(2S)-N-(tert-butyl)-2-pyrrolidinecarboxamide -Drug Synthesis Database

【结构式】

【分子编号】19119

【品名】(2S)-N-(tert-butyl)-2-pyrrolidinecarboxamide

【CA登记号】

【分子式】C₉H₁₈N₂O

【分子量】170.2548

【元素组成】C 63.49% H 10.66% N 16.45% O 9.4%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(X)

The condensation of N-(benzyloxycarbonyl)-N-methyl-L-valine (I) with L-proline methyl ester (II) by means of pivaloyl chloride and triethylamine gives the dipeptide (III), which is deprotected with H2 over Pd/C in methanol yielding N-methyl-L-valyl-L-proline methyl ester (IV). The condensation of (IV) with N-(benzyloxycarbonyl)-L-valine N-carboxyanhydride (V) by means of DIEA in DMG affords the tripeptide (VI), which is deprotected by hydrogenation over Pd/C in methanol giving L-valyl-L-(N-methyl)valyl-L-proline methyl ester (VII). A new condensation of (VII) with (V) yields the tetrapeptide (VIII), which is hydrolyzed with LiOH in methanol affording N-(benzyloxycarbonyl)-L-valyl-L-valyl-L-(N-methyl)valyl-L-proline (IX), which is condensed with L-proline tert-butylamide (X) by means of NMM and EDC in dichloromethane giving the pentapeptide (XI), which is deprotected with H2 over Pd/C in methanol and reductomethylated with formaldehyde and H2 over Pd/C in the same solvent.

参考文献中间体

合成目标

【1】 Amberg, W.; Barlozzari, T.; Bernard, H.; Buschmann, E.; Haupt, A.; Hege, H.-G.; Janssen, B.; Kling, A.; Lietz, H.; Ritter, K.; Ullrich, M.; Weymann, J.; Zierke, T. (BASF AG); Antineoplastic peptides. JP 2000502092; WO 9722621 .
【2】 Barlozzari, T.; Haupt, A. (BASF AG); Dolastatin-15 derivs. in combination with taxanes. WO 9840092 .

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)	29551	(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-methylbutyric acid	42417-65-2	C₁₄H₁₉NO₄	详情	详情
(II)	29552	methyl (2S)-2-pyrrolidinecarboxylate	2133-40-6	C₆H₁₁NO₂	详情	详情
(III)	29553	methyl (2S)-1-[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylate		C₂₀H₂₈N₂O₅	详情	详情
(IV)	29554	methyl (2S)-1-[(2S)-3-methyl-2-(methylamino)butanoyl]-2-pyrrolidinecarboxylate		C₁₂H₂₂N₂O₃	详情	详情
(V)	29555	benzyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate	158257-41-1	C₁₄H₁₅NO₅	详情	详情
(VI)	29556	methyl (2S)-1-[(2S)-2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylate		C₂₅H₃₇N₃O₆	详情	详情
(VII)	29557	methyl (2S)-1-[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylate		C₁₇H₃₁N₃O₄	详情	详情
(VIII)	29558	methyl (2S)-1-[(2S,5S,8S)-2,5,8-triisopropyl-3-methyl-4,7,10-trioxo-12-phenyl-11-oxa-3,6,9-triazadodec-1-anoyl]-2-pyrrolidinecarboxylate		C₃₀H₄₆N₄O₇	详情	详情
(IX)	29559	(2S)-1-[(2S,5S,8S)-2,5,8-triisopropyl-3-methyl-4,7,10-trioxo-12-phenyl-11-oxa-3,6,9-triazadodec-1-anoyl]-2-pyrrolidinecarboxylic acid		C₂₉H₄₄N₄O₇	详情	详情
(X)	19119	(2S)-N-(tert-butyl)-2-pyrrolidinecarboxamide		C₉H₁₈N₂O	详情	详情
(XI)	29560	benzyl (1S)-1-[[((1S)-1-[[((1S)-1-[[(2S)-2-([(2S)-2-[(tert-butylamino)carbonyl]pyrrolidinyl]carbonyl)pyrrolidinyl]carbonyl]-2-methylpropyl)(methyl)amino]carbonyl]-2-methylpropyl)amino]carbonyl]-2-methylpropylcarbamate		C₃₈H₆₀N₆O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

Nitrophenoxyacetate (III) (prepared from 2-nitrophenol (I) and tert-butyl bromoacetate), was reduced with H2 in the presence of Pd/C to give aniline (IV). This was condensed with Z-D-Phe (V) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to yield amide (VI), which was deprotected to amine (VII) by hydrogenolysis in the presence of Pd/C. Subsequent coupling with Z-Pro (VIII), followed by hydrogenolytic deprotection produced (IX). This was coupled with methyl oxalyl chloride (X) to afford (XI). Then, treatment with trifluoroacetic acid in CH2Cl2 gave acid (XII). Finally, dipeptide (XV) (obtained by coupling of protected 3-amino-2-hydroxy-4-phenylbutyric acid (XIII) with tert-butyl prolinamide (XIV)), was condensed with acid (XII) to produce the title compound.

参考文献中间体

合成目标

【1】 Asagarasu, A.; et al.; Synthesis of dipeptide-type human immunodeficiency virus (HIV) protease inhibitors with a binding unit to GP120. Chem Pharm Bull 1998, 46, 5, 867.

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)	19106	2-nitrophenol	88-75-5	C₆H₅NO₃	详情	详情
(II)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(III)	19108	tert-butyl 2-(2-nitrophenoxy)acetate		C₁₂H₁₅NO₅	详情	详情
(IV)	19109	tert-butyl 2-(2-aminophenoxy)acetate		C₁₂H₁₇NO₃	详情	详情
(V)	19110	(2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid		C₁₇H₁₇NO₄	详情	详情
(VI)	19111	tert-butyl 2-[2-[((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)amino]phenoxy]acetate		C₂₉H₃₂N₂O₆	详情	详情
(VII)	19112	tert-butyl 2-(2-[[(2R)-2-amino-3-phenylpropanoyl]amino]phenoxy)acetate		C₂₁H₂₆N₂O₄	详情	详情
(VIII)	19113	(2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid	1148-11-4	C₁₃H₁₅NO₄	详情	详情
(IX)	19114	tert-butyl 2-[2-[((2R)-3-phenyl-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoyl)amino]phenoxy]acetate		C₂₆H₃₃N₃O₅	详情	详情
(X)	19115	[(chlorocarbonyl)oxy](methoxy)methane		C₃H₅ClO₃	详情	详情
(XI)	19116	methyl 2-((2S)-2-[[((1R)-1-benzyl-2-[2-[2-(tert-butoxy)-2-oxoethoxy]anilino]-2-oxoethyl)amino]carbonyl]pyrrolidinyl)-2-oxoacetate		C₂₉H₃₅N₃O₈	详情	详情
(XII)	19117	2-(2-[[(2R)-2-([[(2S)-1-(2-methoxy-2-oxoacetyl)pyrrolidinyl]carbonyl]amino)-3-phenylpropanoyl]amino]phenoxy)acetic acid		C₂₅H₂₇N₃O₈	详情	详情
(XIII)	19118	(2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid		C₁₈H₁₉NO₅	详情	详情
(XIV)	19119	(2S)-N-(tert-butyl)-2-pyrrolidinecarboxamide		C₉H₁₈N₂O	详情	详情
(XV)	19120	(2S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-2-pyrrolidinecarboxamide		C₁₉H₂₉N₃O₃	详情	详情

Extended Information