CN102863507A - Dutasteride refining method - Google Patents
Dutasteride refining method Download PDFInfo
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- CN102863507A CN102863507A CN2012103708319A CN201210370831A CN102863507A CN 102863507 A CN102863507 A CN 102863507A CN 2012103708319 A CN2012103708319 A CN 2012103708319A CN 201210370831 A CN201210370831 A CN 201210370831A CN 102863507 A CN102863507 A CN 102863507A
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Abstract
The invention discloses a dutasteride refining method. The method includes: step one, subjecting a compound shown as a formula (1) to 1,2-dehydrogenation to obtain DTS (dutasteride) crude product shown as a formula (2); and step two, washing the dutasteride crude product shown as the formula (2) with inorganic aqueous solution, aqueous alkali, organic solvent and acidic reagent, and refining to obtain a pure dutasteride product, wherein the purity of the pure dutasteride product is higher than 99.5%, the individual impurity content is smaller than 0.1%, the total impurity content is smaller than 0.5%, and API (active pharmaceutical ingredient) standards are met. The dutasteride refining method has the advantages that the method is convenient to operate, mild in reaction condition, stable and controllable in quality, low in cost consumption, and suitable for massive industrial production, and product purity is improved.
Description
Technical field
The present invention relates to pharmaceutical field, relate to a kind of process for purification of compound, relate in particular to a kind of dutasteride's process for purification.
Background technology
Dutasteride (dutasteride), chemistry (5 α by name, 17 β)-N-[2, two (trifluoromethyl) phenyl of 5-]-3-O-4-azepine androstane-1-alkene-17-carboxylic acid amides, it is the dual 5α-reductase inhibitor of GlaxoSmithKline PLC (GSK) company development, gone on the market by drugs approved by FDA in June, 2003, trade(brand)name Avodart is used for prevention and treatment benign prostatic hyperplasia.
Dutasteride's preparation method is disclosed in WO95/07926, WO95/07927, and US4760071, US4377584, US4179453, US5670643 and Bhattacharya, the people such as A., J. Am. Chem. Soc., 110,3318(1988).In the middle of all multi-routes, all comprise steroidal A ring C-1,2 dehydrogenation reaction, common methods are DDQ (DDQ) dehydriding, but this method is easy to produce excessive dehydrogenation impurity.The people such as document Williams JM, J. Org. Chem., 60,5337(1995) set forth the mechanism of DDQ/BSTFA dehydrogenation reaction, and reported the impurity situation that the excessive dehydrogenation of DDQ produces.
For the aftertreatment impurity-removing method of DDQ dehydrogenation, patent WO95/07926 adopts column chromatography; Patent WO2002/046207 adopts the acetonitrile washing; The open CN101759762A of Chinese patent and document beam gush the people such as great waves, and Jilin University's journal 45(6), 1035(2007) all adopts the washing of 1% sodium pyrosulfate by re-crystallizing in ethyl acetate; The people such as US Patent No. 20050059692A1 and document Satyanarayana K, Org. Process. Res. Dev., 11 (5), 842(2007) all adopt the rare one-tenth solid of water, and by washing with acetone, mixed solvent (methylene dichloride: the recrystallization of methyl alcohol=8:2); The old state of patent WO2002046207 and document extensively waits the people, and Chinese Journal of New Drugs 15(20), 1759(2006) all adopts 1% sodium bisulfite washing and by the acetonitrile recrystallization.Above post-treating method is through experiment confirm, and all not good to the impurity-eliminating effect of excessive dehydrogenation impurity, foreign matter content fails to drop to below 0.1%, does not meet API bulk drug standard.
Summary of the invention
The process for purification that the purpose of this invention is to provide a kind of dutasteride, all not good to overcome the impurity-eliminating effect to excessive dehydrogenation impurity that exists in the existing process for refining, foreign matter content fails to drop to below 0.1%, does not meet the deficiency of API bulk drug standard.
