Preparation method of 3-carbonyl-4-aza-5 alpha-androstane-17 beta-carboxylic acid compound

Abstract

The invention provides a preparation method of a 3-carbonyl-4-aza-5 alpha-androstane-17 beta-carboxylic acid compound, which comprises the following steps: taking a compound with a specific structure as a raw material; the 3-carbonyl-4-aza-5alpha-androstane-17beta-carboxylic acid can be obtained through a side chain cyano hydrolysis reaction, an oxidation ring-opening reaction, a condensation ring-closing reaction, a reduction reaction and a diazotization reaction in sequence, the reaction technological process is shortened, and the production process is simple; and the method is low in cost, high in product yield and suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and more specifically, to a method for preparing a 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound. Background Art

[0002] Benign prostatic hyperplasia (BPH) is a common disease in middle-aged and elderly men. The main cause of the disease is the increase in dihydrotestosterone (DHT) levels in the body. The concentration of DHT in the human body is mainly determined by the degree of conversion of testosterone under the action of 5α-reductase. Therefore, in the process of treating BPH, how to inhibit 5α-reductase in the human body has become the main target of drug screening.

[0003] At present, the drugs finasteride and dutasteride can effectively reduce the conversion of testosterone into DHT, reduce the size of the prostate and improve benign BPH by inhibiting 5α-reductase in the human body during the treatment of BPH. 3-Carbonyl-4-aza-5α-androstane-17β-carboxylic acid (structural formula is shown in Formula I below) is a traditional Chinese medicine intermediate for the synthesis of finasteride and dutasteride.

[0004]

[0005] The traditional method for preparing 3-carbonyl-4-aza-5α-androstane-17β-carboxylic acid has the following reaction process (US20060046994):

[0006]

[0007] The method uses compound 07 as the starting material and prepares 3-carbonyl-4-aza-5α-androstane-17β-carboxylic acid through 4 steps of reaction. However, compound 07 is mainly obtained by multi-step chemical synthesis of Huangjiang extract saponin. The synthetic route is as follows:

[0008]

[0009] The synthesis process is long, has high industrial pollution and low yield. Summary of the invention

[0010] Based on the above technical problems existing in the prior art, the present invention provides a method for preparing a 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound, which shortens the reaction process flow, has low cost, high product yield, and has the advantage of large-scale production.

[0011] In order to achieve the above object, the technical solution of the present invention is as follows:

[0012] A method for preparing a 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound comprises the following steps:

[0013] S1, dissolving compound A in a first solvent, and performing a hydrolysis reaction under the action of a first strong acid to obtain compound B;

[0014] S2, dissolving the compound B in a second solvent, and then adding a weak base, sodium periodate and potassium permanganate to carry out an oxidative ring-opening reaction to obtain a compound C;

[0015] S3, dissolving the compound C in a third solvent, and performing a condensation ring-closing reaction with ammonium acetate to obtain a compound D;

[0016] S4, dissolving the compound D in a fourth solvent, then adding the first catalyst, introducing hydrogen after displacement to perform a hydrogenation reduction reaction, to obtain a compound E;

[0017] S5, dissolving the compound E in a fifth solvent, and performing a diazotization reaction with a nitrite aqueous solution under the catalysis of a second strong acid to obtain 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid;

[0018] Wherein, the structure of the compound A is: The structural formula of the compound B is: The structural formula of the compound C is: The structural formula of the compound D is: The structural formula of the compound E is:

[0019] In some embodiments, in step S1, the mass ratio of compound A, the first organic solvent and the first strong acid is 1.0:(2.0-4.0):(0.8-2.0).

[0020] In some embodiments, in step S2, the mass ratio of compound B, the second solvent, the weak base, sodium periodate, and potassium permanganate is 1.0:(8.0-10.0):(0.8-1.0):(3.0-3.4):0.05.

[0021] In some embodiments, in step S3, the mass ratio of compound C, the third solvent, and ammonium acetate is 1.0:(5.0-6.0):0.5.

[0022] In some embodiments, in step S4, the mass ratio of the compound D, the fourth solvent and the first catalyst is 1.0:8.0:(0.1-0.15).

[0023] In some embodiments, in step S5, the mass ratio of the compound E, the fifth solvent, the second strong acid, the nitrite, and water is 1.0:(6.0-8.0):(2.0-3.0):(1.0-1.2):2.0.

