|
【结 构 式】 
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【分子编号】19170 【品名】ethanethioamide 【CA登记号】62-55-5 |
【 分 子 式 】C2H5NS 【 分 子 量 】75.13444 【元素组成】C 31.97% H 6.71% N 18.64% S 42.68% |
合成路线1
该中间体在本合成路线中的序号：(F)Compound can be prepared in three different related ways: 1) The reaction of 5-(o-clorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine-2-one (I) with P2S5 in pyridine at 80 C gives the corresponding thioketone (II), which by reaction with hydrazine hydrate (A) in methanol yields 2-hydrazino-5-(o-chlorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine (III). Finally, this compound is cyclized with acetic anhydride acetic acid in refluxing benzene. This cyclization can also be carried out with refluxing ethyl orthoacetate (E) and H2SO4, with acetimino ethyl ether (G) in refluxing chloroform, with acetamidine hydrochloride (C) and 2-methylimidazole (D) at 160 C or thioacetamide (F) and H2SO4 at 190 C. 2) The condensation of thioketone (II) with acetohydrazide (B) in refluxing chloroform gives 2-acetylhydrazino-5-(o-chlorophenyl)-7-ethyl-3H-thieno[2,3-e]-1,4-diazepine (IV), which is then cyclized with acetic acid in refluxing benzene or by heating at 205 C. 3) The acetylated compound (IV) can also be obtained by acetylation of (III) with acetic anhydride and triethylamine at room temperature.
| 【1】 Nakanishi, M.; et al.; ZA 7204610 . |
| 【2】 Thorpe, P.J.; Castaner, J.; Etizolam. Drugs Fut 1979, 4, 1, 22. |
| 【3】 Nakanishi, M.; et al.; US 3904641 . |
| 【4】 Tahara, T.; et al.; Syntheses and structure-activity relationship pf 6-aryl-4H-s-triazolo[3,4-c]thieno[2,3-e](1,4)diazepines. Arzneim-Forsch Drug Res 1978, 28, 7, 1153-58. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (G) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (D) | 15670 | 2-Methylimidazole; 2-Methyl-1H-imidazole | 693-98-1 | C4H6N2 | 详情 | 详情 |
| (F) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (A) | 27344 | hydrazine | 302-01-2 | H4N2 | 详情 | 详情 |
| (B) | 29262 | acetohydrazide | 1068-57-1 | C2H6N2O | 详情 | 详情 |
| (E) | 39465 | 1-ethoxy-1,1-ethanediol | C4H10O3 | 详情 | 详情 | |
| (I) | 39461 | 5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-one | C15H13ClN2OS | 详情 | 详情 | |
| (II) | 39462 | 5-(2-chlorophenyl)-7-ethyl-1,3,5a,8a-tetrahydro-2H-thieno[2,3-e][1,4]diazepine-2-thione | C15H15ClN2S2 | 详情 | 详情 | |
| (III) | 39463 | 5-(2-chlorophenyl)-7-ethyl-2-hydrazino-3H-thieno[2,3-e][1,4]diazepine | C15H15ClN4S | 详情 | 详情 | |
| (IV) | 39464 | N'-[5-(2-chlorophenyl)-7-ethyl-3H-thieno[2,3-e][1,4]diazepin-2-yl]acetohydrazide | C17H17ClN4OS | 详情 | 详情 | |
| (C) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Bromination of 6-acetylpyridine-2-carboxylic acid (I) in hot AcOH generated the alpha-bromoketone (II), which was subsequently esterified to (III) upon refluxing in MeOH. Thioamide (VI) was prepared by treatment of 3,4-diethoxybenzonitrile (IV) with thioacetamide (V) in the presence of HCl. The thiazole derivative (VII) was then obtained by condensation of bromoketone (III) with thioamide (VI) in refluxing MeOH. Finally, basic hydrolysis of the methyl ester function of (VII) provided the title carboxylic acid
