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【结 构 式】

【分子编号】16724

【品名】tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal

【CA登记号】69610-41-9

【 分 子 式 】C10H17NO3

【 分 子 量 】199.24992

【元素组成】C 60.28% H 8.6% N 7.03% O 24.09%

与该中间体有关的原料药合成路线共 6 条

合成路线1

该中间体在本合成路线中的序号:(XI)

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:(I)

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3

该中间体在本合成路线中的序号:(X)

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4

该中间体在本合成路线中的序号:(I)

1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with trimethylsulfonium iodide (II) and potassium tert-butoxide gives the epoxide (III), which is treated with benzyl alcohol and NaH to perform epoxide ring opening and simultaneous cyclization to yield the oxazolidinone (IV). The hydrolysis of (IV) with KOH affords compound (V), which is condensed with N-(benzylaminocarbonyl)-L-proline (VI) (prepared in situ with benzyl isocyanate (VII) and L-proline (VIII) in the presence of triethylamine) by means of diphenyl phosphoryl azide (DPPA) giving the dipeptide analogue (IX). The oxidation of (IX) with P2O5 in DMSO yields the benzylated JTP-4819 product (X), which is finally deprotected by hydrogenolysis with H2 over Pd/C.

1 Wroblewski, T.; Silvestre, J.S.; Castañer, J.; JTP-4819. Drugs Fut 1998, 23, 4, 384.
2 Fujiwara, T.; Iwamoto, Y.; Uchida, I.; Shinoda, M.; Abe, H.; Toide, K.; A novel prolyl endopeptidase inhibitor, JTP-4819, for the treatment of Alzheimer's disease: Review of preclinical pharmacology. CNS Drug Rev 1996, 2, 3, 343-62.
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) 16725 trimethylsulfonium iodide 2181-42-2 C3H9IS 详情 详情
(III) 16726 tert-butyl (2S)-2-[(2R)oxiranyl]tetrahydro-1H-pyrrole-1-carboxylate C11H19NO3 详情 详情
(IV) 16727 (1R,7aS)-1-[(benzyloxy)methyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one C14H17NO3 详情 详情
(V) 16728 (1R)-2-(benzyloxy)-1-[(2S)tetrahydro-1H-pyrrol-2-yl]-1-ethanol C13H19NO2 详情 详情
(VI) 16729 (2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid C13H16N2O3 详情 详情
(VII) 16730 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate 3173-56-6 C8H7NO 详情 详情
(VIII) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(IX) 16732 (2S)-N-benzyl-2-([(2S)-2-[(1R)-2-(benzyloxy)-1-hydroxyethyl]tetrahydro-1H-pyrrol-1-yl]carbonyl)tetrahydro-1H-pyrrole-1-carboxamide C26H33N3O4 详情 详情
(X) 16733 (2S)-N-benzyl-2-([(2S)-2-[2-(benzyloxy)acetyl]tetrahydro-1H-pyrrol-1-yl]carbonyl)tetrahydro-1H-pyrrole-1-carboxamide C26H31N3O4 详情 详情

合成路线5

该中间体在本合成路线中的序号:(I)

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6

该中间体在本合成路线中的序号:(XII)

Fischer esterification of L-proline (IX) with MeOH and HCl gave (X). Treatment of (X) with di-tert-butyl dicarbonate provided N-Boc-proline methyl ester (XI). The ester function of (XI) was then reduced to aldehyde (XII) by employing DIBAL in toluene at -78 C. Wittig condensation between aldehyde (XII) and phosphonium bromide (VIII) in the presence of DBU yielded the (indolylvinyl)pyrrolidine (XIII), which was further hydrogenated to (XIV) in the presence of Pd/C. The N-Boc group of (XIV) was then cleaved by treatment with trifluoroacetic acid to furnish (XV).

1 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 .
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) 50434 [(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide C30H26BrN2P 详情 详情
(IX) 16731 L-proline 147-85-3 C5H9NO2 详情 详情
(X) 29552 methyl (2S)-2-pyrrolidinecarboxylate 2133-40-6 C6H11NO2 详情 详情
(XI) 50435 1-(tert-butyl) 2-methyl (2S)-1,2-pyrrolidinedicarboxylate C11H19NO4 详情 详情
(XII) 16724 tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal 69610-41-9 C10H17NO3 详情 详情
(XIII) 50436 tert-butyl (2S)-2-[(E)-2-(6-cyano-1-ethyl-1H-indol-2-yl)ethenyl]-1-pyrrolidinecarboxylate C22H27N3O2 详情 详情
(XIV) 50437 tert-butyl (2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]-1-pyrrolidinecarboxylate C22H29N3O2 详情 详情
(XV) 50438 1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile C17H21N3 详情 详情
Extended Information