allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】50605

【品名】allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate

【CA登记号】

【分子式】C₁₈H₃₄N₂O₅SSi

【分子量】418.62994

【元素组成】C 51.64% H 8.19% N 6.69% O 19.11% S 7.66% Si 6.71%

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：(XV)

Reaction of 4,9(11)-androstadien-3,17-dione (III) with trimethyl orthoformate and TsOH in dioxane gives 3-methoxy-3,5,9(11)-androstatrien-17-one (XI), which is condensed with 1,2-dichloroethylene (XII) by means of MeLi in ethyl ether/THF to yield 17a-(chloroethynyl)-17b-hydroxy-4,9(11)-androstadien-3-one (XIII). Esterification of the OH group of (XIII) with fuming HNO3 and acetic anhydride affords the 17b-(nitrooxy) derivative (XIV), which is treated with formic acid and AgNO3 in N-methylpyrrolidone to provide 21-chloro-17a-(formyloxy)-4,9(11)-pregnadien-3,20-dione (XV). Hydrolysis of the formyloxy group of (XV) by means of KHCO3 in methanol/water gives 21-chloro-17a-hydroxy-4,9(11)-pregnadien-3,20-dione (XVI), which is finally acetylated by means of AcOK and KI in hot DMF.

参考文献中间体

合成目标

【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039.
【2】 Annen, K.; Laurent, H.; Wiechert, R.; Hofmeister, H. (Schering AG); Process for the preparation of pregnane deriv.. DE 3434448; EP 0181442; US 4708823 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	56595	(8S,10R,13S,14S)-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione		C₁₉H₂₄O₂	详情	详情
(XI)	18040	(8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one		C₂₀H₂₆O₂	详情	详情
(XII)	28793	(Z)-1,2-dichloroethene	156-59-2	C₂H₂Cl₂	详情	详情
(XIII)	56603	(8S,10R,13S,14S,17S)-17-(2-chloroethynyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₅ClO₂	详情	详情
(XIV)	56604	(8S,10R,13S,14S,17S)-17-(2-chloroethynyl)-10,13-dimethyl-17-(nitrooxy)-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₄ClNO₄	详情	详情
(XV)	50605	allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate		C₁₈H₃₄N₂O₅SSi	详情	详情
(XVI)	56606	(8S,10R,13S,14S,17R)-17-(2-chloroacetyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₇ClO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The condensation of the formyl pyrrolidine (I) with ethyl (triphenylphosphoranylidene)acetate (II) in dichloromethane gives acrylate (III), which is reduced with DIBAL in THF to yield the substituted allyl alcohol (IV). The condensation of (IV) with phthalimide (V) by means of PPh3 and DEAD in THF affords the adduct (VI), which is treated with hydrazine ethanol to provide the amino derivative (VII). The reaction of (VII) with Ms-Cl and TEA in dichloromethane gives the sulfonamide (VIII), which is desilylated by means of TBAF in THF, yielding the pyrrolidinol (IX). The reaction of (IX) with Ms-Cl and TEA in dichloromethane affords the sulfonate (X), which is treated with potassium thioacetate in refluxing acetonitrile to provide the acetylsulfanylpyrrolidine (XI). The hydrolysis of (XI) with NaOH in methanol gives the thiol (XII), which is condensed with the carbapenem derivative (XIII) by means of DIEA in acetonitrile to yield the protected adduct (XIV). Finally, this compound is treated with PdCl2(PPh3)2 and Bu3SnH in dichloromethane in order to eliminate the allyl protecting groups.

参考文献中间体

合成目标

【1】 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 .

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)	50600	allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate		C₁₅H₂₇NO₄Si	详情	详情
(II)	14182	ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane	1099-45-2	C₂₂H₂₁O₂P	详情	详情
(III)	50601	allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-ethoxy-3-oxo-1-propenyl]-1-pyrrolidinecarboxylate		C₁₉H₃₃NO₅Si	详情	详情
(IV)	50602	allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-hydroxy-1-propenyl]-1-pyrrolidinecarboxylate		C₁₇H₃₁NO₄Si	详情	详情
(V)	12376	Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione	85-41-6	C₈H₅NO₂	详情	详情
(VI)	50603	allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-1-pyrrolidinecarboxylate		C₂₅H₃₄N₂O₅Si	详情	详情
(VII)	50604	allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate		C₁₇H₃₂N₂O₃Si	详情	详情
(VIII)	50605	allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate		C₁₈H₃₄N₂O₅SSi	详情	详情
(IX)	50606	allyl (2S,4R)-4-hydroxy-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate		C₁₂H₂₀N₂O₅S	详情	详情
(X)	50598	allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate		C₁₃H₂₂N₂O₇S₂	详情	详情
(XI)	49451	allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate		C₁₄H₂₂N₂O₅S₂	详情	详情
(XII)	49452	allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate		C₁₂H₂₀N₂O₄S₂	详情	详情
(XIII)	32617	allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₅H₂₆NO₈P	详情	详情
(XIV)	49454	allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate		C₂₅H₃₅N₃O₈S₂	详情	详情

Extended Information