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【结 构 式】 
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【药物名称】Trimexolone, Rimexolone, Org-6216, Rimexel, Vexol 【化学名称】11beta-Hydroxy-16alpha,17alpha,21-trimethylpregna-1,4-dien-3,20-dione 【CA登记号】49697-38-3 【 分 子 式 】C24H34O3 【 分 子 量 】370.53678 |
【开发单位】Organon (Originator), Alcon (Licensee) 【药理作用】Antiinflammatory Ophthalmic Agents, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Corticosteroids |
合成路线1
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.
| 【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2
The methylation of 11-acetoxy-3-tetrahydropyranyloxy-16alpha,17-alpha-dimethyl-5alpha-pregnane-20-one (Ia) with lithium diisopropylamide and methyl iodide in THF gives 11beta-acetoxy-3beta-hydroxy-16alpha,17alpha,21-trimethyl-5alpha-pregnane-20-one (IIa), which is oxidized with chromic acid in acetone yielding 11beta-acetoxy-16alpha,17alpha,21-trimethylpregnane-3,20-dione (IIIa). This compound is dehydrogenated with dichlorodicyanobenzoquinone (A) in refluxing toluene affording 11beta-acetoxy-16alpha,17alpha,21-trimethyl-DELTA1,4-pregnadiene-3,20-dione (IVa), which is finally hydrolyzed with KOH in methanol. This sequence can also be perfomed with the 11beta-propoxy, 11beta-isobutyroxy derivatives of (Ib-c, IIb-c, IIIb-c and IVb-c).
| 【1】 Woods, G.F.; et al.; Alkylated 3,20-diketo-steroids of the pregnane series. DE 2301317; FR 2168006; GB 1416427; JP 50004060; US 3862194 . |
| 【2】 Hillier, K.; Castaner, J.; Trimexolone. Drugs Fut 1977, 2, 10, 695. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 21890 | 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile | 84-58-2 | C8Cl2N2O2 | 详情 | 详情 |
| (Ia) | 33932 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexadecahydro-1H-cyclopenta[a]phenanthren-11-yl acetate | C31H50O5 | 详情 | 详情 | |
| (Ib) | 33933 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexadecahydro-1H-cyclopenta[a]phenanthren-11-yl propionate | C32H52O5 | 详情 | 详情 | |
| (Ic) | 33934 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexadecahydro-1H-cyclopenta[a]phenanthren-11-yl 2-methylpropanoate | C33H54O5 | 详情 | 详情 | |
| (IIa) | 33935 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-3-hydroxy-10,13,16,17-tetramethylhexadecahydro-1H-cyclopenta[a]phenanthren-11-yl acetate | C25H40O4 | 详情 | 详情 | |
| (IIb) | 33936 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-3-hydroxy-10,13,16,17-tetramethylhexadecahydro-1H-cyclopenta[a]phenanthren-11-yl propionate | C26H42O4 | 详情 | 详情 | |
| (IIc) | 33937 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-3-hydroxy-10,13,16,17-tetramethylhexadecahydro-1H-cyclopenta[a]phenanthren-11-yl 2-methylpropanoate | C27H44O4 | 详情 | 详情 | |
| (IIIa) | 33938 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-11-yl acetate | C25H38O4 | 详情 | 详情 | |
| (IIIb) | 33939 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-11-yl propionate | C26H40O4 | 详情 | 详情 | |
| (IIIc) | 33940 | (5S,8S,9S,10S,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-11-yl 2-methylpropanoate | C27H42O4 | 详情 | 详情 | |
| (IVa) | 33941 | (8S,9S,10R,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-11-yl acetate | C25H34O4 | 详情 | 详情 | |
| (IVb) | 33942 | (8S,9S,10R,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-11-yl propionate | C26H36O4 | 详情 | 详情 | |
| (IVc) | 33943 | (8S,9S,10R,11S,13S,14S,16R,17S)-17-acetyl-10,13,16,17-tetramethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-11-yl 2-methylpropanoate | C27H38O4 | 详情 | 详情 |
合成路线3
The methylation of 3beta-tetrahydropyranyloxy-16alpha,17alpha-dimethyl-DELTA9(11)-5alpha-pregnene-20-one (V) with lithium diisopropylamide and methyl iodide in THF gives 3beta-hydroxy-16alpha,17alpha,21-trimethyl-DELTA[9(11)]-5alpha-pregnene-20-one (VI), which is then oxidized with chromic acid in acetone yielding 16alpha,17alpha,21-trimethyl-DELTA[9(11)]-5alpha-pregnene-3,20-dione (VII). This compound is dehydrogenated as before affording 16alpha,17alpha,21-trimethyl-DELTA[1,4,9(11)]-pregnatriene-3,20-dione (VIII), which is finally hydroxylated by treatment first with NBS and then with butanethiol and chromous acetate in DMSO. The pregnene (VII) can also be obtained by methylation of 3-dimethyl-ketal-16alpha,17alpha-dimethyl-DELTA[9(11)]-5alpha-pregnene-3,20-dione (IX) with lithium diisopropylamide and methyl iodide in THF. The pregnatriene (VIII) can also be obtained by dehydrogenation of 16alpha,17alpha,21-trimethyl-DELTA[1,4,9(11)]-pregnatriene-3,20-dione (X), which is with Br2 in acetic acid and dehydrobromination with CaCO3 and LiBr in dimethylacetamide.
| 【1】 Woods, G.F.; et al.; Alkylated 3,20-diketo-steroids of the pregnane series. DE 2301317; FR 2168006; GB 1416427; JP 50004060; US 3862194 . |
| 【2】 Hillier, K.; Castaner, J.; Trimexolone. Drugs Fut 1977, 2, 10, 695. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 21890 | 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile | 84-58-2 | C8Cl2N2O2 | 详情 | 详情 |
| (V) | 33944 | 1-[(5S,8S,10S,13S,14S,16R,17S)-10,13,16,17-tetramethyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-ethanone | C29H46O3 | 详情 | 详情 | |
| (VI) | 33945 | 1-[(5S,8S,10S,13S,14S,16R,17S)-3-hydroxy-10,13,16,17-tetramethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-propanone | C24H38O2 | 详情 | 详情 | |
| (VII) | 33946 | (5S,8S,10S,13S,14S,16R,17S)-10,13,16,17-tetramethyl-17-propionyl-1,2,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C24H36O2 | 详情 | 详情 | |
| (VIII) | 33948 | (8S,10R,13S,14S,16R,17S)-10,13,16,17-tetramethyl-17-propionyl-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one | C24H32O2 | 详情 | 详情 | |
| (IX) | 33947 | 1-[(5S,8S,10S,13S,14S,16S,17S)-3,3-dimethoxy-10,13,16,17-tetramethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-propanone | C26H42O3 | 详情 | 详情 | |
| (X) | 33949 | (5S,8S,10S,13S,14S,16S,17S)-10,13,16,17-tetramethyl-17-propionyl-1,2,4,5,6,7,8,10,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C24H36O2 | 详情 | 详情 |