CN1121409C - Process for preparing medicine - Google Patents
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- CN1121409C CN1121409C CN 01101935 CN01101935A CN1121409C CN 1121409 C CN1121409 C CN 1121409C CN 01101935 CN01101935 CN 01101935 CN 01101935 A CN01101935 A CN 01101935A CN 1121409 C CN1121409 C CN 1121409C
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Abstract
The present invention discloses a new process for producing Feinaxiongan. The process uses 4-pregnene-3, 20-dione(progesterone) as raw material; carboxylic acid reaction, amidate reaction, oxidation ring opening reaction, amine inserting closing cycle reaction, catalytic hydrogenation reaction and dehydrogenation reaction are carried out; a product is extracted by a saturated sodium bicarbonate aqueous solution; a water phase is discarded; drying is carried out by anhydrous sodium sulfate; concentration and recrystallization are carried out; white crystal is obtained by column chromatography, concentration, devitrification and suction filtration; the white crystal is the subject matter-Feinaxiongan. The process has the advantages of low cost, high yield and purity, etc.
Description
The present invention relates to a kind of medicine production method, specifically is the production method of medicine finasteride, belongs to pharmaceutical field.
Finasteride, chemical name are the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-acid amides, molecular formula: C
23H
36N
2O
2, molecular weight: 372.55, structural formula is as follows:
It is a kind of 5 inhibitor.Be used for the treatment of benign prostatic hyperplasia (BPH), serious symptom or slight Benign Prostatic Hypertrophy all are suitable for, and the improvement that serious symptoms is divided is near surgical effect.Can reduce the DHT level, dwindle prostate volume, increase urine speed, not combine again simultaneously, do not reduce testosterone levels in the serum, thereby side effect be less with male sex hormone.The production technique of known finasteride comprises with the Vitarrine being starting raw material, obtains through the reaction of ten steps.Its main synthetic route is as follows:
But the certain defective of the existence of above-mentioned already known processes mainly shows:
1, operational path is oversize, makes production operation numerous and diverse, and is unfavorable for the raising of technology total recovery;
2, the crude product of compound (6) is an oily matter in this operational path, is difficult to crystallization, makes next step reaction be difficult to feed intake if feed intake after refining, and then loss is very big, and yield is lower;
3, the synthetic of compound (8) is to pass through PtO in this operational path
2Catalytic hydrogenation and obtaining because granules of catalyst is less, causes the separation and purification of compound (8) difficulty that becomes;
4, in this operational path, the post-treatment of final products method is general recrystallization, can not guarantee that the purity of finasteride reaches requirement.
In order to overcome above-mentioned defective, the contriver has invented a kind of new production technique through lot of experiments, is used to produce finasteride.
Therefore, the object of the invention provides a kind of novel process of producing finasteride.
As shown in drawings, the present invention produces the technical scheme of finasteride and is:
With 4-pregnene-3,20-diketone (Progesterone) is a raw material, in the presence of bromine, sodium hydroxide, dioxane and concentrated hydrochloric acid, carries out the carboxylic acid reaction, through concentrate, crystallization and suction filtration, light yellow crystal; This crystal carries out amidate action in the presence of oxalyl chloride, TERTIARY BUTYL AMINE, dry toluene, with aqueous hydrochloric acid extraction, aqueous phase discarded, concentrate, crystallization and suction filtration, light yellow crystal; This crystal carries out oxidative cleavage in the presence of TERTIARY BUTYL AMINE and sodium periodate, through concentrate, crystallization and suction filtration, white crystal; This crystal is inserted amine cyclization reaction in the presence of ethylene glycol and ammonia, through concentrate, crystallization and suction filtration, white crystal; This crystal carries out catalytic hydrogenation in the presence of platinum dioxide, acetic acid and perchloric acid, filter, and filtrate is concentrated into dried, recrystallization, and crystallization and suction filtration get white crystal; This crystal carries out dehydrogenation reaction in the presence of benzene seleninic acid acid anhydride and chlorobenzene, with saturated sodium bicarbonate aqueous solution extraction, aqueous phase discarded, with anhydrous sodium sulfate drying, concentrate and recrystallization, through column chromatography, concentrate, crystallization and suction filtration, obtain white crystal, be the subject matter finasteride.