| 【1】 Chihiro, M.; Nagamoto, H.; Takemura, I.; Kitano, K.; Komatsu, H.; Sekiguchi, K.; Tabusa, F.; Mori, T.; Tominaga, M.; Yabuuchi, Y.; Novel thiazole derivatives as inhibitors of superoxide production by human neutrophils: Synthesis and structure-activity relationships. J Med Chem 1995, 38, 2, 353. |
| 【2】 Chihiro, M.; Matsuzaki, T.; Nagamoto, T.; Toda, G.; Sueyoshi, S.; Mori, T.; Kitano, K.; Takemura, I.; Yamashita, H.; Kurimura, M.; Tabusa, F. (Otsuka Pharmaceutical Co., Ltd.); Cytokine production inhibitors and adhesion inhibitors. JP 1998152437; US 2002013469; US 6583163; WO 9814191 . |
| 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) | 62323 | 6-acetyl-2-pyridinecarboxylic acid | C8H7NO3 | 详情 | 详情 | |
| (II) | 62324 | C9H10BrNO3 | 详情 | 详情 | ||
| (III) | 62325 | methyl 6-(2-bromoacetyl)-2-pyridinecarboxylate | C9H8BrNO3 | 详情 | 详情 | |
| (IV) | 62326 | 3,4-diethoxybenzonitrile | C11H13NO2 | 详情 | 详情 | |
| (V) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (VI) | 62327 | 3,4-diethoxybenzenecarbothioamide | C11H15NO2S | 详情 | 详情 | |
| (VII) | 62328 | methyl 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]-2-pyridinecarboxylate | C20H20N2O4S | 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 silylation of 3(S)-hydroxytetrahydrofuran-2-one (I) with TBDMS-Cl and imidazole gives the silyl ether (II), which is methylated with MeLi in THF yields the 3(S)-(TBDMSO)-5-hydroxy-2-pentanone (IV), through the hemiketal intermediate (III). Simultaneously, the cyclization of 1,3-dichloropropanone (V) with thioacetamide (VI) in refluxing ethanol affords 4-(chloromethyl)-2-methylthiazole (VII), which is treated with tributylphosphine to provide the phosphonium salt (VIII). The condensation of (VIII) with the ketone (IV) gives the unsaturated alcohol (IX), which is oxidized to the corresponding aldehyde (X) by means of oxalyl chloride in DMSO. The condensation of (X) with 2-phosphonopropionic acid triethyl ester (XI) by means of KHMDS gives the dienoic acid ethyl ester (XII), which is reduced with DIBAL in THF yielding the corresponding primary alcohol (XIII). The condensation of (XIII) with the chiral sulfone intermediate (XIV) by means of KHMDS and PPh3 affords the corresponding adduct (XV), which is desulfurized with Na/Hg in THF/methanol giving the silylated diol (XVI). The selective monodesilylation of (XVI) with CSA in methanol/dichloromethane yields the primary alcohol (XVII), which is oxidized with Dess Martin periodinane (DMP) to the aldehyde (XVIII). The condensation of (XVIII) with the intermediate chiral ketone (XIX) by means of LDA in THF affords the hydroxy ketone (XX).
