M-274773, ZM-274773, -Drug Synthesis Database

【结构式】

【药物名称】M-274773, ZM-274773

【化学名称】N-[2(S)-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidin-1-yl]butyl]-N-methylbenzamide dihydrochloride

【CA登记号】164518-66-5

【分子式】C₂₇H₃₆Cl₄N₄O₂

【分子量】590.42557

【开发单位】AstraZeneca (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RENAL-UROLOGIC DRUGS, RESPIRATORY DRUGS, Urinary Incontinence Therapy, Tachykinin NK2 Antagonists

合成路线1 合成路线2

合成路线1

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

【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

合成路线2

The trifluoroacetylated intermediate (XIII) has been obtained as follows: The reductocondensation of 1-(benzyloxycarbonyl)-4-piperidone (XVI) with propylene-1,3-diamine (XVII) by means of NaBH3CN in methanol/acetic acid gives 4-(3-aminopropylamino)-1-(benzyloxycarbonyl)piperidine (XVIII), which is acylated with trifluoroacetyl anhydride and triethylamine in chloroform yielding the protected diacylated piperidine (XIX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in ethanol to afford the target intermediate (XIII).

参考文献中间体

【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
(XIII)	26944	2,2,2-trifluoro-N-(4-piperidinyl)-N-[3-[(2,2,2-trifluoroacetyl)amino]propyl]acetamide		C₁₂H₁₇F₆N₃O₂	详情	详情
(XVI)	26947	benzyl 4-oxo-1-piperidinecarboxylate; N-Benzyloxycarbonyl-4-piperidone	19099-93-5	C₁₃H₁₅NO₃	详情	详情
(XVII)	19331	3-aminopropylamine; 1,3-propanediamine	109-76-2	C₃H₁₀N₂	详情	详情
(XVIII)	26948	benzyl 4-[(3-aminopropyl)amino]-1-piperidinecarboxylate		C₁₆H₂₅N₃O₂	详情	详情
(XIX)	26949	benzyl 4-((2,2,2-trifluoroacetyl)[3-[(2,2,2-trifluoroacetyl)amino]propyl]amino)-1-piperidinecarboxylate		C₂₀H₂₃F₆N₃O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)