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【结 构 式】

【分子编号】23520

【品名】(2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid

【CA登记号】

【 分 子 式 】C14H25NO5

【 分 子 量 】287.35624

【元素组成】C 58.52% H 8.77% N 4.87% O 27.84%

与该中间体有关的原料药合成路线共 9 条

合成路线1

该中间体在本合成路线中的序号:(XV)

The reaction of N-Boc-L-proline (IX) with O-methylhydroxylamine (II) gives the corresponding amide (X), which is reduced with LiAlH4 to N-Boc-L-prolinal (XI). The condensation of (XI) with boronate (XII) yields the carbinol (XIII) as the greater isomer, and it is methylated with Me-I and NaH to afford the methyl ether (XIV). Finally, the terminal double bond of (XIV) is oxidated by means of RuO4 to furnish the desired intermediate, the amino acid (XV).

1 Roux, F.; et al.; Synthesis of dolastatin-10 and [R-Doe]-dolastatin-10. Tetrahedron 1994, 50, 18, 5345.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 46320 tert-butyl (2S)-2-[[methoxy(methyl)amino]carbonyl]-1-pyrrolidinecarboxylate C12H22N2O4 详情 详情
(IX) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(X) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(XI) 16724 tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal 69610-41-9 C10H17NO3 详情 详情
(XII) 54600 2-[(Z)-2-butenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane C10H19BO2 详情 详情
(XIII) 54601 tert-butyl (2S)-2-[(1R,2S)-1-hydroxy-2-methyl-3-butenyl]-1-pyrrolidinecarboxylate C14H25NO3 详情 详情
(XIV) 54602 tert-butyl (2S)-2-[(1R,2S)-1-methoxy-2-methyl-3-butenyl]-1-pyrrolidinecarboxylate C15H27NO3 详情 详情
(XV) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XV)

The condensation of intermediate (XXI) with intermediate (XV) by means of BOP and DIEA gives the dipeptide (XXIV) partially racemized, which is easily purified by chromatography. The deprotection of (XXIV) by means of TFA yields dipeptide (XXV), which is condensed with intermediate (VIII) by means of BOP and DIEA to afford tripeptide (XXVI). The deprotection of (XXVI) by means of TFA yields tripeptide (XXVII), which is condensed with N-(benzyloxycarbonyl)-L-valine (XXVIII) by means of BrOP and DIEA to afford tetrapeptide (XXIX). The deprotection of (XXIX) by means of HBr provides tetrapeptide (XXX), which is finally condensed with N,N-dimethyl-L-valine (XXXI) by means of COMMOD to afford the target dolastatine.

1 Roux, F.; et al.; Synthesis of dolastatin-10 and [R-Doe]-dolastatin-10. Tetrahedron 1994, 50, 18, 5345.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 54599 (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid C15H29NO5 详情 详情
(XV) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情
(XXI) 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
(XXIV) 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
(XXV) 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
(XXVI) 54610 tert-butyl (1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl(methyl)carbamate C35H54N4O6S 详情 详情
(XXVII) 54611 (2R,3R)-3-methoxy-3-{(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoyl]pyrrolidinyl}-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]propanamide C30H46N4O4S 详情 详情
(XXVIII) 49332 (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid C13H17NO4 详情 详情
(XXIX) 54612 benzyl (1S)-1-{[{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}(methyl)amino]carbonyl}-2-methylpropylcarbamate C43H61N5O7S 详情 详情
(XXX) 54613 (2S)-2-amino-N-{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N,3-dimethylbutanamide C35H55N5O5S 详情 详情
(XXXI) 23518 (2S)-2-(dimethylamino)-3-methylbutyric acid C7H15NO2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(V)