| 【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 . |
| 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) | 40815 | (3S)-3-hydroxydihydro-2(3H)-furanone | 19444-84-9 | C4H6O3 | 详情 | 详情 |
| (II) | 40816 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone | C10H20O3Si | 详情 | 详情 | |
| (III) | 40817 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol | C11H24O3Si | 详情 | 详情 | |
| (IV) | 40818 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone | C11H24O3Si | 详情 | 详情 | |
| (V) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (VI) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (VII) | 40819 | 4-(chloromethyl)-2-methyl-1,3-thiazole | C5H6ClNS | 详情 | 详情 | |
| (VIII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (IX) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (X) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XI) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (XII) | 40823 | ethyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C21H35NO3SSi | 详情 | 详情 | |
| (XIII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIV) | 40825 | tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone | C17H30O3SSi | 详情 | 详情 | |
| (XV) | 40826 | (1R,3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-1-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl phenyl sulfone; 4-[(1E,3S,5Z,8R,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-8-(phenylsulfonyl)-1,5-undecadienyl]-2-methyl-1,3-thiazole | C36H61NO4S2Si2 | 详情 | 详情 | |
| (XVI) | 40827 | tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole | C30H57NO2SSi2 | 详情 | 详情 | |
| (XVII) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XVIII) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 | |
| (XIX) | 40830 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C21H46O3Si2 | 详情 | 详情 | |
| (XX) | 40831 | (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one | C45H87NO5SSi3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The intermediate phosphonate (X) has been obtained as follows. The cyclization of thioacetamide (IV) with ethyl 3-bromopiruvate (V) in ethanol gives 2-methylthiazole-4-carboxylic acid ethyl ester (VI), which is reduced by means of LiAlH4 in ethyl ether to yield the carbinol (VII). The bromination of (VII) with CBr4 and PPh3 in CCl4 affords the 4-bromomethyl-2-methylthiazole (VIII), which is finally condensed with triethyl phosphite (IX) to provide the target phosphonate intermediate (X). Alternatively, the cyclization of thioacetamide (IV) with 1,3-dichloroacetone (XI) gives 4-(chloromethyl)-2-methylthiazole (XII), which is condensed with triethyl phosphite (IX) to also provide the target phosphonate intermediate (X).
| 【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (V) | 63904 | propyl 3-bromo-2-oxopropanoate | C6H9BrO3 | 详情 | 详情 | |
| (VI) | 63905 | propyl 2-methyl-1,3-thiazole-4-carboxylate | C8H11NO2S | 详情 | 详情 | |
| (VII) | 63906 | (2-methyl-1,3-thiazol-4-yl)methanol | C5H7NOS | 详情 | 详情 | |
| (VIII) | 63909 | 4-(bromomethyl)-2-methyl-1,3-thiazole | C5H6BrNS | 详情 | 详情 | |
| (IX) | 15487 | triethyl phosphite | 122-52-1 | C6H15O3P | 详情 | 详情 |
| (X) | 63908 | dipropyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C11H20NO3PS | 详情 | 详情 | |
| (XI) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XII) | 40819 | 4-(chloromethyl)-2-methyl-1,3-thiazole | C5H6ClNS | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The reaction of m-xylenediamine (I) with triethylamine and di-tert-butyldicarbonate (II) gives the corresponding tert-butyl N-[3-(aminomethyl)benzyl] carbamate hydrochloride (III), which is converted into the tert-butyl N-[3-((acetimidoyl)aminomethyl]benzyl) carbamate hydrochloride (VII) by reaction with S-benzylthioacetimidate hydrochloride (VI). This intermediate (VI) could be obtained by reaction of thioacetamide (IV) with benzyl chloride (V). Finally, compound (VII) is deprotected with HCl to afford the corresponding N-[3-(aminomethyl)benzyl] acetamidine hydrochloride.
| 【1】 Itabashi, K.; Takido, T.; An efficient synthesis of unsymmetrical sulfides using liquid-liquid phase transfer catalysis. Synthesis 1987, 817. |
| 【2】 Oplinger, J.A.; Garvey, E.P.; Furfine, E.S.; Shearer, B.G.; Collins, J.L. (Glaxo Wellcome plc); Acetamidine derivs. and their use as inhibitors for the nitric oxide synthase. EP 0799191; JP 1999500711; US 5866612; WO 9619440 . |
| 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) | 19167 | 3-(aminomethyl)benzylamine; [3-(aminomethyl)phenyl]methanamine | 1477-55-0 | C8H12N2 | 详情 | 详情 |
| (II) | 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 |
| (III) | 19169 | tert-butyl N-[3-(aminomethyl)benzyl]carbamate; tert-butyl 3-(aminomethyl)benzylcarbamate | 108467-99-8 | C13H20N2O2 | 详情 | 详情 |
| (IV) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (V) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (VI) | 19172 | benzyl ethanimidothioate | C9H11NS | 详情 | 详情 | |
| (VII) | 19173 | tert-butyl 3-[(ethanimidoylamino)methyl]benzylcarbamate | C15H23N3O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The intermediate phosphonate (X) has been obtained as follows. The cyclization of thioacetamide (IV) with ethyl 3-bromopiruvate (V) in ethanol gives 2-methylthiazole-4-carboxylic acid ethyl ester (VI), which is reduced by means of LiAlH4 in ethyl ether to yield the carbinol (VII). The bromination of (VII) with CBr4 and PPh3 in CCl4 affords the 4-bromomethyl-2-methylthiazole (VIII), which is finally condensed with triethyl phosphite (IX) to provide the target phosphonate intermediate (X). Alternatively, the cyclization of thioacetamide (IV) with 1,3-dichloroacetone (XI) gives 4-(chloromethyl)-2-methylthiazole (XII), which is condensed with triethyl phosphite (IX) to also provide the target phosphonate intermediate (X).