The technical scheme that realizes the object of the invention is as follows:
A kind of dutasteride's process for purification may further comprise the steps:
Step 1: formula (1) compound through 1,2 DDQ dehydriding, is obtained formula (2) dutasteride (DTS) crude product, can generate series of process impurity in this reaction, crude product purity is lower than 99%;
Step 2: formula (2) dutasteride's crude product is refining through the washing of inorganic salt solution, alkaline solution, organic solvent and acid reagent, obtain dutasteride's sterling, its purity is greater than 99.5%, and single assorted content is less than 0.1%, total assorted content reaches API bulk drug standard less than 0.5%.Described inorganic salt solution is sodium pyrosulfate, sodium bisulfite, S-WAT, sodium thiosulfate solution etc., preferred aqueous solution of sodium bisulfite, described inorganic salt solution mass concentration between 1% ~ 10%, preferred 5%; Described alkaline solution is sodium hydroxide, potassium hydroxide, yellow soda ash or wet chemical, preferred aqueous sodium hydroxide solution, described alkaline concentration between 1% ~ 30%, preferred 5%; Described organic solvent is conventional solvent, wherein the lipid solvent is selected from: ethyl acetate, isopropyl acetate, ether solvent is selected from: THF, 1, the 4-dioxane, the cyanogen kind solvent is selected from C1 ~ C4 cyanogen kind solvent, the haloalkane kind solvent is selected from: methylene dichloride, chloroform, described organic solvent ethyl acetate, acetonitrile, methylene dichloride, tetrahydrofuran (THF); Described acid reagent is sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, formic acid etc., preferred hydrochloric acid.
Further, in the step 1, the compound of formula (1) is dissolved in the organic solvent, adds DDQ (DDQ), room temperature drips N, two (TMS) trifluoroacetamides of O-, drip complete room temperature reaction 6 ~ 10h, be warming up to afterwards 60 ~ 100 ℃ of reaction 10 ~ 20h, cooling, remove organic solvent, obtain dutasteride's crude product (2).
The process contaminants that generates in the step 1 is formula (3) Compound D TSI-01, formula (4) Compound D TSI-02, formula (5) Compound D TSI-03.These impurity are all owing to the excessive dehydrogenation of DDQ produces.
Preferably, in the step 1, the compound of formula (1) is dissolved in the benzene class organic solvent of 5 ~ 30 times of amounts, adds 1 ~ 1.5 mole of doubly DDQ of amount, room temperature drips 3 ~ 8 moles of doubly N of amount, two (TMS) trifluoroacetamides of O-, drip complete room temperature reaction 4 ~ 16h, be warming up to afterwards 80 ℃ of reaction 9 ~ 20h, cooling, revolve and desolventize, obtain dutasteride's crude product (2).
Further preferably, in the step 1, formula (2) compound is dissolved in the toluene of 15 times of amounts, adds 1.2 moles of doubly DDQ of amount, room temperature drips 4 moles of doubly N of amount, two (TMS) trifluoroacetamides of O-, drip complete room temperature reaction 8h, be warming up to afterwards 80 ℃ of reaction 12h, cooling, revolve except toluene, obtain dutasteride's crude product (2).
Further, in the step 2, formula (2) dutasteride's crude product is dissolved in organic solvent entirely, add inorganic salt solution and stir 10 ~ 60min, suction filtration is told organic layer, add the alkaline solution washing, the saturated common salt water washing is revolved and is desolventized, adding organic solvent room temperature is stirred and is washed, and suction filtration is dissolved in solid in the organic solvent, intensification is stirred and is washed, and adds acid reagent, cooling, suction filtration, solid is dissolved in organic solvent, adds deionized water wash, anhydrous sodium sulfate drying, suction filtration, revolve and desolventize, solid is added in the mixed solvent, stir and wash, suction filtration, decompression drying.
Preferably, in the step 2, formula (2) dutasteride's crude product is dissolved in the haloalkane kind solvent entirely, the inorganic salt solution that adds 0.5 ~ 1 times of amount of solvent stirs 10 ~ 60min, suction filtration is told organic layer, adds the alkaline solution washing of 0.5 ~ 1 times of amount of solvent, the saturated common salt water washing, revolve and desolventize, the esters solvent room temperature that adds 1 ~ 10 times of amount of product is stirred and is washed 1 ~ 10h, suction filtration, solid is dissolved in the cyanogen kind solvent of 1 ~ 30 times of amount of product, be warming up to 30 ~ 60 ℃ and stir and wash 10 ~ 60min, add the acid reagent of 1 ~ 20 times of amount of product, be down to room temperature, suction filtration, solid is dissolved in the organic solvent entirely, adds deionized water wash, anhydrous sodium sulfate drying, suction filtration, revolve and desolventize, solid is added in the mixed solvent of 1 ~ 50 times of amount, stir and wash 1 ~ 10h, suction filtration, decompression drying 1 ~ 20h.