It is as follows to describe new process of production synthetic route of the present invention with chemical structural formula:
In conjunction with said synthesis route synthetic experimental implementation step is described as follows:
1) preparation of 3-carbonyl-4-androstene-17 β-carboxylic acid (II)
1. sodium hydroxide 35.0g (0.876mol) is dissolved in the 300ml water, is cooled to-15 ℃, and slowly (11.52ml 0.225mol), drips and finishes dripping bromine 36.0g, and 200ml slowly adds with dioxane.In the dropping process, keep temperature of reaction system to be no more than-15 ℃.
2. Progesterone 21.0g (0.066mol) is dissolved in 780ml dioxane and the 240ml water, the ice-water bath cooling makes its interior temperature be lower than 25 ℃.
3. step reaction mixture is 1. slowly splashed in the step reaction mixture 2., keep temperature to be lower than 25 ℃, reacted 5 hours.Add 10% sodium sulfite aqueous solution 90ml, reflux 15 minutes is put to room temperature, uses 22ml concentrated hydrochloric acid acidification reaction liquid to PH ≈ 6.Pressure reducing and steaming solvent, the debris of an amount of volume are placed and are spent the night, and suction filtration promptly gets II, pale yellow powder shape crystallization 15.9g, and mp.223-228 ℃, molar yield is 75.24%.
2) preparation of the N-tertiary butyl-3-carbonyl-4-androstene-17 β-acid amides (III)
3-carbonyl-4-androstene-17 β-carboxylic acid (II) 10.0g (0.0316mol) is dissolved in the 100ml dry toluene, be cooled to 10 ℃, slowly splash into oxalyl chloride 4.0ml (0.0461mol), drip and finish, reaction is 1 hour under the room temperature.(0.173mol of TERTIARY BUTYL AMINE/dry toluene=18.4ml/18.4ml), temperature is lower than 20 ℃ in the control slowly to drip the TERTIARY BUTYL AMINE anhydrous toluene solution.Drip to finish, removed under the ice-water bath room temperature stirring reaction 1 hour.With 6N hydrochloric acid 140ml extractive reaction liquid, it is colourless that water layer continues to be extracted to organic layer with the gradation of 50ml toluene.Merge organic phase, anhydrous sodium sulfate drying.Be evaporated to an amount of volume, low temperature is placed and is spent the night, suction filtration, and oven dry gets faint yellow crystallization 8.85g, and mp214-218 ℃, molar yield is 75.4%.
3) the N-tertiary butyl-5-carbonyl-17 β-carbamyl-A-loses carbon-3, the preparation of 5-cracking-androstane-3-carboxylic acid (IV)
1. the N-tertiary butyl-3-carbonyl-4-androstene-17 β-acid amides (III) 6.0g (0.0162mol) is joined in the 90ml trimethyl carbinol, (anhydrous sodium sulphate/water=6.0g (0.0566mol)/18ml is warming up to 85 ℃ of the interior temperature of reaction flask to add the Carbon Dioxide sodium water solution under stirring.
2. with NaIO
424.0g (0.104mol) be dissolved in the 100ml water, and be preheated to 80 ℃.
3. mixing solutions that will be 2. slowly drops in 1. the reactant, drips and finishes insulation reaction 30 minutes.
Suction filtration after reaction mixture is cooled to 20 ℃, filter cake washs with a small amount of trimethyl carbinol.Filtrate and washings are evaporated to an amount of volume, and the ice-water bath cooling transfers to PH ≈ 2 with 6N hydrochloric acid down, leave standstill, and crystallization, suction filtration, drying gets white powder crystallization 6.04g, and mp:112-115 ℃, molar yield is 95.5%.
4) preparation of the N-tertiary butyl-3-carbonyl-4-azepine-5-androstene-17 β-acid amides (V)
Ethylene glycol 25.6ml, ice-water bath are cooled to 0-5 ℃, feed ammonia 1.73g, add compound IV 5.11g, slowly are warming up to 80 ℃, insulated and stirred reaction 30 minutes.Be cooled to room temperature, add entry 51ml and stir, suction filtration, filter cake is washed to neutrality, and drying, re-crystallizing in ethyl acetate get white powder crystal 4 .12g, and mp290-293 ℃, molar yield is 84.7%.
