CN108752415B - Synthesis and purification method of finasteride chiral impurity (5 β -finasteride) - Google Patents
Synthesis and purification method of finasteride chiral impurity (5 β -finasteride) Download PDFInfo
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Abstract
The invention discloses a method for synthesizing and purifying finasteride chiral impurities (5 β -finasteride), which adopts bisamide (formula 1) as a raw material to obtain a target product (formula 3) through catalytic hydrogenation, refining, dehydrogenation and purification, wherein the synthetic route is as follows:
Description
Technical Field
The invention belongs to the field of chemical synthesis of steroid drugs, and particularly relates to a preparation method of finasteride chiral impurity 5 β -finasteride.
Background
Finasteride, chemical name Finasteride, molecular formula C23H36N2O, molecular weight 372.54, CAS registry number 98319-26-7, and the structural formula is shown below.
Finasteride is a 4-azasteroid that is a specific inhibitor of the intracellular enzyme type II 5 α reductase in the metabolism of testosterone to more potent dihydrotestosterone whereas benign prostatic hyperplasia, or prostatic hypertrophy, depends on the conversion of testosterone in the prostate to dihydrotestosterone.
In the process development of the bulk drug of the drug, a synthetic route taking bisamide as a starting material is often adopted, and the route is shown as follows:
we have found in their studies that finasteride products prepared by this route contain a chiral impurity, 5 β -finasteride, having the formula:
the yield is about 0.1%, and a pure reference substance is difficult to obtain by a conventional method for separating and purifying raw medicine impurities. Through literature search, no report is found on the synthesis method of the impurity. Therefore, the invention develops a method for synthesizing finasteride chiral impurities by using a bisamide compound as a starting material.
Disclosure of Invention
The invention aims to solve the technical problems that a finasteride chiral impurity 5 β -finasteride synthesis method in the prior art is not reported, and the invention develops a finasteride chiral impurity synthesis method.
The invention provides a scheme that the method for preparing 5 β -finasteride by using bisamide as a starting material comprises the following steps:
(1) catalytic hydrogenation: introducing hydrogen into bisamide compounds of formula 1, palladium carbon, a sulfonic acid catalyst and glacial acetic acid for reaction to obtain hydride compounds of formula 2A and formula 2B,
the method comprises the following specific steps: under the protection of nitrogen, heating a bisamide compound (formula 1), palladium carbon, a sulfonic acid catalyst and glacial acetic acid to 40-80 ℃, introducing hydrogen, continuing to react for 6-12 hours, stopping the reaction by using nitrogen, filtering out the palladium carbon while hot, and concentrating the filtrate under reduced pressure to obtain hydrides (formula 2A and formula 2B), wherein the reaction formula is shown in the specification;
in the reported synthetic route of finasteride, the generation amount of 5 β -chiral hydride (formula 2B) in hydrogenation reaction is about 5%, the content is low, and it is difficult to obtain 5 β -chiral hydride (formula 2B) with high purity by conventional separation means such as recrystallization, etc. the present application finds that the use amount of the catalyst has an important effect on the content of 5 β -chiral hydride, and then sulfonic acid catalysts with different proportions are added to optimize the catalytic hydrogenation reaction, as shown in the following table, the result shows that the target compound 5 β -chiral hydride can be increased from 5% to about 30% after the sulfonic acid catalysts are used.
(2) Refining, namely stirring and dissolving hydride in a 20-fold volume of solvent A, washing with a sodium carbonate solution and water in sequence, collecting an organic phase, concentrating the organic phase under reduced pressure to paste, adding a 10-fold volume of solvent B, continuously concentrating to 3-6 times of volume, cooling for 1-4 h at-5 ℃, carrying out first suction filtration to obtain a mother solution, concentrating the mother solution to 0.5-1 time of volume, cooling for 1-4 h at 5-15 ℃, carrying out second suction filtration to obtain a filter cake of 5 β -chiral hydride (formula 2B), and carrying out the following steps:
the effect of different solvents on the enrichment of 5 β -chiral hydride (formula 2B) is evident as shown in the following table:
| serial number | Solvent(s) | 5 β -chiral hydride purity | Mass yield |
| 1 | Methylene dichloride | 52.4％ | 36.2％ |
| 2 | Ethanol | 58.8％ | 48.6％ |
| 3 | Acetone (II) | 77.4％ | 20.4％ |
| 4 | Toluene | 87.3％ | 17.8％ |
| 5 | Acetonitrile | 89.1％ | 21.4％ |
| 6 | Ethyl acetate | 94.2％ | 22.7％ |
| 7 | Formic acid ethyl ester | 93.5％ | 21.3％ |
| 8 | Acetic acid isopropyl ester | 94.7％ | 21.5％ |
Experiments show that the purity of the product 5 β -chiral hydride obtained in the step is a key step for determining whether the target compound 5 β -finasteride with high purity can be obtained, when the purity of the obtained second-step product 5 β -chiral hydride is less than 90%, the purity of the target product obtained by subsequent dehydrogenation and purification is below 98%, and therefore, the selection range of the refining solvent B in the step is ethyl acetate, ethyl formate and isopropyl acetate.
