benzhydryl (6R,7R)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】37977

【品名】benzhydryl (6R,7R)-3-hydroxy-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

【CA登记号】

【分子式】C₂₈H₂₄N₂O₅S

【分子量】500.57504

【元素组成】C 67.18% H 4.83% N 5.6% O 15.98% S 6.41%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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：(I)

Alternatively, derivative (XV) can be obtained from the corresponding mesylate derivative: Treatment of alcohol (I) with MsCl and Et3N in CH2Cl2 yields methansulfonyl derivative (XVI), which is then converted into mesylated aminochlorocephalosporanic acid derivative (XVII) by following these steps: First treatment with metachloroperbenzoic acid (MCPBA) in dichloromethane, followed by reaction with KI and Tf2O in acetonitrile, chlorination with PCl5 and pyridine in dichloromethane, treatment with iBuOH and acidic treatment with TosOH. Condensation of derivative (XVII) with 7-chlorothiazole derivative (VII) by means of (PhO)2POCl in THF provides acetamido derivative (XVIII), which is then treated with chloropyridine derivative (XIV) and NaSH in DMF in DMF to afford compound (XV).

参考文献中间体

合成目标

【1】 Glinka, T.W.; et al.; SAR studies of anti-MRSA non-zwitterionic 3-heteroarylthiocephems. J Antibiot 2000, 53, 10, 1045.

中间体序号	中间体编号	品名	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
(VII)	48463	2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid	C₂₄H₁₈ClN₃O₃S	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
(XVI)	48470	benzhydryl (6R,7R)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₁H₃₀N₂O₅S₂	详情	详情
(XVII)	48471	(6R,7R)-2-[(benzhydryloxy)carbonyl]-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-aminium 4-methylbenzenesulfonate	C₃₀H₃₂N₂O₇S₃	详情	详情
(XVIII)	48472	benzhydryl (6R,7R)-7-([2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetyl]amino)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₄₇H₄₀ClN₅O₆S₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The title compound has been prepared by two related procedures: Treatment of 3-hydroxy cephem derivative (I) with methanesulfonyl chloride and K2CO3 afforded mesylate (II), which was condensed with 2-mercapto-5-methyl-1,3,4-thiadiazole (III) in the presence of potassium tert-butoxide to give thioether (IV). The benzhydryl ester of (IV) was then deprotected by treatment with trifluoroacetic acid.

参考文献中间体

合成目标

【1】 Tawara, S.; Sasaki, H.; Matsumoto, S.; Takasugi, H.; Yoshida, Y.; Matsumoto, Y.; Matsuda, K.; Studies of anti-Helicobacter pylori agents. Part 2: New cephem derivatives. Bioorg Med Chem 2000, 8, 9, 2317.
【2】 Sasaki, H.; Takasugi, H.; Matsumoto, Y.; Yoshida, Y.; Matsuda, K.; Matsumoto, s.; Synthesis and anti-Helicobacter pylori activity of FR182024, a new cephem derivative. Bioorg Med Chem Lett 1999, 9, 21, 3123.
【3】 Yoshida, Y.; Sasaki, H.; Matsuda, K.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Cephem cpds. and pharmaceutical use thereof. EP 0796263; JP 1998510258; WO 9617850 .

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)	25091	benzhydryl (6R,7R)-3-[(methylsulfonyl)oxy]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₉H₂₆N₂O₇S₂	详情	详情
(III)	37978	5-methyl-1,3,4-thiadiazole-2-thiol; 5-methyl-1,3,4-thiadiazol-2-ylhydrosulfide	29490-19-5	C₃H₄N₂S₂	详情	详情
(IV)	37979	benzhydryl (6R,7R)-3-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₃₁H₂₆N₄O₄S₃	详情	详情

Extended Information