2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】20405

【品名】2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride

【CA登记号】

【分子式】C₁₄H₈Cl₂O₂S₂

【分子量】343.25372

【元素组成】C 48.99% H 2.35% Cl 20.66% O 9.32% S 18.68%

与该中间体有关的原料药合成路线共 9 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8 合成路线9

合成路线1

该中间体在本合成路线中的序号：(I)

By condensation of 2,2'-dithiobis(benzoylchloride) (I) with 2-hydroxypropylamine (II) in dioxane.

参考文献中间体

合成目标

【1】 Naruse, M.; Niino, H.; Yamada, K.; Murayama, Y.; Hashimoto, T. (Kyowa Hakko Kogyo Co., Ltd.); Antithrombotic pharmaceutical preparation containing 2,2'-dithiobis benzamide derivs. and new 2,2'-dithiobis benzamide derivs.. EP 0006227 .
【2】 Grau, M.; KF-4939. Drugs Fut 1983, 8, 10, 857.

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)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(II)	22186	(S)-(+)-1-Amino-2-propanol; (2S)-1-amino-2-propanol	2799-17-9	C₃H₉NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

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)

The protection of aniline (I) with di-tert-butyl dicarbonate in THF gives the carbamate (II), which is treated with BuLi and 14C labeled CO2 in THF yielding 2-(tert-butoxycarbonylamino)benzoic acid (III). The deprotection of (III) with TFA in dichloromethane affords labeled 2-aminobenzoic acid (IV), which is diazotized with NaNO2 /HCl and treated with Na2S, S and NaOH to give the disulfide (V). The reaction of (V) with refluxing SOCl2 yields the acid dichloride (VI), which is condensed with L-isoleucine tert-butyl ester (VII), by means of N-methylmorpholine (NMM) in dichloromethane to afford the final intermediate (VIII). Finally, this compound is deprotected with TFA in dichloromethane to give the labeled target compound.

参考文献中间体

合成目标

【1】 Fiore, P.J.; et al.; Development and pilot-scale demonstration of a process for inhibitors of the HIV nucleocapsid protein, NCp7. Org Process Res Dev 1998, 2, 3, 151.

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)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(II)	32735	tert-butyl phenylcarbamate	3422-01-3	C₁₁H₁₅NO₂	详情	详情
(III)	32736	2-[(tert-butoxycarbonyl)amino]benzoic acid	68790-38-5	C₁₂H₁₅NO₄	详情	详情
(III)	45324	2-[(tert-butoxycarbonyl)amino]benzoic acid		C₁₂H₁₅NO₄	详情	详情
(IV)	11661	2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid	118-92-3	C₇H₇NO₂	详情	详情
(IV)	45325	2-aminobenzoic acid		C₇H₇NO₂	详情	详情
(V)	20404	2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid	119-80-2	C₁₄H₁₀O₄S₂	详情	详情
(V)	45326	2-[(2-carboxyphenyl)disulfanyl]benzoic acid		C₁₄H₁₀O₄S₂	详情	详情
(VI)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(VI)	45327	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(VII)	32737	tert-butyl (2S,3S)-2-amino-3-methylpentanoate		C₁₀H₂₁NO₂	详情	详情
(VIII)	32738	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	详情	详情
(VIII)	45328	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	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 reaction of disulfide (I) with SOCl2 gives the corresponding acyl chloride (II), which is then condensed with L-isoleucine (III) by means of NaHCO3 in THF.

参考文献中间体

合成目标

【1】 Fiore, P.J.; et al.; Development and pilot-scale demonstration of a process for inhibitors of the HIV nucleocapsid protein, NCp7. Org Process Res Dev 1998, 2, 3, 151.

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)	26404			C₇₂H₈₁Br₂Cl₂IO₂₂S₂	详情	详情
(II)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(III)	32739	L-2-Amino-3-methylpentanoic acid; L-isoleucine	73-32-5	C₆H₁₃NO₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VI)

The protection of aniline (I) with di-tert-butyl dicarbonate in THF gives the carbamate (II), which is treated with BuLi and 14C labeled CO2 in THF yielding 2-(tert-butoxycarbonylamino)benzoic acid (III). The deprotection of (III) with TFA in dichloromethane affords labeled 2-aminobenzoic acid (IV), which is diazotized with NaNO2 /HCl and treated with Na2S, S and NaOH to give the disulfide (V). The reaction of (V) with refluxing SOCl2 yields the acid dichloride (VI), which is condensed with L-isoleucine tert-butyl ester (VII), by means of N-methylmorpholine (NMM) in dichloromethane to afford the intermediate (VIII). The deprotectionof (VIII) with TFA in dichloromethane to give the labeled dimeric isoleucine derivative (IX), which is finally cyclized to the target benazoisothiazolone by oxidative cyclization with Br2 in dichloromethane.