Further preferably, in the step 2, entirely be dissolved in dutasteride (2) crude product in the methylene dichloride, 5% sodium sulfite aqueous solution that adds 0.75 times of amount of solvent stirs 30min, suction filtration is told organic layer, and the alkaline solution that adds 1 times of amount of solvent washs three times, saturated common salt water washing three times, revolve and desolventize, product is added in the ethyl acetate of 5 times of amounts room temperature and stir and wash 2h, suction filtration, solid is dissolved in the acetonitrile of 10 times of amounts of product, be warming up to 40 ℃ and stir and wash 10min, add the hydrochloric acid of 1 times of amount of product, be down to room temperature, suction filtration, solid is dissolved in the methylene dichloride entirely, adds deionized water wash three times, anhydrous sodium sulfate drying, suction filtration, revolve and desolventize, solid is added the mixed solvent (tetrahydrofuran (THF): in the water=1:1), stir and wash 3h of 30 times of amounts, suction filtration, decompression drying 10 ~ 15h.
Beneficial effect of the present invention: present method convenient operation, not only improved the purity of product, and reaction conditions is gentle, stable and controllable for quality, Expenses Cost is little, is fit to large-scale industrial production.
Embodiment
Further specify by the following examples the present invention, but not as restriction of the present invention
Embodiment 1, formula (2) dutasteride's is synthetic
5 g compounds (1) are dissolved in the 150 L toluene, add 2.8 g DDQ, room temperature drips 15 mL BSTFA, drips complete room temperature reaction 8 h, is warming up to afterwards 120 ℃ of reaction 18 h; Cooling is revolved except toluene, obtains dutasteride's crude product.
Embodiment 2, formula (2) dutasteride's is synthetic
70 g compounds (1) are dissolved in the 1.05 L toluene, add 36 g DDQ, room temperature adds 142 mL BSTFA, drips complete room temperature reaction 8 h, is warming up to afterwards 80 ℃ of reaction 12 h; Cooling is revolved except toluene, obtains dutasteride's crude product.
Embodiment 3, formula (2) dutasteride's is synthetic
200 g compounds (1) are dissolved in the 3 L toluene, add 103 g DDQ, room temperature adds 406 mL BSTFA, drips complete room temperature reaction 8 h, is warming up to afterwards 100 ℃ of reaction 14 h; Cooling is revolved except toluene, obtains dutasteride's crude product.
Embodiment 4, formula (2) dutasteride's is refining
40 g dutasteride crude products are added 5% NaHSO
3In the mixed solvent of (1.4 L) and methylene dichloride (2.1 L), stirring at room 30min, suction filtration, get filtrate, tell organic layer, the 5%NaOH aqueous solution and saturated aqueous common salt respectively wash three times successively, the pressure reducing and steaming solvent, get off-white color solid 60 g, add 300 mL ethyl acetate, room temperature is stirred and is washed 2 h, suction filtration, drying gets white solid 53 g, adds 530 mL acetonitriles, being warming up to 40 ℃ stirs and washes 10min, add 53 mL hydrochloric acid, be down to room temperature, suction filtration, entirely be dissolved in solid in the methylene dichloride, add deionized water wash three times, anhydrous sodium sulfate drying, suction filtration, revolve and desolventize, faint yellow solid 45 g, solid is added 1.35 L mixed solvents (tetrahydrofuran (THF): in the water=1:1), stir and wash 3h, suction filtration, 60 ℃ of decompression drying 10 ~ 15h obtain the sterling that white solid 40g is the dutasteride, purity 99.7%(HPLC area normalization method).
[M+H]
+=529；[M+CH
3CN+H]
+=570；H
1NMR?(CDCl
3)?δ:?0.8(s,?3H,?18-CH
3?),?1.0(s,?3H,?19-CH
3?),?2.35(t,?1H,?17-H),?3.35(q,?1H,?5α-H),?5.5?(s,?1H,?CONH),?5.8(d,?
J=1.5,?1H,?=CH-),?6.8(d,?
J=7.5?Hz,?1H,?=CH-),?7.4~7.5(m,?2H,?ArH)?,?7.75(d,?
