Preparation method of a 3-oxo-4-aza-5α-androstane-17β-carboxylic acid compound

Abstract

The present invention provides a method for preparing a 3-oxo-4-aza-5α-androstane-17β-carboxylic acid compound. Using a compound with a specific structure as a raw material, through a side-chain cyano hydrolysis reaction, an oxidative ring-opening reaction, a condensation ring-closure reaction, a reduction reaction, and a diazotization reaction in sequence, 3-oxo-4-aza-5α-androstane-17β-carboxylic acid can be obtained. The reaction process flow is shortened, the production process is simple, the cost is low, the product yield is high, and it is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and more particularly to a method for preparing a 3-oxo-4-aza-5α-androstane-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 the level of dihydrotestosterone (DHT) in the body. The concentration of DHT in the human body is mainly determined by the conversion degree 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 for drug screening.

[0003] Currently, during the treatment of BPH, drugs such as finasteride and dutasteride can effectively reduce the conversion of testosterone into DHT by inhibiting 5α-reductase in the human body, thereby reducing the prostate volume and improving BPH. And 3-oxo-4-aza-5α-androstane-17β-carboxylic acid (the structural formula is as follows Formula I) is an important intermediate for the synthesis of finasteride and dutasteride.

[0004]

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

[0006]

[0007] This method uses compound 07 as the starting material and prepares 3-oxo-4-aza-5α-androstane-17β-carboxylic acid through 4 steps of reactions. However, compound 07 is mainly obtained through multiple steps of chemical synthesis from Huangjiang extract saponin, and its synthesis route is as follows:

[0008]

[0009] This synthesis process has a long process, large 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-oxo-4-aza-5α-androstane-17β-carboxylic acid compound. This method shortens the reaction process flow, has low cost, high product yield, and has more advantages in large-scale production.

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

[0012] A preparation method of a 3-oxo-4-aza-5α-androstane-17β-carboxylic acid compound, comprising the following steps:

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

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

[0015] S3. Dissolve the compound C in a third solvent, and carry out a condensation and ring-closure reaction with ammonium acetate to obtain compound D;

[0016] S4. Dissolve the compound D in a fourth solvent, then add a first catalyst, carry out replacement, and introduce hydrogen to carry out a hydrogenation reduction reaction to obtain compound E;

[0017] S5. Dissolve the compound E in a fifth solvent, and carry out a diazotization reaction with an aqueous nitrite solution under the catalysis of a second strong acid to obtain 3-oxo-4-aza-5α-androstane-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 the 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 the compound B, the second solvent, the weak base, sodium periodate, 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 the compound C, the third solvent, 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; the third solvent, the fourth solvent, and the fifth solvent are each 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 on carbon; the second strong acid is one of concentrated hydrochloric acid and concentrated sulfuric acid.

[0026] In some embodiments, in step S1, specifically: Add the compound A to the first solvent, then add the first strong acid, stir and heat up to 50 - 60 °C, keep warm and react for 8 - 10 h; after the reaction is completed, drop the reaction solution into water, cool down to below 30 °C, filter, wash, and dry to obtain the compound B.

[0027] In some embodiments, in step S2, specifically: Add the compound B to the second solvent, then add the weak base, heat up to 60 - 70 °C, and then dropwise add a mixed solution of sodium periodate and potassium permanganate. After the addition is completed, keep the temperature at 60 - 70 °C and react for 2 - 3 h; after the reaction is completed, cool down and add sodium bisulfite to quench, concentrate, cool down, filter, and dry to obtain the compound C.

[0028] In some embodiments, in step S3, add the compound C to the third solvent, then add ammonium acetate, heat up to 115 - 120 °C and reflux to separate water for 3 - 4 h, cool down and concentrate, add methanol and reflux for purification, cool down to crystallize, filter, and dry to obtain the compound D.

[0029] In some embodiments, in step S4, specifically: Add the compound D to the fourth solvent, then add the first catalyst, displace and then introduce hydrogen, control the pressure at 0.4 - 0.5 MPa and the temperature at 25 - 30 °C for the reaction. After the reaction is completed, filter, concentrate, cool down to crystallize, and filter twice to obtain the compound E.

[0030] In some embodiments, in step S5, specifically: Add the compound E to the fifth solvent, dropwise add the second strong acid, control the temperature below 40 °C; after the addition is completed, cool down to -5 - 0 °C, dropwise add an aqueous solution of sodium nitrite for the reaction. After the reaction is completed, add an aqueous solution of ammonium chloride to quench, add water to crystallize, filter, and dry, and then crystallize with methanol to obtain the 3-oxo-4-aza-5α-androstane-17β-carboxylic acid.

[0031] In some embodiments, Compound A is prepared by subjecting 4-androstenedione to cyanation reaction, ketal protection reaction, hydroxy elimination reaction, and hydrogenation reaction in sequence.

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

[0033]

[0034] Specifically, it includes the following steps:

[0035] 1) Dissolve 4-androstenedione in an organic solvent, then add an inorganic base and acetone cyanohydrin, and raise the temperature 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) Dissolve Compound 1 in toluene, then add p-toluenesulfonic acid and a diol, and raise the temperature 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) Mix Compound 2 and tetrahydrofuran, cool down to -50 to -40 °C, then add phosphorus pentachloride, and keep the temperature at -50 to -40 °C for heat preservation 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) Dissolve Compound 3 in toluene, and carry out hydrogenation reaction under the action of palladium-carbon to obtain the said Compound A; the palladium-carbon is 5% palladium-carbon.