5) preparation of the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-acid amides (VI)
With Glacial acetic acid 25ml, platinum dioxide 0.482g (2.12mmol) joins among the compound V4.82g (0.0129mol), and vacuumizing feeds hydrogen, is warming up to 80 ℃ and carries out the normal pressure catalytic hydrogenation 8 hours.The elimination catalyzer, the pressure reducing and steaming Glacial acetic acid, solid washes with water, and suction filtration drying, re-crystallizing in ethyl acetate get white powder solid 2.69g, and mp270-273 ℃, molar yield is 55.6%.
6) (VII) synthetic of the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-acid amides (Finasteride)
Compound VI 2.08g (5.55mmol), benzene seleninic acid acid anhydride 2.70g (7.50mmol) are joined in the 60ml chlorobenzene, be warming up to 190 ℃ after insulation reaction 10 hours.Be cooled to room temperature, with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing reaction mixture successively, organic phase is concentrated into about 5ml after with anhydrous sodium sulfate drying, column chromatography for separation gets crude product, re-crystallizing in ethyl acetate gets white crystal 0.943g, and mp254-256 ℃, molar yield is 47.40%.Total recovery: in the starting raw material Progesterone, total recovery is 12.1%.
The advantage of present patent application technology mainly contains:
1, the operational path of application this patent had only for six steps altogether, than short many of known route, make production operation more simple, and help the input of minimizing equipment and other resources in industrial production, reduced cost;
2, in this operational path, carry out amidate action earlier, carry out oxidative cleavage again, avoided the generation of compound (6) in the already known processes, make that the aftertreatment of ring-opening product is easy, and be convenient to feeding intake of next step;
3, in this operational path, the catalyzer that catalytic hydrogenation is used is Pd/C, and it has overcome uses PtO in the already known processes
2The hydride that catalyzer brings is difficult to the deficiency of purifying, and the yield of catalytic hydrogenation also is not less than uses PtO
2As the yield of the hydrogenation of catalyzer, and the reaction times is shorter than already known processes;
4, in this operational path, the 6th step was that finasteride was obtained by column chromatography separation method, so the purity of finasteride can be guaranteed after the final step reaction finished.
Three wastes treatment process in the middle of the experimentation is:
1) organic waste materials: toluene, pyridine, sherwood oil, acetone, ethylene glycol, dioxane, the trimethyl carbinol, ethanol, methyl alcohol, acetic acid, ethyl acetate, chlorobenzene, dimethyl formamide, chloroform treatment process:
Adopt methods such as distillation, fractionation to reclaim organic solvent.
2) inorganic wastes: NaOH, NaCl, KOH, Na
2SO
3, NaSO
4, Na
3CO
3, KmnO
4, NaZO
4, PtO
2
3) treatment process: PtO
2The method of taking to sterilize and recycling.
Other salt is dissolved in the waste water more, takes to concentrate, the method for crystallization reclaims solids component.
Other waste water send waste water station to handle the back discharging.
Accompanying drawing is the schema that relevant the present patent application is produced lab scale technology.
Now in conjunction with the accompanying drawings the detailed embodiment of the present patent application being done one describes.
Embodiment
The first step: choose raw material according to table one.
