N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide -Drug Synthesis Database

【结构式】

【分子编号】26943

【品名】N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide

【CA登记号】

【分子式】C₁₈H₁₇Cl₂NO₂

【分子量】350.24392

【元素组成】C 61.73% H 4.89% Cl 20.24% N 4% O 9.14%

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：(XXVI)

In a different procedure, 3,4-dichlorophenylacetic acid (XIV) was condensed with the lithiated chiral oxazolidinone (XV), via activation as the mixed anhydride with pivaloyl chloride, to afford the N-acyl oxazolidinone (XVI). Diastereoselective alkylation of the sodium enolate of (XVI) with allyl iodide (XVII) afforded the (S)-pentenyl oxazolidinone (XVIII), which was further hydrolyzed to the chiral acid (XIX) by means of lithium peroxide. Alternatively, acid (XIX) was obtained by alkylation of the lithium dianion of 3,4-dichlorophenylacetic acid (XIV) with allyl bromide (XX), followed by resolution of the resultant racemic acid (XXI) with (S)-1-phenylethylamine. Acid (XIX) was converted to the amide (XXII) via the corresponding acid chloride. Reduction of amide (XXII) with DIBAL gave the secondary amine (XXIII), which was subsequently acylated with benzoyl chloride, yielding benzamide (XXIV). Dihydroxylation of the olefin double bond with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage of the resultant diol (XXV) with sodium periodate furnished aldehyde (XXVI). Finally, reductive amination of aldehyde (XXVI) with piperidine (III) in the presence of NaBH3CN provided the title compound

参考文献中间体

合成目标

【1】 Hale, J.J.; Finke, P.E.; MacCross, M.; A facile synthesis of the novel neurokinin A antagonist SR 48968. Bioorg Med Chem Lett 1993, 3, 2, 319.
【2】 Finke, P.E.; Mills, S.G.; Hale, J.J.; MacCoss, M. (Merck & Co., Inc.); Process of making chiral 2-aryl-1,4-butanediamine derivs.. WO 9407839 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	59283	N-(4-phenyl-4-piperidinyl)acetamide		C₁₃H₁₈N₂O	详情	详情
(XIV)	30414	2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid	5807-30-7	C₈H₆Cl₂O₂	详情	详情
(XV)	58942			C₁₀H₁₀LiNO₂	详情	详情
(XVI)	62381	(4S)-4-benzyl-3-[2-(3,4-dichlorophenyl)acetyl]-1,3-oxazolidin-2-one		C₁₈H₁₅Cl₂NO₃	详情	详情
(XVII)	32112	3-iodo-1-propene;3-iodo-propen;allyl iodide	556-56-9	C₃H₅I	详情	详情
(XVIII)	62382	(4S)-4-benzyl-3-[(2S)-2-(3,4-dichlorophenyl)-4-pentenoyl]-1,3-oxazolidin-2-one		C₂₁H₁₉Cl₂NO₃	详情	详情
(XIX)	62383	(2S)-2-(3,4-dichlorophenyl)-4-pentenoic acid		C₁₁H₁₀Cl₂O₂	详情	详情
(XX)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XXI)	50421	2-(3,4-dichlorophenyl)-4-pentenoic acid		C₁₁H₁₀Cl₂O₂	详情	详情
(XXII)	62384	(2S)-2-(3,4-dichlorophenyl)-N-methyl-4-pentenamide		C₁₂H₁₃Cl₂NO	详情	详情
(XXIII)	62385	(2S)-2-(3,4-dichlorophenyl)-N-methyl-4-penten-1-amine; N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylamine		C₁₂H₁₅Cl₂N	详情	详情
(XXIV)	62386	N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylbenzamide		C₁₉H₁₉Cl₂NO	详情	详情
(XXV)	62387	N-[(2S)-2-(3,4-dichlorophenyl)-4,5-dihydroxypentyl]-N-methylbenzamide		C₁₉H₂₁Cl₂NO₃	详情	详情
(XXVI)	26943	N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide		C₁₈H₁₇Cl₂NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

