(4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl diphenylphosphinate -Drug Synthesis Database

【结构式】

【分子编号】16206

【品名】(4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl diphenylphosphinate

【CA登记号】

【分子式】C₂₉H₂₇N₂O₈P

【分子量】562.515822

【元素组成】C 61.92% H 4.84% N 4.98% O 22.75% P 5.51%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XI)

The hydrolysis of N-(tert-butoxycarbonyl)-4(R)-(tert-butyldimethylsilyloxy)-L-proline methyl ester (I) with NaOH gives the corresponding protected amino acid (II), which is condensed with malonic acid monomethyl ester (II) by means of carbonyldiimidazole (CDI) in THF to afford the L-prolylacetate (IV). The reduction of (IV) with NaBH4 in refluxing THF-methanol gives (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-(1,3-dihydroxypropyl)pyrrolidine (V), which is acylated with tosyl chloride to the primary monotosylate (VI). The chromatographic separation of (VI) over SiO2 yields the [2S(1'R),4R]-enantiomer (VII), which by treatment first with methylamine followed by 4,6-dimethyl-2-(4-nitrobenzyloxycarbonylthio)pyrimidine (PNZ-Pym) affords the N-protected methylamino derivative (VIII). The mesylation of (VIII) with methanesulfonyl chloride followed by reaction with potassium thioacetate gives (2S,4S)-4-acetylthio-2-[1(R)-hydroxy-3-(4-nitrobenzyloxycarbonylamino) propyl]-1-(4-nitrobenzyl)pyrrolidine (IX), which is treated with NaOH in methanol-water to afford the corresponding thiol (X). The condensation of (X) with (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester (XI) by means of diisopropylethylamine in acetonitrile yields the protected compound (XII), which is finally hydrolyzed and deprotected by hydrogenation with H2 over Pd/C and treatment with HCl.

参考文献中间体

合成目标

【1】 Nakagawa, S.; Kato, S.; Murase, S.; Okamoto, O.; Mitomo, R.; Yamamoto, K.; Yamada, K.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); Aminoalkylpyrrolidinylthiocarbapenem derivs. EP 0545290; JP 1994087858; US 5550121; WO 9311128 .
【2】 Graul, A.; Rabasseda, X.; Castaner, J.; Prous, J.; BO-2727. Drugs Fut 1994, 19, 8, 731.
【3】 Rabasseda, X.; Prous, J.; Castaner, J.; Biapenem. Drugs Fut 1994, 19, 7, 631.

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)	16196	1-(tert-butyl) 2-methyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate		C₁₇H₃₃NO₅Si	详情	详情
(II)	16197	(2S,4R)-1-(tert-butoxycarbonyl)-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₆H₃₁NO₅Si	详情	详情
(III)	16198	3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester	16695-14-0	C₄H₆O₄	详情	详情
(IV)	16199	tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-methoxy-3-oxopropanoyl)tetrahydro-1H-pyrrole-1-carboxylate		C₁₉H₃₅NO₆Si	详情	详情
(V)	16200	tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(1,3-dihydroxypropyl)tetrahydro-1H-pyrrole-1-carboxylate		C₁₈H₃₇NO₅Si	详情	详情
(VI)	16201	tert-butyl (2S,4R)-2-[3-[(benzylsulfonyl)oxy]-1-hydroxypropyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1-carboxylate		C₂₅H₄₃NO₇SSi	详情	详情
(VII)	16202	tert-butyl (2S,4R)-2-[(1R)-3-[(benzylsulfonyl)oxy]-1-hydroxypropyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1-carboxylate		C₂₅H₄₃NO₇SSi	详情	详情
(VIII)	16203	4-nitrobenzyl (2S,4R)-4-hydroxy-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate		C₂₄H₂₈N₄O₁₀	详情	详情
(IX)	16204	4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate		C₂₆H₃₀N₄O₁₀S	详情	详情
(X)	16205	4-nitrobenzyl (2S,4S)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-4-sulfanyl-1-pyrrolidinecarboxylate		C₂₄H₂₈N₄O₉S	详情	详情
(XI)	16206	(4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl diphenylphosphinate		C₂₉H₂₇N₂O₈P	详情	详情
(XII)	16207	4-nitrobenzyl (2S,4S)-4-([(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrophenyl)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]sulfanyl)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate		C₄₁H₄₄N₆O₁₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The chiral epoxide (VIII) was prepared as follows. 4-Hydroxy-3-nitroacetophenone (I) was protected as the silyl derivative (II) and then subjected to a Baeyer-Villiger rearrangement to afford the phenol acetate ester (III). Hydrogenation of the nitro group of (III) over Raney nickel provided aniline (IV), which was acylated by methanesulfonyl chloride producing sulfonamide (V). After protection of the sulfonamide NH of (V) with Boc2O, basic hydrolysis of the acetate ester furnished phenol (VI). Mitsunobu coupling between phenol (VI) and (R)-glycidol (VII) led to the glycidyl ether (VIII).

参考文献中间体

合成目标

【1】 Mulvey, R.; Ashwell, M.A.; Solvibile, W.R. Jr.; Han, S.; Tillet, J.; Largis, E.; 4-Aminopiperidine ureas as potent selective agonists of the human beta3-adrenergic receptor. Bioorg Med Chem Lett 2001, 11, 24, 3123.

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)	20626	1-(4-hydroxy-3-nitrophenyl)-1-ethanone	6322-56-1	C₈H₇NO₄	详情	详情
(II)	59660	1-(4-{[tert-butyl(diphenyl)silyl]oxy}-3-nitrophenyl)-1-ethanone		C₂₄H₂₅NO₄Si	详情	详情
(III)	59661	4-{[tert-butyl(diphenyl)silyl]oxy}-3-nitrophenyl acetate		C₂₄H₂₅NO₅Si	详情	详情
(IV)	59662	3-amino-4-{[tert-butyl(diphenyl)silyl]oxy}phenyl acetate		C₂₄H₂₇NO₃Si	详情	详情
(V)	59663	4-{[tert-butyl(diphenyl)silyl]oxy}-3-[(methylsulfonyl)amino]phenyl acetate		C₂₅H₂₉NO₅SSi	详情	详情
(VI)	59664	tert-butyl 2-{[tert-butyl(diphenyl)silyl]oxy}-5-hydroxyphenyl(methylsulfonyl)carbamate		C₂₈H₃₅NO₆SSi	详情	详情
(VII)	16206	(4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl diphenylphosphinate		C₂₉H₂₇N₂O₈P	详情	详情
(VIII)	59665	tert-butyl 2-{[tert-butyl(diphenyl)silyl]oxy}-5-[(2S)oxiranylmethoxy]phenyl(methylsulfonyl)carbamate		C₃₁H₃₉NO₇SSi	详情	详情

Extended Information