J=6.3?Hz,?1H,?ArH),?8.8(s,?1H,?CONH)。
Embodiment 5, formula (2) dutasteride's is refining
40 g dutasteride crude products (2) are added 1%NaHSO
3In the mixed solvent of (1.4 L) and methylene dichloride (2.1 L), stirring at room 30min, suction filtration is got filtrate, tells organic layer, 20%K
2CO
3The aqueous solution, saturated aqueous common salt respectively washs three times successively, and the pressure reducing and steaming solvent gets off-white color solid 65 g, add 300 mL ethyl acetate, room temperature is stirred and is washed 2 h, suction filtration, dry, get white solid 53 g, add 530 mL acetonitriles, be warming up to 40 ℃, stir and wash 10min, add 53 mL hydrochloric acid, be down to room temperature, suction filtration, entirely be dissolved in solid in the methylene dichloride, add deionized water wash three times, anhydrous sodium sulfate drying, suction filtration, revolve and desolventize, faint yellow solid 45 g, solid is added 1.35 L mixed solvents (tetrahydrofuran (THF): in the water=1:1), stir and wash 3h, suction filtration, 60 ℃ of decompression drying 10 ~ 15h obtain the sterling that white solid 40g is the dutasteride, purity 99.8%(HPLC area normalization method).
Embodiment 6, formula (2) dutasteride's is refining
40 g dutasteride crude products are added 5%NaHSO
3In the mixed solvent of (1.4 L) and methylene dichloride (2.1 L), stirring at room 30min, suction filtration is got filtrate, tells organic layer, 20% K
2CO
3The aqueous solution, saturated aqueous common salt respectively wash three times successively, the pressure reducing and steaming solvent, off-white color solid 65 g, add 650 mL acetonitriles, be warming up to 40 ℃ and stir and wash 10min, add 65 mL hydrochloric acid, be down to room temperature, suction filtration is dissolved in solid in the methylene dichloride entirely, add deionized water wash three times, anhydrous sodium sulfate drying, suction filtration revolves and desolventizes, get faint yellow solid 55 g, adding 275 mL ethyl acetate room temperatures stirs and washes 3h, suction filtration, 60 ℃ of decompression drying 10 ~ 15h, obtain the sterling that white solid 45 g are the dutasteride, purity is the 99.8%(HPLC area normalization method).
Embodiment 7, formula (2) dutasteride's is refining
40 g dutasteride crude products (2) are added 5%NaHSO
3In the mixed solvent of (1.4 L) and methylene dichloride (2.1 L), stirring at room 30min, suction filtration is got filtrate, tells organic layer, 20% K
2CO
3The aqueous solution, saturated aqueous common salt respectively washs three times successively, the pressure reducing and steaming solvent gets off-white color solid 65 g, adds 650 mL acetonitriles, being warming up to 40 ℃ stirs and washes 10min, add 65 mL hydrochloric acid, be down to room temperature, suction filtration, entirely be dissolved in solid in the methylene dichloride, add deionized water wash three times, anhydrous sodium sulfate drying, suction filtration, revolve and desolventize, faint yellow solid 55 g, solid is added 1.65 L mixed solvents (tetrahydrofuran (THF): in the water=1:1), stir and wash 3h, suction filtration, 60 ℃ of decompression drying 10 ~ 15h obtain white solid 48 g and are dutasteride's sterling, and purity is the 99.7%(HPLC area normalization method).
The HPLC testing conditions:
Chromatographic column: C18,150*5.6 mm, 3 μ m(Féraud door luna; L1-185);
Moving phase: phosphate buffered saline buffer (10 mmol/L biphosphate sodium water solutions are regulated pH to 3.0 with dilute phosphoric acid (1 mL phosphoric acid is dissolved in the 10 mL water)): acetonitrile=55:45;
Flow velocity: 1.0 mL/min;
Column temperature: 20 ℃;
Detect wavelength: 210 nm;
Sampling volume: 10 μ L;
Working time: 90 min.
Claims (9)
1. a dutasteride process for purification is characterized in that, may further comprise the steps:
Step 1: formula (1) compound through 1,2 dehydrogenation, is obtained formula (2) dutasteride (DTS) crude product;
Step 2: formula (2) dutasteride's crude product is refining through the washing of inorganic salt solution, alkaline solution, organic solvent and acid reagent, obtains dutasteride's sterling.
2. dutasteride's according to claim 1 process for purification, it is characterized in that: in the step 2, described inorganic salt solution is sodium pyrosulfate, sodium bisulfite, S-WAT or sodium thiosulfate solution, and described inorganic salt solution mass concentration is between 1% ~ 10%; Described alkaline solution is sodium hydroxide, potassium hydroxide, yellow soda ash or wet chemical, and described alkaline solution mass concentration is between 1% ~ 30%; Described organic solvent is conventional solvent; Described acid reagent is sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid or formic acid.
3. dutasteride's according to claim 2 process for purification is characterized in that: described inorganic salt solution mass concentration preferred 5%.
4. dutasteride's according to claim 2 process for purification is characterized in that: the preferred aqueous sodium hydroxide solution of described alkaline solution.