The enantioselective condensation of N-Boc-L-prolinal (I) with the chiral 3-propionyloxazolidinone (II) by means of Bu2B-OTf in dichloromethane gives the chiral beta-hydroxyamide (III), which is submitted to elimination of the chiral auxiliary by hydrolysis with LiOH and H2O2 in THF/water to yield the hydroxyacid (IV). The methylation of (IV) with Me-I and NaH in THF affords the methoxyacid (V). The condensation of intermediate (V) with 2-phenyl-1(S)-(2-thiazolyl)ethylamine (VI) by means of (EtO)2P(O)CN and DIEA gives the dipeptide (VII). The deprotection of (VII) by means of TFA yields dipeptide (VIII), which is condensed with the beta-methoxy-gamma-aminoacid (IX) as before to afford tripeptide (X). The deprotection of (X) by means of TFA yields tripeptide (XI), which is condensed with N-Boc-L-valine (XII) by means of BopCl and DIEA to afford tetrapeptide (XIII). The deprotection of (XIII) by means of TFA provides tetrapeptide (XIV), which is finally condensed with N,N-dimethyl-L-valine (XV) by means of (EtO)2P(O)CN and TEA to afford the target dolastatine.

1 Hayashi, K.; et al.; An efficient total synthesis of dolastatin 10, an antineoplastic pentapeptide of marine origin. Pept Chem 1990, Pub. 1991, 43.
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) 46163 (4R,5S)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one C13H15NO3 详情 详情
(III) 54614 tert-butyl (2S)-2-{(1R,2R)-1-hydroxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}-1-pyrrolidinecarboxylate C23H32N2O6 详情 详情
(IV) 54615 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-hydroxy-2-methylpropanoic acid C13H23NO5 详情 详情
(V) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情
(VI) 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
(VII) 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
(VIII) 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
(IX) 54599 (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid C15H29NO5 详情 详情
(X) 54610 tert-butyl (1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl(methyl)carbamate C35H54N4O6S 详情 详情
(XI) 54611 (2R,3R)-3-methoxy-3-{(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoyl]pyrrolidinyl}-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]propanamide C30H46N4O4S 详情 详情
(XII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XIII) 54616 tert-butyl (1S)-1-{[{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}(methyl)amino]carbonyl}-2-methylpropylcarbamate C40H63N5O7S 详情 详情
(XIV) 23518 (2S)-2-(dimethylamino)-3-methylbutyric acid C7H15NO2 详情 详情
(XV) 54613 (2S)-2-amino-N-{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N,3-dimethylbutanamide C35H55N5O5S 详情 详情

合成路线4

该中间体在本合成路线中的序号:(XII)

The reaction of N-Boc-L-prolinal (VII) with the boron enolate (VIII) in ethyl ether gives the chiral beta-hydroxythioester (IX), which is transesterified with K2CO3 and ethanol to afford the beta-hydroxypropionate (X). The methylation of the OH group of (X) with LiHMDS and Me-OTf as before provides the methoxyester (XI), which is finally hydrolyzed with LiOH in aq. ethanol to furnish the desired intermediate, the methoxy amino acid (XII).

1 Tomioka, K.; et al.; An expeditious synthesis of dolastatin 10. Tetrahedron 1991, 32, 21, 2395.
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) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(VIII) 54620 9-{[(E)-1-(phenylsulfanyl)-1-propenyl]oxy}-9-borabicyclo[3.3.1]nonane; (E)-1-(9-borabicyclo[3.3.1]non-9-yloxy)-1-propenyl phenyl sulfide C17H23BOS 详情 详情
(IX) 54621 tert-butyl (2S)-2-[(1R,2R)-1-hydroxy-2-methyl-3-oxo-3-(phenylsulfanyl)propyl]-1-pyrrolidinecarboxylate C19H27NO4S 详情 详情
(X) 54622 tert-butyl (2S)-2-[(1R,2R)-3-ethoxy-1-hydroxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate C15H27NO5 详情 详情
(XI) 54623 tert-butyl (2S)-2-[(1R,2R)-3-ethoxy-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate C16H29NO5 详情 详情
(XII) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线5

该中间体在本合成路线中的序号:(XII)

The condensation of intermediate (XIX) with intermediate (XII) by means of DEC and TEA gives the dipeptide (XX). The deprotection of (XX) by means of HCl yields dipeptide (XXI), which is condensed with intermediate (VI) by means of DEC and TEA to afford tripeptide (XXII). The deprotection of (XXII) by means of HBr yields tripeptide (XXIII), which is condensed with N-Boc-L-valine (XXIV) by means of BOPCl and TEA to afford tetrapeptide (XXV). The deprotection of (XXV) by means of HCl provides tetrapeptide (XXVI), which is finally condensed with N,N-dimethyl-L-valine (XXVII) by means of DEC and TEA to afford the target dolastatine.

