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【结 构 式】 
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【分子编号】48462 【品名】2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid；(Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetic acid 【CA登记号】128438-01-7 |
【 分 子 式 】C24H19N3O3S 【 分 子 量 】429.49928 【元素组成】C 67.12% H 4.46% N 9.78% O 11.18% S 7.47% |
合成路线1
该中间体在本合成路线中的序号：(VI)Conversion of alcohol (I) into chloro derivative (II) by reaction with PCl3 in DMF, followed by reaction with PCl5/pyridine in CH2Cl2, treatment with iBuOH and acidic treatment with TsOH, provides 7-amino-3-chlorocephalosporanic acid diphenylmethyl ester toluene sulfonic acid salt (III). Separately, O-protection of thiazole derivative (IV) by reaction with TrtCl and tert-BuOK in THF affords trityl protected compound (V), whose ethyl carboxylate group is hydrolyzed by means of KOH in EtOH to furnish carboxylic acid (VI). Chlorination of the thiazol ring of (VI) by means of N-chlorosuccinimide (NCS) in DMF yields chlorothiazole derivative (VII), which is then condensed with 7-amino-3-chlorocephalosporanic acid derivative (III) by means of POCl3 in THF to give acetamido derivative (VIII). Separately, the synthesis of pyridine derivative (XIV) is performed by following these steps: alkylation of chloropyridine (IX) by means of LDA and ethyl formate provides derivative (X), which is then reduced by means of NaBH4 to furnish alcohol (XI). Finally, (XIV) is obtained by first chlorination of (XI) with SOCl2 in DMF to afford chloromethyl derivative (XII), and subsequent condensation of (XII) with N-Boc-ethanethiol (XIII) either by means of Et3N in CH2Cl2 or by means of NaI and DIEA in DMF. Treatment of derivative (VIII) with NaSH in DMF, followed by coupling with chloropyridine derivative (XIV) in DMF, furnishes compound (XV), which is finally converted into the desired product by protecting groups removal with TFA/anisole or TFA/triethylsilane in CH2Cl2, and treatment with MsOH in H2O.
| 【1】 Hecker, S.J.; et al.; Discovery of RWJ-54428 (MC-02,479), a new cephaolosporin active against resistant Gram-positive bacteria. J Antibiot 2000, 53, 11, 1272. |
| 【2】 Glinka, T.W.; et al.; SAR studies of anti-MRSA non-zwitterionic 3-heteroarylthiocephems. J Antibiot 2000, 53, 10, 1045. |
| 【3】 Cho, I.-S.; Hecker, S.; Glinka, T.; Lee, V.J.; Zhang, Z.J. (Microcide Pharmaceuticals, Inc.); Cephalosporin antibiotics. EP 0874854; JP 1999513670; US 6057312; US 6066630; US 6087355; WO 9713772 . |
| 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) | 37977 | benzhydryl (6R,7R)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H24N2O5S | 详情 | 详情 | |
| (II) | 48459 | benzhydryl (6R,7R)-3-chloro-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H23ClN2O4S | 详情 | 详情 | |
| (III) | 48460 | (6R,7R)-2-[(benzhydryloxy)carbonyl]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-aminium 4-methylbenzenesulfonate | C27H25ClN2O6S2 | 详情 | 详情 | |
| (IV) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
| (V) | 48461 | (Z)-ethyl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate；ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetate | C26H23N3O3S | 详情 | 详情 | |
| (VI) | 48462 | 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid；(Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetic acid | 128438-01-7 | C24H19N3O3S | 详情 | 详情 |
| (VII) | 48463 | 2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid | C24H18ClN3O3S | 详情 | 详情 | |
| (VIII) | 48464 | benzhydryl (6R,7R)-7-([2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetyl]amino)-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C44H33Cl2N5O5S2 | 详情 | 详情 | |
| (IX) | 32889 | 4-chloropyridine | 7379-35-3 | C5H4ClN | 详情 | 详情 |
| (X) | 48465 | ethyl 4-chloro-2-pyridinecarboxylate | C8H8ClNO2 | 详情 | 详情 | |
| (XI) | 48466 | (4-chloro-2-pyridinyl)methanol | C6H6ClNO | 详情 | 详情 | |
| (XII) | 48467 | 4-chloro-2-(chloromethyl)pyridine | C6H5Cl2N | 详情 | 详情 | |
| (XIII) | 33079 | tert-butyl 2-sulfanylethylcarbamate | C7H15NO2S | 详情 | 详情 | |
| (XIV) | 48468 | tert-butyl 2-[[(4-chloro-2-pyridinyl)methyl]sulfanyl]ethylcarbamate | C13H19ClN2O2S | 详情 | 详情 | |
| (XV) | 48469 | benzhydryl (6R,7R)-7-([2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetyl]amino)-3-([2-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-4-pyridinyl]sulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C57H52ClN7O7S4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)
| 【1】 Huwiler A,Teund L.Production of 2-(2-aminothiazole-4-yl)-2- (syn)-methoxyimino acetic esters:EP,Patent 45,005,1982. |
| 【2】 胡艾希，徐娟娟，伍小云.氨噻肟酸乙酯的合成.中国医药工业杂 志.2206,37.229 |
| 【3】 程清蓉，刘志雄，李翔，等.去甲氨噻肟酸乙酯的合成研究.化学世界，2007,48:480 |
| 【4】 郑庚修，李贺，赵叶青.制备去甲氨噻肟酸乙酯的方法：CN,Patent 101,007,793,2007. |
| 【5】 Defossa E,Fischer G,Gerlach U,et al.Synthesis of HR 916 K.Am efficient route to the pure diastereomers of the 1-(pivaloyloxy)ethyl esters of cephalosporins.Liebigs Annalen,1996,(11):1743. |
| 【6】 Yamanaka H,Chiba T,Kawabata K,et al.Studies on β-lactam antibiotics.IX.Synthesis and biological activity of new orally active cephalosporin,cefixime(FK027).J Antibiotics,1985,38:1738. |
| 【7】 Takaya T,Takasugi H,Masugi T,et al.7-Acylamino-3-substituted cephalosporanic acid derivatives,processes for their preparation and pharmaceutical compositions containing them:EP,Patent 29,557,1995. |
| 【8】 Kameyama Y,Fukae K.Method for producing 3-vinyl-cephem compound:JP,Patent 2,001,294,590,2001. |
| 【9】 Takaya T,Shirai F,Nakamura H,et al.Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer):EP,Patent 304,019,1989. |
| 【10】 Lee GS,Chang YK,Chun JP,et al.Process for preparation of cefdinir:WO,Patent 9,724,358,1997. |
| 【11】 Sturm H,Wolf S,Ludescher J.Crystalline amine salt of cefdinir:WO,Patent 9,845,299,1998. |
| 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) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (II) | 39961 | ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate | C6H8ClNO4 | 详情 | 详情 | |
| (III) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
| (IV) | 48461 | (Z)-ethyl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate；ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetate | C26H23N3O3S | 详情 | 详情 | |
| (V) | 48462 | 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid；(Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetic acid | 128438-01-7 | C24H19N3O3S | 详情 | 详情 |
| (VI) | 69620 | 1-(2,5-dimethoxyphenyl)propan-2-amine (Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate | C24H19N3O3S.C11H17NO2 | 详情 | 详情 | |
| (VII) | 69619 | (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)ethanethioate | C31H22N4O2S3 | 详情 | 详情 | |
| (VIII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |