3-chloro-1,2-benzisothiazole -Drug Synthesis Database

【结构式】

【分子编号】16279

【品名】3-chloro-1,2-benzisothiazole

【CA登记号】

【分子式】C₇H₄ClNS

【分子量】169.6342

【元素组成】C 49.56% H 2.38% Cl 20.9% N 8.26% S 18.9%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(V)

Reaction of the dicarboxylic acid (I) with thionyl chloride in hot toluene gives the di-acid chloride (II). Treatment of (II) with Cl2 in CH2Cl2 gives the sulfenyl chloride (III), which upon reaction with NH4OH affords the benzisothiazole (IV). Chlorination of (IV) in heat POCl3 yields the chlorobenzisothiazole (V). Reaction of (V) and piperazine (VI) in excess molten pipeazine gives the monosubstituted piperazine (VII). Reaction of (VII) with the dibromide (VIII) in refluxing ethanol yields the spiroquaternary (IX). Finally, BMY-13859-1 is obtained by treatment of (IX) with the glutarimide (X) in refluxing xylene followed by treatment with HCl in isopropanol.

参考文献中间体

合成目标

【1】 Eison, M.S.; Taylor, D.P.; New, J.S.; Minielli, J.L.; BMY-13859. Drugs Fut 1985, 10, 9, 731.

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)	10404	Ethyl vanillin; 3-Ethoxy-4-hydroxybenzaldehyde	121-32-4	C₉H₁₀O₃	详情	详情
(II)	10405	2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile		C₁₅H₂₀ClNO₂	详情	详情
(III)	28018	2-(chlorosulfanyl)benzoyl chloride		C₇H₄Cl₂OS	详情	详情
(IV)	16278	1,2-benzisothiazol-3(2H)-one; 1,2-Benzisothiazolin-3-one	2634-33-5	C₇H₅NOS	详情	详情
(V)	16279	3-chloro-1,2-benzisothiazole		C₇H₄ClNS	详情	详情
(VI)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(VII)	16280	3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl)	87691-87-0	C₁₁H₁₃N₃S	详情	详情
(VIII)	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
(IX)	28019	8-(1,2-benzisothiazol-3-yl)-8-aza-5-azoniaspiro[4.5]decane bromide		C₁₅H₂₀BrN₃S	详情	详情
(X)	28020	8-azaspiro[4.5]decane-7,9-dione	1075-89-4	C₉H₁₃NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

This compound can be obtained by two related ways: 1) The reaction of cis-octahydroisobenzofuran-1,3-dione (I) with ammonia in water at 180-90 gives cis-octahydro-1H-isoindole-1,3-dione (II), which is alkylated with 1,4-dibromobutane (III) and K2CO3 in refluxing acetone to yield cis-2-(4-bromobutyl)octahydro-1H-isoindole-1,3-dione (IV). The condensation of (IV) with piperazine (V) in refluxing toluene affords cis-2-(4-piperazinobutyl)octahydro-1H-isoindole-1,3-dione (VI), which is finally condensed with 3-chloro-1,2-benzisothiazole (VII) and K2CO3 in refluxing toluene. 2) The condensation of benzisothiazole (VII) with piperazine (V) by heating at 120 C gives 3-piperazino-1,2-benzisothiazole (VIII), which is then condensed with isoindole (IV) by means of K2CO3 and KI in hot DMF. 3) The 3-chloro-1,2-benzisothiazole (VII) is obtained as follows: The reaction of 2,2'-dithiobenzoic acid (IX) with refluxing SOCl2 gives the corresponding acyl chloride (X), which by treatment with methylamine in THF is converted into the diamide (XI). The reaction of (XI) with PCl5 in refluxing benzene affords 3-chloro-2-methyl-1,2-benzisothiazolium chloride (XII), which is finally heated in refluxing 1,2-dichlorobenzene to give (VII).

参考文献中间体

合成目标

【1】 Ishizumi, N.; Antoku, F.; Maruyama, I.; Kojima, A. (Sumitomo Pharmaceuticals Co., Ltd.); Imide derivs., their production and use. EP 0196096; ES 8800219; JP 1987123179; JP 1987277355; JP 1987277356; US 4745117 .
【2】 Prous, J.; Castaner, J.; SM-9018. Drugs Fut 1991, 16, 2, 122.

