2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione -Drug Synthesis Database

【结构式】

【分子编号】17043

【品名】2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione

【CA登记号】

【分子式】C₁₁H₁₂BrNO₃S

【分子量】318.19122

【元素组成】C 41.52% H 3.8% Br 25.11% N 4.4% O 15.08% S 10.08%

与该中间体有关的原料药合成路线共 7 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7

合成路线1

该中间体在本合成路线中的序号：(VII)

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

合成目标

【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

该中间体在本合成路线中的序号：(XII)

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

合成目标

【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

该中间体在本合成路线中的序号：(VIII)

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

合成目标

【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

合成路线4

该中间体在本合成路线中的序号：(II)

The title compound was prepared by alkylation of 1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (I) with N-(4-bromobutyl)saccharin (II) in the presence of K2CO3 in methylethylketone (MEK).

参考文献中间体

合成目标

【1】 Regan, J.; Bruno, J.; McGarry, D.; Poli, G.; Hanney, B.; Bower, S.; Travis, J.; Sweeney, D.; Miller, B.; Souness, J.; Djuric, S.; 2-Substituted-4-methoxybenzimidazole-based PDE4 inhibitors. Bioorg Med Chem Lett 1998, 8, 19, 2737.

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)	25111	1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)piperazine		C₁₂H₁₅ClN₂O₂	详情	详情
(II)	17043	2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₁₁H₁₂BrNO₃S	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VII)

The sulfonylation of 1-benzylpyrrolidin-3-ol by means of mesyl or tosyl chlorides gives the corresponding sulfonates (II) or (III), which are condensed with the diphenyl cuprate lithium (IV) yielding 1-benzyl-3-phenylpyrrolidine (V). The debenzylation of (V) with ammonium formate over Pd/C in methanol affords 3-phenylpyrrolidine (VI), which is finally condensed with 2-(4-bromobutyl)-1,2-benzoisothiazol-3-one S,S-dioxide (VII) by means of triethylamine in acetonitrile.

参考文献中间体

合成目标

【1】 Lee, C.-H.; Ahn, K.H.; Lee, S.J.; Park, T.K.; Hong, C.Y.; N-Substituted-3-arylpyrrolidines: Potent and selective ligands at serotonin 1A receptor. Bioorg Med Chem Lett 1999, 9, 10, 1379.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	13975	p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride	98-59-9	C₇H₇ClO₂S	详情	详情
(I)	22746	1-benzyl-3-pyrrolidinol		C₁₁H₁₅NO	详情	详情
(II)	30988	1-benzyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]pyrrolidine		C₁₄H₂₁NOS	详情	详情
(III)	30989	1-benzyl-3-pyrrolidinyl 4-methylbenzenesulfonate		C₁₈H₂₁NO₃S	详情	详情
(V)	30990	1-benzyl-3-phenylpyrrolidine		C₁₇H₁₉N	详情	详情
(VI)	30991	3-phenylpyrrolidine		C₁₀H₁₃N	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6

该中间体在本合成路线中的序号：(VII)

The sulfonylation of 1-benzylpyrrolidin-3-ol by means of mesyl or tosyl chlorides gives the corresponding sulfonates (II) or (III), which are condensed with the bis(4-fluorophenyl)cuprate lithium (IV) yielding 1-benzyl-3-(4-fluorophenyl) pyrrolidine (V). The debenzylation of (V) with ammonium formate over Pd/C in methanol affords 3-(4-fluorophenyl)pyrrolidine (VI), which is finally condensed with 2-(4-bromobutyl)-1,2-benzoisothiazol-3-one S,S-dioxide (VII) by means of triethylamine in acetonitrile.

参考文献中间体

合成目标

【1】 Lee, C.-H.; Ahn, K.H.; Lee, S.J.; Park, T.K.; Hong, C.Y.; N-Substituted-3-arylpyrrolidines: Potent and selective ligands at serotonin 1A receptor. Bioorg Med Chem Lett 1999, 9, 10, 1379.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	22746	1-benzyl-3-pyrrolidinol	C₁₁H₁₅NO	详情	详情
(II)	30988	1-benzyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]pyrrolidine	C₁₄H₂₁NOS	详情	详情
(III)	30989	1-benzyl-3-pyrrolidinyl 4-methylbenzenesulfonate	C₁₈H₂₁NO₃S	详情	详情
(V)	30992	1-benzyl-3-(4-fluorophenyl)pyrrolidine	C₁₇H₁₈FN	详情	详情
(VI)	30993	3-(4-fluorophenyl)pyrrolidine	C₁₀H₁₂FN	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7

该中间体在本合成路线中的序号：(VI)

Treatment of 1-benzyl-3-hydroxypyrrolidine (I) with methanesulfonyl chloride in the presence of DMAP and Et3N affords mesylate (II). Subsequent displacement of the mesylate group of (II) with the diarylcuprate reagent generated from 4-fluorophenyllithium (III) and cuprous bromide gives the 3-aryl pyrrolidine (IV). The N-benzyl group of (IV) is then removed by transfer hydrogenolysis with ammonium formate and Pd/C, yielding the secondary amine (V). This is finally alkylated with 2-(4-bromobutyl)-3-oxo-1,2-benzisothiazole 1,1-dioxide (VI) in the presence of Et3N in refluxing acetonitrile.

参考文献中间体

合成目标

【1】 Lee, C.-H.; Ahn, K.H.; Lee, S.J.; Park, T.K.; Hong, C.Y.; N-Substituted-3-arylpyrrolidines: Potent and selective ligands at serotonin 1A receptor. Bioorg Med Chem Lett 1999, 9, 10, 1379.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	22746	1-benzyl-3-pyrrolidinol	C₁₁H₁₅NO	详情	详情
(II)	62833	1-benzyl-3-pyrrolidinyl methanesulfonate	C₁₂H₁₇NO₃S	详情	详情
(III)	62834	(4-fluorophenyl)lithium	C₆H₄FLi	详情	详情
(IV)	30992	1-benzyl-3-(4-fluorophenyl)pyrrolidine	C₁₇H₁₈FN	详情	详情
(V)	30993	3-(4-fluorophenyl)pyrrolidine	C₁₀H₁₂FN	详情	详情
(VI)	17043	2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione	C₁₁H₁₂BrNO₃S	详情	详情

Extended Information