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【结 构 式】 
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【分子编号】33079 【品名】tert-butyl 2-sulfanylethylcarbamate 【CA登记号】 |
【 分 子 式 】C7H15NO2S 【 分 子 量 】177.26764 【元素组成】C 47.43% H 8.53% N 7.9% O 18.05% S 18.09% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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：(IV)The condensation of 1,3-dichloroacetone (I) with thiourea (II) provided 2-amino-4-(chloromethyl)thiazole (III). Further displacement of the chlorine atom of (III) with N-Boc-2-mercaptoethylamine (IV) gave thioether (V). Thiocyanation of the thiazole ring of (V) using thiocyanogen, generated from KSCN and Br2, provided (VI). Reductive cleavage of the thiocyanate group of (VI) with NaBH4 gave rise to the mercaptothiazole (VII), which was subsequently coupled with the chlorocephem (VIII) to yield adduct (IX). Incorporation of a N-Boc-alanine unit to (IX) to afford (XI) was then achieved by condensation with N-Boc-alanine pentafluorophenyl ester (X) in 1,2-dichloroethane. Finally, the protecting groups of (XI) were cleaved by treatment with trifluoroacetic acid in the presence of triethylsilane.
| 【1】 Glinka, T.; Price, M.; Halas, S.; Calkins,T.; Frith, R.; Nudelman, G.; Whitehead, C.; Cho, A.; Hecker, S.; Ludwikow, M.; Chamberland, S.; Crawford, J.; Lee, V.; Design, synthesis and in vitro antibacterial properties of novel 3-heteroarylthio cephems with anti-MRSA activity: Amino acid prodrug approach to solubility improvement. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F391. |
| 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) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 33078 | 4-(chloromethyl)-1,3-thiazol-2-amine; 4-(chloromethyl)-1,3-thiazol-2-ylamine | C4H5ClN2S | 详情 | 详情 | |
| (IV) | 33079 | tert-butyl 2-sulfanylethylcarbamate | C7H15NO2S | 详情 | 详情 | |
| (V) | 33080 | tert-butyl 2-[[(2-amino-1,3-thiazol-4-yl)methyl]sulfanyl]ethylcarbamate | C11H19N3O2S2 | 详情 | 详情 | |
| (VI) | 33081 | tert-butyl 2-([[2-amino-5-(cyanosulfanyl)-1,3-thiazol-4-yl]methyl]sulfanyl)ethylcarbamate | C12H18N4O2S3 | 详情 | 详情 | |
| (VII) | 33082 | tert-butyl 2-[[(2-amino-5-sulfanyl-1,3-thiazol-4-yl)methyl]sulfanyl]ethylcarbamate | C11H19N3O2S3 | 详情 | 详情 | |
| (VIII) | 33083 | benzyl 3-chloro-7-([2-[4-chloro-2-(tritylamino)-1,3-thiazol-5-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C57H43Cl2N5O5S2 | 详情 | 详情 | |
| (IX) | 33084 | benzyl 3-([2-amino-4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,3-thiazol-5-yl]sulfanyl)-7-([2-[4-chloro-2-(tritylamino)-1,3-thiazol-5-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C68H61ClN8O7S5 | 详情 | 详情 | |
| (X) | 33085 | 2,3,4,5,6-pentafluorophenyl (2S)-2-[(tert-butoxycarbonyl)amino]propanoate | C14H14F5NO4 | 详情 | 详情 | |
| (XI) | 33086 | benzyl 3-[[4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-5-yl]sulfanyl]-7-([2-[4-chloro-2-(tritylamino)-1,3-thiazol-5-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; benzyl 3-[[4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-5-yl]sulfanyl]-7-([2-[4-chloro-2-(tritylamino)-1,3-thiazol-5-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C76H74ClN9O10S5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)Borane reduction of 3-tert-butylthiopyridine-2-carboxylic acid (X) provided alcohol (XI), which was chlorinated to (XII) with SOCl2 and subsequently displaced with N-Boc-2-mercaptoethylamine (XIII), yielding thioether (XIV). Acid deprotection of the tert-butyl groups of (XIV), followed by air oxidation in the presence of FeCl3, produced the dimeric disulfide (XV). This was reprotected with Boc2O to afford the biscarbamate (XVI). Disulfide (XVI) was reduced in situ with PPh3 to the corresponding thiol, which was coupled with the cephem mesylate (IX) to produce adduct (XVII). The title compound was finally obtained by cleavage of the protecting groups of (XVII) by means of trifluoroacetic acid.