| 【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (V) | 63904 | propyl 3-bromo-2-oxopropanoate | C6H9BrO3 | 详情 | 详情 | |
| (VI) | 63905 | propyl 2-methyl-1,3-thiazole-4-carboxylate | C8H11NO2S | 详情 | 详情 | |
| (VII) | 63906 | (2-methyl-1,3-thiazol-4-yl)methanol | C5H7NOS | 详情 | 详情 | |
| (VIII) | 63909 | 4-(bromomethyl)-2-methyl-1,3-thiazole | C5H6BrNS | 详情 | 详情 | |
| (IX) | 15487 | triethyl phosphite | 122-52-1 | C6H15O3P | 详情 | 详情 |
| (X) | 63908 | dipropyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C11H20NO3PS | 详情 | 详情 | |
| (XI) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XII) | 40819 | 4-(chloromethyl)-2-methyl-1,3-thiazole | C5H6ClNS | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)By cyclization of 6-bromo-1H-indole-3-carbothioamide (V) with 6-bromo-3-(2-bromoacetyl)-1-tosyl-1H-indole (VIII) in refluxing ethanol, followed by elimina-tion of the tosyl protecting group with NaOH in refluxing methanol. The intermediates 6-bromo-1H-indole-3-carbothioamide (V) and 6-bromo-3-(2-bromoacetyl)-1-tosyl-1H-indole (VIII) have been obtained as follows: 6-Bromo-1H-indole-3-carbothioamide (V): The reaction of 6-bromoindole (I) with POCl3 and DMF, followed by hydrolysis with NaOH in refluxing water gives 6-bomoindole-3-carbaldehyde (II), which is treated with propyl nitrite and diammonium phosphate in refluxing acetic acid to yield the nitrile (III). Finally, the reaction of (III) with thioacetamide and HCl in refluxing DMF affords the interme-diate carbothioamide (V). 6-Bromo-3-(2-bromoacetyl)-1-tosyl-1H-indole (VIII): The protection of 6-bromoindole (I) with tosyl chloride and NaOH in toluene/water gives the 6-bromo-1-tosylindole (VI), which is acetylated with acetic anhydride and AlCl3 in dichloro-methane yielding the 3-acetyl derivative (VII). Finally, the bromination of (VII) with CuBr2 in refluxing ethyl acetate/chloroform affords the target 3-(bromoacetyl) derivative (VIII).