(3) Dehydrogenation reaction, namely dissolving 5 β -chiral hydride in an organic solvent, adding DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone) and BSTFA (N, O-bis (trimethylsilyl) trifluoroacetamide) to react under the protection of nitrogen to obtain a crude product of 5 β -finasteride formula 3,
the method comprises the following specific steps of dissolving 5 β -chiral hydride in dioxane, adding DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone) and BSTFA (N, O-bis (trimethylsilyl) trifluoroacetamide) under the protection of nitrogen, reacting for 8 hours at 110 ℃, cooling to room temperature after the reaction is finished, quenching the reaction by using a sodium bisulfite solution, adding toluene for extraction, washing the obtained toluene layer by using a sodium carbonate solution, a sodium bisulfite solution, a sodium carbonate solution and saturated salt water in sequence, collecting the toluene layer, adding activated carbon and anhydrous sodium sulfate, heating and refluxing for 1 hour, filtering, concentrating the filtrate to a small amount under reduced pressure, adding a solvent C, continuously concentrating to a small amount, adding the solvent C, continuously concentrating to about 5 times of volume, cooling, carrying out suction filtration, and drying to obtain a 5 β -finasteride type 3 crude product, wherein the reaction formula is as follows:
optionally, the purification step of the step (4) is carried out, namely, the 5 β -finasteride crude product is added with 100 times volume of solvent D according to the mass of 5 β -finasteride as 1, heated, refluxed, dissolved and cleared, concentrated to about 20 times volume, cooled for 1-4 h at the temperature of-5 ℃ to 5 ℃, filtered, and filter cake is dried under reduced pressure to obtain 5 β -finasteride refined product.
Further, the sulfonic acid catalyst in the step (1) is selected from one of p-toluenesulfonic acid and methanesulfonic acid, and the dosage of the sulfonic acid catalyst is 0.01-0.5 times of the weight of the bisamide compound shown in the formula 1.
Further, the effective content of the palladium carbon in the step (1) is 5-10%.
Further, the mass ratio of the bisamide compound, the glacial acetic acid, the sulfonic acid catalyst and the palladium-carbon in the step (1) is 1:5:0.05: 0.25-1: 10:0.5: 0.5.
Further, in the step (2), the solvent A is one of dichloromethane or chloroform, and the solvent B is one of ethyl formate, ethyl acetate and isopropyl acetate.
Further, in the step (3), the solvent C is one of ethyl acetate and isopropyl acetate.
Further, in the step (4), the solvent D is one of ethyl acetate and isopropyl acetate.
The invention has the beneficial effects that 5 β -finasteride with high purity can be prepared by utilizing the designed process conditions, a proper amount of sulfonic acid catalyst is added in the first step of catalytic hydrogenation reaction, the HPLC content of 5 β -chiral hydride in hydride is improved from 5% to 30%, the refining solvent is selected from one of ethyl acetate, ethyl formate and isopropyl acetate, 5 β -chiral hydride refined substance with the yield of about 20% and the HPLC content of more than 94% can be obtained, the 5 β -chiral hydride refined substance can be subjected to subsequent dehydrogenation reaction and purification to obtain 5 β -finasteride with the purity of 99.5%, and the 5 β -finasteride obtained by utilizing the invention can be used as a finasteride quality impurity reference substance.
Detailed Description
The present invention will now be described in further detail with reference to examples, but the present invention is not limited to the following examples, and any modifications made thereto will fall within the scope of the present invention.
In the following examples, the catalytic hydrogenation reaction of the first step is represented by the following reaction formula:
the refining process of the second step is as follows:
the reaction formula of the dehydrogenation reaction in the third step is as follows:
comparative example: zhongguo Xinyao Zazhi,20(22), 2248-; 2011
Firstly, adding bisamide compound (20g,1W), 5% palladium carbon (10g,0.5W), glacial acetic acid (140g,7W) into a reaction bottle, carrying out nitrogen protection, carrying out hydrogen replacement for three times, introducing hydrogen, keeping the temperature of 60 ℃ for reaction for 8h, carrying out nitrogen replacement to stop the hydrogenation reaction, heating to 80 ℃, filtering out the palladium carbon while hot, carrying out reduced pressure concentration on the filtrate until the filtrate is dried to obtain hydride, and carrying out sampling detection to obtain the 5 β -chiral hydride main peak content in the hydride, wherein the hydrogen is 5.2%.
