methyl (2R)-2-pyrrolidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】36811

【品名】methyl (2R)-2-pyrrolidinecarboxylate

【CA登记号】

【分子式】C₆H₁₁NO₂

【分子量】129.15888

【元素组成】C 55.8% H 8.58% N 10.84% O 24.77%

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：(III)

The reaction of 2-nitrobenzoic acid with SOCl2 gives the acyl chloride (II), which is condensed with D-proline (III) by means of TEA in dichloromethane yielding the acyl proline (IV). The reductive cyclization of (IV) with H2 over Pd/C in methanol affords the pyrrolobenzodiazepinedione (V). The reduction of both lactam groups of (V) with LiAlH4 gave the pyrrolobenzodiazepine (VI), which is finally coupled with 4-[(2-phenylbenzoyl)amino]-benzoyl chloride (VII) furnishing the title compound.

参考文献中间体

合成目标

【1】 Naito, A.; Ohtake, Y.; Hasegawa, H.; et al.; Novel vasopressin V2 receptor-selective antagonists, pyrrolo[2,1-a]quinoxaline and pyrrolo[2,1-c][1,4]benzodiazepine derivatives. Bioorg Med Chem 1999, 7, 6, 1247.
【2】 Matsukawa, H.; Toyofuku, H.; Naito, A.; Ohtake, Y.; Saito, Y.; Naito, K. (Wakamoto Pharmaceutical Co., Ltd.); Biphenyl derivs. and medicinal compsns.. EP 0987266; WO 9843976 .

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)	20951	2-nitrobenzoic acid；o-Nitrobenzoic acid	552-16-9	C₇H₅NO₄	详情	详情
(II)	21099	o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride	610-14-0	C₇H₄ClNO₃	详情	详情
(III)	36811	methyl (2R)-2-pyrrolidinecarboxylate		C₆H₁₁NO₂	详情	详情
(IV)	36807	methyl (2R)-1-(2-nitrobenzoyl)-2-pyrrolidinecarboxylate		C₁₃H₁₄N₂O₅	详情	详情
(V)	36808	(11aR)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione		C₁₂H₁₂N₂O₂	详情	详情
(VI)	36809	(11aR)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine		C₁₂H₁₆N₂	详情	详情
(VII)	36810	4-[([1,1'-biphenyl]-2-ylcarbonyl)amino]benzoyl chloride		C₂₀H₁₄ClNO₂	详情	详情
(VIII)	29797	2H-3,1-benzoxazine-2,4(1H)-dione；Isatoic anhydride;4H-3,1-Benzoxazine-2,4(1H)-dione；1,2-Dihydro-4H-3,1-benzoxazine-2,4-dione;1H-benzo[d][1,3]oxazine-2,4-dione	118-48-9	C₈H₅NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Esterification of N-benzyloxycarbonyl-D-proline (I) with MeOH in the presence of EDC, followed by deprotection of the resultant N-Cbz amino ester (II) with H2 and Pd(OH)2 leads to D-proline methyl ester (III). Subsequent coupling of (III) with N-benzyloxycarbonyl-O-t-butyl-L-4-trans-hydroxyproline (IV) yields the protected dipeptide (V). After removal of the N-benzyloxycarbonyl group of (V) by catalytic hydrogenolysis, the free amine (VI) is acylated by 3,3,3-triphenylpropionic acid (VII), producing amide (VIII). The methyl ester group of (VIII) is then hydrolyzed under alkaline conditions to furnish acid (IX).

参考文献中间体

合成目标

【1】 Sagara, Y.; Kimura, T.; Fujikawa, T.; Noguchi, K.; Ohtake, N.; Identification of novel muscarinic M3 selective antagonists with a conformationally restricted Hyp-Pro spacer. Bioorg Med Chem Lett 2003, 13, 1, 57.
【2】 Kimura, T.; Noguchi, K.; Otake, N.; Uchiyama, M.; Naya, A.; Sagara, Y.; Numazawa, T.; Fujikawa, T. (Banyu Pharmaceutical Co., Ltd.); Novel amide derivs.. EP 1213281; WO 0107406 .

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)	17005	(2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₃H₁₅NO₄	详情	详情
(II)	62798	1-benzyl 2-methyl (2R)-1,2-pyrrolidinedicarboxylate		C₁₄H₁₇NO₄	详情	详情
(III)	36811	methyl (2R)-2-pyrrolidinecarboxylate		C₆H₁₁NO₂	详情	详情
(IV)	62799	(2S,4R)-1-[(benzyloxy)carbonyl]-4-(tert-butoxy)-2-pyrrolidinecarboxylic acid		C₁₇H₂₃NO₅	详情	详情
(V)	62800	benzyl (2S,4R)-4-(tert-butoxy)-2-{[(2R)-2-(methoxycarbonyl)pyrrolidinyl]carbonyl}-1-pyrrolidinecarboxylate		C₂₃H₃₂N₂O₆	详情	详情
(VI)	62801	methyl (2R)-1-{[(2S,4R)-4-(tert-butoxy)pyrrolidinyl]carbonyl}-2-pyrrolidinecarboxylate		C₁₅H₂₆N₂O₄	详情	详情
(VII)	57640	3,3,3-Triphenylpropionic acid; Tritylacetic acid	900-91-4	C₂₁H₁₈O₂	详情	详情
(VIII)	62802	methyl (2R)-1-{[(2S,4R)-4-(tert-butoxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidinyl]carbonyl}-2-pyrrolidinecarboxylate		C₃₆H₄₂N₂O₅	详情	详情
(IX)	62803	(2R)-1-{[(2S,4R)-4-(tert-butoxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidinyl]carbonyl}-2-pyrrolidinecarboxylic acid		C₃₅H₄₀N₂O₅	详情	详情

Extended Information