2S)pyrrolidinyl]propanoate | C16H23NO3 | 详情 | 详情 | |
| (VI) | 23505 | (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C22H43N3O5 | 详情 | 详情 | |
| (VII) | 23506 | benzyl (2R,3R)-3-((2S)-1-[(3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoyl]pyrrolidinyl)-3-methoxy-2-methylpropanoate | C38H64N4O7 | 详情 | 详情 | |
| (VIII) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Intermediate (VI) has been obtained as follows: The condensation of benzyloxycarbonyl-L-isoleucine (IX) with malonic acid monomethyl ester potassium salt (X) by means of carbonyldiimidazole (CDI) and MgCl2 in THF gives the ketoester (XI), which is reduced to the hydroxyester (XII) with NaBH4 in methanol. The methylation of (XII) with methyl iodide and silver oxide in DMF affords the N-methyl methoxyester (XIII). The hydrolysis of (XIII) with NaOH in dioxane/water followed by reesterification with isobutylene gives the tert-butyl ester (XIV), which is deprotected by hydrogenation over Pd/C, yielding the amino acid (XV). The condensation of (XV) with benzyloxycarbonyl-L-valine (XVI) by means of DCC in dichloromethane gives the protected dipeptide (XVII), which is debenzylated as usual, yielding (XVIII). The condensation of (XVIII) with N,N-dimethyl-L-valine (XIX) affords the tripeptide ter-butyl ester (XX). Finally, (XX) is hydrolyzed by treatment with trifluoroacetic acid to the free acid intermediate (VI).
| 【1】 Tsukagoshi, S.; Sakakibara, K.; Gondo, M.; Natsume, T.; Mikami, T.; Kobayashi, M.; Miyazaki, K.; Synthesis and antitumor activity of novel dolastat. Chem Pharm Bull 1995, 43, 10, 1706. |
| 【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404. |
| 【3】 Sakakibara, K.; Gondo, M.; Miyazaki, K. (Teikoku Hormone Manufacturing Co., Ltd.); Novel tetrapeptide derivs.. EP 0598129; JP 1993503479; US 5654399; WO 9303054 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 | |
| (VI) | 23505 | (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C22H43N3O5 | 详情 | 详情 | |
| (IX) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (X) | 23509 | 3-methoxy-3-oxopropanoate | C4H5O4 | 详情 | 详情 | |
| (XI) | 23510 | methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate | C17H23NO5 | 详情 | 详情 | |
| (XII) | 23511 | methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylheptanoate | C17H25NO5 | 详情 | 详情 | |
| (XIII) | 23512 | methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate | C19H29NO5 | 详情 | 详情 | |
| (XIV) | 23513 | tert-butyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate | C22H35NO5 | 详情 | 详情 | |
| (XV) | 23514 | tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate | C14H29NO3 | 详情 | 详情 | |
| (XVI) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (XVII) | 23516 | tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate | C27H44N2O6 | 详情 | 详情 | |
| (XVIII) | 23517 | tert-butyl (3R,4S,5S)-4-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate | C19H38N2O4 | 详情 | 详情 | |
| (XIX) | 23518 | (2S)-2-(dimethylamino)-3-methylbutyric acid | C7H15NO2 | 详情 | 详情 | |
| (XX) | 23519 | tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate | C26H51N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)2) The reaction of 3(R)-[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]-3-methoxy-2(R)-methylpropionic acid (XXI) with 2-phenylethylamine (VIII) by means of DEPC in dichloromethane gives the amide (XXII), which is deprotected with trifluoroacetic acid to yield the amide (XXIII). Finally, this compound is condensed with the previously described intermediate (VI) by means of DEPC in dichloromethane.
| 【1】 Hamel, E.; Williams, M.D.; Srirangam, J.K.; Chapuis, J.-C.; Durkin, K.P.M.; Barkoczy, J.; Schmidt, J.M.; Bai, R.; Boyd, M.R.; Pettit, G.R.; Antineoplastic agents 337. Synthesis of dolastatin. Anti-Cancer Drug Des 1995, 10, 7, 529. |
| 【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404. |
| 【3】 Petit, G.R.; Barkoczy, J. (Arizona State University); The elucidation and synthesis of antineoplastic te. EP 0600745; JP 1995002894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 65169 | (2R,3R)-3-methoxy-2-methyl-N-phenethyl-3-[(2S)pyrrolidinyl]propanamide | C17H26N2O2 | 详情 | 详情 | ||
| (VI) | 23505 | (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C22H43N3O5 | 详情 | 详情 | |
| (VIII) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (XXI) | 23520 | (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid | C14H25NO5 | 详情 | 详情 | |
| (XXII) | 23521 | tert-butyl (2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-(phenethylamino)propyl]-1-pyrrolidinecarboxylate | C22H34N2O4 | 详情 | 详情 |