[0024] In some embodiments, the first solvent is selected from at least one of glacial acetic acid and tetrahydrofuran; the second solvent is tert-butanol; and the third solvent, the fourth solvent and the fifth solvent are respectively glacial acetic acid.

[0025] In some embodiments, the first strong acid is concentrated sulfuric acid; the weak base is at least one of sodium bicarbonate, sodium carbonate, and potassium carbonate; the first catalyst is palladium carbon; and the second strong acid is one of concentrated hydrochloric acid and concentrated sulfuric acid.

[0026] In some embodiments, step S1 is specifically as follows: compound A is added to a first solvent, and then a first strong acid is added, stirred and heated to 50-60°C, and kept warm for reaction for 8-10 hours; after the reaction is completed, the reaction solution is dripped into water, cooled to below 30°C, filtered, washed, and dried to obtain the compound B.

[0027] In some embodiments, step S2 is specifically as follows: compound B is added to a second solvent, a weak base is added, the temperature is raised to 60-70°C, and then a mixed solution of sodium periodate and potassium permanganate is added dropwise. After the addition is complete, the temperature is maintained at 60-70°C for 2-3 hours. After the reaction is completed, the temperature is lowered, sodium bisulfite is added for quenching, the mixture is concentrated, cooled, filtered, and dried to obtain compound C.

[0028] In some embodiments, in step S3, compound C is added to a third solvent, and then ammonium acetate is added, the temperature is raised to 115-120°C and refluxed to separate water for 3-4 hours, the temperature is lowered and concentrated, methanol is added to reflux and purify, the temperature is lowered for crystallization, filtered, and dried to obtain the compound D.

[0029] In some embodiments, step S4 is specifically as follows: adding the compound D to the fourth solvent, then adding the first catalyst, introducing hydrogen after displacement, controlling the pressure to 0.4-0.5 MPa and the temperature to 25-30°C for reaction, and after the reaction is completed, filtering, concentrating, cooling and crystallizing, and filtering a second time to obtain the compound E.

[0030] In some embodiments, step S5 is specifically as follows: adding the compound E to the fifth solvent, adding a second strong acid dropwise, and controlling the temperature below 40°C; after the addition is completed, cooling to -5-0°C, adding a sodium nitrite aqueous solution dropwise for reaction, adding an ammonium chloride aqueous solution for quenching, adding water for crystallization, filtering, drying, and then crystallizing with methanol to obtain the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid.

[0031] In some embodiments, the compound A is prepared by sequentially subjecting 4-androstenedione to cyanation reaction, ketal protection reaction, hydroxyl elimination reaction, and hydrogenation reaction.

[0032] In some embodiments, specifically, the reaction route for preparing compound A from 4-androstenedione is as follows:

[0033]

[0034] The specific steps include:

[0035] 1) dissolving 4-androstenedione in an organic solvent, then adding an inorganic base and acetone cyanohydrin, heating to 40-60° C. for reaction, to obtain compound 1; the mass ratio of 4-androstenedione, inorganic base and organic solvent is 1.0:0.02-0.1:1.0-3.0; the inorganic base includes sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; the organic solvent includes at least one of methanol, ethanol and tetrahydrofuran;

[0036] 2) dissolving compound 1 in toluene, then adding p-toluenesulfonic acid and diol, heating to 30-50° C. for reaction, to obtain compound 2; the mass ratio of compound 1, p-toluenesulfonic acid and diol is: 1.0: 0.01-0.1: 1.2-2.0; the diol is preferably ethylene glycol;

[0037] 3) Compound 2 and tetrahydrofuran are mixed, cooled to -50 to -40°C, and then phosphorus pentachloride is added, and the mixture is kept at -50 to -40°C for elimination reaction to obtain compound 3; the mass ratio of compound 2, tetrahydrofuran and phosphorus pentachloride is 1.0:8-15:0.7-1.0;

[0038] 4) Compound 3 is dissolved in toluene, and subjected to hydrogenation reaction under the action of palladium carbon to obtain the compound A; the palladium carbon is 5% palladium carbon.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] The invention uses a compound of a specific structure as a raw material, and sequentially undergoes side chain cyano hydrolysis reaction, oxidation ring-opening reaction, condensation ring-closing reaction, reduction reaction and diazotization reaction to obtain 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid, thereby shortening the reaction process and simplifying the production process; the invention also has low cost and high product yield, and is suitable for large-scale production.