These specification standards of testing employed chemical feedstocks are as described in the following table: table one: the specification standards of chemical feedstocks
| Material name | Specification | Purity | The place of production |
| Progesterone | 5kg | Technical grade | The Hunan hormone company limited of just speeding |
| Dioxane | 500ml | ?AR | Shanghai chemical reagents corporation |
| Toluene | 500ml | ?AR | The state-run weathering chemical reagent work that prolongs in Changsha |
| Sherwood oil | 500ml | ?AR | Jiaozhuo, Henan high chemical industry three factories |
| The trimethyl carbinol | 500ml | ?AR | Shanghai chemical reagents corporation |
| Ethylene glycol | 500ml | ?AR | Hunan chemical reagents corporation of Normal University |
| Glacial acetic acid | 500ml | ?AR | Hunan chemical reagents corporation of Normal University |
| The vitriol oil | 500ml | ?AR | Zhuzhou,hunan chemical industry institute |
| Concentrated hydrochloric acid | 500ml | ?AR | Zhuzhou,hunan development area chemical reagent work of ancient quartzification glass limited liability company |
| Monochloro-benzene | 500ml | ?AR | Shanghai chemical reagents corporation |
| Sodium hydroxide | 500g | ?AR | Tianjin chemical reagent three factories |
| Bromine | 500g | ?AR | Shanghai chemical reagent one factory |
| Sodium sulphite anhydrous 99.3 | 500g | ?AR | Henan Jiaozuo City chemical industry three factories |
| Oxalyl chloride | 100g | ?98％ | New?Fersey.USA |
| The benzene seleninic acid acid anhydride | 25g | Import reagent | |
| TERTIARY BUTYL AMINE | 250ml | ?CP | Shanghai chemical reagents corporation |
| Sodium-chlor | 500g | ?AR | Hunan chemical reagent head factory |
| Anhydrous sodium carbonate | 500g | ?AR | Last marine rainbow photoinitiator chemical factory |
| Sodium periodate | 100g | ?CP | Shanghai chemical reagents corporation |
| PtO 2 | 1g | ?AR | Shanghai chemical reagents corporation |
| Ethyl acetate | 500ml | ?AR | Tianjin Jin Dong days positive fine chemistry chemical reagent works |
| Acetone | 500ml | ?AR | Chemical reagent factory of Hunan Normal University |
| Dehydrated alcohol | 500ml | ?CD | Chemical reagent factory of Hunan Normal University |
| Methyl alcohol | 500ml | ?AR | Chemical reagent factory of Hunan Normal University |
| Anhydrous sodium sulphate | 500g | ?AR | Jiaozhuo, Henan chemical industry three factories |
| Trichloromethane | 500ml | ?AR | Chemical reagent factory of Hunan Normal University |
| Silica GF254 | 500g | ?CP | China Qingdao Haiyang Chemical Industry Group Corp. |
| Dimethyl formamide | 500ml | ?AR | Guangzhou Chemical Reagent Factory |
| Sodium bicarbonate | 500g | ?AR | Beijing chemical reagents corporation |
Second step: operate according to following steps:
1) preparation of 3-carbonyl-4-androstene-17 β-carboxylic acid (II)
1. sodium hydroxide 35.0g (0.876mol) is dissolved in the 300ml water, is cooled to-15 ℃, and slowly (11.52ml 0.225mol), drips and finishes dripping bromine 36.0g, and 200ml slowly adds with dioxane.In the dropping process, keep temperature of reaction system to be no more than-15 ℃.
2. Progesterone 21.0g (0.066mol) is dissolved in 780ml dioxane and the 240ml water, the ice-water bath cooling makes its interior temperature be lower than 25 ℃.
3. step reaction mixture is 1. slowly splashed in the step reaction mixture 2., keep temperature to be lower than 25 ℃, reacted 5 hours.Add 10% sodium sulfite aqueous solution 90ml, reflux 15 minutes is put to room temperature, uses 22ml concentrated hydrochloric acid acidification reaction liquid to PH ≈ 6.Pressure reducing and steaming solvent, the debris of an amount of volume are placed and are spent the night, and suction filtration promptly gets II, pale yellow powder shape crystallization 15.9g, and mp.223-228 ℃, molar yield is 75.24%.
