(1R,2S)-4-methylene-1,2-cyclopentanedicarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】27276

【品名】(1R,2S)-4-methylene-1,2-cyclopentanedicarboxylic acid

【CA登记号】

【分子式】C₈H₁₀O₄

【分子量】170.165

【元素组成】C 56.47% H 5.92% O 37.61%

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：(II)

Basic hydrolysis of cis-4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (I) with LiOH gives the free acid (II), which by refluxing with propionic anhydride yields the cyclic anhydride (III). Rearrangement using trimethylsilyl azide in dioxane at 80 C produces the oxazinedione (IV), which is hydrolyzed to (±)-cis-2-amino-4-methylenecyclopentane-1-carboxylic acid ethyl ester (V) by means of acetyl chloride in EtOH. Further hydrolysis of ester (V) with aqueous HCl provides the racemic amino acid (VI), which is coupled with N-(9-fluorenylmethoxycarbonyl)succinimide (VII) to afford the Fmoc-amino acid (VIII). Racemic (VIII) is resolved by treatment with (+)-(R)-1-phenylethylamine (IX) and crystallization of the resulting salt (X) in EtOH/methyl tert-butyl ether. Finally, acidification of salt (X) and extraction of the (1R,2S)-free acid, followed by removal of the Fmoc group with liquid ammonia, provides PLD-118 isolated as its hydrochloride salt.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castañer, J.; Bozzo, J.; PLD-118. Drugs Fut 2002, 27, 11, 1049.
【2】 Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.; Endermann, R.; Metzger, K.G.; Bremm, K.-D.; Plempel, M. (Bayer AG); Cyclopentane- and pentene-beta-amino-acids. DE 4217776; EP 0571870; JP 1994056751 .

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)	27275	diethyl (1R,2S)-4-methylene-1,2-cyclopentanedicarboxylate		C₁₂H₁₈O₄	详情	详情
(II)	27276	(1R,2S)-4-methylene-1,2-cyclopentanedicarboxylic acid		C₈H₁₀O₄	详情	详情
(III)	56629	(3aR,6aS)-5-methylenetetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione		C₈H₈O₃	详情	详情
(IV)	56630	(4aR,7aS)-6-methylenehexahydrocyclopenta[d][1,3]oxazine-2,4-dione		C₈H₉NO₃	详情	详情
(V)	27279	ethyl (1R,2S)-2-amino-4-methylenecyclopentanecarboxylate		C₉H₁₅NO₂	详情	详情
(VI)	27280	(1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid		C₇H₁₁NO₂	详情	详情
(VII)	21011	1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5-pyrrolidinedione	82911-69-1	C₁₉H₁₅NO₅	详情	详情
(VIII)	27281	(1R,2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylenecyclopentanecarboxylic acid		C₂₂H₂₁NO₄	详情	详情
(IX)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(X)	27282	(1R)-1-phenyl-1-ethanaminium (1R,2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylenecyclopentanecarboxylate		C₃₀H₃₂N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Hydrolysis of diester (I) with KOH in water/EtOH at 55 C gives the dicarboxylic acid (II), which is subjected to cyclization by refluxing with propionic anhydride to provide anhydride (III). Cyclic anhydride (III) is opened with allyl alcohol (XI) in diethyl ether in the presence of ()-quinine as asymmetric inducer to yield ()-1,2-cis-4-methylenecyclopentane-1,2-dicarboxylic acid monoallyl ester ()-(XII), which is then converted into the amide derivative ()-(XIII) by activation of the carboxylic acid group with isobutyl chloroformate in ethyl acetate in the presence of N-ethylmorpholine at 6 C, followed by reaction with aqueous ammonia. Removal of the allyl group of ()-(XIII) with triphenylphosphine, tetrakis(triphenylphosphine)palladium and 2-ethylhexanoic acid sodium salt in ethyl acetate affords ()-1,2-cis-2-(aminocarbonyl)-4-methylenecyclopentane-1-carboxylic acid sodium salt ()-(XIV). Compound ()-(XIV) is subjected to a Hofmann rearrangement with KOH and KOCl in water to provide a crude aqueous solution containing PLD-118, which is finally purified by protection of the free amine group with N-(9-fluorenylmethoxycarbonyloxy)succinimide by means of Na2CO3 in dioxane followed by Fmoc removal with piperidine in diethyl ether.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castañer, J.; Bozzo, J.; PLD-118. Drugs Fut 2002, 27, 11, 1049.
【2】 Fey, P.; Mohrs, K.-H.; Matzke, M.; Mittendorf, J.; Militzer, H.-C.; Arold, H. (Bayer AG); High enantio-selective process for producing pure enantiomeric cyclopentane and cyclopentene-(beta)-amino acids. DE 4400749; US 5962724; WO 9519337 .

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)	27275	diethyl (1R,2S)-4-methylene-1,2-cyclopentanedicarboxylate		C₁₂H₁₈O₄	详情	详情
(II)	27276	(1R,2S)-4-methylene-1,2-cyclopentanedicarboxylic acid		C₈H₁₀O₄	详情	详情
(III)	56629	(3aR,6aS)-5-methylenetetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione		C₈H₈O₃	详情	详情
(XI)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(XII)	56631	(1S,2R)-2-[(allyloxy)carbonyl]-4-methylenecyclopentanecarboxylic acid		C₁₁H₁₄O₄	详情	详情
(XIII)	56632	allyl (1R,2S)-2-(aminocarbonyl)-4-methylenecyclopentanecarboxylate		C₁₁H₁₅NO₃	详情	详情
(XIV)	56633	sodium (1R,2S)-2-(aminocarbonyl)-4-methylenecyclopentanecarboxylate		C₈H₁₀NNaO₃	详情	详情

Extended Information