[0041] In addition, the raw material used is prepared by sequentially subjecting 4-androstenedione to cyanation reaction, ketal protection reaction, hydroxyl elimination reaction and hydrogenation reaction, and the yield of the raw material is effectively improved through a specific process route, thereby improving the yield of 3-carbonyl-4-aza-5α-androstane-17β-carboxylic acid. DETAILED DESCRIPTION

[0042] Many specific details are set forth in the following description to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar modifications without violating the connotation of the present invention, so the present invention is not limited to the specific implementation disclosed below.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0044] The raw materials used in the following examples were prepared as follows:

[0045]

[0046] The specific preparation method is:

[0047] 1) Add 30 g of raw material 4AD, 30 mL of methanol, and 30 mL of acetone cyanohydrin to a 250 mL three-necked round-bottom flask, stir evenly, then add a sodium carbonate aqueous solution with a mass concentration of 0.02 g / mL, heat to 40°C, and keep warm for 24 hours; after the reaction is completed, cool to 0-10°C for crystallization, filter, soak the filter cake in 10% dilute hydrochloric acid for 30 minutes, filter, and obtain a crude compound 1, which is refined with methanol to obtain 29.7 g of a fine product with a yield of 99%;

[0048] 2) Add 5 g of compound 1, 50 mL of toluene, 0.05 g of p-toluenesulfonic acid and 6 g of ethylene glycol to a 250 mL three-necked round-bottom flask, stir and heat to 110 ° C, reflux and separate water to react for 1 h; after the reaction is completed, the reaction solution is neutralized with 0-5 ° C sodium hydroxide solution, concentrated, added with water for crystallization, filtered, the filter cake is precipitated to neutrality and recrystallized, and dried to obtain 6 g of compound 2, with a yield of 120%;

[0049] 3) Add 5 g of compound 2 and 50 g of tetrahydrofuran to a 100 mL three-necked round-bottom flask, cool to -50°C, add 3.5 g of phosphorus pentachloride with stirring, keep at -50°C to -40°C for 3 h, TLC shows that the reaction is complete, control the temperature below 10°C, add water for crystallization, filter and rinse with water until neutral to obtain a wet product; add methanol to the wet product, heat to 60°C, stir for 2 hours, freeze (cool to -10 to 0°C), filter, rinse with ice methanol, and dry to obtain 4 g of compound 3, with a yield of 80%;

[0050] 4) A 100 mL three-necked round-bottom flask was evacuated, replaced with nitrogen several times, 10 mL of toluene was added, and 0.05 g of palladium carbon was added under nitrogen protection; 4 g of compound 3 was added to 40 mL of toluene, and then added to the three-necked round-bottom flask, stirred thoroughly until dissolved, hydrogen was introduced to replace the system and maintained in a hydrogen environment, and the reaction was carried out at room temperature for 3-5 h. After the reaction was completed, it was filtered, concentrated, and crystallized to obtain 3.8 g of compound A with a yield of 95%.

[0051] Example 1

[0052] A method for preparing a 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound, the process flow of which is as follows:

[0053]

[0054] The specific steps include:

[0055] S1. At room temperature, add 150g of glacial acetic acid to a 500mL three-necked round-bottom flask, start stirring, add 75g of concentrated sulfuric acid dropwise, and control the temperature below 50°C; after the addition is complete, add 50g of compound 01, keep warm at 50°C and stir to react for 10 hours; after the reaction is complete, drop the reaction solution into 1000mL of water to precipitate a solid, cool to below 30°C, stir and crystallize for 2 hours, filter, wash with water, and dry to obtain 45g of compound 02, with a mass yield of 90.0%;

[0056] S2. At room temperature, add 240g of tert-butanol, 120g of water, and 24g of sodium carbonate to a 1000mL three-necked round-bottom flask, add 30g of compound 02 under stirring, heat to 65°C, and dropwise add a mixed hot solution (90°C) prepared from 90g of sodium periodate, 1.5g of potassium permanganate and 300mL of water. After the addition is complete, keep the temperature at 70°C for 3 hours; after the reaction is completed, filter, add sodium sulfite to quench, and then concentrate the tert-butanol, cool to room temperature and stir for 2 hours, filter, wash with water, and dry to obtain 28.7g of compound 03, with a mass yield of 95.6%;

[0057] S3. At room temperature, 150 g of glacial acetic acid, 15 g of ammonium acetate and 30 g of compound 03 were added to a 500 mL three-necked round-bottom flask, and the mixture was heated to 118°C with stirring and refluxed for 3 hours, cooled to 70-80°C, concentrated to 1 / 10 of the original volume, and methanol was added for reflux and purification. The mixture was cooled to below 20°C and stirred for 2 hours, filtered and dried to obtain 25.8 g of compound 04 with a mass yield of 86.0%.

