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【结 构 式】 
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【分子编号】54210 【品名】17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon 【CA登记号】58-22-0 |
【 分 子 式 】C19H28O2 【 分 子 量 】288.43012 【元素组成】C 79.12% H 9.78% O 11.09% |
合成路线1
该中间体在本合成路线中的序号：(IX)The Birch reduction of 4-butylbenzoic acid (I) with Li in dry ammonia gives 4-butyl-3,4-dihydrobenzoic acid (II), which is submitted to a new Birch reduction to yield 4-butyl-2-cyclohexenecarboxylic acid (III). The methylation of (III) with methanol in acidic medium or with diazomethane, affords the corresponding methyl ester (IV), which is reduced with H2 over PtO2 in ethyl acetate to provide 4-butylcyclohexanecarboxylic acid methyl ester (V). This compound is hydrolyzed with NaOMe in methanol to give the expected carboxylic acid (VI) as a cis/trans mixture. This mixture is dissolved in a minimum amount of methanol, then thiourea and methanol are added and heated until a homogeneous mixture is obtained. The solution is allowed to cool and finally cools at -20 C; the resulting crystalline inclusion complex is filtered and decomposed with aq. KOH to yield trans-4-butylcyclohexanecarboxylic acid (VII). This compound is treated with SOCl2 in benzene to give the corresponding acyl chloride (VIII), which is finally condensed with testosterone (IX) by means of pyridine in benzene to provide the target testosterone ester. Alternatively, the intermediate trans-4-butylcyclohexanecarboxylic acid (VII) can also be obtained as follows: The reduction of 4-butylbenzoic acid (I) with H2 over PtO2 in acetic acid gives 4-butylcyclohexanecarboxylic acid (X) predominantly as the cis-isomer, which is treated with SOCl2 in dichloromethane to yield the acyl chloride (XI). The reaction of (XI) with anhydrous ethanol affords the ethyl ester (XII), which is submitted to a cis/trans isomerization with sodium ethoxide in refluxing ethanol to provide the target intermediate (VII).
| 【1】 Acosta, C.K.; et al.; Tritium labeled trans-4-N-butyl-2,3-3H-cyclohexanecarboxylic acid. Preparation of testosterone 17beta-trans-4-N-butyl-2,3-3H-cyclohexanecarboxylate and [4-14C]-testosterone 17beta-trans-4-N-butylcyclohexane carboxylate. J Label Compd Radiopharm 1990, 28, 10, 1201. |
| 【2】 Kim, H.K.; Blye, R.P.; Bialy, G.; Archer, S.; Fried, J.; Crabbe, P.; Djerassi, C.; Diczfalusy, E.R.; Long-acting androgenic cpds. and pharmaceutical compsns. thereof. US 4948790 . |
| 【3】 Leysen, D.; Van der Louw, J.; Van der Voort, H.A.A. (Akzo Nobel N.V.); Cycloalkyl-carboxylic acid esters of 7alpha methyl-estr-4-en-3-one 17beta-ol (19-nor 7alpha-methyltestosterone). WO 9967270 . |
| 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) | 54202 | 4-Butylbenzoic acid; 4-n-Butylbenzoic acid | 20651-71-2 | C11H14O2 | 详情 | 详情 |
| (II) | 54203 | 4-butyl-1,5-cyclohexadiene-1-carboxylic acid | n/a | C11H16O2 | 详情 | 详情 |
| (III) | 54204 | 4-butyl-2-cyclohexene-1-carboxylic acid | n/a | C11H18O2 | 详情 | 详情 |
| (IV) | 54205 | methyl 4-butyl-2-cyclohexene-1-carboxylate | n/a | C12H20O2 | 详情 | 详情 |
| (V) | 54206 | methyl 4-butylcyclohexanecarboxylate | n/a | C12H22O2 | 详情 | 详情 |
| (VI) | 54207 | 4-butylcyclohexanecarboxylic acid | n/a | C11H20O2 | 详情 | 详情 |
| (VII) | 54208 | trans-4-n-Butylcyclohexanecarboxylic acid | 38289-28-0 | C11H20O2 | 详情 | 详情 |
| (VIII) | 54209 | 4-butylcyclohexanecarbonyl chloride | n/a | C11H19ClO | 详情 | 详情 |
| (IX) | 54210 | 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon | 58-22-0 | C19H28O2 | 详情 | 详情 |
| (X) | 54211 | 4-butylcyclohexanecarboxylic acid | 38289-28-0 | C11H20O2 | 详情 | 详情 |
| (XI) | 54212 | 4-butylcyclohexanecarbonyl chloride | n/a | C11H19ClO | 详情 | 详情 |