2) preparation of the N-tertiary butyl-3-carbonyl-4-androstene-17 β-acid amides (III)
3) 3-carbonyl-4-androstene-17 β-carboxylic acid (II) 10.0g (0.0316mol) is dissolved in the 100ml dry toluene, be cooled to 10 ℃, slowly splash into oxalyl chloride 4.0ml (0.0461mol), drip and finish, reaction is 1 hour under the room temperature.(0.173mol of TERTIARY BUTYL AMINE/dry toluene=18.4ml/18.4ml), temperature is lower than 20 ℃ in the control slowly to drip the TERTIARY BUTYL AMINE anhydrous toluene solution.Drip to finish, removed under the ice-water bath room temperature stirring reaction 1 hour.With 6N hydrochloric acid 140ml extractive reaction liquid, it is colourless that water layer continues to be extracted to organic layer with the gradation of 50ml toluene.Merge organic phase, anhydrous sodium sulfate drying.Be evaporated to an amount of volume, low temperature is placed and is spent the night, suction filtration, and oven dry gets faint yellow crystallization 8.85g, and mp214-218 ℃, molar yield is 75.4%.
3) the N-tertiary butyl-5-carbonyl-17 β-carbamyl-A-loses carbon-3, the preparation of 5-cracking-androstane-3-carboxylic acid (IV)
1. the N-tertiary butyl-3-carbonyl-4-androstene-17 β-acid amides (III) 6.0g (0.0162mol) is joined in the 90ml trimethyl carbinol, (anhydrous sodium sulphate/water=6.0g (0.0566mol)/18ml is warming up to 85 ℃ of the interior temperature of reaction flask to add the Carbon Dioxide sodium water solution under stirring.
2. with NaIO
424.0g (0.104mol) be dissolved in the 100ml water, and be preheated to 80 ℃.
3. mixing solutions that will be 2. slowly drops in 1. the reactant, drips and finishes insulation reaction 30 minutes.
Suction filtration after reaction mixture is cooled to 20 ℃, filter cake washs with a small amount of trimethyl carbinol.Filtrate and washings are evaporated to an amount of volume, and the ice-water bath cooling transfers to PH ≈ 2 with 6N hydrochloric acid down, leave standstill, and crystallization, suction filtration, drying gets white powder crystallization 6.04g, and mp:112-115 ℃, molar yield is 95.5%.
4) preparation of the N-tertiary butyl-3-carbonyl-4-azepine-5-androstene-17 β-acid amides (V)
Ethylene glycol 25.6ml, ice-water bath are cooled to 0-5 ℃, feed ammonia 1.73g, add compound IV 5.11g, slowly are warming up to 80 ℃, insulated and stirred reaction 30 minutes.Be cooled to room temperature, add entry 51ml and stir, suction filtration, filter cake is washed to neutrality, and drying, re-crystallizing in ethyl acetate get white powder crystal 4 .12g, and mp290-293 ℃, molar yield is 84.7%.
5) preparation of the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-acid amides (VI)
With Glacial acetic acid 25ml, platinum dioxide 0.482g (2.12mmol) joins among the compound V4.82g (0.0129mol), and vacuumizing feeds hydrogen, is warming up to 80 ℃ and carries out the normal pressure catalytic hydrogenation 8 hours.The elimination catalyzer, the pressure reducing and steaming Glacial acetic acid, solid washes with water, and suction filtration drying, re-crystallizing in ethyl acetate get white powder solid 2.69g, and mp270-273 ℃, molar yield is 55.6%.6) (VII) synthetic of the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-acid amides (Finasteride)
Compound VI 2.08g (5.55mmol), benzene seleninic acid acid anhydride 2.70g (7.50mmol) are joined in the 60ml chlorobenzene, be warming up to 190 ℃ after insulation reaction 10 hours.Be cooled to room temperature, with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing reaction mixture successively, organic phase is concentrated into about 5ml after with anhydrous sodium sulfate drying, column chromatography for separation gets crude product, re-crystallizing in ethyl acetate gets white crystal 0.943g, and mp254-256 ℃, molar yield is 47.40%.
Claims (9)
1, a kind of production method of medicine finasteride is characterized in that this method is with 4-pregnene-3, and the 20-diketone is a raw material, through the carboxylic acid reaction, amidate action, oxidative cleavage, insert amine cyclization reaction, catalytic hydrogenation, and dehydrogenation reaction, product extracts with saturated sodium bicarbonate aqueous solution, aqueous phase discarded, drying, concentrate and recrystallization, again through column chromatography, concentrate, crystallization and suction filtration, obtain white crystal thing finasteride.
