CRA-0316, -Drug Synthesis Database

【结构式】

【药物名称】CRA-0316

【化学名称】1-[7-[2,6-Dibromo-4-(trifluoromethyl)phenyl]-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide

【CA登记号】291538-79-9

【分子式】C₂₂H₂₀Br₂F₃N₅O

【分子量】587.2408

【开发单位】Taisho (Originator)

【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, CRF1 Antagonists

合成路线1 合成路线2

合成路线1

The preparation of the intermediate 1,2,3,6-tetrahydropyridine-4-carboxamide (VI) is illustrated in Scheme 1. Demethylation of tetrahydropyridine (I) with ethyl chloroformate in refluxing benzene affords carbamate (II), which is further hydrolyzed to the aminoacid (III) upon heating with concentrated HBr. Subsequent protection of (III) by means of di-t-butyl dicarbonate leads to N-Boc tetrahydropyridine-4-carboxylic acid (IV). Coupling of acid (IV) with ammonia in the presence of EDC/HOBt provides amide (V). The N-Boc protecting group of (V) is then removed with trifluoroacetic acid in CHCl3, yielding tetrahydropyridine (VI)

参考文献中间体

【1】 Tomisawa, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Carbamoyl tetrahydropyridine derivs.. EP 1176146 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	43676	methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate	C₁₀H₁₆N₂O₆	详情	详情
(II)	43674	diethyl 3,6-dihydro-1,4(2H)-pyridinedicarboxylate	C₁₁H₁₇NO₄	详情	详情
(III)	62072	1,2,3,6-tetrahydro-4-pyridinecarboxylic acid	C₆H₉NO₂	详情	详情
(IV)	62073	1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-pyridinecarboxylic acid	C₁₁H₁₇NO₄	详情	详情
(V)	62074	tert-butyl 4-(aminocarbonyl)-3,6-dihydro-1(2H)-pyridinecarboxylate	C₁₁H₁₈N₂O₃	详情	详情
(VI)	60299	1,2,3,6-tetrahydro-4-pyridinecarboxamide	C₆H₁₀N₂O	详情	详情

合成路线2

Condensation of 2,6-dibromo-4-(trifluoromethyl)aniline (VII) with acetoin (VIII), followed by heating the intermediate imine (IX) with malononitrile at 180 C gives rise to the N-aryl pyrrole (X). Acylation of aminopyrrole (X) with Ac2O provides acetamide (XI), which undergoes ring closure to the pyrrolopyrimidine (XII) in hot phosphoric acid. Chlorination of (XII) employing POCl3 furnishes aryl chloride (XIII). This is finally condensed with tetrahydropyridine (VI) to produce the title compound

参考文献中间体

【1】 Oshida, Y.; Kumagai, T.; Okubo, T.; Chaki, S.; Okuyama, S.; Nakazato, A.; Synthesis, SARs and biological activities of CRH1 receptor: Novel 3- or 4-carbamoyl-1,2,5,6-tetrahydropyridinopyrrolopyrimidine derivative. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 259.
【2】 Okubo, T.; et al.; 4- or 5-Carbamoyl-1,2,3,6-tetrahydropyridinopyrrolopyrimidine derivative as a CRH1 receptor antagonist. Drugs Fut 2002, 27, Suppl. A.
【3】 Tomisawa, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Carbamoyl tetrahydropyridine derivs.. EP 1176146 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	60299	1,2,3,6-tetrahydro-4-pyridinecarboxamide		C₆H₁₀N₂O	详情	详情
(VII)	62075	2,6-dibromo-4-(trifluoromethyl)phenylamine; 2,6-dibromo-4-(trifluoromethyl)aniline; 4-Amino-3,5-dibromobenzotrifluoride; 2,6-Dibromo-4-trifluoromethylaniline	72678-19-4	C₇H₄Br₂F₃N	详情	详情
(VIII)	62081	acetoin; 2-Butanone, 3-hydroxy-, (+-)-; 3-hydroxy-2-butanone; Acetyl methyl carbinol; 2-butanol-3-one; 3-Hydroxybutan-2-one; Dimethylketol; (R)-Acetoin; (R)-2-Acetoin; (R)-Dimethylketol; 2-acetoin; 2,3-Butanolone; Gamma-hydroxy-beta-oxobutane; ACETOIN, NATURAL; Acetoin, 85% Aqueous Soln.; Acetylmethylcarbinol, 85% Aqueous Soln.; 3-Hydroxy-2-Butanone, 85% Aqueous Soln.; Acetyl methyl carbinol, 85 wt. % solutionin water; Acetyl-methylcarbinol; Acetyl methyl carbinol pract.,; Methylacetylcarbinol; Acetylmethylcarbinol; (ACETOIN)	513-86-0	C₄H₈O₂	详情	详情
(IX)	62076	3-{[2,6-dibromo-4-(trifluoromethyl)phenyl]imino}-2-butanol		C₁₁H₁₀Br₂F₃NO	详情	详情
(X)	62077	2-amino-1-[2,6-dibromo-4-(trifluoromethyl)phenyl]-4,5-dimethyl-1H-pyrrole-3-carbonitrile		C₁₄H₁₀Br₂F₃N₃	详情	详情
(XI)	62078	N-{3-cyano-1-[2,6-dibromo-4-(trifluoromethyl)phenyl]-4,5-dimethyl-1H-pyrrol-2-yl}acetamide		C₁₆H₁₂Br₂F₃N₃O	详情	详情
(XII)	62079	7-[2,6-dibromo-4-(trifluoromethyl)phenyl]-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol		C₁₆H₁₂Br₂F₃N₃O	详情	详情
(XIII)	62080	4-chloro-7-[2,6-dibromo-4-(trifluoromethyl)phenyl]-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine		C₁₆H₁₁Br₂ClF₃N₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)