The reaction of 2-bromoethanol (I) with dihydropyran by means of a strong acid ion exchange resin gives the tetrahydropyranyl ether (II), which is condensed with 2-(3,4-dichlorophenyl)acetonitrile (III) by means of NaH in THF yielding thebutyronitrile (IV). The reduction of (IV) with H2 over RaNi in ethanol/NH4OH affords the butylamine (V), which is deprotected with HCl in methanol providing racemic 2-(3,4-dichlorophenyl)-4-hydroxybutylamine (VI). The optical resolution of (VI) with D-tartaric acid affords the corresponding (S) isomer (VII), which is treated with ethyl chloroformate and triethylamine in dichloromethane to give the carbamate (VIII). The reduction of (VIII) with LiAlH4 in THF yields N-[2(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylamine (IX), which is acylated with benzoyl chloride (X) and triethylamine in dichloromethane to affords the amide (XI). Oxidation of the hydroxyl group of (XI) with Dess-Martin periodinane yields the corresponding aldehyde (XII), which is reductocondensed with 4-[N-(trifluoroacetyl)-N-[3-(trifluoroacetamido)propyl]amino]piperidine (XIII) by means of NaBH3CN in methanol/acetic acid providing the bis(trifluoroacetylated) intermediate (XIV). The deprotection of (XIV) with KOH in methanol/water gives the diamine intermediate (XV), which is finally cyclized with carbonyldiimidazole (CDI) in chloroform.

参考文献中间体

合成目标

【1】 Miller, S.C. (AstraZeneca plc); Therapeutic heterocycles which antagonize neurokinin receptors. JP 1997501439; US 5567700; US 5990130; US 6124279; WO 9505377 .

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)	10059	Ethylene bromohydrin; 2-Bromo-1-ethanol	540-51-2	C₂H₅BrO	详情	详情
(II)	26934	2-bromoethyl tetrahydro-2H-pyran-2-yl ether		C₇H₁₃BrO₂	详情	详情
(III)	26935	2-(3,4-dichlorophenyl)acetonitrile	3218-49-3	C₈H₅Cl₂N	详情	详情
(IV)	26936	2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile		C₁₅H₁₇Cl₂NO₂	详情	详情
(V)	26937	2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine		C₁₅H₂₁Cl₂NO₂	详情	详情
(VI)	26938	4-amino-3-(3,4-dichlorophenyl)-1-butanol		C₁₀H₁₃Cl₂NO	详情	详情
(VII)	26939	(3S)-4-amino-3-(3,4-dichlorophenyl)-1-butanol		C₁₀H₁₃Cl₂NO	详情	详情
(VIII)	26940	ethyl (2S)-2-(3,4-dichlorophenyl)-4-hydroxybutylcarbamate		C₁₃H₁₇Cl₂NO₃	详情	详情
(IX)	26941	(3S)-3-(3,4-dichlorophenyl)-4-(methylamino)-1-butanol		C₁₁H₁₅Cl₂NO	详情	详情
(X)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(XI)	26942	N-[(2S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylbenzamide		C₁₈H₁₉Cl₂NO₂	详情	详情
(XII)	26943	N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide		C₁₈H₁₇Cl₂NO₂	详情	详情
(XIII)	26944	2,2,2-trifluoro-N-(4-piperidinyl)-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]acetamide		C₁₂H₁₇F₆N₃O₂	详情	详情
(XIV)	26945	N-[(2S)-2-(3,4-dichlorophenyl)-4-[4-((2,2,2-trifluoroacetyl)[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino)-1-piperidinyl]butyl]-N-methylbenzamide		C₃₀H₃₄Cl₂F₆N₄O₃	详情	详情
(XV)	26946	N-[(2S)-4-[4-[(3-aminopropyl)amino]-1-piperidinyl]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide		C₂₆H₃₆Cl₂N₄O	详情	详情

Extended Information