Ciclesonide, BTR-15, B-9207-015, BY-9010, Alvesco, -Drug Synthesis Database

【结构式】

【药物名称】Ciclesonide, BTR-15, B-9207-015, BY-9010, Alvesco

【化学名称】(R)-11beta,16alpha,17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with cyclohexanecarboxaldehyde, 21-isobutyrate
　　　　　　16alpha,17alpha-[(R)-Cyclohexylmethylenedioxy]-11beta-hydroxy-21-(isobutyryloxy)pregna-1,4-dien-3-one

【CA登记号】126544-47-6, 141845-82-1 (deleted CAS)

【分子式】C₃₂H₄₄O₇

【分子量】540.70328

【开发单位】Altana (Originator), Teijin (Licensee), Aventis Pharma (Codevelopment)

【药理作用】Asthma Therapy, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Corticosteroids

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

参考文献中间体

【1】应明华，关定伟，陈鸿鹏．2005．一锅法制备淡尼橙龙衍生物，发明专利公开说明书．CN1699395A

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)	32675	(8S,9S,10R,11S,13S,14S,16R,17S)-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		C₂₁H₂₈O₆	详情	详情
(II)	22334	1-methylpropionic anhydride	97-72-3	C₈H₁₄O₃	详情	详情
(III)	38915	2-[(10R,11S,13S,16R,17S)-11-hydroxy-16,17-bis(isobutyryloxy)-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-methylpropanoate		C₃₃H₄₆O₉	详情	详情
(V)	38917	2-[(4aR,5S,6aS,8R,9aR)-8-cyclohexyl-5-hydroxy-4a,6a-dimethyl-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 2-methylpropanoate		C₃₂H₄₄O₇	详情	详情

合成路线2

参考文献中间体

【1】彭璃螭，赣开智．2004．一种哮啮治疗药物环索奈德的新的制备方法，发明专7f4V开说明书，CN1626546A

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)	66189	2-((6aS,7R,8aR,8bR)-7-hydroxy-6a,8a,10,11a-tetramethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethyl isobutyrate		C₂₈H₃₈O₇	详情	详情
(II)	33694	cyclohexanecarbaldehyde	2043-61-0	C₇H₁₂O	详情	详情
(III)	38917	2-[(4aR,5S,6aS,8R,9aR)-8-cyclohexyl-5-hydroxy-4a,6a-dimethyl-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 2-methylpropanoate		C₃₂H₄₄O₇	详情	详情

合成路线3

参考文献中间体

【1】 Pierluigi R,MacDonald P.2007.Improved process for the preparation of ciclesonide. W0 2007056181

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)	22334	1-methylpropionic anhydride	97-72-3	C₈H₁₄O₃	详情	详情
(II)	66190	(6aS,7R,8aR,8bR,11aS,12bR)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a,10,10-tetramethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4(2H)-one		C₂₄H₃₂O₆	详情	详情
(III)	66191	(6aR,7S,8aS,8bS,11aR,12bS)-7-hydroxy-8b-isobutyryl-6a,8a,10,10-tetramethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4(2H)-one		C₂₆H₃₆O₅	详情	详情
(IV)	38916	2-[(4aR,5S,6aS,8S,9aR)-8-cyclohexyl-5-hydroxy-4a,6a-dimethyl-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 2-methylpropanoate		C₃₂H₄₄O₇	详情	详情
(IV)	33694	cyclohexanecarbaldehyde	2043-61-0	C₇H₁₂O	详情	详情

合成路线4

参考文献中间体

【1】 Amschler H,Flockerzi D,Gutterer B 1998. Process for R-epimer enrichmmt of16,17-acetalderivatives of 21-acyloxyprqWrl,4-dien-11,16,17-trlol-3,20-dione. W09809982

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)	66192	(6aS,7R,8aR,8bR,11aS,12bR)-10-cyclohexyl-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-4(2H)-one		C₂₈H₃₈O₆	详情	详情
(II)	22334	1-methylpropionic anhydride	97-72-3	C₈H₁₄O₃	详情	详情

合成路线5

The acylation of 11beta,16alpha,17alpha,21-tetrahydroxypregna-1,4-diene-3,20-dione (I) with isobutyric anhydride in pyridine gives the 16,17,21-triester (III), which is condensed with cyclohexanecarbaldehyde (IV) by means of HCl and HClO4 in dioxane yielding the cyclic ketal (Va-b) as a diastereomeric mixture. Finally, this mixture is resolved by preparative HPLC over Lichrosorb RP-18 affording the desired (R)-isomer, the target compound. Alternatively, the monoacylation of the ketal 11beta,16alpha,17alpha,21-tetrahydroxypregan-1,4-diene-3,20-dione 16,17-O-cyclohexylmethylene ketal (VI) with isobutyric anhydride (II) by means of K2CO3 in acetone gives the previously described diastereomeric mixture (Va-b), which is resolved by crystallization in ethanol/water.

参考文献中间体

【1】 Calatayud, J.; Conde, J.R.; Luna, M. (Byk Elmu SA); Acetals and esters of 16alpha-hydroxyprednisolone and fluocinolone. BE 1005876; CH 683343; DE 4129535; ES 2034893; FR 2666585; GB 2247680; JP 1992257599; US 5482934 .
【2】 Gutterer, B.; Amschler, H.; Flockerzi, D. (Byk Gulden Lomberg Chemische Fabrik GmbH); Process for R-epimer enrichment of 16,17-acetal derivs. of 21-acyloxy pregnan-1,4-dien-11beta,16alpha,17alpha-triol-3,20-dione derivs.. DE 19635498; WO 9809982 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Va)	38916	2-[(4aR,5S,6aS,8S,9aR)-8-cyclohexyl-5-hydroxy-4a,6a-dimethyl-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 2-methylpropanoate		C₃₂H₄₄O₇	详情	详情
(Vb)	38917	2-[(4aR,5S,6aS,8R,9aR)-8-cyclohexyl-5-hydroxy-4a,6a-dimethyl-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 2-methylpropanoate		C₃₂H₄₄O₇	详情	详情
(I)	32675	(8S,9S,10R,11S,13S,14S,16R,17S)-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		C₂₁H₂₈O₆	详情	详情
(II)	22334	1-methylpropionic anhydride	97-72-3	C₈H₁₄O₃	详情	详情
(III)	38915	2-[(10R,11S,13S,16R,17S)-11-hydroxy-16,17-bis(isobutyryloxy)-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-methylpropanoate		C₃₃H₄₆O₉	详情	详情
(IV)	33694	cyclohexanecarbaldehyde	2043-61-0	C₇H₁₂O	详情	详情
(VI)	38918	(4aR,5S,6aS,6bS,9aR)-8-cyclohexyl-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-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		C₂₈H₃₈O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)