2, according to the said production method of claim 1, it is characterized in that said carboxylic acid reaction is with 4-pregnene-3, the 20-diketone is a raw material, in the presence of bromine, sodium hydroxide, dioxane and concentrated hydrochloric acid, carry out the carboxylic acid reaction, through concentrate, crystallization and suction filtration, light yellow crystal.
3, according to the said production method of claim 1, it is characterized in that said amidate action is meant through carboxylic acid reaction's gained crystal in the presence of oxalyl chloride, TERTIARY BUTYL AMINE, dry toluene, carry out amidate action, extract with aqueous hydrochloric acid, aqueous phase discarded, concentrate, crystallization and suction filtration, light yellow crystal.
4, according to the said production method of claim 1, it is characterized in that said oxidative cleavage is meant that amidate action gained crystal in the presence of TERTIARY BUTYL AMINE and sodium periodate, carries out oxidative cleavage, through concentrate, crystallization and suction filtration, white crystal.
5, according to the said production method of claim 1, it is characterized in that said slotting amine cyclization reaction is meant oxidative cleavage gained crystal in the presence of ethylene glycol and ammonia, insert amine cyclization reaction, through concentrated, crystallization and suction filtration, get white crystal.
6, according to the said production method of claim 1, it is characterized in that said catalytic hydrogenation is meant that slotting amine cyclization reaction process gained crystal is in the presence of platinum dioxide, acetic acid and perchloric acid, carry out catalytic hydrogenation, filter, filtrate is concentrated into dried, recrystallization, crystallization and suction filtration get white crystal.
7,, it is characterized in that said dehydrogenation reaction is meant that catalytic hydrogenation process gained crystal in the presence of benzene seleninic acid acid anhydride and chlorobenzene, carries out dehydrogenation reaction according to the said production method of claim 1.
8, a kind of novel process of producing finasteride is characterized in that this processing step comprises:
1) preparation of 3-carbonyl-4-androstene-17 β-carboxylic acid (II)
1. sodium hydroxide 35.0g (0.876mol) is dissolved in the 300ml water, is cooled to-15 ℃, and slowly (11.52ml 0.225mol), drips and finishes dripping bromine 36.0g, and 200ml slowly adds with dioxane.In the dropping process, keep temperature of reaction system to be no more than-15 ℃;
2. Progesterone 21.0g (0.066mol) is dissolved in 780ml dioxane and the 240ml water, the ice-water bath cooling makes its interior temperature be lower than 25 ℃;
3. step reaction mixture is 1. slowly splashed in the step reaction mixture 2., keep temperature to be lower than 25 ℃, reacted 5 hours.Add 10% sodium sulfite aqueous solution 90ml, reflux 15 minutes is put to room temperature, uses 22ml concentrated hydrochloric acid acidification reaction liquid to PH ≈ 6.Pressure reducing and steaming solvent, the debris of an amount of volume are placed and are spent the night, and suction filtration promptly gets II, pale yellow powder shape crystallization 15.9g, and mp.223-228 ℃, molar yield is 75.24%;
2) preparation of the N-tertiary butyl-3-carbonyl-4-androstene-17 β-acid amides (III)
3-carbonyl-4-androstene-17 β-carboxylic acid (II) 10.0g (0.0316mol) is dissolved in the 100ml dry toluene, be cooled to 10 ℃, slowly splash into oxalyl chloride 4.0ml (0.0461mol), drip and finish, reaction is 1 hour under the room temperature, slowly drip the TERTIARY BUTYL AMINE anhydrous toluene solution (0.173mol of TERTIARY BUTYL AMINE/dry toluene=18.4ml/18.4ml), temperature is lower than 20 ℃ in the control, drip and finish, removed under the ice-water bath room temperature stirring reaction 1 hour, with 6N hydrochloric acid 140ml extractive reaction liquid, it is colourless that water layer continues to be extracted to organic layer with the gradation of 50ml toluene.Merge organic phase, anhydrous sodium sulfate drying is evaporated to an amount of volume, and low temperature is placed and spent the night, suction filtration, and oven dry gets faint yellow crystallization 8.85g, and mp214-218 ℃, molar yield is 75.4%;