[0039] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0040] The present invention uses a compound with a specific structure as a raw material, and 3-oxo-4-aza-5α-androstane-17β-carboxylic acid can be obtained through side-chain cyano hydrolysis reaction, oxidative ring-opening reaction, condensation ring-closure reaction, reduction reaction, and diazotization reaction in sequence, shortening the reaction process flow, with a simple production process; and it has low cost, high product yield, and is suitable for large-scale production.

[0041] In addition, the raw material used is prepared by subjecting 4-androstenedione to cyanation reaction, ketal protection reaction, hydroxyl elimination reaction and hydrogenation reaction in sequence. The yield of this raw material is effectively increased through a specific process route, thereby increasing the yield of 3-oxo-4-aza-5α-androstane-17β-carboxylic acid. Detailed implementation manners

[0042] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific implementations disclosed below.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this invention belongs. The terms used in the description 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 are prepared as follows:

[0045]

[0046] The specific preparation method is as follows:

[0047] 1) Add 30 g of the 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 an aqueous sodium carbonate solution with a mass concentration of 0.02 g / mL, heat up to 40 °C, and keep the temperature for reaction for 24 h; after the reaction is completed, cool down to 0-10 °C for crystallization, filter, soak the filter cake with 10% dilute hydrochloric acid for 30 min, filter to obtain the crude product of compound 1, and refine the crude product with methanol to obtain 29.7 g of the refined 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 up to 110 °C for reflux and water separation for reaction for 1 h; after the reaction is completed, neutralize the reaction solution with a sodium hydroxide solution at 0-5 °C, concentrate, add water for crystallization, filter, and recrystallize the filter cake by water washing until neutral and dry 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 the temperature to -50 °C, stir and add 3.5 g of phosphorus pentachloride. Keep the temperature at -50 °C to -40 °C and react for 3 h. TLC shows that the reaction is complete. Control the temperature below 10 °C, add water to crystallize, filter and wash with water until neutral to obtain the wet product. Add methanol to the wet product, heat to 60 °C and stir for 2 hours, freeze (cool to -10 to 0 °C), filter, wash with ice methanol, and dry to obtain 4 g of Compound 3 with a yield of 80%;

[0050] 4) Evacuate a 100 mL three-necked round-bottom flask, replace it with nitrogen multiple times, add 10 mL of toluene, and add 0.05 g of palladium carbon under nitrogen protection. Add 4 g of Compound 3 to 40 mL of toluene, then add it to the three-necked round-bottom flask, stir well until dissolved, introduce hydrogen to replace the system and keep it in a hydrogen environment, and react at room temperature for 3 - 5 h. After the reaction is completed, filter, concentrate, and crystallize to obtain 3.8 g of Compound A with a yield of 95%.

[0051] Example 1

[0052] A preparation method of 3-oxo-4-aza-5α-androstane-17β-carboxylic acid compound, and its process flow is as follows:

[0053]

[0054] Specifically, it includes the following steps:

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

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

[0057] S3. At room temperature, add 150 g of glacial acetic acid, 15 g of ammonium acetate, and 30 g of Compound 03 into a 500 mL three-necked round-bottom flask. Stir and heat up to 118 °C for reflux and water separation for 3 hours. Cool down to 70 - 80 °C, concentrate to 1 / 10 of the original volume, add methanol for reflux purification, then cool down to below 20 °C and stir for 2 hours. Filter and dry to obtain 25.8 g of Compound 04, with a mass yield of 86.0%;

[0058] S4. At room temperature, add 300 mL of glacial acetic acid, 3 g of 4% palladium on carbon, and 30 g of Compound 04 into a 500 mL stainless steel hydrogenation reactor. Stir and displace air with nitrogen 3 times, then displace nitrogen with hydrogen 3 times. Control the pressure at 0.4 MPa and the reaction temperature at 28 °C, and stir and react for 24 hours; after the reaction is complete, filter, concentrate, add 100 mL of water and stir for crystallization for 2 hours, filter and dry to obtain 28.8 g of Compound 05, with a mass yield of 96.0%;

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

[0060] Example 2

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

[0062] Example 3

[0063] The specific synthesis method of this example is the same as that of Example 1, except that in this example, the amount of glacial acetic acid in step S1 of Example 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 example is the same as that of Example 1, except that in this example, the glacial acetic acid in step S1 of Example 1 is replaced with tetrahydrofuran in an amount of 150 g to obtain 45.2 g of Compound 02 with a mass yield of 90.4%; the sodium carbonate in step S2 of Example 1 is replaced with sodium bicarbonate in an amount of 24 g to obtain 28.6 g of Compound 03 with a mass yield of 95.3%; the concentrated sulfuric acid in step S5 is replaced with concentrated hydrochloric acid in an amount of 60 g to obtain 27.0 g of Compound 06 with a mass yield of 90%.

[0066] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0067] The above-described embodiments merely represent several implementation manners of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent should be subject to the appended 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 for reflux purification, 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; The specific steps include: (1) dissolving 4-androstenedione in an organic solvent, then adding an inorganic base and acetone cyanohydrin, heating to 40-60° C. to react, to obtain compound 1; (2) Compound 1 is dissolved in toluene, and then p-toluenesulfonic acid and diol are added, and the temperature is raised to 30-50° C. to react to obtain Compound 2; (3) Compound 2 and tetrahydrofuran are mixed, the temperature is lowered to -50 to -40°C, phosphorus pentachloride is added, and the mixture is kept at -50 to -40°C for elimination reaction to obtain Compound 3; (4) dissolving compound 3 in toluene and performing a hydrogenation reaction under the action of palladium on carbon to obtain compound A; Wherein, the structure of compound 1 is: The structure of compound 2 is: The structure of compound 3 is:

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