| (XII) | 54213 | ethyl 4-butylcyclohexanecarboxylate | n/a | C13H24O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The Birch reduction of 4-butylbenzoic acid (I) with Li in dry ammonia gives 4-butyl-3,4-dihydrobenzoic acid (II), which is submitted to a new Birch reduction to yield 4-butyl-2-cyclohexenecarboxylic acid (III). The methylation of (III) with methanol in acidic medium or with diazomethane, affords the corresponding methyl ester (IV), which is reduced with 3H2 over PtO2 in ethyl acetate to provide tritium-labeled 4-butylcyclohexanecarboxylic acid methyl ester (V). This compound is hydrolyzed with NaOMe in methanol to give the expected carboxylic acid (VI) as a cis/trans mixture. This mixture is dissolved in a minimum amount of methanol, then thiourea and methanol are added and heated until a homogeneous mixture is obtained. The solution is allowed to cool and finally cools at -20 C; the resulting crystalline inclusion complex is filtered and decomposed with aq. KOH to yield tritium-labeled trans-4-butylcyclohexanecarboxylic acid (VII) (1). This compound is treated with SOCl2 in benzene to give the corresponding acyl chloride (VIII), which is finally condensed with testosterone (IX) by means of pyridine in benzene to provide the target labeled testosterone ester.
| 【1】 Acosta, C.K.; et al.; Tritium labeled trans-4-N-butyl-2,3-3H-cyclohexanecarboxylic acid. Preparation of testosterone 17beta-trans-4-N-butyl-2,3-3H-cyclohexanecarboxylate and [4-14C]-testosterone 17beta-trans-4-N-butylcyclohexane carboxylate. J Label Compd Radiopharm 1990, 28, 10, 1201. |
| 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) | 54202 | 4-Butylbenzoic acid; 4-n-Butylbenzoic acid | 20651-71-2 | C11H14O2 | 详情 | 详情 |
| (II) | 54203 | 4-butyl-1,5-cyclohexadiene-1-carboxylic acid | n/a | C11H16O2 | 详情 | 详情 |
| (III) | 54204 | 4-butyl-2-cyclohexene-1-carboxylic acid | n/a | C11H18O2 | 详情 | 详情 |
| (IV) | 54205 | methyl 4-butyl-2-cyclohexene-1-carboxylate | n/a | C12H20O2 | 详情 | 详情 |
| (V) | 54206 | methyl 4-butylcyclohexanecarboxylate | n/a | C12H22O2 | 详情 | 详情 |
| (V) | 54246 | methyl 4-butylcyclohexanecarboxylate | n/a | C12H22O2 | 详情 | 详情 |
| (VI) | 54207 | 4-butylcyclohexanecarboxylic acid | n/a | C11H20O2 | 详情 | 详情 |
| (VI) | 54247 | 4-butylcyclohexanecarboxylic acid | 71101-89-8 | C11H20O2 | 详情 | 详情 |
| (VII) | 54208 | trans-4-n-Butylcyclohexanecarboxylic acid | 38289-28-0 | C11H20O2 | 详情 | 详情 |
| (VII) | 54248 | 4-butylcyclohexanecarboxylic acid | 71101-89-8 | C11H20O2 | 详情 | 详情 |
| (VIII) | 54209 | 4-butylcyclohexanecarbonyl chloride | n/a | C11H19ClO | 详情 | 详情 |
| (VIII) | 54249 | 4-butylcyclohexanecarbonyl chloride | n/a | C11H19ClO | 详情 | 详情 |
| (IX) | 54210 | 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon | 58-22-0 | C19H28O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The Birch reduction of 4-butylbenzoic acid (I) with Li in dry ammonia gives 4-butyl-3,4-dihydrobenzoic acid (II), which is submitted to a new Birch reduction to yield 4-butyl-2-cyclohexenecarboxylic acid (III). The methylation of (III) with methanol in acidic medium or with diazomethane, affords the corresponding methyl ester (IV), which is reduced with H2 over PtO2 in ethyl acetate to provide 4-butylcyclohexanecarboxylic acid methyl ester (V). This compound is hydrolyzed with NaOMe in methanol to give the expected carboxylic acid (VI) as a cis/trans mixture. This mixture is dissolved in a minimum amount of methanol, then thiourea and methanol are added and heated until a homogeneous mixture is obtained. The solution is allowed to cool and finally cools at -20 C; the resulting crystalline inclusion complex is filtered and decomposed with aq. KOH to yield trans-4-butylcyclohexanecarboxylic acid (VII) (1). This compound is treated with SOCl2 in benzene to give the corresponding acyl chloride (VIII), which is finally condensed with 14C-labeled testosterone (IX) by means of pyridine in benzene to provide the target labeled testosterone ester.
