Cianopramine, Ro-112465, -Drug Synthesis Database

【结构式】

【药物名称】Cianopramine, Ro-112465

【化学名称】5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine-3-carbonitrile
　　　　　　3-Cyano-N-[3-(dimethylamino)propyl]iminodibenzyl

【CA登记号】66834-24-0, 66834-20-6 (HCl)

【分子式】C₂₀H₂₃N₃

【分子量】305.42641

【开发单位】Roche (Originator)

【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS

合成路线1 合成路线2

合成路线1

1) The acetylation of iminodibenzyl (I) with acetyl chloride (A) in refluxing toluene gives N-acetyl-iminodibenzyl (II), which by a Friedel-Kraft's reaction with methyl oxalyl chloride (B) and AlCl3 in CH2Cl2 or CS2 is converted to N-acetyl-3-(methyloxalyl)iminodibenzyl (III). The hydrolysis of (III) with NaOH in methanol-water yields N-acetyl-5-oxalyliminodibenzyl (IV), which by treatment with NaOH in water-ethanol at high temperature affords 3-oxalyliminodibenzyl (V). The reaction of (V) with hydroxylamine and acetic acid gives 3-hydroxylaminooxalyliminodibenzyl (VI), which by heating at 100 C in water is converted into 3-cyanoiminodibenzyl (VII). Finally, this compound is condensed with 3-(dimethylamino)propyl chloride (VIII) by means of NaH in DMF. 2) Compound (VII) can also be condensed with dimethylaminopropyl N,N-dimethylcarbamate (IX) by heating at 250 C. 3) The reaction of (VII) with phosgene gives N-chlorocarbonyl-3-cyanoiminodibenzyl (X), which is condensed with 3-dimethylaminopropanol (XI) to afford 3-cyanoiminodibenzyl-N-carboxylic acid 3-dimethylaminopropyl ester (XII). Finally, this compound is heated at 250 C under reduced pressure.

参考文献中间体

【1】 Dostert, P. (Hoffmann-La Roche, Inc.); 3-Cyano-N-(N,N-dimethylaminopropyl)-iminodibenzyl and salts thereof. US 4138482 .
【2】 Blancafort, P.; Castaner, J.; Owen, R.T.; Serradell, M.N.; RO-11-2465. Drugs Fut 1981, 6, 1, 41.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	19273	acetyl chloride	75-36-5	C₂H₃ClO	详情	详情
(B)	26971	2-methoxy-2-oxoacetyl chloride	5781-53-3	C₃H₃ClO₃	详情	详情
(I)	37165	10,11-dihydro-5H-dibenzo[b,f]azepine	494-19-9	C₁₄H₁₃N	详情	详情
(II)	37166	1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-ethanone		C₁₆H₁₅NO	详情	详情
(III)	37167	methyl 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetate		C₁₉H₁₇NO₄	详情	详情
(IV)	37168	2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetic acid		C₁₈H₁₅NO₄	详情	详情
(V)	37169	2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetic acid		C₁₆H₁₃NO₃	详情	详情
(VI)	37170	2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-(hydroxyimino)acetic acid		C₁₆H₁₄N₂O₃	详情	详情
(VII)	37171	10,11-dihydro-5H-dibenzo[b,f]azepine-3-carbonitrile		C₁₅H₁₂N₂	详情	详情
(VIII)	24581	3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine	5407-04-5	C₅H₁₂ClN	详情	详情
(IX)	37175	3-(dimethylamino)propyl dimethylcarbamate		C₈H₁₈N₂O₂	详情	详情
(X)	37172	3-cyano-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl chloride		C₁₆H₁₁ClN₂O	详情	详情
(XI)	37173	3-(dimethylamino)-1-propanol	3179-63-3	C₅H₁₃NO	详情	详情
(XII)	37174	3-(dimethylamino)propyl 3-cyano-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxylate		C₂₁H₂₃N₃O₂	详情	详情

合成路线2

The reaction of 3-bromoiminodibenzyl (XIII) with 3-(dimethylamino)propyl chloride (VIII) at 100 C gives N-(3-dimethylaminopropyl)-3-bromoiminodibenzyl (XIV), which is treated with cuprous cyanide in refluxing DMF.

参考文献中间体

【1】 Dostert, P. (Hoffmann-La Roche, Inc.); 3-Cyano-N-(N,N-dimethylaminopropyl)-iminodibenzyl and salts thereof. US 4138482 .
【2】 Blancafort, P.; Castaner, J.; Owen, R.T.; Serradell, M.N.; RO-11-2465. Drugs Fut 1981, 6, 1, 41.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	24581	3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine	5407-04-5	C₅H₁₂ClN	详情	详情
(XIII)	37176	3-bromo-10,11-dihydro-5H-dibenzo[b,f]azepine		C₁₄H₁₂BrN	详情	详情
(XIV)	37177	N-[3-(3-bromo-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propyl]-N,N-dimethylamine; 3-(3-bromo-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethyl-1-propanamine		C₁₉H₂₃BrN₂	详情	详情

Extended Information