(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone -Drug Synthesis Database

【结构式】

【分子编号】13538

【品名】(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone

【CA登记号】50-24-8

【分子式】C₂₁H₂₈O₅

【分子量】360.45032

【元素组成】C 69.98% H 7.83% O 22.19%

与该中间体有关的原料药合成路线共 8 条

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6 合成路线7 合成路线8

合成路线1

该中间体在本合成路线中的序号：(I)

The esterification of prednisolone (I) with ethyl orthocarbonate (II) by means of p-toluenesulfonic acid in dioxane gives prednisolone 17,21-(diethylorthocarbonate) (III), which is carefully hydrolyzed with acetic acid water yielding cyclic prednisolone 17-(ethyl carbonate) (IV). Finally, this compound is esterified with propionyl chloride or propionyl anhydride in pyridine or CH2Cl2-dimethylaminopyridine, respectively.

参考文献中间体

合成目标

【1】 Zhao, H.-W.; Li, X.-Y.; Ginkgolide A, B, and huperzine A inhibit nitric oxide production from rat C6 and human BT325 glioma cells. Acta Pharm Sin 1999, 20, 10, 941.
【2】 Prous, J.; Castaner, J.; Prednicarbate. Drugs Fut 1986, 11, 6, 460.

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)	13538	(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone	50-24-8	C₂₁H₂₈O₅	详情	详情
(II)	28711	1-(triethoxymethoxy)ethane	78-09-1	C₉H₂₀O₄	详情	详情
(III)	24004	2',2'-Diethoxy-11-beta-hydroxyspiro[androsta-1,4-diene-17,4'-[1,3]-dioxane]-3,5'-dione; 2',2'-Diethoxy-11-beta-hydroxyspiro[androsta-1,4-diene-17,4'-[1,3]-dioxane]-3,5'-dione		C₂₆H₃₆O₇	详情	详情
(IV)	24005	ethyl (11S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl carbonate		C₂₄H₃₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

A new synthesis of rimexolone from prednisolone has been described: The reaction of prednisolone (I) with tosyl chloride in pyridine gave the 21-tosylate (II), which was treated with sodium iodide in acetone to yield the 21-iodo derivative (III). The deiodination of (III) with refluxing acetic acid afforded 21-deoxyprednisolone (IV), which was dehydrated with semicarbazide in water at 80-5 C yielding the trienone (V). The silylation of (V) with TMS-Cl and pyridine gave the protected compound (VI), which was methylated with methyl iodide and lithium bis(trimethylsilyl)amide to the 21-methyl derivative (VII). A new methylation of (VII) with Me2Cu(CN)Li2 followed by silylation with TMS-Cl afforded the silylated dimethyl enol ether (VIII), which was submitted to a third methylation with methyl iodide and benzyltrimethylammonium fluoride in THF giving the silylated 16,17,21-trimethyl derivative (IX). Finally, this compound is desilylated to rimexolone with 6M HCl in methanol.

参考文献中间体

合成目标

【1】 Conrow, R.E.; Synthesis of the 16alpha,17alpha,21-trimethyl corticosteroid rimexolone from prednisolone. J Org Chem 1999, 64, 3, 1042.

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)	13538	(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone	50-24-8	C₂₁H₂₈O₅	详情	详情
(II)	28673	2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-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 4-methylbenzenesulfonate		C₂₈H₃₄O₇S	详情	详情
(III)	28674	(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-iodoacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₇IO₄	详情	详情
(IV)	28680	(8S,9S,10R,11S,13S,14S,17R)-17-acetyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₈O₄	详情	详情
(V)	28675	(8S,9S,10R,11S,13S,14S)-17-acetyl-11-hydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15-decahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₁H₂₆O₃	详情	详情
(VI)	28676	(8S,9S,10R,11S,13S,14S)-17-acetyl-10,13-dimethyl-11-[(trimethylsilyl)oxy]-6,7,8,9,10,11,12,13,14,15-decahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₄H₃₄O₃Si	详情	详情
(VII)	28677	(8S,9S,10R,11S,13S,14S)-10,13-dimethyl-17-propionyl-11-[(trimethylsilyl)oxy]-6,7,8,9,10,11,12,13,14,15-decahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₅H₃₆O₃Si	详情	详情
(VIII)	28678	(8S,9S,10R,11S,13S,14S,16R)-10,13,16-trimethyl-11-[(trimethylsilyl)oxy]-17-[(Z)-1-[(trimethylsilyl)oxy]propylidene]-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthren-3(6H)-one		C₂₉H₄₈O₃Si₂	详情	详情
(IX)	28679	(8S,9S,10R,11S,13S,14S,16R,17S)-10,13,16,17-tetramethyl-17-propionyl-11-[(trimethylsilyl)oxy]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one		C₂₇H₄₂O₃Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

