-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(1R,5S,6S)-6-[1(R)-Hydroxyethyl]-2-[5(S)-[3-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl]pyrrolidin-3(S)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid isomer 1

【CA登记号】

【分子式】C₁₈H₂₅N₃O₆S

【分子量】411.48045

【开发单位】LG Chem (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems

合成路线1 合成路线2

合成路线1

Treatment of trans-4-hydroxy-L-proline (I) with p-nitrobenzyl chloroformate gave the N-protected 4-hydroxyproline (II), which was esterified to afford the N-protected methyl ester (II). Protection of the hydroxyl group of (III) with t-butyl-dimethylsilyl chloride in the presence of imidazole, followed by reduction of the resulting ester (IV) with lithium borohydride, provided the alcohol (V). This was oxidized using pyridine-sulfur trioxide complex to give the formylpyrrolidine (VI). The vinylpyrrolidine (VII) was obtained by Wittig reaction of aldehyde (VI) with methylene triphenylphosphorane. Dipolar cycloaddition of the nitrile oxide resulting from ethyl chlorooximidoacetate (VIII) and Et3N to vinylpyrrolidine (VII) gave iso-oxazolidine (IX) as a mixture of diastereoisomers. After desilylation of (IX) with tetrabutylammonium fluoride, the resulting alcohol (X) was converted into the diastereomeric mixture of mesylates (XI). Chromatographic separation of the required isomer, followed by reduction with LiBH4, yielded alcohol (XII).

参考文献中间体

【1】 Park, S.W.; Yoo, K.H.; Shin, K.J.; Kang, Y.K.; Hong, C.Y.; Seo, K.J.; Park, S.Y.; Lee, C.-S.; Kim, D.J.; Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety. Bioorg Med Chem Lett 2000, 10, 2, 95.

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)	14489	(2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline	51-35-4	C₅H₉NO₃	详情	详情
(II)	22581	(2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid		C₁₃H₁₄N₂O₇	详情	详情
(III)	44922	2-methyl 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate		C₁₄H₁₆N₂O₇	详情	详情
(IV)	44923	2-methyl 1-(4-nitrobenzyl) (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,2-pyrrolidinedicarboxylate		C₂₀H₃₀N₂O₇Si	详情	详情
(V)	44924	4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-1-pyrrolidinecarboxylate		C₁₉H₃₀N₂O₆Si	详情	详情
(VI)	44925	4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate		C₁₉H₂₈N₂O₆Si	详情	详情
(VII)	44926	4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-vinyl-1-pyrrolidinecarboxylate		C₂₀H₃₀N₂O₅Si	详情	详情
(VIII)	30424	2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride	14337-43-0	C₄H₆ClNO₃	详情	详情
(IX)	44927	ethyl (5R)-5-((2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate		C₂₄H₃₅N₃O₈Si	详情	详情
(X)	44928	ethyl (5R)-5-((2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate		C₁₈H₂₁N₃O₈	详情	详情
(XI)	44929	ethyl (5R)-5-((2S,4R)-4-[(methylsulfonyl)oxy]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate		C₁₉H₂₃N₃O₁₀S	详情	详情
(XII)	44930	4-nitrobenzyl (2S,4R)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate		C₁₇H₂₁N₃O₉S	详情	详情

合成路线2

Displacement of the mesylate group of (XII) with potassium thioacetate gave thioester (XIII), which was further hydrolyzed to thiol (XIV). This was condensed with enol phosphate (XV) to afford the protected 1-methylcarbapenem (XVI). Finally, deprotection of the p-nitrobenzyl groups of (XVI) by zinc powder in the presence of phosphate buffer (pH 6.0) provided the title compound.

参考文献中间体

【1】 Park, S.W.; Yoo, K.H.; Shin, K.J.; Kang, Y.K.; Hong, C.Y.; Seo, K.J.; Park, S.Y.; Lee, C.-S.; Kim, D.J.; Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety. Bioorg Med Chem Lett 2000, 10, 2, 95.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	44930	4-nitrobenzyl (2S,4R)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate		C₁₇H₂₁N₃O₉S	详情	详情
(XIII)	44931	4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-1-pyrrolidinecarboxylate		C₁₈H₂₁N₃O₇S	详情	详情
(XIV)	44932	4-nitrobenzyl (2S,4S)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-4-sulfanyl-1-pyrrolidinecarboxylate		C₁₆H₁₉N₃O₆S	详情	详情
(XV)	13224	4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	90776-59-3	C₂₉H₂₇N₂O₁₀P	详情	详情
(XVI)	44933	4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[((3S,5S)-5-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₃₃H₃₅N₅O₁₂S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)