(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one -Drug Synthesis Database

【结构式】

【分子编号】46292

【品名】(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one

【CA登记号】

【分子式】C₂₄H₃₀F₂O₆

【分子量】452.4954064

【元素组成】C 63.71% H 6.68% F 8.4% O 21.21%

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：(VI)

This compound has been obtained by several related ways: 1. The selective reduction of 6alpha,9alpha-difluoro-16alpha-prednisolone (I) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,16alpha,17alpha,21-tetrahydroxypregn-4-ene-3,20-dione (II), which is cyclized with butanal (III) catalyzed by HClO4 in dioxane to yield the butylidenedioxy derivative (IV) as a diastereomeric mixture. Finally, the desired (R)-diastereomer is separated by column chromatography over Sephadex LH-20. 2. By selective reduction of 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregna-1,4-diene-3,20-dione (V) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol. 3. The selective reduction of fluocinolone acetonide (VI) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,21-dihydroxy-16alpha,17alpha-(isopropylidenedioxy)pregen-4-ene-3,20-dione (VII), which is then treated with butanal (III) and HClO4 over SiO2 in heptane.

参考文献中间体

合成目标

【1】 Andersson, P.; Axelsson, B.; Brattssand, R.; Thalen, A. (AstraZeneca plc); Novel steroids. JP 1994505232; US 5674861; US 5939409; WO 9213872 .

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)	47567	(6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₆F₂O₆	详情	详情
(II)	47568	(6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₈F₂O₆	详情	详情
(III)	23694	butyraldehyde	123-72-8	C₄H₈O	详情	详情
(IV)	47569	(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₅H₃₄F₂O₆	详情	详情
(V)	47570	(4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₅H₃₂F₂O₆	详情	详情
(VI)	46292	(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₄H₃₀F₂O₆	详情	详情
(VII)	47571	(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₄H₃₂F₂O₆	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 intermediate 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregn-4-ene-3,20-dione (V) has been obtained in several related ways: 1. The selective reduction of 6alpha, 9alpha-difluoro-16alpha-prednisolone (I) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,16alpha,17alpha,21-tetrahydroxypregn-4-ene-3,20-dione (II), which is cyclized with butanal (III) catalyzed by HClO4 in dioxane to yield the butylidenedioxy derivative (IV) as a diastereomeric mixture. Finally, the desired (R)-diastereomer, the intermediate (V), is separated by column chromatography over Sephadex LH-20. 2. The selective reduction of 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregna-1,4-diene-3,20-dione (VI) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol also yields intermediate (V). 3. The selective reduction of fluocinolone acetonide (VII) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,21-dihydroxy-16alpha,17alpha-(isopropylidenedioxy)pregen-4-ene-3,20-dione (VIII), which is then treated with butanal (III) and HClO4 over SiO2 in heptane to afford intermediate (V). The target compound is finally obtained by esterification of intermediate (V) with hexadecanoyl chloride (IX) in pyridine.

参考文献中间体

合成目标

【1】 Axelsson, B.; Brattsand, R.; Kallstrom, L.; Thalen, A. (AstraZeneca plc); Novel steroid esters. JP 1994505233; US 5614514; US 5888995; WO 9213873 .
【2】 Andersson, P.; Axelsson, B.; Brattssand, R.; Thalen, A. (AstraZeneca plc); Novel steroids. JP 1994505232; US 5674861; US 5939409; WO 9213872 .

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)	47567	(6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₆F₂O₆	详情	详情
(II)	47568	(6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₈F₂O₆	详情	详情
(III)	23694	butyraldehyde	123-72-8	C₄H₈O	详情	详情
(IV)	47569	(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₅H₃₄F₂O₆	详情	详情
(V)	47572	(4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₅H₃₄F₂O₆	详情	详情
(VI)	47570	(4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₅H₃₂F₂O₆	详情	详情
(VII)	46292	(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₄H₃₀F₂O₆	详情	详情
(VIII)	47571	(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one		C₂₄H₃₂F₂O₆	详情	详情
(IX)	16480	Palmitoyl Chloride; hexadecanoyl chloride	112-67-4	C₁₆H₃₁ClO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Fluocinolone acetonide (I) was selectively mesylated at the primary alcohol group by means of methanesulfonyl chloride and pyridine. Treatment of the resulting mesylate (II) with alpha-mercapto-gamma-butyrolactone (IV) in the presence of NaH in THF produced the desired thioether derivative.

参考文献中间体

合成目标

【1】 Burgess, C.M.; Biggadike, K.; Angell, R.M.; et al.; Selective plasma hydrolysis of glucocorticoid gamma-lactones and cyclic carbonates by the enzyme paraoxonase: An ideal plasma inactivation mechanism. J Med Chem 2000, 43, 1, 19.
【2】 Farrell, R.M.; Biggadike, K. (Glaxo Wellcome Inc.); 21-(2-Oxo-tetrahydrofuran)-thio pregnane derivs., a process for their production and pharmaceutical compsns. containing them. US 6013244; WO 9724367 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	46292	(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one	C₂₄H₃₀F₂O₆	详情	详情
(II)	46293	2-[(4aS,4bR,5S,6aS,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a,8,8-tetramethyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-6-yl]-2-oxoethyl methanesulfonate	C₂₅H₃₂F₂O₈S	详情	详情
(III)	46294	3-sulfanyldihydro-2(3H)-furanone	C₄H₆O₂S	详情	详情

Extended Information