Repinotan hydrochloride, X-3702, Bay-x-3702, Branosyn, -Drug Synthesis Database

【结构式】

【药物名称】Repinotan hydrochloride, X-3702, Bay-x-3702, Branosyn

【化学名称】(-)-(R)-2-[4-[(3,4-Dihydro-2H-1-benzopyran-2-yl)methylamino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride
　　　　　　(-)-(R)-2-[4-[(Chroman-2-ylmethyl)amino]butyl]-1,1-dioxo-1,2-benzisothiazol-3(2H)-one monohydrochloride

【CA登记号】144980-77-8, 129091-16-3 (fee base undefined isomer), 144980-29-0 (free base), 149021-62-5 (racemic free base), 129091-55-0 (und

【分子式】C₂₁H₂₅ClN₂O₄S

【分子量】436.9614

【开发单位】Bayer (Originator)

【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Neurologic Drugs (Miscellaneous), Stroke, Treatment of, 5-HT1A Receptor Agonists

合成路线1 合成路线2 合成路线3

合成路线1

The synthesis of BAY x 3702 was carried out as outlined: Chroman-2-carboxylic acid (I) was activated with thionyl chloride. The acid chloride (II) was treated with (S)-phenethylamine (III), affording a (1:1)-mixture of diastereomers. Fractional crystallization from ethanol gave the isomer (IV) in high diastereomerical purity; basic epimerization of the undesired diastereomer is feasible. The amide (IV) was reduced with diborane in THF, yielding the amine (V), which was submitted to catalytic hydrogenation over palladium-on-charcoal. The resulting optically pure (R)-2-aminomethyl chroman (VI) was alkylated with 4-bromobutyl saccharin (VII), which is easily available from saccharin sodium and 1,4-dibromobutane. BAY x 3702 was isolated as the hydrochloride salt. White, odorless crystals, m.p. 195 C, alpha(20,D) -42.2 (c 0.9, CHCl3). BAY x 3702 is soluble in water (2.1 g/100 ml), acetone (2.2 g/100 ml) and DMSO. The solid substance is heat-stable, nonhygroscopic and nonsensitive to light. It is unstable in alkaline medium (hydrolysis), sensitive to hydrolysis in aqueous dilute solutions/suspensions at weak acidic and neutral pH, but stable in acidic medium (pH less than or equal to 4). The UV spectrum shows maxima at 272 and 279 nm. BAY x 3702 can be assayed by HPLC.

参考文献中间体

【1】 Opitz, W.; Heine, H-G.; Mauler, F.; Schohe-Loop, R.; Maertins, T.; Jork, R.; Dietrich, H.; Glaser, T.; Horvath, E.; Scherling, D.; De Vry, J.; Bay-x-3702. Drugs Fut 1997, 22, 4, 341.
【2】 Junge, B.; Schohe, R.; Seidel, P.-R.; Glaser, T.; Traber, J.; Benz, U.; Schuurman, T.; De Vry, J.-M.-V. (Bayer AG); Substd. amino methyl tetralines, and their heterocyclic analogous cpds. EP 0352613; JP 1990096552; US 5137901; US 5506246 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
	33704	1,1-Dioxide-1,2-benzisothiazol-3(2H)-one, sodium salt; 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt (1:1)	38279-26-4	C₇H₄NNaO₃S	详情	详情
	65068	2-(4-{[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₂₁H₂₄N₂O₄S	详情	详情
(I)	17037	2-chromanecarboxylic acid		C₁₀H₁₀O₃	详情	详情
(II)	17038	2-chromanecarbonyl chloride		C₁₀H₉ClO₂	详情	详情
(IV)	17040	(2R)-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide		C₁₈H₁₉NO₂	详情	详情
(V)	17041	(1S)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1S)-1-phenylethyl]amine		C₁₈H₂₁NO	详情	详情
(VI)	17042	(2R)-3,4-dihydro-2H-chromen-2-ylmethanamine; (2R)-3,4-dihydro-2H-chromen-2-ylmethylamine		C₁₀H₁₃NO	详情	详情
(VII)	17043	2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₁₁H₁₂BrNO₃S	详情	详情