参考文献中间体

合成目标

【1】 Fiore, P.J.; et al.; Development and pilot-scale demonstration of a process for inhibitors of the HIV nucleocapsid protein, NCp7. Org Process Res Dev 1998, 2, 3, 151.

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)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(II)	32735	tert-butyl phenylcarbamate	3422-01-3	C₁₁H₁₅NO₂	详情	详情
(III)	32736	2-[(tert-butoxycarbonyl)amino]benzoic acid	68790-38-5	C₁₂H₁₅NO₄	详情	详情
(III)	45324	2-[(tert-butoxycarbonyl)amino]benzoic acid		C₁₂H₁₅NO₄	详情	详情
(IV)	11661	2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid	118-92-3	C₇H₇NO₂	详情	详情
(IV)	45325	2-aminobenzoic acid		C₇H₇NO₂	详情	详情
(V)	20404	2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid	119-80-2	C₁₄H₁₀O₄S₂	详情	详情
(V)	45326	2-[(2-carboxyphenyl)disulfanyl]benzoic acid		C₁₄H₁₀O₄S₂	详情	详情
(VI)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(VI)	45327	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(VII)	32737	tert-butyl (2S,3S)-2-amino-3-methylpentanoate		C₁₀H₂₁NO₂	详情	详情
(VIII)	32738	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	详情	详情
(VIII)	45328	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	详情	详情
(IX)	32740	(2S,3S)-2-[(2-[[2-([[(1S,2S)-1-carboxy-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoic acid		C₂₆H₃₂N₂O₆S₂	详情	详情
(IX)	45329	(2S,3S)-2-[(2-[[2-([[(1S,2S)-1-carboxy-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoic acid		C₂₆H₃₂N₂O₆S₂	详情	详情

合成路线6

该中间体在本合成路线中的序号：(II)

The reaction of disulfide (I) with SOCl2 gives the corresponding acyl chloride (II), which is condensed with L-isoleucine (III) by means of NaHCO3 in THF yielding the disulfide intermediate (IV). Finally, this compound is submitted to an oxidative cyclization with Br2 in acetic acid.

参考文献中间体

合成目标

【1】 Fiore, P.J.; et al.; Development and pilot-scale demonstration of a process for inhibitors of the HIV nucleocapsid protein, NCp7. Org Process Res Dev 1998, 2, 3, 151.

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)	26404			C₇₂H₈₁Br₂Cl₂IO₂₂S₂	详情	详情
(II)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(III)	32739	L-2-Amino-3-methylpentanoic acid; L-isoleucine	73-32-5	C₆H₁₃NO₂	详情	详情
(IV)	32740	(2S,3S)-2-[(2-[[2-([[(1S,2S)-1-carboxy-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoic acid		C₂₆H₃₂N₂O₆S₂	详情	详情

合成路线7

该中间体在本合成路线中的序号：(VIII)

Mixed anhydride (II), prepared from N-Boc-L-norleucine (I) and isobutyl chloroformate in the presence of Et3N, was reacted with ethereal diazomethane to afford diazoketone (III). Then, homologation of (III) into b-amino ester (IV) was accomplished by treatment with silver benzoate and Et3N in MeOH. Subsequent hydrolysis of (IV) of the ester function with K2CO3 in aqueous MeOH, followed by Boc deprotection with HCl in dioxan furnished the b-amino acid (VI). After conversion to the trimethylsilyl amine with N-methyl-N-(trimethylsilyl)acetamide, amino acid (VI) was coupled with 2,2'-dithiobisbenzoyl cloride (VIII), prepared from acid (VII) and thionyl chloride, to yield the target bisamide.

参考文献中间体

合成目标

【1】 Vara Prasad, J.V.N.; Loo, J.A.; Boyer, F.E.; Stier, M.A.; Gogliotti, R.D.; Turner, W.J.; Harvey, P.J.; Kramer, M.R.; Mack, D.P.; Scholten, J.D.; Gracheck, S.J.; Domagala, J.M.; 2,2'-Dithiobisbenzamides derived from alpha-, beta- and gamma-amino acids possessing anti-HIV activities: Synthesis and structure-activity relationship. Bioorg Med Chem 1998, 6, 10, 1707.

