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【结 构 式】 
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【分子编号】20404 【品名】2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid 【CA登记号】119-80-2 |
【 分 子 式 】C14H10O4S2 【 分 子 量 】306.363 【元素组成】C 54.89% H 3.29% O 20.89% S 20.93% |
合成路线1
该中间体在本合成路线中的序号：(IX)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).
| 【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2
该中间体在本合成路线中的序号：(V)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.
| 【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3
该中间体在本合成路线中的序号：(V)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.
| 【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4
该中间体在本合成路线中的序号：(VII)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.
| 【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5
该中间体在本合成路线中的序号：(I)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.
| 【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6
该中间体在本合成路线中的序号：(I)2,2'-Dithiosalicylic acid (I) is activated as the bis-succinimidyl ester (II) upon treatment with N-hydroxysuccinimide and DIC. Coupling of the active ester (II) with 3-aminopropionamide (III) gives rise to the corresponding dithiosalicylamide (IV). Reductive cleavage of the disulfide bond of (IV) using tris(2-carboxyethyl)phosphine (TCEP) affords thiol (V). The desired thiolcarbamate is then obtained by condensation of (V) with tert-butyl isocyanate in DMF.
| 【1】 Goel, A.; et al.; Benzamide-based thiocarbamates: A new class of HIV-1 NCp7 inhibitors. Bioorg Med Chem Lett 2002, 12, 5, 767. |
| 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) | 58510 | 1-({2-[(2-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}phenyl)disulfanyl]benzoyl}oxy)-2,5-pyrrolidinedione | C22H16N2O8S2 | 详情 | 详情 | |
| (III) | 58511 | 3-aminopropanamide | C3H8N2O | 详情 | 详情 | |
| (IV) | 58512 | N-(3-amino-3-oxopropyl)-2-[(2-{[(3-amino-3-oxopropyl)amino]carbonyl}phenyl)disulfanyl]benzamide | C20H22N4O4S2 | 详情 | 详情 | |
| (V) | 58513 | N-(3-amino-3-oxopropyl)-2-sulfanylbenzamide | C10H12N2O2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIX)In an alternative method, reaction of 6-nitroindazole (I) with iodine and K2CO3 gives the 3-iodo derivative (II), which is protected as the 1-tetrahydropyranyl indazole (XIV) with dihydropyran and methanesulfonic acid. Palladium-catalyzed coupling of iodoindazole (XIV) with 2-vinylpyridine (XV), followed by reduction of the resulting adduct (XVI) with iron and NH4Cl, provides the THP-protected 6-amino-3-(pyridylvinyl)indazole (XVII). After diazotization of aminoindazole (XVII) with NaNO2/HCl in AcOH, treatment of the intermediate diazonium salt with I2/KI yields the 6-iodoindazole (XVIII). The intermediate 2-mercapto-N-methylbenzamide (XXI) is prepared as follows. 2,2’-Dithiosalicylic acid (XIX) is chlorinated with SOCl2, followed by condensation with methylamine, to give the dithiosalicylamide (XX), which is reductively cleaved to the mercaptobenzamide (XXI) employing NaBH4. Then, coupling between iodoindazole (XVIII) and 2-mercapto-N-methylbenzamide (XXI) by means of PdCl2(dppf)2 and Cs2CO3 affords the tetrahydropyranyl-protected axitinib (XXII), which is finally deprotected by treatment with p-toluenesulfonic acid in hot MeOH (2). Scheme 2.
| 【2】 Babu, S., Dagnino, R. Jr., Ouellette, M.A., Shi, B., Tian, Q., Zook, S.E. (Pfizer, Inc.). Methods for preparing indazole compounds. WO 2006048745. |
| 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) | 65335 | 6-Nitroindazole | 7597-18-4 | C7H5N3O2 | 详情 | 详情 |
| (II) | 65336 | 3-Iodo-6-nitroindazole; 3-Iodo-6-nitro-1H-indazole | 70315-70-7 | C7H4IN3O2 | 详情 | 详情 |
| (XIV) | 65347 | 3-Iodo-6-nitro-1-tetrahydropyranyl-1H-indazole | C13H12IN3O3 | 详情 | 详情 | |
| (XV) | 65348 | 2-vinylpyridine | 100-69-6 | C7H7N | 详情 | 详情 |
| (XVI) | 65349 | 6-Nitro-3-(pyrid-2-ylvinyl)-1-tetrahydropyranyl-1H-indazole | C19H18N4O3 | 详情 | 详情 | |
| (XVII) | 65350 | 6-Amino-3-(pyrid-2-ylvinyl)-1-tetrahydropyranyl-1H-indazole | C19H20N4O | 详情 | 详情 | |
| (XVIII) | 65351 | 6-Iodo-3-(pyrid-2-ylvinyl)-1-tetrahydropyranyl-1H-indazole | C19H18IN3O | 详情 | 详情 | |
| (XIX) | 20404 | 2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid | 119-80-2 | C14H10O4S2 | 详情 | 详情 |
| (XX) | 31248 | N-methyl-2-([2-[(methylamino)carbonyl]phenyl]disulfanyl)benzamide | 2527-58-4 | C16H16N2O2S2 | 详情 | 详情 |
| (XXI) | 65352 | 2-Mercapto-N-methylbenzamide | 20054-45-9 | C8H9NOS | 详情 | 详情 |
| (XXII) | 65353 | C27H26N3O2S | 详情 | 详情 |