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【结 构 式】

【分子编号】23514

【品名】tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate

【CA登记号】

【 分 子 式 】C14H29NO3

【 分 子 量 】259.3892

【元素组成】C 64.83% H 11.27% N 5.4% O 18.5%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(VII)

The methylation of N-(benzyloxycarbonyl)-L-isoleucine (I) with Me-I and NaH in THF gives the N-methyl derivative (II), which is reduced with BH3 in THF to yield the isoleucinol (III). The oxidation of (III) with SO3/pyridine in DMSO affords the isoleucinal (IV), which is condensed with tert-butyl acetate (V) by means of BuLi and THF to afford the chiral beta-hydroxyheptanoate (VI). Finally, this compound is O-methylated by means of diazomethane and BF3 in ethyl ether/dichloromethane and N-deprotected by hydrogenation with H2 over Pd/C in ethyl acetate/methanol to provide the desired intermediate, the chiral tert-butyl heptanoate (VII).

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
(I) 23508 (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid 3160-59-6 C14H19NO4 详情 详情
(II) 54627 (2S,3S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-methylpentanoic acid C15H21NO4 详情 详情
(III) 54628 benzyl (1S,2S)-1-(hydroxymethyl)-2-methylbutyl(methyl)carbamate C15H23NO3 详情 详情
(IV) 54629 benzyl (1S,2S)-1-formyl-2-methylbutyl(methyl)carbamate C15H21NO3 详情 详情
(V) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(VI) 54630 tert-butyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-hydroxy-5-methylheptanoate C21H33NO5 详情 详情
(VII) 23514 tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate C14H29NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

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3

该中间体在本合成路线中的序号:(XV)

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
Extended Information