(2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide -Drug Synthesis Database

【结构式】

【分子编号】31617

【品名】(2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide

【CA登记号】

【分子式】C₄₁H₆₅BrN₄O₆

【分子量】789.89446

【元素组成】C 62.34% H 8.29% Br 10.12% N 7.09% O 12.15%

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：(XV)

The condensation of dimethyl malonate (I) with 2-cloroallyl chloride (II) by means of sodium methoxide in hot methanol gives the alkylmalonate (III), which is treated with tert-butyl bromoacetate (IV), NaOH and benzyltriethylammonium chloride to yield the tricarboxylic ester (V). Partial decarboxylation of (V) with KOH in hot methanol/water affords the succinic acid derivative (VI), which is submitted to enzymatic hydrolysis with Alcalase 2.4L to provide the chiral monoester (VII). The condensation of monoacid (VII) with amine (VIII) by means of HOBT, DCC, and DIEA in THF gives the amide (IX), which is treated with TFA to eliminate the tert-butyl protecting group yielding the acid (X). The condensation of (X) with amine (XI) by means of NMM and pivaloyl chloride affords the amide (XII), which is treated with 2-methoxypropene (XIII) and TsOH in dichloromethane to protect the vicinal hydroxy groups giving the dioxolane (XIV). The bromination of the allyl double bond of (XIV) with NBS in tert-butyl methyl ether/water gives 3-bromo-2-oxopropyl derivative (XV).

参考文献中间体

合成目标

【1】 Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622.

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)	19373	dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester	108-59-8	C₅H₈O₄	详情	详情
(II)	31608	2,3-dichloro-1-propene	78-88-6	C₃H₄Cl₂	详情	详情
(III)	31609	dimethyl 2-(2-chloro-2-propenyl)malonate		C₈H₁₁ClO₄	详情	详情
(IV)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(V)	31610	1-(tert-butyl) 2,2-dimethyl 4-chloro-4-pentene-1,2,2-tricarboxylate		C₁₄H₂₁ClO₆	详情	详情
(VI)	31611	4-(tert-butyl) 1-methyl 2-(2-chloro-2-propenyl)succinate		C₁₂H₁₉ClO₄	详情	详情
(VII)	31612	(2S)-2-[2-(tert-butoxy)-2-oxoethyl]-4-chloro-4-pentenoic acid		C₁₁H₁₇ClO₄	详情	详情
(VIII)	29543	(2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol		C₁₄H₂₉NO₂	详情	详情
(IX)	31613	tert-butyl (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoate		C₂₅H₄₄ClNO₅	详情	详情
(X)	31614	(3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid		C₂₁H₃₆ClNO₅	详情	详情
(XI)	29540	2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide		C₁₇H₂₇N₃O	详情	详情
(XII)	31615	(2S)-2-(2-chloro-2-propenyl)-N(4)-(cyclohexylmethyl)-N(1)-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide		C₃₈H₆₁ClN₄O₅	详情	详情
(XIII)	17354	isopropenyl methyl ether; 2-methoxy-1-propene	116-11-0	C₄H₈O	详情	详情
(XIV)	31616	(2S)-2-(2-chloro-2-propenyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide		C₄₁H₆₅ClN₄O₅	详情	详情
(XV)	31617	(2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide		C₄₁H₆₅BrN₄O₆	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 thiazole ring formation by cyclization of (XV) with thiourea (XVI) gives intermediate (XVII), which is finally deprotected with methanesulfonic acid in dichloromethane.

参考文献中间体

合成目标

【1】 Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	31617	(2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide		C₄₁H₆₅BrN₄O₆	详情	详情
(XVI)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(XVII)	31618	(2R)-2-[(2-amino-1,3-thiazol-4-yl)methyl]-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide		C₄₂H₆₆N₆O₅S	详情	详情

Extended Information