| 【1】 Wan, X.-Z.; Jiang, B.; Gu, X.-H.; Syntheses and biological activities of bis(3-indolyl)thiazoles, analogues of marine bis(indole)alkaloid nortopsentins. Bioorg Med Chem Lett 1999, 9, 4, 569. |
| 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) | 30014 | 6-Bromoindole; 6-Bromo-1H-indole | 52415-29-9 | C8H6BrN | 详情 | 详情 |
| (II) | 30013 | 6-bromo-1H-indole-3-carbaldehyde | C9H6BrNO | 详情 | 详情 | |
| (III) | 30015 | 6-bromo-1H-indole-3-carbonitrile | C9H5BrN2 | 详情 | 详情 | |
| (IV) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (V) | 30016 | 6-bromo-1H-indole-3-carbothioamide | C9H7BrN2S | 详情 | 详情 | |
| (VI) | 30017 | 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indole | C15H12BrNO2S | 详情 | 详情 | |
| (VII) | 30018 | 1-[6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl]-1-ethanone | C17H14BrNO3S | 详情 | 详情 | |
| (VIII) | 30019 | 2-bromo-1-[6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl]-1-ethanone | C17H13Br2NO3S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)The reaction of 3-formylbenzonitrile (I) with methyl 2-bromoacetate (II) by means of activated Zn in hot THF gives 3-(3-cyanophenyl)-3-hydroxypropionic acid methyl ester (III), which is oxidized with activated MnO2 in hot dichloromethane yielding the oxoester (IV). The bromination of (IV) with NBS in CCl4 affords the alpha bromo derivative (V), which is cyclized with thioacetamide (VI) in hot THF affording 4-(3-cyanophenyl)-2-methylthiazole-5-carboxylic acid methyl ester (VII). The condensation of (VII) with 4'-amino-N-tert-butylbiphenyl-2-sulfonamide (VIII) by means of trimethylaluminum in toluene/dichloromethane gives the corresponding amide (IX), which is treated with hot TFA to eliminate the ter-butyl protecting group yielding intermediate (X). Finally, the cyano group of (X) is treated first with anhydrous HCl in methanol, and finally with ammonium carbonate in the same solvent to obtain the target amidine.
| 【1】 Quan, M.L.; Pinto, D.J.P.; Fevig, J.M.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Oxygen or sulfur containing heteroaromatics as fac. WO 9828282 . |
| 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) | 13245 | 3-Formylbenzonitrile; 3-Cyanobenzaldehyde | 24964-64-5 | C8H5NO | 详情 | 详情 |
| (II) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (III) | 28346 | methyl 3-(3-cyanophenyl)-3-hydroxypropanoate | C11H11NO3 | 详情 | 详情 | |
| (IV) | 28347 | methyl 3-(3-cyanophenyl)-3-oxopropanoate | C11H9NO3 | 详情 | 详情 | |
| (V) | 28348 | methyl 2-bromo-3-(3-cyanophenyl)-3-oxopropanoate | C11H8BrNO3 | 详情 | 详情 | |
| (VI) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (VII) | 28349 | methyl 4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxylate | C13H10N2O2S | 详情 | 详情 | |
| (VIII) | 23363 | 4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide | C16H20N2O2S | 详情 | 详情 | |
| (IX) | 28350 | N-[2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]-4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxamide | C28H26N4O3S2 | 详情 | 详情 | |
| (X) | 28351 | N-[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]-4-(3-cyanophenyl)-2-methyl-1,3-thiazole-5-carboxamide | C24H18N4O3S2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)The exchange reaction of (1,5-cyclooctadiene)diiodoplatinum (I) with silver nitrate produced the platinum nitrate derivative (II). Complexation of (II) with 2,2':6',2''-terpyridine (III) produced the terpyridine-platinum complex (IV), which was subsequently treated with thioacetamide (V) to furnish the title compound.
| 【1】 Becker, K.; et al.; Human thioredoxin reductase is efficently inhibited by (2,2':6',2''-terpyridine)platinum(II) complexes. Possible implications for a novel antitumor strategy. J Med Chem 2001, 44, 17, 2784. |
| 【2】 Lowe, G. (Isis Innovation Ltd.); Platinum(II) cpds.. EP 1155025; WO 0050431 . |
合成路线10
该中间体在本合成路线中的序号：(IV)Chloroacetyl chloride (I) is condensed with bis(trimethylsilyl)acetylene (II) in the presence of AlCl3 to provide 1-chloro-4-(trimethylsilyl)-3-butyn-2-one (III). Cyclization of chloro ketone (III) with thioacetamide (IV) affords the ethynylthiazole derivative (V). Finally, palladium-catalyzed coupling of (V) with 3-bromopyridine (VI) gives rise to the target diarylacetylene.
