methyl 2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetate -Drug Synthesis Database

【结构式】

【分子编号】30412

【品名】methyl 2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetate

【CA登记号】

【分子式】C₂₂H₂₇ClN₂O₃

【分子量】402.92076

【元素组成】C 65.58% H 6.75% Cl 8.8% N 6.95% O 11.91%

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：(XIV)

In a further procedure, racemic (4-chlorophenyl)phenylmethyl amine (V) was resolved by means of L-tartaric acid. The undesired (S)-enantiomer (VII) could be recovered by racemization to (V) upon treatment with 2-hydroxybenzaldehyde and NaOMe. The required (R)-enantiomer (VI) was condensed with N,N-bis(chloroethyl)-p-toluenesulfonamide (VIII) in refluxing diisopropylethylamine to provide the N-tosyl piperazine (IX). Deprotection of the p-toluenesulfonamide of (IX) was achieved by treatment with HBr in the presence of 4-hydroxybenzoic acid. The resulting piperazine (X) was alkylated with either (2-chloroethoxy)acetamide (XI) or methyl (2-chloroethoxy)acetate (XIII), affording the N-alkylated piperazines (XII) and (XIV), respectively. The title carboxylic acid was then obtained by hydrolysis of amide (XII) with aqueous HCl or, alternatively, by hydrolysis of ester (XIV) with ethanolic KOH.

参考文献中间体

合成目标

【1】 Bodson, G.; Gobert, J.; Cossement, E. (UCB SA); Enantiomers of 1-[4-(chlorophenyl)phenylmethyl]-4-(methylphenyl)sulfonyl piperazine. EP 0617028 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	30407	p-Chloro benzhydryl amine; (4-Chlorophenyl)(phenyl)methylamine; (4-Chlorophenyl)(phenyl)methanamine		C₁₃H₁₂ClN	详情	详情
(VI)	30408	(R)-(4-chlorophenyl)(phenyl)methylamine; (R)-(4-chlorophenyl)(phenyl)methanamine		C₁₃H₁₂ClN	详情	详情
(VII)	30413	(S)-(4-chlorophenyl)(phenyl)methylamine; (S)-(4-chlorophenyl)(phenyl)methanamine		C₁₃H₁₂ClN	详情	详情
(VIII)	30409	N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide	42137-88-2	C₁₁H₁₅Cl₂NO₂S	详情	详情
(IX)	30410	1-[(R)-(4-chlorophenyl)(phenyl)methyl]-4-[(4-methylphenyl)sulfonyl]piperazine		C₂₄H₂₅ClN₂O₂S	详情	详情
(X)	30404	1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine		C₁₇H₁₉ClN₂	详情	详情
(XI)	16839	2-(2-chloroethoxy)acetamide		C₄H₈ClNO₂	详情	详情
(XII)	30411	2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetamide		C₂₁H₂₆ClN₃O₂	详情	详情
(XIII)	16841	methyl 2-(2-chloroethoxy)acetate		C₅H₉ClO₃	详情	详情
(XIV)	30412	methyl 2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetate		C₂₂H₂₇ClN₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The reaction of racemic cetiricine (I) with SOCl2 in toluene gives the acyl chloride (II), which is treated with ammonia to yield the corresponding racemic amide (III). The optical resolution of (III) by preparative chiral chromatography on a Chiralpak AD column affords the (R)-isomer (IV), which is treated with HCl in refluxing methanol to provide the chiral methyl ester (V). Finally, ester (V) is hydrolyzed with aqueous HCl to provide the chiral target compound. The hydrolysis of amide (IV) is not performed directly to the target acid owing to purification problems (separation of the ammonium chloride formed in the hydrolysis with HCl).

参考文献中间体

合成目标

【1】 Pflum, D.A.; et al.; A large-scale synthesis of enantiomerically pure cetirizine dihydrochloride using preparative chiral HPLC. Org Process Res Dev 2001, 5, 2, 110.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	46613	2-(2-[4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetic acid	C₂₁H₂₅ClN₂O₃	详情	详情
(II)	46614	2-(2-[4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetyl chloride	C₂₁H₂₄Cl₂N₂O₂	详情	详情
(III)	46615	2-(2-[4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetamide	C₂₁H₂₆ClN₃O₂	详情	详情
(IV)	30411	2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetamide	C₂₁H₂₆ClN₃O₂	详情	详情
(V)	30412	methyl 2-(2-[4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl]ethoxy)acetate	C₂₂H₂₇ClN₂O₃	详情	详情

Extended Information