Example 1:
the first step is catalytic hydrogenation, namely adding bisamide (20g,1W), 5% palladium carbon (10g,0.5W), p-toluenesulfonic acid (4g,0.2W) and glacial acetic acid (140g,7W) into a reaction bottle, carrying out nitrogen protection, carrying out hydrogen replacement for three times, introducing hydrogen, keeping the temperature at 60 ℃ for reaction for 8 hours, carrying out nitrogen replacement to stop hydrogenation reaction, heating to 80 ℃, filtering out palladium carbon while hot, concentrating the filtrate under reduced pressure to dryness to obtain hydride, and sampling and detecting the main peak content of 5 β -chiral hydride in the hydride to be 28.8%.
And secondly, refining, namely adding dichloromethane (400ml,20V) into the hydride, stirring to dissolve the mixture, sequentially washing and separating the mixture by using 10% sodium carbonate solution (180ml,9V), water (100ml,5V) and water (100ml,5V), collecting a dichloromethane layer, concentrating the dichloromethane layer to be pasty under reduced pressure, adding ethyl acetate (200ml,10V) to concentrate the mixture to be about (80ml,4V), cooling the mixture for 2 hours at 0-5 ℃, filtering to obtain mother liquor, concentrating the mother liquor to be about (10ml,0.5V), cooling the mother liquor for 3 hours at 5-10 ℃, filtering, drying the filtered product for 12 hours at 60 ℃ under reduced pressure to obtain 5 β -chiral hydride (4.54g, the mass yield is 22.7%) and the main peak content is 94.2%.
And thirdly, dehydrogenation reaction, namely adding 5 β -chiral hydride (3g,1W), DDQ (3g,1W), BSTFA (15ml,5V) and dioxane (60ml,20V) into a reaction bottle, carrying out nitrogen protection, keeping the temperature for 110 ℃, reacting for 8h, reducing the temperature to below 30 ℃, adding a 10% sodium bisulfite solution (60ml,20V), stirring for 15 min, adding toluene (180ml,60V), stirring for 10 min, separating, washing the obtained toluene layer with a 10% sodium carbonate solution (30ml,10V), a 10% sodium bisulfite solution (30ml,10V), a 10% sodium carbonate solution (30ml,10V) and saturated saline (30ml,10V) in sequence, adding activated carbon (0.75g,0.25W) and anhydrous sodium sulfate (3g,1W) into the obtained toluene layer, heating and refluxing at 110 ℃ for 1h, filtering, concentrating the filtrate under reduced pressure to a small amount, adding isopropyl acetate (60ml,20V), continuously concentrating under reduced pressure to a small amount, adding isopropyl acetate (60V), filtering, reducing the content of the filtrate to 3544V), and drying the product under a non-7 ℃ to obtain a non-10% crude product.
And fourthly, purifying, namely taking 5 β -finasteride crude product (1g,1W), adding isopropyl acetate (100ml,100V), heating, refluxing, dissolving, concentrating to about 20ml,20V, cooling at 0-5 ℃ for 2h, filtering, drying the product at 90 ℃ under reduced pressure for 12h to obtain 5 β -finasteride refined product (0.81g, the mass yield of 81%) with the main peak content of 99.5%.
Example 2
The first step is catalytic hydrogenation, namely adding bisamide (20g,1W), 5% palladium carbon (10g,0.5W), p-toluenesulfonic acid (10g,0.5W) and glacial acetic acid (200g,10W) into a reaction bottle, carrying out nitrogen protection, carrying out hydrogen replacement for three times, introducing hydrogen, keeping the temperature of 40 ℃ for reaction for 12 hours, carrying out nitrogen replacement to stop hydrogenation reaction, heating to 80 ℃, filtering out palladium carbon while hot, concentrating the filtrate under reduced pressure to dryness to obtain hydride, and sampling and detecting the main peak content of 5 β -chiral hydride in the hydride, namely 30.2%.
And secondly, refining, namely adding trichloromethane (400ml,20V) into the hydride, stirring to dissolve the trichloromethane, washing and separating by using 10% sodium carbonate solution (180ml,9V), water (100ml,5V) and water (100ml,5V) in sequence, collecting a chloroform layer, concentrating the chloroform layer to be pasty under reduced pressure, adding ethyl formate (200ml,10V) to concentrate the chloroform layer to be about (60ml,3V), cooling the chloroform layer at 5-0 ℃ for 1h, filtering the chloroform layer to obtain mother liquor, concentrating the mother liquor to be about (10ml,0.5V), cooling the mother liquor at 5-10 ℃ for 1h, filtering the mother liquor, drying the filtered product at 60 ℃ under reduced pressure for 12h to obtain 5 β -chiral hydride (4.26g, the mass yield is 21.3 percent), and the content of a main peak is 93..