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)	27329	(3aR,7aS)hexahydro-2-benzofuran-1,3-dione	13149-00-3	C₈H₁₀O₃	详情	详情
(II)	31245	(3aR,7aS)hexahydro-1H-isoindole-1,3(2H)-dione	7506-66-3	C₈H₁₁NO₂	详情	详情
(III)	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
(IV)	31246	(3aR,7aS)-2-(4-bromobutyl)hexahydro-1H-isoindole-1,3(2H)-dione		C₁₂H₁₈BrNO₂	详情	详情
(V)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(VI)	31247	(3aR,7aS)-2-[4-(1-piperazinyl)butyl]hexahydro-1H-isoindole-1,3(2H)-dione		C₁₆H₂₇N₃O₂	详情	详情
(VII)	16279	3-chloro-1,2-benzisothiazole		C₇H₄ClNS	详情	详情
(VIII)	16280	3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl)	87691-87-0	C₁₁H₁₃N₃S	详情	详情
(IX)	20404	2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid	119-80-2	C₁₄H₁₀O₄S₂	详情	详情
(X)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(XI)	31248	N-methyl-2-([2-[(methylamino)carbonyl]phenyl]disulfanyl)benzamide	2527-58-4	C₁₆H₁₆N₂O₂S₂	详情	详情
(XII)	31249	3-chloro-2-methyl-1,2-benzisothiazol-2-ium chloride		C₈H₇Cl₂NS	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Wolff-Kishner reduction of 6-chloroisatin (I) gives 6-chlorooxindole (II), which is treated with chloroacetyl chloride under Friedel-Crafts conditions to yield 5-chloroacetyl-6-chlorooxindole (III). The ketone (III) is reduced using triethylsilane in trifluoroacetic acid to produce 6-chloro-5-(2-chloroethyl)oxindole (IV). 1,2-Benzisothiazolin-3-one (V) is converted to 3-chloro-1,2-benzisothiazole (VI) using phosphorus oxychloride and is then condensed with piperazine to provide 1-(1,2-benzisothiazol-3-yl)piperazine (VII). Finally, intermediate (VII) is alkylated by compound (IV) in the presence of sodium carbonate in water and is converted to the salt with aqueous hydrochloric acid.

参考文献中间体

合成目标

【1】 Lowe, J.A. III; Nagel, A.A. (Pfizer Inc.); Piperazinyl-heterocyclic cpds. US 4831031 .
【2】 Bowles, P. (Pfizer Inc.); Process for preparing aryl piperazinyl-heterocyclic cpds. EP 1029861; JP 1994184143; US 5206366 .
【3】 Howard, H.R. Jr.; Busch, F.R.; Grobin, A.W.; Leeman, K.R. (Pfizer Products Inc.); Controlled synthesis of ziprasidone and compsns. thereof. WO 0370246 .
【4】 Seeger, T.F.; Prakash, C.; Howard, H.R.; Ziprasidone Hydrochloride. Drugs Fut 1994, 19, 6, 560.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(I)	16274	6-chloro-1H-indole-2,3-dione; 6-Chloroisatin	6341-92-0	C₈H₄ClNO₂	详情	详情
(II)	16275	6-chloro-1,3-dihydro-2H-indol-2-one	56341-37-8	C₈H₆ClNO	详情	详情
(III)	16276	6-chloro-5-(2-chloroacetyl)-1,3-dihydro-2H-indol-2-one		C₁₀H₇Cl₂NO₂	详情	详情
(IV)	16277	6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one; 5-chloroethyl-6-chloro-1,3-dihydro-1H-indol-2-one-		C₁₀H₉Cl₂NO	详情	详情
(V)	16278	1,2-benzisothiazol-3(2H)-one; 1,2-Benzisothiazolin-3-one	2634-33-5	C₇H₅NOS	详情	详情
(VI)	16279	3-chloro-1,2-benzisothiazole		C₇H₄ClNS	详情	详情
(VII)	16280	3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl)	87691-87-0	C₁₁H₁₃N₃S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

The bromination of 3-chloro-1,2-benzoisothiazole (I) with Br2 in AcOH using FeCl3 as catalyst gives a mixture of 3,5-dibromo-1,2-benzoisothiazole (II) and 3,7-dibromo-1,2-benzoisothiazole (III) that are separated by flash chromatography. The desired isomer (III) is condensed with piperazine (IV) in refluxing diglyme to yield 7-bromo-3-(1-piperazinyl)-1,2-benzoisothiazole (V), which is condensed with 6-chloro-5-(2-chloroethyl)indolin-2-one (VI) by means of Na2CO3 in refluxing water to afford the brominated adduct (VII). Finally, this compound is debrominated with tritium gas over a Pd/BaSO4 catalyst in THF to provide the target radiolabeled compound.

参考文献中间体

合成目标

【1】 Howard, H.R.; Shenk, K.D.; Smolarek, T.A.; Marx, M.H.; Windels, J.H.; Roth, R.W.; Synthesis of H-3- and C-14-labelled CP-88,059: A potent atypical antipsychotic agent. J Label Compd Radiopharm 1994, 34, 2, 117.

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)	16279	3-chloro-1,2-benzisothiazole		C₇H₄ClNS	详情	详情
(II)	62886	3,5-dibromo-1,2-benzisothiazole		C₇H₃Br₂NS	详情	详情
(III)	62887	3,7-dibromo-1,2-benzisothiazole		C₇H₃Br₂NS	详情	详情
(IV)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(V)	62888	7-bromo-3-(1-piperazinyl)-1,2-benzisothiazole		C₁₁H₁₂BrN₃S	详情	详情
(VI)	16277	6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one; 5-chloroethyl-6-chloro-1,3-dihydro-1H-indol-2-one-		C₁₀H₉Cl₂NO	详情	详情
(VII)	62889	5-{2-[4-(7-bromo-1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one		C₂₁H₂₀BrClN₄OS	详情	详情

Extended Information