| 【1】 Acosta, C.K.; et al.; Tritium labeled trans-4-N-butyl-2,3-3H-cyclohexanecarboxylic acid. Preparation of testosterone 17beta-trans-4-N-butyl-2,3-3H-cyclohexanecarboxylate and [4-14C]-testosterone 17beta-trans-4-N-butylcyclohexane carboxylate. J Label Compd Radiopharm 1990, 28, 10, 1201. |
| 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) | 54202 | 4-Butylbenzoic acid; 4-n-Butylbenzoic acid | 20651-71-2 | C11H14O2 | 详情 | 详情 |
| (II) | 54203 | 4-butyl-1,5-cyclohexadiene-1-carboxylic acid | n/a | C11H16O2 | 详情 | 详情 |
| (III) | 54204 | 4-butyl-2-cyclohexene-1-carboxylic acid | n/a | C11H18O2 | 详情 | 详情 |
| (IV) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (V) | 54206 | methyl 4-butylcyclohexanecarboxylate | n/a | C12H22O2 | 详情 | 详情 |
| (VI) | 54207 | 4-butylcyclohexanecarboxylic acid | n/a | C11H20O2 | 详情 | 详情 |
| (VII) | 54208 | trans-4-n-Butylcyclohexanecarboxylic acid | 38289-28-0 | C11H20O2 | 详情 | 详情 |
| (VIII) | 54209 | 4-butylcyclohexanecarbonyl chloride | n/a | C11H19ClO | 详情 | 详情 |
| (IX) | 54210 | 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon | 58-22-0 | C19H28O2 | 详情 | 详情 |
| (IX) | 54245 | (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | n/a | C19H28O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The reaction of testosterone (I) with isobutylene (II) in dichloromethane catalyzed by trifluoromethanesulfonic acid gives the tert-butyl ether (III), which is ozonolyzed with O3 and H2O2 in AcOH/ethyl acetate to yield the seco-steroid (IV). The cyclization of (IV) by means of acetic anhydride and potassium acetate at 135 C affords the 4-oxa steroid (V), which is methylated with 14C-labeled methylmagnesium iodide in ether to provide the intermediate (VI). The rearrangement of (VI) by means of NaOH in ethanol gives the labeled testosterone tert-butyl ether (VII), which is deprotected by means of 6N HCl in refluxing ethanol to yield the labeled testosterone (VIII). The reduction of the double bond of (VIII) with Li in liquid ammonia affords the dihydro compound (IX), which is oxidized with Jones oxidant in acetone to provide the labeled androstane-3.17-dione (X). The selective reduction of the 3-oxo group of (X) by means of tri-tert-butoxy lithium aluminum hydride in hot THF gives the labeled 3-beta-hydroxyandrostan-17-one (XI), which is brominated with CuBr2 in refluxing methanol to yield the target alpha-bromo derivative, along with some beta-isomer that is separated by column chromatography
| 【1】 Han, M.C.; Hayes B.A.; Prendergast, P.T.; Gupta, S.; Inhibition of HIV replication: Synthesis of [4-14C]-5alpha-androstan-16alpha-bromo-3 beta-ol-17-one. J Label Compd Radiopharm 2000, 43, 12, 1149. |
| 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) | 54210 | 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon | 58-22-0 | C19H28O2 | 详情 | 详情 |
| (II) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (III) | 62424 | (10R,13S,17S)-17-(tert-butoxy)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C23H36O2 | 详情 | 详情 | |
| (IV) | 62425 | 3-[(3S,3aS,6R)-3-(tert-butoxy)-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propanoic acid | C22H36O4 | 详情 | 详情 | |
| (V) | 62426 | (4aR,6aS,7S)-7-(tert-butoxy)-4a,6a-dimethyl-4,4a,4b,5,6,6a,7,8,9,9a,9b,10-dodecahydroindeno[5,4-f]chromen-2(3H)-one | C22H34O3 | 详情 | 详情 | |
| (VI) | 62427 | (1R,5S,6S)-6-(tert-butoxy)-13-hydroxy-1,5,13-trimethyltetracyclo[10.3.1.0~2,10~.0~5,9~]hexadecan-16-one | C23H38O3 | 详情 | 详情 | |
| (VII) | 62424 | (10R,13S,17S)-17-(tert-butoxy)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C23H36O2 | 详情 | 详情 | |