And thirdly, dehydrogenation reaction, namely adding 5 β -chiral hydride (3g,1W), DDQ (3g,1W), BSTFA (15ml,5V) and dioxane (60ml,20V) into a reaction bottle, carrying out nitrogen protection, keeping the temperature for 110 ℃, reacting for 8h, reducing the temperature to below 30 ℃, adding a 10% sodium bisulfite solution (60ml,20V), stirring for 15 min, adding toluene (180ml,60V), stirring for 10 min, separating, washing the obtained toluene layer with a 10% sodium carbonate solution (30ml,10V), a 10% sodium bisulfite solution (30ml,10V), a 10% sodium carbonate solution (30ml,10V) and saturated saline (30ml,10V) in sequence, adding activated carbon (0.25g,0.75W) and anhydrous sodium sulfate (3g,1W) into the obtained toluene layer, heating and refluxing at 110 ℃ for 1h, filtering, concentrating the filtrate under reduced pressure to a small amount, adding ethyl acetate (60ml,20V), continuously concentrating the filtrate under reduced pressure to a small amount, filtering the ethyl acetate (60ml,20V), and drying the product under reduced pressure to a reduced pressure, and drying at 358-7 ℃ to obtain a crude product yield of 7-38%.
And fourthly, purifying, namely taking 5 β -finasteride crude product (1g,1W), adding ethyl acetate (100ml,100V), heating, refluxing, dissolving, concentrating to about (20ml,20V), cooling at 5-0 ℃ for 1h, filtering, drying the product at 90 ℃ under reduced pressure for 12h to obtain 5 β -finasteride refined product (0.83g, the mass yield is 83%) with the main peak content of 99.0%.
Example 3
Firstly, adding bisamide (20g,1W), 10% palladium carbon (5g,0.25W), methanesulfonic acid (1g,0.05W) and glacial acetic acid (100g,5W) into a reaction bottle, carrying out nitrogen protection, carrying out hydrogen replacement for three times, introducing hydrogen, keeping the temperature at 80 ℃ for reaction for 6 hours, carrying out nitrogen replacement to stop the hydrogenation reaction, filtering out the palladium carbon while hot, carrying out reduced pressure concentration on the filtrate to dryness to obtain hydride, and carrying out sampling detection to obtain the hydride with the main peak content of 5 β -chiral hydride in the hydride of 26.1%.
And secondly, refining, namely adding dichloromethane (400ml,20V) into the hydride, stirring to dissolve the mixture, sequentially washing and separating the mixture by using 10% sodium carbonate solution (180ml,9V), water (100ml,5V) and water (100ml,5V), collecting a dichloromethane layer, concentrating the dichloromethane layer to be pasty under reduced pressure, adding isopropyl acetate (200ml,10V) into the mixture to be concentrated to be about (120ml,6V), cooling the mixture at 0-5 ℃ for 4h, filtering, concentrating the obtained mother solution to be about (20ml,1V), cooling the mixture at 10-15 ℃ for 4h, filtering, drying the filtered product at 60 ℃ under reduced pressure for 12h, and obtaining 5 β -chiral hydride (4.08g, the mass yield is 20.4%) and the main peak content is 92.8%.
And thirdly, dehydrogenation reaction, namely adding 5 β -chiral hydride (3g,1W), DDQ (3g,1W), BSTFA (15ml,5V) and dioxane (60ml,20V) into a reaction bottle, carrying out nitrogen protection, keeping the temperature for 110 ℃, reacting for 8h, reducing the temperature to below 30 ℃, adding a 10% sodium bisulfite solution (60ml,20V), stirring for 15 min, adding toluene (180ml,60V), stirring for 10 min, separating, washing the obtained toluene layer with a 10% sodium carbonate solution (30ml,10V), a 10% sodium bisulfite solution (30ml,10V), a 10% sodium carbonate solution (30ml,10V) and saturated saline (30ml,10V) in sequence, adding activated carbon (0.75g,0.25W) and anhydrous sodium sulfate (3g,1W) into the obtained toluene layer, heating and refluxing at 110 ℃ for 1h, filtering, concentrating the filtrate under reduced pressure to a small amount, adding isopropyl acetate (60ml,20V), continuously concentrating under reduced pressure to a small amount, adding isopropyl acetate (60V), filtering, reducing the content of the filtrate to 5 β V), and drying the product under a non-15 h to obtain a crude product yield of 10%, and drying at a non-15 h.
