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【结 构 式】 
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【分子编号】24086 【品名】benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetate 【CA登记号】 |
【 分 子 式 】C25H25N3O6S 【 分 子 量 】495.55612 【元素组成】C 60.59% H 5.08% N 8.48% O 19.37% S 6.47% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of 2-(tert-butoxycarbonylmethoxyimino)-2-(4 thiazolyl)acetic acid (I) with 7-amino 3-cephem-4-carboxylic acid (II) by means of the Vusmejer reagent (POCl3 and dimethylformamide) in ethyl acetate gives 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (III), which is then de protected with trifluoroacetic acid and anisole in methylene chloride. The starting acetic acid derivative (I) can be obtained by several different ways: 1) The partial hydrolysis of 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4yl) acetic acid (IV) with concentrated HCl in methanol gives 2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid (V), which is then deaminated with tert butyl nitrite in refluxing THF. 2) The preceding deamination of (IV) can be performed in a similar way with previous esterification with diphenyldiazomethane, through compounds (VI), (VII) and (VIII). Compound (VIII) is submitted to a partial hydrolysis with trifluoroacetic acid. 3) Compound (I) can also be obtained by condensation of 2-(4-thiazolylglyoxylic acid (IX) with tert-butyl-2-(aminooxy)acetate (X) by means of NaHCO3 in ethyl acetate.
| 【1】 Takaya, T.; Takasugi, H.; Yamanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Cephem compounds. EP 0071891; US 4515788; US 4649136; US 4736039 . |
| 【2】 Prous, J.; Castaner, J.; FK-089. Drugs Fut 1986, 11, 2, 103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 | |
| (A) | 23003 | Diphenyldiazomethane | C13H10N2 | 详情 | 详情 | |
| (I) | 24081 | 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetic acid | C11H14N2O5S | 详情 | 详情 | |
| (II) | 24082 | 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C7H8N2O3S | 详情 | 详情 | |
| (III) | 24083 | 7-[[2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C18H20N4O7S2 | 详情 | 详情 | |
| (IV) | 24084 | 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid | C12H15N3O6S | 详情 | 详情 | |
| (V) | 24085 | 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetic acid | C11H15N3O5S | 详情 | 详情 | |
| (VI) | 24086 | benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetate | C25H25N3O6S | 详情 | 详情 | |
| (VII) | 24087 | benzhydryl 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetate | C24H25N3O5S | 详情 | 详情 | |
| (VIII) | 24088 | benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetate | C24H24N2O5S | 详情 | 详情 | |
| (IX) | 24089 | 2-oxo-2-(1,3-thiazol-4-yl)acetic acid | C5H3NO3S | 详情 | 详情 | |
| (X) | 24090 | tert-butyl 2-(aminooxy)acetate | C6H13NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The condensation of 2-fluoronitrobenzene (I) with acetone oxime (II) by means of NaH in DMF gives acetone O-(2-nitrophenyl)oxime (III), which is cyclized to 2-methyl-7-nitrobenzofuran (IV) by means of H2SO4. The Friedel Crafts acylation of (IV) with acetyl chloride and AlCl3 in dichloromethane affords 3-acetyl-2-methyl-7-nitrobenzofuran (V), which is reduced to the corresponding amino derivative (VI) with Fe and HCl in ethanol. The condensation of (VI) with 2,6-dichlorobenzoyl chloride (VII) by means of triethylamine in dichloroethane yields N-(3-acetyl-2-methylbenzofuran-7-yl)-2,6-dichlorobenzamide (VIII), which is finally submitted to a Grignard reaction with methylmagnesium bromide in THF.
| 【1】 Yamazaki, H.; et al.; Synthesis and pharmacological activities of novel benzofuran derivatives as vacuolar type H+-ATPase inhibitors. Symp Med Chem 1998, Abst 2-P-32. |
| 【2】 Kawai, Y.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K.; Yatabe, T.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Benzofuran derivs. useful as inhibitors of bone resorption. EP 0757682; JP 1997512795; US 5858995; WO 9529907 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 17791 | acetone oxime; Acetoxime | 127-06-0 | C3H7NO | 详情 | 详情 |
| (III) | 25083 | acetone O-(2-nitrophenyl)oxime | C9H10N2O3 | 详情 | 详情 | |
| (IV) | 25084 | 2-methyl-7-nitro-1-benzofuran | C9H7NO3 | 详情 | 详情 | |
| (V) | 25086 | 1-(7-amino-2-methyl-1-benzofuran-3-yl)-1-ethanone | C11H11NO2 | 详情 | 详情 | |
| (VI) | 24086 | benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetate | C25H25N3O6S | 详情 | 详情 | |
| (VII) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (VIII) | 25088 | N-(3-acetyl-2-methyl-1-benzofuran-7-yl)-2,6-dichlorobenzamide | C18H13Cl2NO3 | 详情 | 详情 |