3) the N-tertiary butyl-5-carbonyl-17 β-carbamyl-A-loses carbon-3, the preparation of 5-cracking-androstane-3-carboxylic acid (IV)
1. the N-tertiary butyl-3-carbonyl-4-androstene-17 β-acid amides (III) 6.0g (0.0162mol) is joined in the 90ml trimethyl carbinol, (anhydrous sodium sulphate/water=6.0g (0.0566mol)/18ml is warming up to 85 ℃ of the interior temperature of reaction flask to add the Carbon Dioxide sodium water solution under stirring;
2. with NaIO
424.0g (0.104mol) be dissolved in the 100ml water, and be preheated to 80 ℃;
3. mixing solutions that will be 2. slowly drops in 1. the reactant, drips and finishes insulation reaction 30 minutes, suction filtration after reaction mixture is cooled to 20 ℃, filter cake washs with a small amount of trimethyl carbinol, and filtrate and washings are evaporated to an amount of volume, the ice-water bath cooling transfers to PH ≈ 2 with 6N hydrochloric acid down, leaves standstill, crystallization, suction filtration, drying gets white powder crystallization 6.04g, mp:112-115 ℃, molar yield is 95.5%; 4) preparation of the N-tertiary butyl-3-carbonyl-4-azepine-5-androstene-17 β-acid amides (V)
Ethylene glycol 25.6ml, ice-water bath are cooled to 0-5 ℃, feed ammonia 1.73g, add compound IV 5.11g, slowly be warming up to 80 ℃, insulated and stirred reaction 30 minutes, be cooled to room temperature, add entry 51ml and stir, suction filtration, filter cake is washed to neutrality, dry, re-crystallizing in ethyl acetate gets white powder crystal 4 .12g, and mp290-293 ℃, molar yield is 84.7%; 5) preparation of the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-acid amides (VI)
With Glacial acetic acid 25ml, platinum dioxide 0.482g (2.12mmol) joins among the compound V4.82g (0.0129mol), vacuumizing, feed hydrogen, be warming up to 80 ℃ and carried out the normal pressure catalytic hydrogenation 8 hours, the elimination catalyzer, the pressure reducing and steaming Glacial acetic acid, solid washes with water, and suction filtration drying, re-crystallizing in ethyl acetate get white powder solid 2.69g, mp270-273 ℃, molar yield is 55.6%; 6) the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-1-alkene-17 β-acid amides (VII) is synthetic
Compound VI 2.08g (5.55mmol), benzene seleninic acid acid anhydride 2.70g (7.50mmol) are joined in the 60ml chlorobenzene, insulation reaction is 10 hours after being warming up to 190 ℃, be cooled to room temperature, with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing reaction mixture successively, organic phase is concentrated into about 5ml after with anhydrous sodium sulfate drying, and column chromatography for separation gets crude product, and re-crystallizing in ethyl acetate gets white crystal 0.943g, mp254-256 ℃, molar yield is 47.40%.
9, a kind of novel process of producing finasteride is characterized in that the synthetic route of this processing step is:
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| CN 01101935 CN1121409C (en) | 2001-01-18 | 2001-01-18 | Process for preparing medicine |
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|---|---|---|---|
| CN 01101935 CN1121409C (en) | 2001-01-18 | 2001-01-18 | Process for preparing medicine |
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| CN1121409C true CN1121409C (en) | 2003-09-17 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1619200A1 (en) * | 2004-07-05 | 2006-01-25 | Lonza Ag | Process for the preparation of 4-azasteroids |
| CN101863956A (en) * | 2010-06-04 | 2010-10-20 | 上海应用技术学院 | Method for synthesizing finasteride |
| CN105017363B (en) * | 2015-06-25 | 2016-12-07 | 湖南科瑞生物制药股份有限公司 | 3-ketone-4-androstene-17 β carboxylic acid and the synthetic method of methyl ester thereof |
| CN106632559B (en) * | 2016-12-11 | 2018-10-30 | 湖北竹溪人福药业有限责任公司 | A method of preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object |
| EP3875464A1 (en) * | 2020-03-06 | 2021-09-08 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Process for the purification of etiocholenic acid |
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