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)	20398	(2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid		C₁₁H₂₁NO₄	详情	详情
(II)	20399	N-(Tert-butoxycarbonyl)-L-norleucine isobutoxycarbonyl anhydride		C₁₆H₂₉NO₆	详情	详情
(III)	20400	tert-butyl (1S)-1-[2-(1lambda(5)-diazynyl)acetyl]pentylcarbamate		C₁₂H₂₃N₃O₃	详情	详情
(IV)	20401	methyl (3S)-3-[(tert-butoxycarbonyl)amino]heptanoate		C₁₃H₂₅NO₄	详情	详情
(V)	20402	(3S)-3-[(tert-butoxycarbonyl)amino]heptanoic acid		C₁₂H₂₃NO₄	详情	详情
(VI)	20403	(3S)-3-aminoheptanoic acid		C₇H₁₅NO₂	详情	详情
(VII)	20404	2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid	119-80-2	C₁₄H₁₀O₄S₂	详情	详情
(VIII)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情

合成路线8

该中间体在本合成路线中的序号：(II)

Treatment of 2,2'-dithiobis(benzoic acid) (I) with thionyl chloride produced the corresponding acid chloride (II), which was further condensed with thiazolidine-2-carboxylic acid (III) in the presence of Na2CO3 to furnish diamide (IV). Reductive cleavage of the disulfide group of (IV) by means of NaBH4 in refluxing EtOH yielded thiol (V). Finally, intramolecular cyclization of (V) to give the title tricyclic compound was achieved by treatment with carbonyl diimidazole in boiling THF.

参考文献中间体

合成目标

【1】 Neamati, N.; Winslow, H.E.; Turpin, J.A.; et al.; Thiazolothiazepine inhibitors of HIV-1 integrase. J Med Chem 1999, 42, 17, 3334.
【2】 Garofalo, A.; Pommier, Y.; Neamati, N.; Nacci, V. (US Department of Health & Human Services); Thiazepine inhibitors of HIV-1 integrase. WO 0068235 .

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)	20404	2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid	119-80-2	C₁₄H₁₀O₄S₂	详情	详情
(II)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(III)	47083	1,3-thiazolidine-2-carboxylic acid		C₄H₇NO₂S	详情	详情
(IV)	47084	3-[2-([2-[(2-carboxy-1,3-thiazolidin-3-yl)carbonyl]phenyl]disulfanyl)benzoyl]-1,3-thiazolidine-2-carboxylic acid		C₂₂H₂₀N₂O₆S₄	详情	详情
(V)	47085	3-(2-sulfanylbenzoyl)-1,3-thiazolidine-2-carboxylic acid		C₁₁H₁₁NO₃S₂	详情	详情

合成路线9

该中间体在本合成路线中的序号：(I)

Condensation of 2,2’-dithiodibenzoyl chloride (I) with sulfacetamide (II) in pyridine afforded diamide (III). Reductive celavage of the disulfide bond of (III) by means of tris(2-carboxyethyl)phosphine produced the corresponding thiol (IV), which was subsequently acylated with 5-bromovaleryl chloride (V) yielding thioester (VI). Finally, displacement of the bromide with pyridine furnished the title pyridinium salt.

参考文献中间体

合成目标

【1】 Turpin, J.A.; Song, Y.; Inman, J.K.; Huang, M.; Wallqvist, A.; Maynard, A.; Covell, D.G.; Rice, W.G.; Appella, E.; Synthesis and biological properties of novel pyridinioalkanoyl thiolesters (PATE) as anti-HIV-1 agents that target the viral nucleocapsid protein zinc fingers. J Med Chem 1999, 42, 1, 67.
【2】 Song, Y.; Turpin, J.A.; Huang, M.; Inman, J.K.; Walqvist, A.; Appella, E.; Maynard, A.; Rice, W.G.; Covell, D.G. (US Department of Health & Human Services); Novel thiolesters and uses thereof. WO 9965871 .

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)	20405	2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride		C₁₄H₈Cl₂O₂S₂	详情	详情
(II)	41626	N-acetyl-4-aminobenzenesulfonamide	144-80-9	C₈H₁₀N₂O₃S	详情	详情
(III)	41627	2-[[2-([4-[(acetamido)sulfonyl]anilino]carbonyl)phenyl]disulfanyl]-N-[4-[(acetamido)sulfonyl]phenyl]benzamide		C₃₀H₂₆N₄O₈S₄	详情	详情
(IV)	41628	N-[4-[(acetamido)sulfonyl]phenyl]-2-sulfanylbenzamide	n/a	C₁₅H₁₄N₂O₄S₂	详情	详情
(V)	39700	5-bromopentanoyl chloride	4509-90-4	C₅H₈BrClO	详情	详情
(VI)	41629	S-[2-([4-[(acetamido)sulfonyl]anilino]carbonyl)phenyl] 5-bromopentanethioate		C₂₀H₂₁BrN₂O₅S₂	详情	详情

Extended Information