P16CM is synthesized from prednisolone (I) via the key 16,17-dehydro intermediate (III). The compound (III) is prepared by literature procedures from prednisolone by its conversion to prednisolone 17,21-diacetate (II), followed by a potassium acetate-induced acyloxy elimination reaction. Michael addition to (III) with KCN provides the 21-acetoxy-16alpha-cyano compound, which is deprotected at C-21 and reprotected with a base-stable tetrahydropyranyl (THP) group to provide (IV). A base hydrolysis of (IV), followed by deprotection at C-21 and esterification at the 16-carboxylate, gives (V), the 17-desoxy analogue of P16CM. 17alpha-Hydroxylation of (V) via the intermediate 17,20-enol acetate, using dilute peroxyacetic acid solution at low temperature, yields P16CM.

参考文献中间体

合成目标

【1】 Salce, L.; Hazen, G.C.; Schoenwaldt, E.F.; J Org Chem 1970, 35, 1681.
【2】 Teraporewala, I.B.; Kim, H.P.; Heiman, A.S.; Lee, H.J.; A novel class of local antiinflammatory steroids. 1st communication: Analogues of methyl 11beta,17alpha,21-trihydroxy-3,20-dioxopregna-1,4-diene-16alpha -carboxylate. Arzneim-Forsch Drug Res 1989, 398, 21.
【3】 Lee, H.J. (Florida Agricultural and Mechanical Univ.); Anti-inflammatory carboxy pregnane derivatives. US 4762919; WO 8705028 .
【4】 Lee, H.-J.; Taraporewala, I.B.; P16CM. Drugs Fut 1989, 14, 10, 960.

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)	13538	(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone	50-24-8	C₂₁H₂₈O₅	详情	详情
(II)	21357	(10R,11S,13S,17R)-17-[2-(acetoxy)acetyl]-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl acetate		C₂₅H₃₂O₇	详情	详情
(III)	21358	2-[(10R,11S,13S)-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15-decahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate		C₂₃H₂₈O₅	详情	详情
(IV)	21359	(10R,11S,13S,16R,17S)-11-hydroxy-10,13-dimethyl-3-oxo-17-[3-(tetrahydro-2H-pyran-2-yloxy)propanoyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-16-carbonitrile		C₂₈H₃₇NO₅	详情	详情
(V)	21360	methyl (10R,11S,13S,16R,17S)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-16-carboxylate		C₂₃H₃₀O₆	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

By reaction of prednisolone (11beta,12alpha-dihydroxypregna-1,4-diene-3,20-dione) (I) with either I) 2E,6E-farnesylic acid (3,7,11-trimethyl-2(E),6(E),10-dodecatrienoic acid (II) with a suitable condensing agent (e.g., DDC) and a disubstituted aminopyridine (e.g., DMAP) in an organic solvent (e.g., CH2Cl2), or II) 2E,6E-farnesylic anhydride (III) in the presence of DMAP in CH2Cl2, or with III) 2E,6E-farnesilyl chloride (IV) in the presence of pyridine in a mixture of CH2Cl2 and THF.

参考文献中间体

合成目标

【1】 Mizushima, Y.; Hoshi, K.; Igarashi, R.; Ajioka, H.; Yamamoto, N.; Komuro, M.; Kanehira, K.; Inoue, M.; Nishida, T.; Shiono, M.; Terasawa, M.; Arizono, K. (Kuraray Co., Ltd.; Taiho Pharmaceutical Co., Ltd.); 11beta,17alpha-Trihydroxy-1,4-pregnadiene-3,20-dione 21-[(E,E)-3,7,11-trimethyl-2,6,10-dodecatrienoate]. EP 0332143; JP 1989316396; JP 1989316397; US 5278156 .
【2】 Okada, M.; Kanehira, K. (Kuraray Co., Ltd.; Taiho Pharmaceutical Co., Ltd.); Anti-asthmatic agents. JP 1991223214 .
【3】 Castaner, J.; Graul, A.; Prous, J.; Prednisolone Farnesylate. Drugs Fut 1993, 18, 9, 805.