1 Tomioka, K.; et al.; An expeditious synthesis of dolastatin 10. Tetrahedron 1991, 32, 21, 2395.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 54599 (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid C15H29NO5 详情 详情
(XII) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情
(XIX) 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
(XX) 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
(XXI) 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
(XXII) 54610 tert-butyl (1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl(methyl)carbamate C35H54N4O6S 详情 详情
(XXIII) 54611 (2R,3R)-3-methoxy-3-{(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoyl]pyrrolidinyl}-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]propanamide C30H46N4O4S 详情 详情
(XXIV) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XXV) 54616 tert-butyl (1S)-1-{[{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}(methyl)amino]carbonyl}-2-methylpropylcarbamate C40H63N5O7S 详情 详情
(XXVI) 54613 (2S)-2-amino-N-{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N,3-dimethylbutanamide C35H55N5O5S 详情 详情
(XXVII) 23518 (2S)-2-(dimethylamino)-3-methylbutyric acid C7H15NO2 详情 详情

合成路线6

该中间体在本合成路线中的序号:(XV)

The reaction of L-prolinol (VIII) with Boc2O gives N-Boc-L-prolinol (IX), which is oxidized with SO3/pyridine in DMSO to afford N-Boc-L-prolinal (X). The condensation of (X) with the propionate ester (XI), by means of LDA in THF, affords the 3-hydroxy-3-(2-pyrrolidinyl)propionate ester (XII), which is methylated with diazomethane and BF3 in dichloromethane to provide the corresponding methoxy derivative (XIII). The epimerization of the (S)-methyl group of group of (XIII) by means of t-Bu-OK in THF gives the corresponding (R)-methyl derivative (XIV), which is finally hydrogenolyzed with H2 over Pd/C in ethyl acetate/methanol to yield the desired pyrrolidinylpropionic acid intermediate (XV).

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
(VIII) 21347 (2S)pyrrolidinylmethanol 23356-96-9 C5H11NO 详情 详情
(IX) 49819 (S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinenemethanol C10H19NO3 详情 详情
(X) 16724 tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal 69610-41-9 C10H17NO3 详情 详情
(XI) 54631 (1S)-2-hydroxy-1,2,2-triphenylethyl propionate C23H22O3 详情 详情
(XII) 54632 tert-butyl (2S)-2-((1R,2S)-1-hydroxy-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate C33H39NO6 详情 详情
(XIII) 54633 tert-butyl (2S)-2-((1R,2S)-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate C34H41NO6 详情 详情
(XIV) 54634 tert-butyl (2S)-2-((1R,2R)-3-{[(1S)-2-hydroxy-1,2,2-triphenylethyl]oxy}-1-methoxy-2-methyl-3-oxopropyl)-1-pyrrolidinecarboxylate C34H41NO6 详情 详情
(XV) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线7

该中间体在本合成路线中的序号:(XV)

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8

该中间体在本合成路线中的序号:(V)

The enantioselective condensation of N-Boc-L-prolinal (I) with the chiral 2-bromopropionyloxazolidinone (II) by means of Co(PPh3)4 in THF gives the chiral beta-hydroxyamide (III), which is methylated by means of trimethyloxonium tetrafluoroborate in dichloromethane to yield the methyl ether (IV). Finally, elimination of the chiral auxiliary of (IV) by means of LiOH and H2O2 affords the target amino acid intermediate (V) (see scheme no. 14950701a , intermediate (XV)).

1 Pettit, G.R.; Grealish, M.P.; A cobalt-phosphine complex directed reformatsky approach to a stereospecific synthesis of the dolastatin 10 unit dolaproine (Dap). J Org Chem 2001, 66, 25, 8640.
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) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(II) 54635 (4R,5S)-3-(2-bromopropanoyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one C13H14BrNO3 详情 详情
(III) 54614 tert-butyl (2S)-2-{(1R,2R)-1-hydroxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}-1-pyrrolidinecarboxylate C23H32N2O6 详情 详情
(IV) 54636 tert-butyl (2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}-1-pyrrolidinecarboxylate C24H34N2O6 详情 详情
(V) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线9

该中间体在本合成路线中的序号:(XXI)

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
Extended Information