[0058] S4. At room temperature, 300 mL of glacial acetic acid, 3 g of 4% palladium carbon, and 30 g of compound 04 were added to a 500 mL stainless steel hydrogenation reactor. The air was replaced by nitrogen three times and the nitrogen was replaced by hydrogen three times under stirring. The pressure was controlled at 0.4 MPa and the reaction temperature was 28 ° C. The reaction was stirred for 24 hours. After the reaction was complete, the mixture was filtered, concentrated, and 100 mL of water was added to stir and crystallize for 2 hours. The mixture was filtered and dried to obtain 28.8 g of compound 05 with a mass yield of 96.0%.

[0059] S5. At room temperature, add 180g of glacial acetic acid and 30g of compound 05 to a 1000mL three-necked round-bottom flask, add 60g of concentrated sulfuric acid dropwise, control the temperature below 40°C, and after the addition is complete, cool to -5-0°C, add a mixed solution of 30g of sodium nitrite and 60g of water dropwise, control the temperature below 5°C, and after the addition is complete, keep at -5-0°C for reaction for 5 hours; after the reaction is completed, add an aqueous solution of ammonium chloride to quench the reaction, add water to crystallize, filter, wash, dry, and then slurry with methanol to obtain 27.2g of compound 06 with a mass yield of 90.6%.

[0060] Example 2

[0061] The specific synthesis method of this embodiment is the same as that of Example 1, except that in this embodiment, the reaction temperature in step S1 of Example 1 is adjusted to 60°C to obtain 44.8g of compound 02 with a mass yield of 89.6%; the amount of sodium periodate in step S2 is adjusted to 102g to obtain 28.5g of compound 03 with a mass yield of 95.0%; the amount of glacial acetic acid in step S3 is adjusted to 180g to obtain 26g of compound 04 with a mass yield of 86%; the hydrogenation pressure in step S4 is adjusted from 0.4Mpa to 0.5Mpa to obtain 28.7g of compound 05 with a mass yield of 95.6%; the amount of glacial acetic acid in step S5 is adjusted to 240g to obtain 27.0g of compound 06 with a mass yield of 90%.

[0062] Example 3

[0063] The specific synthesis method of this embodiment is the same as that of Embodiment 1, except that in this embodiment, the amount of glacial acetic acid in step S1 of Embodiment 1 is adjusted to 100 g to obtain 45.2 g of compound 02 with a mass yield of 90.4%; the reaction temperature in step S2 is adjusted to 60°C to obtain 28.8 g of compound 03 with a mass yield of 96%; the amount of palladium carbon in step S4 is adjusted to 4 g to obtain 28.5 g of compound 04 with a mass yield of 95.0%; the amount of sodium nitrite in step S5 is adjusted to 36 g to obtain 27.1 g of compound 05 with a mass yield of 90.3%.

[0064] Example 4

[0065] The specific synthesis method of this embodiment is the same as that of Embodiment 1, except that in this embodiment, the glacial acetic acid in step S1 of Embodiment 1 is replaced by tetrahydrofuran in an amount of 150 g, and 45.2 g of compound 02 is obtained, with a mass yield of 90.4%; the sodium carbonate in step S2 of Example 1 is replaced by sodium bicarbonate in an amount of 24 g, and 28.6 g of compound 03 is obtained, with a mass yield of 95.3%; the concentrated sulfuric acid in step S5 is replaced by concentrated hydrochloric acid in an amount of 60 g, and 27.0 g of compound 06 is obtained, with a mass yield of 90%.