合成路线2

The reaction of uniformly 14C-labeled phenol (I) with acetylenedicarboxylic acid dimethyl ester (II) gives the adduct (III), which is reduced with ammonium formate and Pd/C to yield the 2-phenoxysuccinic acid dimethyl ester (IV). The hydrolysis of (IV) in acidic medium (HCl) affords the succinic acid derivative (V), which is cyclized by means of P2O5 to provide 4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (VI). The reduction of (VI) by means of Ph3SiH and TFA gives 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (VII), which is condensed with 1(R)-phenylethylamine (VIII) by means of CDI to yield the corresponding amide (IX) as a diastereomeric mixture. The reduction of (IX) by means of NaAlH2(OC2H4OMe)2 affords the secondary amine (X), also as a diastereomeric mixture, which is resolved by chromatography. The desired isomer (XI) is condensed with the butyl bromide derivative (XII) by means of NaHCO3 and KI to provide the tertiary amine (XIII), which is finally debenzylated by hydrogenation with H2 over Pd/C to furnish the target labeled Repinotan.

参考文献中间体

【1】 Seidel, D.; et al.; Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6. J Label Compd Radiopharm 2002, 45, 13, 1115.

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)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(II)	24551	Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester	762-42-5	C₆H₆O₄	详情	详情
(III)	62010	dimethyl (E)-2-phenoxy-2-butenedioate		C₁₂H₁₂O₅	详情	详情
(IV)	62011	dimethyl 2-phenoxysuccinate		C₁₂H₁₄O₅	详情	详情
(V)	62012	2-phenoxysuccinic acid		C₁₀H₁₀O₅	详情	详情
(VI)	62013	4-oxo-2-chromanecarboxylic acid		C₁₀H₈O₄	详情	详情
(VII)	17037	2-chromanecarboxylic acid		C₁₀H₁₀O₃	详情	详情
(VIII)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(IX)	17040	(2R)-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide		C₁₈H₁₉NO₂	详情	详情
(X)	17041	(1S)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1S)-1-phenylethyl]amine		C₁₈H₂₁NO	详情	详情
(XI)	62014	(1R)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1R)-1-phenylethyl]amine		C₁₈H₂₁NO	详情	详情
(XII)	17043	2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₁₁H₁₂BrNO₃S	详情	详情
(XIII)	62015	2-(4-{[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl][(1R)-1-phenylethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₂₉H₃₂N₂O₄S	详情	详情

合成路线3

The reaction of labeled 2-hydroxyacetophenone (I) with dimethyl oxalate and NaOMe gives 4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester (II), which is hydrogenated with H2 over Pd/C to yield 3,4-dihydro-2H-1-benzopyran-2(R)-carboxylic acid methyl ester (III). The optical resolution of (III) by chiral chromatography affords the labeled (R)-enantiomer (IV), which is condensed with benzylamine (V) to provide the corresponding amide (VI). The reduction of (VI) by means of NaAlH2(OC2H4OMe)2 gives the labeled chiral amine (VII), which is condensed with the butyl bromide derivative (VIII) to yield the tertiary amine (IX). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C to afford the target labeled Repinotan.

参考文献中间体

【1】 Seidel, D.; et al.; Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6. J Label Compd Radiopharm 2002, 45, 13, 1115.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	37412	methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate	553-90-2	C₄H₆O₄	详情	详情
(I)	29654	2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone	118-93-4	C₈H₈O₂	详情	详情
(II)	62016	methyl 4-oxo-4H-chromene-2-carboxylate		C₁₁H₈O₄	详情	详情
(III)	62017	methyl 2-chromanecarboxylate		C₁₁H₁₂O₃	详情	详情
(IV)	62018	methyl (2R)-3,4-dihydro-2H-chromene-2-carboxylate		C₁₁H₁₂O₃	详情	详情
(V)	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(VI)	62019	(2R)-N-benzyl-3,4-dihydro-2H-chromene-2-carboxamide		C₁₇H₁₇NO₂	详情	详情
(VII)	62020	N-benzyl-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amine; N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine		C₁₇H₁₉NO	详情	详情
(VIII)	17043	2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₁₁H₁₂BrNO₃S	详情	详情
(IX)	62021	2-(4-{benzyl[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₂₈H₃₀N₂O₄S	详情	详情

Extended Information