And fourthly, purifying, namely taking 5 β -finasteride crude product (1g,1W), adding isopropyl acetate (100ml,100V), heating, refluxing, dissolving, concentrating to about 20ml,20V, cooling at 0-5 ℃ for 4h, filtering, drying the product at 90 ℃ under reduced pressure for 12h to obtain 5 β -finasteride refined product (0.77g, the mass yield of 77%) with the main peak content of 99.4%.
The 5 β -finasteride prepared in the above examples was tested, mass spectrum M/z373 (M + H +), and HPLC (EP8.5) calibration of finasteride standard with RRT of 1.17 (with finasteride RRT of 1) was performed in comparison with 5 β -finasteride standard, which completely met the characteristics of 5 β -finasteride.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (4)
1. A preparation method of finasteride chiral impurity 5 β -finasteride, which has a structure shown in formula 3, is characterized by comprising the following steps:
(1) catalytic hydrogenation: introducing hydrogen into bisamide compounds shown in formula 1, palladium carbon, a sulfonic acid catalyst and glacial acetic acid for reaction to obtain hydride compounds shown in formula 2A and hydride compounds shown in formula 2B, wherein the reaction formulas are as follows:
the sulfonic acid catalyst is p-toluenesulfonic acid or methanesulfonic acid;
the mass ratio of the bisamide compound to the glacial acetic acid to the sulfonic acid catalyst to the palladium-carbon is 1:5:0.05: 0.25-1: 10:0.5: 0.5;
the method specifically comprises the following steps: under the protection of nitrogen, heating the bisamide compound formula 1, palladium carbon, a sulfonic acid catalyst and glacial acetic acid to 40-80 ℃, introducing hydrogen, continuing to react for 6-12 h, stopping the reaction by using nitrogen, filtering out the palladium carbon while hot, and concentrating the filtrate under reduced pressure to obtain a hydride compound formula 2A and a hydride compound formula 2B;
(2) refining, namely stirring and dissolving hydride in 20 times of volume of solvent A, washing with sodium carbonate solution and water in sequence, collecting an organic phase, concentrating the organic phase to be pasty under reduced pressure, adding 10 times of volume of solvent B, continuously concentrating to 3-6 times of volume, cooling for 1-4 h at-5 ℃, carrying out first suction filtration, concentrating the obtained mother liquor to 0.5-1 time of volume, cooling for 1-4 h at 5-15 ℃, carrying out second suction filtration, wherein a filter cake is 5 β -chiral hydride formula 2B,
the solvent A is one of dichloromethane or trichloromethane, and the solvent B is one of ethyl formate, ethyl acetate and isopropyl acetate;
(3) and (3) dehydrogenation, namely dissolving 5 β -chiral hydride in an organic solvent, adding DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone) and BSTFA (N, O-bis (trimethylsilyl) trifluoroacetamide) to react under the protection of nitrogen to obtain a crude product of 5 β -finasteride formula 3, wherein the reaction formula is as follows:
2. the method of claim 1, wherein the effective amount of palladium on carbon in step (1) is 5% to 10%.
3. The method for preparing 5 β -finasteride according to claim 1, wherein the step (3) comprises dissolving 5 β -chiral hydride in dioxane, adding DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone), BSTFA (N, O-bis (trimethylsilyl) trifluoroacetamide) under nitrogen protection, reacting at 110 ℃ for 8h, cooling to room temperature, quenching the reaction with sodium bisulfite solution, adding toluene, extracting, washing the obtained toluene layer with sodium carbonate solution, sodium bisulfite solution, sodium carbonate solution, and saturated brine, collecting the toluene layer, adding activated carbon and anhydrous sodium sulfate, heating and refluxing for 1 hour, filtering, concentrating the filtrate under reduced pressure to a small amount, adding solvent C, concentrating to about 5 times of volume, cooling, suction filtering, and drying to obtain the crude 5 β -finasteride formula 3, wherein the solvent C is one of ethyl acetate and isopropyl acetate.
4. The method for preparing 5 β -finasteride according to claim 1, further comprising a purification step of step (4), which comprises adding 100 times volume of solvent D into crude 5 β -finasteride, heating, refluxing, dissolving, concentrating to about 20 times volume, cooling at-5 deg.C for 1-4 h, filtering, and drying the filter cake under reduced pressure to obtain refined 5 β -finasteride, wherein the solvent D is one of ethyl acetate and isopropyl acetate.
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