Batanopride hydrochloride, BMY-25801-01, BMY-25801 free base, -Drug Synthesis Database

【结构式】

【药物名称】Batanopride hydrochloride, BMY-25801-01, BMY-25801 free base

【化学名称】(±)-4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide hydrochloride

【CA登记号】102670-59-7, 102670-46-2 (free base)

【分子式】C₁₇H₂₇Cl₂N₃O₃

【分子量】392.32904

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists

合成路线1 合成路线2

合成路线1

A new synthesis for [14C]-labeled batanopride has been described: The starting material is 4-amino-2-hydroxybenzoic acid labeled with [14C] at the carboxy group (I). The methylation of (I) in the usual way gives 4-amino-2-methoxybenzoic acid methyl ester (II), which is treated with acetic anhydride to yield the corresponding acetamido derivative (III). Chlorination of (III) with Cl2 in acetic acid affords 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester (IV), which is hydrolyzed with aqueous NaOH to 4-amino-5-chloro-2-methoxybenzoic acid (V). The condensation of (V) with 2-(diethylamino)ethylamine (VI) by means of triethylamine and isobutyl chloroformate in THF gives the corresponding amide (VII), which is demethylated with sodium ethanethiolate in DMF to yield the phenolate (VIII). The condensation of (VIII) with 3-chloro-2-butanone (IX) in DMF affords batanopride free base (X), which is finally treated with HCl in acetone - water.

参考文献中间体

【1】 Standridge, R.T.; Swigor, J.E.; Synthesis of 4-amino-5-chloro-N[2-(diethylamino)ethyl]-2-[(butan-2-on-3-yl)oxy]-[carbonyl-C-14]benzamide hydrochloride (C-14-batanopride). J Label Compd Radiopharm 1991, 29, 9, 983.

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)	12415	4-Aminosalicylic Acid; 4-Amino-2-hydroxybenzoic acid	65-49-6	C₇H₇NO₃	详情	详情
(I)	45126	4-amino-2-hydroxybenzoic acid		C₇H₇NO₃	详情	详情
(II)	12416	methyl 4-amino-2-methoxybenzoate	27492-84-8	C₉H₁₁NO₃	详情	详情
(II)	45127	methyl 4-amino-2-methoxybenzoate		C₉H₁₁NO₃	详情	详情
(III)	12417	methyl 4-(acetamido)-2-methoxybenzoate; Methyl 4-acetamido-2-methoxybenzoate	4093-28-1	C₁₁H₁₃NO₄	详情	详情
(III)	45128	methyl 4-(acetamido)-2-methoxybenzoate		C₁₁H₁₃NO₄	详情	详情
(IV)	12418	4-Acetamido-5-chloro-2-methoxy methyl benzoate; methyl 4-(acetamido)-5-chloro-2-methoxybenzoate; Methyl 4-acetamido-5-chloro-2-methoxybenzoate; 4-Acetamido-5-chloro-2-methoxybenzoic acid methyl ester; 4-Acetamido-5-chloro-o-anisic acid methyl ester	4093-31-6	C₁₁H₁₂ClNO₄	详情	详情
(IV)	45129	methyl 4-(acetamido)-5-chloro-2-methoxybenzoate		C₁₁H₁₂ClNO₄	详情	详情
(V)	12419	4-Amino-5-chloro-2-methoxybenzoic acid	7206-70-4	C₈H₈ClNO₃	详情	详情
(V)	45130	4-amino-5-chloro-2-methoxybenzoic acid		C₈H₈ClNO₃	详情	详情
(VI)	12420	N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine	100-36-7	C₆H₁₆N₂	详情	详情
(VII)	12421	4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide	364-62-5	C₁₄H₂₂ClN₃O₂	详情	详情
(VII)	45131	4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide		C₁₄H₂₂ClN₃O₂	详情	详情
(VIII)	12422	sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate		C₁₃H₁₉ClN₃NaO₂	详情	详情
(VIII)	45132	sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate		C₁₃H₁₉ClN₃NaO₂	详情	详情
(IX)	12423	3-Chloro-2-butanone	4091-39-8	C₄H₇ClO	详情	详情
(X)	12424	4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide		C₁₇H₂₆ClN₃O₃	详情	详情
(X)	45133	4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide		C₁₇H₂₆ClN₃O₃	详情	详情

合成路线2

The demethylation of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide (I) with EtS-Na in hot DMF gives the hydroxy compound (II), which is acylated with 3-chloro-2-butanone (III) by means of K2CO3 and NaI in DMF to yield 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide (IV). Finally, this compound is treated with HCl to furnish the target hydrochloride. Alternatively, the alkylation of the hydroxy compound (II) can also be performed by reaction of (II) with tetrabutylammonium bisulfate and NaOH to give the tetrabutylammonium phenolate (V), which is alkylated with the chlorobutanone (III) to give (IV).

参考文献中间体

【1】 Monkovic, I.; NEW BENZAMIDE ANTI-EMETICS. Drugs Fut 1989, 14, 1, 41.
【2】 Monkovic, I.; Willner, D.; Adam, M.A.; Brown, M.; Crenshaw, R.R.; Fuller, C.E.; Juby, P.F.; Luke, G.M.; Matiskella, J.A.; Montzka, T.A.; Substituted benzamides. 1. Potential nondopaminergic antagonists of chemotherapy-induced nausea and emesis. J Med Chem 1988, 31, 8, 1548-58.

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)	12421	4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide	364-62-5	C₁₄H₂₂ClN₃O₂	详情	详情
(II)	43739	4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide		C₁₃H₂₀ClN₃O₂	详情	详情
(III)	12423	3-Chloro-2-butanone	4091-39-8	C₄H₇ClO	详情	详情
(IV)	12424	4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide		C₁₇H₂₆ClN₃O₃	详情	详情
(V)	43740	N,N,N-tributyl-1-butanaminium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate		C₂₉H₅₅ClN₄O₂	详情	详情

Extended Information