| 【1】 Cosford, N.D.P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N.D.; Anderson, J.; Bristow, L.; Brodkin, J..; Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M.A.; 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]- pyridine: A potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J Med Chem 2003, 46, 2, 204. |
| 【2】 McDonald, I.A.; Munoz, B.; Vernier, J.-M.; Cosford, N.D.P.; Varney, M.A.; Hess, S.D.; Bleicher, L.S.; Cube, R.V.; Schweiger, E.J. (Merck & Co., Inc.); Heterocyclic cpds. and methods of use thereof. JP 2003508390; WO 0116121 . |
| 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) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (II) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (III) | 63351 | 1-chloro-4-(trimethylsilyl)-3-butyn-2-one | C7H11ClOSi | 详情 | 详情 | |
| (IV) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (V) | 63352 | 2-methyl-4-[2-(trimethylsilyl)ethynyl]-1,3-thiazole | C9H13NSSi | 详情 | 详情 | |
| (VI) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Cyclocondensation of formic hydrazide (I) with thioacetamide (II) at 150 °C gives 3-methyl-1,2,4-triazole (III), which by condensation with 7-chloro-4-methoxy-pyrrolo[2,3-c]pyridine (IV) in the presence of CuI and K2CO3 at 173 °C provides 4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine (V). Friedel-Crafts acylation of compound (V) with methyl chloro(oxo)acetate (VI) using AlCl3 in CH2Cl2/MeNO2 affords the keto ester (VII), which is hydrolyzed using NaOH in MeOH to yield the carboxylic acid (VIII). Condensation of acid (VIII) with 1-benzoylpiperazine (IX) by means of EDC and Et3N in DMF gives piperazinamide (X). Treatment of intermediate (X) with NaH and I2 in THF followed by N-alkylation of di-tert-butyl chloromethyl phosphate (XI) (obtained by the chloromethylation of the tetrabutylammonium salt of di-tert-butyl hydrogen phosphate (XII) with chloroiodomethane (XIII) optionally in benzene) in acetone/H2O, or the direct condensation of intermediate (X) with chloromethyl phosphate (XI) in the presence of CsCO3 and KI in NMP affords the di-tert-butyl phosphate ester (XIV). Finally, O-deprotection of intermediate (XIV) is performed by treatment with TFA in CH2Cl2, or by heating in acetone/H2O at 40 °C .
| 【1】 Ueda, Y., Connolly, T.P., Kadow, J.F. et al. (Bristol-Myers Squibb Co.). Prodrugs of piperazine and substituted piperidine antiviral agents. CN 101941990; US 7745625; EP 1725569; JP 2007529519; US 2005209246; WO 2005090367. |
| 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) | 15486 | formic hydrazide; Formylhydrazine | 624-84-0 | CH4N2O | 详情 | 详情 |
| (II) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (III) | 67601 | 3-methyl-1,2,4-triazole；3-Methyltriazole；3-Methyl-1H-1,2,4-triazole；3-Methyl-4H-1,2,4-triazole | 7170-01-6 | C3H5N3 | 详情 | 详情 |
| (IV) | 67602 | 7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridine | C8H7ClN2O | 详情 | 详情 | |
| (V) | 67603 | 4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine | C11H11N5O | 详情 | 详情 | |
| (VI) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (VII) | 67604 | methyl 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate | C14H13N5O4 | 详情 | 详情 | |
| (VIII) | 67605 | 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid | C13H11N5O4 | 详情 | 详情 | |
| (IX) | 67606 | 1-benzoylpiperazine;4-Benzoylpiperazine;N-Benzoylpiperazine;(Phenyl)(piperazin-1-yl)methanone | 13754-38-6 | C11H14N2O | 详情 | 详情 |
| (X) | 67607 | 1-(4-benzoylpiperazin-1-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione | C24H23N7O4 | 详情 | 详情 | |
| (XI) | 42239 | di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate；PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER | 229625-50-7 | C9H20ClO4P | 详情 | 详情 |
| (XII) | 67608 | tetra-tert-butylammonium di-tert-butyl phosphate | C8H18O4P.C16H36N | 详情 | 详情 | |
| (XIII) | 42238 | chloro(iodo)methane | 593-71-5 | CH2ClI | 详情 | 详情 |
| (XIV) | 67609 | (3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl di-tert-butyl phosphate | C33H42N7O8P | 详情 | 详情 |