5. dutasteride's according to claim 2 process for purification is characterized in that: described alkaline concentration preferred 5%.
6. dutasteride's according to claim 2 process for purification, it is characterized in that: described organic solvent is selected from following wherein a kind of: ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, C1 ~ C4 cyanogen kind solvent, methylene dichloride and chloroform.
7. dutasteride's according to claim 2 process for purification is characterized in that: in the step 2, formula (2) dutasteride's crude product is dissolved in organic solvent entirely, add inorganic salt solution and stir 10 ~ 60min, suction filtration is told organic layer, add the alkaline solution washing, the saturated common salt water washing is revolved and is desolventized, adding organic solvent room temperature is stirred and is washed, and suction filtration is dissolved in solid in the organic solvent, intensification is stirred and is washed, and adds acid reagent, cooling, suction filtration, solid is dissolved in organic solvent, adds deionized water wash, anhydrous sodium sulfate drying, suction filtration, revolve and desolventize, solid is added in the mixed solvent, stir and wash, suction filtration, decompression drying.
8. dutasteride's according to claim 2 process for purification, it is characterized in that: in the step 2, formula (2) dutasteride's crude product is dissolved in the haloalkane kind solvent entirely, the inorganic salt solution that adds 0.5 ~ 1 times of amount of solvent stirred 10 ~ 60 minutes, suction filtration is told organic layer; The alkaline solution washing that adds 0.5 ~ 1 times of amount of solvent, the saturated common salt water washing is revolved and is desolventized, and the esters solvent room temperature that adds 1 ~ 10 times of amount of product is stirred and is washed 1 ~ 10 hour, suction filtration; Solid is dissolved in the cyanogen kind solvent of 1 ~ 30 times of amount of product, is warming up to 30 ~ 60 ℃ and stirs and wash 10 ~ 60 minutes, add the acid reagent of 1 ~ 20 times of amount of product, be down to room temperature, suction filtration; Solid is dissolved in the organic solvent entirely, adds deionized water wash, anhydrous sodium sulfate drying, suction filtration revolves and desolventizes, and solid is added in the mixed solvent of 1 ~ 50 times of amount, stirs and washes 1 ~ 10 hour, suction filtration, decompression drying 1 ~ 20 hour.
9. dutasteride's according to claim 2 process for purification, it is characterized in that: in the step 2, entirely be dissolved in dutasteride's crude product in the methylene dichloride formula (2), 5% sodium sulfite aqueous solution that adds 0.75 times of amount of solvent stirred 30 minutes, and suction filtration is told organic layer, the alkaline solution that adds 1 times of amount of solvent washs three times, saturated common salt water washing three times is revolved and is desolventized, and product is added in the ethyl acetate of 5 times of amounts room temperature and stirs and wash 2h, suction filtration, solid is dissolved in the acetonitrile of 10 times of amounts of product, is warming up to 40 ℃ and stirs and wash 10min, add the hydrochloric acid of 1 times of amount of product, be down to room temperature, suction filtration is dissolved in solid in the methylene dichloride entirely, adds deionized water wash three times, anhydrous sodium sulfate drying, suction filtration revolves and desolventizes, and solid is added in the mixed solvent of 30 times of amounts, described mixed solvent by tetrahydrofuran (THF) and water by volume 1:1 form, stir and wash 3 hours, suction filtration, decompression drying 10 ~ 15 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111484542A (en) * | 2020-04-30 | 2020-08-04 | 湖北葛店人福药业有限责任公司 | Method for treating finasteride mother liquor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007120263A2 (en) * | 2005-11-10 | 2007-10-25 | Dr. Reddy's Laboratories Ltd. | Preparation of dutasteride |
| CN102382165A (en) * | 2011-12-02 | 2012-03-21 | 北京赛科药业有限责任公司 | Preparation method of dutasteride |
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- 2012-09-29 CN CN2012103708319A patent/CN102863507A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007120263A2 (en) * | 2005-11-10 | 2007-10-25 | Dr. Reddy's Laboratories Ltd. | Preparation of dutasteride |
| CN102382165A (en) * | 2011-12-02 | 2012-03-21 | 北京赛科药业有限责任公司 | Preparation method of dutasteride |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111484542A (en) * | 2020-04-30 | 2020-08-04 | 湖北葛店人福药业有限责任公司 | Method for treating finasteride mother liquor |
| CN111484542B (en) * | 2020-04-30 | 2024-01-30 | 湖北葛店人福药业有限责任公司 | Treatment method of finasteride mother liquor |
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Application publication date: 20130109 |