| 【1】 Griffith, D.; Blais, J.; Hevker, S.; Price, M.; Huie, K.; Halas, S.; Cho, A.; Dudley, M.; Lee, V.; Ludwikow, M.; Chen, S.; Chemberland, S.; Glinka, T.; Discovery of novel anti-MRSA cephalosporin RWJ-333441 (MC-04,546). Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in a series of (3-heteroarylthio)cephems. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1071. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 45485 | benzhydryl (6R,7R)-7-([2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetyl]amino)-3-[(methylsulfonyl)oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C46H38N6O10S3 | 详情 | 详情 | |
| (X) | 45486 | 3-(tert-butylsulfanyl)-2-pyridinecarboxylic acid | 178811-41-1 | C10H13NO2S | 详情 | 详情 |
| (XI) | 45487 | [3-(tert-butylsulfanyl)-2-pyridinyl]methanol | C10H15NOS | 详情 | 详情 | |
| (XII) | 45488 | 3-(tert-butylsulfanyl)-2-(chloromethyl)pyridine; tert-butyl 2-(chloromethyl)-3-pyridinyl sulfide | C10H14ClNS | 详情 | 详情 | |
| (XIII) | 33079 | tert-butyl 2-sulfanylethylcarbamate | C7H15NO2S | 详情 | 详情 | |
| (XIV) | 45489 | tert-butyl 2-([[3-(tert-butylsulfanyl)-2-pyridinyl]methyl]sulfanyl)ethylcarbamate | C17H28N2O2S2 | 详情 | 详情 | |
| (XV) | 45490 | 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]ethylamine; 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]-1-ethanamine | C16H22N4S4 | 详情 | 详情 | |
| (XVI) | 45491 | tert-butyl 2-([[3-([2-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-3-pyridinyl]disulfanyl)-2-pyridinyl]methyl]sulfanyl)ethylcarbamate | C26H38N4O4S4 | 详情 | 详情 | |
| (XVII) | 45492 | benzhydryl (6R,7R)-3-([2-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-3-pyridinyl]sulfanyl)-7-([2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C58H54N8O9S4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)Borane reduction of 3-tert-butylthiopyridine-2-carboxylic acid (X) provided alcohol (XI), which was chlorinated to (XII) with SOCl2 and subsequently displaced with N-Boc-2-mercaptoethylamine (XIII), yielding thioether (XIV). Acid deprotection of the tert-butyl groups of (XIV), followed by air oxidation in the presence of FeCl3, produced the dimeric disulfide (XV). This was acylated with the protected aspartate pentafluorophenyl ester (XVI) to afford the diamide (XVII). Disulfide (XVII) was reduced in situ with PPh3 to the corresponding thiol, which was coupled with the cephem mesylate (IX) to produce adduct (XVIII). The title compound was finally obtained by cleavage of the protecting groups of (XVIII) by means of trifluoroacetic acid.
| 【1】 Hecker, S.J.; et al.; Prodrugs of anti-MRSA cephalosporin RWJ-333441 (MC-04,546) with improved aqueous solubility. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1076. |
| 【2】 Griffith, D.; Blais, J.; Hevker, S.; Price, M.; Huie, K.; Halas, S.; Cho, A.; Dudley, M.; Lee, V.; Ludwikow, M.; Chen, S.; Chemberland, S.; Glinka, T.; Discovery of novel anti-MRSA cephalosporin RWJ-333441 (MC-04,546). Relationships between structure, antibacterial activity, serum stability, pharmacokinetics and efficacy in a series of (3-heteroarylthio)cephems. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1071. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 45485 | benzhydryl (6R,7R)-7-([2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetyl]amino)-3-[(methylsulfonyl)oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C46H38N6O10S3 | 详情 | 详情 | |
| (X) | 45486 | 3-(tert-butylsulfanyl)-2-pyridinecarboxylic acid | 178811-41-1 | C10H13NO2S | 详情 | 详情 |
| (XI) | 45487 | [3-(tert-butylsulfanyl)-2-pyridinyl]methanol | C10H15NOS | 详情 | 详情 | |
| (XII) | 45488 | 3-(tert-butylsulfanyl)-2-(chloromethyl)pyridine; tert-butyl 2-(chloromethyl)-3-pyridinyl sulfide | C10H14ClNS | 详情 | 详情 | |
| (XIII) | 33079 | tert-butyl 2-sulfanylethylcarbamate | C7H15NO2S | 详情 | 详情 | |
| (XIV) | 45489 | tert-butyl 2-([[3-(tert-butylsulfanyl)-2-pyridinyl]methyl]sulfanyl)ethylcarbamate | C17H28N2O2S2 | 详情 | 详情 | |
| (XV) | 45490 | 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]ethylamine; 2-[([3-[(2-[[(2-aminoethyl)sulfanyl]methyl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]-1-ethanamine | C16H22N4S4 | 详情 | 详情 | |
| (XVI) | 45493 | 4-(tert-butyl) 1-(2,3,4,5,6-pentafluorophenyl) (2S)-2-[(tert-butoxycarbonyl)amino]butanedioate | C19H22F5NO6 | 详情 | 详情 | |
| (XVII) | 45494 | tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-([2-[([3-[(2-[(7S)-7-[2-(tert-butoxy)-2-oxoethyl]-11,11-dimethyl-6,9-dioxo-10-oxa-2-thia-5,8-diazadodec-1-yl]-3-pyridinyl)disulfanyl]-2-pyridinyl]methyl)sulfanyl]ethyl]amino)-4-oxobutanoate | C42H64N6O10S4 | 详情 | 详情 | |
| (XVIII) | 45495 | benzhydryl (6R,7R)-3-[(2-[(7S)-7-[2-(tert-butoxy)-2-oxoethyl]-11,11-dimethyl-6,9-dioxo-10-oxa-2-thia-5,8-diazadodec-1-yl]-3-pyridinyl)sulfanyl]-7-([2-[5-[(methoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1 | C66H67N9O12S4 | 详情 | 详情 |