| (VIII) | 54210 | 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon | 58-22-0 | C19H28O2 | 详情 | 详情 |
| (IX) | 62428 | (5S,10S,13S,17S)-17-hydroxy-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one | C19H30O2 | 详情 | 详情 | |
| (X) | 62429 | (5S,10S,13S)-10,13-dimethyldodecahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,4H)-dione | C19H28O2 | 详情 | 详情 | |
| (XI) | 62430 | (3S,5S,10S,13S)-3-hydroxy-10,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H30O2 | 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 reaction of testosterone (I) with isobutylene (II) in dichloromethane catalyzed by trifluoromethanesulfonic acid gives the tert-butyl ether (III), which is ozonolyzed with O3 and H2O2 in AcOH/ethyl acetate to yield the seco-steroid (IV). The cyclization of (IV) by means of acetic anhydride and potassium acetate at 135 C affords the 4-oxa steroid (V), which is methylated with 14C-labeled methylmagnesium iodide in ether to provide the intermediate (VI). The rearrangement of (VI) by means of NaOH in ethanol gives the labeled testosterone tert-butyl ether (VII), which is deprotected by means of 6N HCl in refluxing ethanol to yield the labeled testosterone (VIII). The reduction of the double bond of (VIII) with Li in liquid ammonia affords the dihydro compound (IX), which is oxidized with Jones oxidant in acetone to provide the labeled androstane-3.17-dione (X). The selective reduction of the 3-oxo group of (X) by means of tri-tert-butoxy lithium aluminum hydride in hot THF gives the labeled 3-beta-hydroxyandrostan-17-one (XI), which is brominated with CuBr2 in refluxing methanol to yield the target alpha-bromo derivative, along with some beta-isomer that is separated by column chromatography
| 【1】 Han, M.C.; Hayes B.A.; Prendergast, P.T.; Gupta, S.; Inhibition of HIV replication: Synthesis of [4-14C]-5alpha-androstan-16alpha-bromo-3 beta-ol-17-one. J Label Compd Radiopharm 2000, 43, 12, 1149. |
| 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) | 54210 | 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon | 58-22-0 | C19H28O2 | 详情 | 详情 |
| (II) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (III) | 62424 | (10R,13S,17S)-17-(tert-butoxy)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C23H36O2 | 详情 | 详情 | |
| (IV) | 62425 | 3-[(3S,3aS,6R)-3-(tert-butoxy)-3a,6-dimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propanoic acid | C22H36O4 | 详情 | 详情 | |
| (V) | 62426 | (4aR,6aS,7S)-7-(tert-butoxy)-4a,6a-dimethyl-4,4a,4b,5,6,6a,7,8,9,9a,9b,10-dodecahydroindeno[5,4-f]chromen-2(3H)-one | C22H34O3 | 详情 | 详情 | |
| (VI) | 62427 | (1R,5S,6S)-6-(tert-butoxy)-13-hydroxy-1,5,13-trimethyltetracyclo[10.3.1.0~2,10~.0~5,9~]hexadecan-16-one | C23H38O3 | 详情 | 详情 | |
| (VII) | 62424 | (10R,13S,17S)-17-(tert-butoxy)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C23H36O2 | 详情 | 详情 | |
| (VIII) | 54210 | 17beta-Hydroxyandrost-4-en-3-one; 4-Androsten-17-beta-ol-3-one; Android; Androlin; delta4-Androsten-17beta-ol-3-one; Halotensin; Oreton; Testex; Testoderm; Testosterone; Testred; Virilon | 58-22-0 | C19H28O2 | 详情 | 详情 |
| (IX) | 62428 | (5S,10S,13S,17S)-17-hydroxy-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one | C19H30O2 | 详情 | 详情 | |
| (X) | 62429 | (5S,10S,13S)-10,13-dimethyldodecahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,4H)-dione | C19H28O2 | 详情 | 详情 | |
| (XI) | 62430 | (3S,5S,10S,13S)-3-hydroxy-10,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H30O2 | 详情 | 详情 |