[0066] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0067] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing a 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound, characterized in that: The following steps are involved: S1, dissolving compound A in a first solvent, and performing a hydrolysis reaction under the action of a first strong acid to obtain compound B; S2, dissolving the compound B in a second solvent, and then adding a weak base, sodium periodate and potassium permanganate to carry out an oxidative ring-opening reaction to obtain a compound C; S3, dissolving the compound C in a third solvent, and performing a condensation ring-closing reaction with ammonium acetate to obtain a compound D; S4, dissolving the compound D in a fourth solvent, then adding the first catalyst, introducing hydrogen after displacement to perform a hydrogenation reduction reaction, to obtain a compound E; S5, dissolving the compound E in a fifth solvent, and performing a diazotization reaction with a nitrite aqueous solution under the catalysis of a second strong acid to obtain 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid; Wherein, the structure of the compound A is: The structural formula of the compound B is: The structural formula of the compound C is: The structural formula of the compound D is: The structural formula of the compound E is:

2. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: In step S1, the mass ratio of compound A, the first organic solvent and the first strong acid is 1.0: (2.0-4.0): (0.8-2.0); and / or, in step S2, the mass ratio of compound B, the second solvent, the weak base, sodium periodate and potassium permanganate is 1.0: (8.0-10.0): (0.8-1.0): (3.0-3.4): 0.05; and / or, in step S3, the mass ratio of compound C, the third solvent, The mass ratio of ammonium acetate is 1.0:(5.0-6.0):0.5; and / or, in step S4, the mass ratio of the compound D, the fourth solvent and the first catalyst is 1.0:8.0:(0.1-0.15); and / or, in step S5, the mass ratio of the compound E, the fifth solvent, the second strong acid, the nitrite and water is 1.0:(6.0-8.0):(2.0-3.0):(1.0-1.2):2.

0.

3. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: The first solvent is selected from at least one of glacial acetic acid and tetrahydrofuran; the second solvent is tert-butyl alcohol; and the third solvent, the fourth solvent and the fifth solvent are respectively glacial acetic acid.

4. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: The first strong acid is concentrated sulfuric acid; the weak base is at least one of sodium bicarbonate, sodium carbonate, and potassium carbonate; the first catalyst is palladium carbon; and the second strong acid is one of concentrated hydrochloric acid and concentrated sulfuric acid.

5. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: In step S1, specifically: compound A is added to a first solvent, and then a first strong acid is added, stirred and heated to 50-60°C, and kept warm for reaction for 8-10 hours; after the reaction is completed, the reaction solution is dropped into water, cooled to below 30°C, filtered, washed, and dried to obtain the compound B.

6. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: In step S2, specifically: compound B is added to the second solvent, and then a weak base is added, the temperature is raised to 60-70°C, and then a mixed solution of sodium periodate and potassium permanganate is added dropwise. After the addition is completed, the temperature is maintained at 60-70°C for 2-3 hours; after the reaction is completed, the temperature is lowered, sodium bisulfite is added for quenching, and the mixture is concentrated, cooled, filtered, and dried to obtain compound C.

7. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: In step S3, compound C is added to a third solvent, and then ammonium acetate is added, the temperature is raised to 115-120° C., refluxed and separated by water for 3-4 hours, the temperature is lowered and concentrated, methanol is added to reflux and purify, the temperature is lowered for crystallization, filtered, and dried to obtain the compound D.

8. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: In step S4, specifically: the compound D is added to the fourth solvent, and then the first catalyst is added, hydrogen is introduced after displacement, the pressure is controlled to be 0.4-0.5MPa, and the temperature is 25-30°C for reaction. After the reaction is completed, filtering, concentrating, cooling and crystallizing, and secondary filtering are performed to obtain the compound E.

9. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: In step S5, specifically, the compound E is added to the fifth solvent, and the second strong acid is added dropwise, and the temperature is controlled below 40°C; after the addition is completed, the temperature is lowered to -5-0°C, and an aqueous sodium nitrite solution is added dropwise to react, and after the reaction is completed, an aqueous ammonium chloride solution is added to quench, water is added to crystallize, filtered, dried, and then crystallized with methanol to obtain the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid.

10. The method for preparing the 3-carbonyl-4-aza-5α-androsterone-17β-carboxylic acid compound according to claim 1, characterized in that: The compound A is prepared by sequentially subjecting 4-androstenedione to cyanation reaction, ketal protection reaction, hydroxyl elimination reaction and hydrogenation reaction.

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