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)	13538	(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone	50-24-8	C₂₁H₂₈O₅	详情	详情
(II)	13539	(2E,6E)-3,7,11-Trimethyl-2,6,10-dodecatrienoic acid		C₁₅H₂₄O₂	详情	详情
(III)	13540	(2E,6E)-2,6,10-Trimethyl-2,6,10-dodecatrienoic anhydride		C₃₀H₄₆O₃	详情	详情
(IV)	13541	(2E,6E)-3,7,11-Trimethyl-2,6,10-dodecatrienoyl chloride		C₁₅H₂₃ClO	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

The oxidation of 11beta,17,21-trihydroxypregnan-1,4-diene-3,20-dione (I) with sodium metaperiodate in THF/methanol gives 11beta,17alpha-dihydroxy-3-oxoandrosta-1,4-diene-17beta-carboxylic acid (II), which is treated with ethyl chloroformate and triethylamine in dichloromethane yielding 17alpha-(ethoxycarbonyloxy)-11beta-hydroxy-3-oxoandrosta-1,4-diene-17beta-carboxylic acid (III). Finally, this compound is esterified with chloromethyl iodide and NaOH in methanol/water.

参考文献中间体

合成目标

【1】 Graul, A.; Martin, L.; Castaner, J.; Loteprednol Etabonate. Drugs Fut 1997, 22, 10, 1086.
【2】 Bodor, N.S. (N.S. Bodor); Steroids with antiinflammatory activity. BE 0889563; US 4996335 .
【3】 Druzgala, P.; Hochhaus, G.; Bodor, N.; Soft drugs - 10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: Loteprednol etabonate. J Steroid Biochem Mol Biol 1991, 38, 2, 149-154.

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)	13538	(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone	50-24-8	C₂₁H₂₈O₅	详情	详情
(II)	14612	(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid		C₂₀H₂₆O₅	详情	详情
(III)	14613	(8S,9S,10R,11S,13S,14S,17R)-17-[(ethoxycarbonyl)oxy]-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid		C₂₃H₃₀O₇	详情	详情

合成路线6

该中间体在本合成路线中的序号：(III)

The title compound is prepared by two alternative methods. Sulfonation of benzoic acid (I) with hot chlorosulfonic acid affords 3-carboxybenzenesulfonyl chloride (II). After conversion of (II) to the pyridine complex, coupling with prednisolone (III) produces the target 21-sulfobenzoate ester, which is finally isolated as the title sodium salt by treatment with aqueous NaOH.

参考文献中间体

合成目标

【1】 Girault, P.; Allais, A. (Aventis Pharma SA); Process for the preparation of 21-m-sulfo benzoates of DELTA1,4-dehydrocorticosteroids. US 3032568 .

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)	10202	Benzoic acid	65-85-0	C₇H₆O₂	详情	详情
(II)	59291	3-(Chlorosulfonyl)benzoic acid; m-(Chlorosulfonyl)benzoic acid	4025-64-3	C₇H₅ClO₄S	详情	详情
(III)	13538	(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone	50-24-8	C₂₁H₂₈O₅	详情	详情

合成路线7

该中间体在本合成路线中的序号：(I)

The esterification of prednisolone (I) with 4-(chloromethyl)benzoyl chloride (II) by means of TEA in THF gives the corresponding benzoate (II),which is treated with silver nitrate in refluxing acetonitrile/THF to yield the target nitrate ester.

参考文献中间体

合成目标

【1】 Del Soldato, P.; Ongini, E. (NicOx SA); New corticosteroids. WO 0364443 .

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)	13538	(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone	50-24-8	C₂₁H₂₈O₅	详情	详情
(II)	49112	4-(Chloromethyl)benzoyl chloride; p-(Chloromethyl)benzoyl chloride	876-08-4	C₈H₆Cl₂O	详情	详情
(III)	64757	2-(11,17-dihydroxy-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 4-(chloromethyl)benzoate		C₂₉H₃₃ClO₆	详情	详情

合成路线8

该中间体在本合成路线中的序号：(I)

The oxidative cleavage of prednisolone (I) using sodium metaperiodate produces carboxylic acid (II). Regioselective esterification of diol (II) with dichloroacetyl chloride (III) under phase-transfer conditions gives the 17-ester (IV). The title ethyl ester is then obtained by esterification of (IV) with iodoethane in the presence of NaHCO3 and tetrabutylammonium hydrogensulfate.

参考文献中间体

合成目标

【1】 Bodor, N.S. (Soft Drugs, Inc.); Androstene derivs.. WO 9742214 .

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)	13538	(8S,9S,10R,11S,13S,14S,17R)-17-Glycoloyl-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one; Prednisolone	50-24-8	C₂₁H₂₈O₅	详情	详情
(II)	14612	(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid		C₂₀H₂₆O₅	详情	详情
(III)	17829	2,2-dichloroacetyl chloride; dichloroacetyl chloride	79-36-7	C₂HCl₃O	详情	详情
(IV)	58347	(8S,9S,10R,11S,13S,14S,17R)-17-[(2,2-dichloroacetyl)oxy]-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid		C₂₂H₂₆Cl₂O₆	详情	详情

Extended Information