Preparation method of tibolone intermediate

Abstract

The invention belongs to the technical field of preparation of steroid hormone intermediates, and particularly relates to a preparation method of a tibolone intermediate, which comprises the following steps: 7 alpha-methyl acid, orthoacid methyl ester, methanol and a catalyst are mixed and reacted to obtain a polyetherate, the catalyst is p-toluenesulfonic acid or methanesulfonic acid, the molar ratio of 7 alpha-methyl acid to orthoacid methyl ester is 1: (4-10), and the molar ratio of 7 alpha-methyl acid to orthoacid methyl ester is 1: (4-10); the mass ratio of the 7alpha-methyl acid to the methanol is 1: (1-8), and the molar ratio of the 7alpha-methyl acid to the catalyst is 1: (0.1-0.3); the preparation method comprises the following steps: adding 7 alpha-methyl acid into a reaction kettle, then adding water, controlling the mass ratio of 7 alpha-methyl acid to water to be 1: (0.05-0.5), controlling the temperature to be 0-15 DEG C, carrying out hydrolysis, and after hydrolysis is completed, terminating the reaction and treating to obtain a tibolone intermediate; the method has the advantages of high yield and high purity.

Description

Technical Field

[0001] This invention belongs to the field of preparation technology of steroid hormone intermediates, and specifically relates to a method for preparing tibolone intermediate. Background Technology

[0002] Tibolone is a steroidal drug with the chemical name 17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one. It has androgenic and progestin-stimulating activities, as well as the effect of promoting anabolic metabolism. It can prevent osteoporosis in postmenopausal women and alleviate menopausal symptoms such as hot flashes and sweating. Tibolone belongs to the class of anabolic hormones and androgens, and is used to treat menopause and postmenopausal syndrome. Clinically, it is also used for menopause caused by natural or surgical procedures. The etherified form (7α-methyl-3,3-dimethoxy-5(10)-androsten-17-one) is the key intermediate in the preparation of tibolone. Tibolone is prepared by acetylation and hydrolysis. The reaction route is as follows: .

[0003] The original research company reported in Recl. Trav. Chim. Pays Bas 1986, 105 (4), 111-115, that a 7α-methyl aldehyde compound was obtained from 17β,19-dihydroxyandrost-4,6-dien-3-one-17,19-diacetate as the starting material, through Grignard reaction, hydrolysis, oxidation, and preparative chromatographic purification. Subsequently, the aldehyde group was removed and a dimethyl ether was added at the 3-position to obtain the etherified compound (7α-methyl-3,3-dimethoxy-5(10)-androsten-17-one). This synthetic method has difficult-to-obtain starting materials, a long synthetic route, and requires dealdehyde removal in magnesium ethanol and liquid ammonia to construct the 5,10 double bond, resulting in harsh reaction conditions that are unfavorable for industrial production. The reaction route is as follows: .

[0004] CN114249789A discloses a method for preparing 7α-methyl-3,3-dimethoxy-5(10)-androsten-17-one, reporting a process starting with acid dehydrogenation, followed by esterification, debromination with bromine to obtain dehydrogenated acid dehydrogenation, and then Grignard reaction to obtain 7α-methyl acid dehydrogenation (7α-19-nor-4-androstenedione). This is then protected with 3,17-diethylene glycol to construct a 5(10) double bond, followed by hydrolysis and dimethyl etherification at the 3-position to prepare the substituted ether. The best yield of 7α-methyl acid dehydrogenation to the substituted ether is 82.8%. However, during the hydrolysis of the ketal, side reactions inevitably occur, leading back to 7α-methyl acid dehydrogenation. The overall reaction steps are relatively long, which is not conducive to large-scale production. The reaction route is as follows: .

[0005] CN114409717A discloses a method for preparing tibolone intermediate ethers and tibolone, reporting the preparation of 7α-methyl acid dehydrogenase (7α-19-nor-4-androstenedione) via a Grignard reaction using dehydrogenase as the starting material. Then, ethylene glycol protection at the 3-position is performed to construct a 5(10) double bond, followed by hydrolysis and dimethyl etherification at the 3-position to prepare the tibolone ether. The best yield of 7α-methyl acid dehydrogenase to the tibolone ether is 85.5%. This method improves the yield to some extent, but side reactions inevitably occur during the hydrolysis of the ketal, leading back to 7α-methyl acid dehydrogenase. Overall, the reaction steps are relatively long, which is not conducive to scale-up production. The reaction route is as follows: .

[0006] CN117887795A discloses a method for preparing tibolone intermediates, reporting a process using 7α-methyl acid desaturation (7α-19-nor-4-androstenedione) as the starting material. The 17-keto group is selectively reduced to a 17β-hydroxyl group using a reductase, followed by 3-position dimethyl etherification to construct a 5(10) double bond, and then oxidation of the 17β-hydroxyl group to prepare the tibolone ether. The best yield of the 7α-methyl acid desaturation to the tibolone ether was 79.2%. Although this method uses a mild enzymatic reaction, the yield is low, the reaction steps are lengthy, and the cost is high, making it unsuitable for large-scale production. The reaction route is as follows: .

[0007] The key to synthesizing etherified compounds is constructing a 5(10) double bond functional group. Currently reported methods only involve reacting a substrate containing a 3-keto-4-ene structure with ethylene glycol to generate a 3-ethylene glycol ketal, transferring the 4(5) double bond to a 5(10) double bond. However, during the hydrolysis of the 3-ethylene glycol ketal, due to the conjugated stability of the 3-keto-4-ene structure, it is easy to revert to the starting material with the 3-keto-4-ene structure, resulting in low purity of the obtained 5(10) double bond product. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a method for preparing tibolone intermediates, thereby improving the yield and purity.

[0009] This invention provides a method for preparing a tibolone intermediate, comprising the following steps: 7α-methyl acid desulfate, orthocyanin methyl ester, methanol, and catalyst are mixed and reacted to obtain a polyether compound. The catalyst is p-toluenesulfonic acid or methanesulfonic acid. The molar ratio of 7α-methyl acid desulfate to orthocyanin methyl ester is 1:4~10, the mass ratio of 7α-methyl acid desulfate to methanol is 1:1~8, and the molar ratio of 7α-methyl acid desulfate to catalyst is 1:0.1~0.5. Then water is added, and the mass ratio of 7α-methyl acid to water is 1:0.05~0.5. The temperature is controlled at 0~15℃ for hydrolysis. After hydrolysis is completed, the reaction is terminated and processed to obtain tibolone intermediate. The structural formula of the 7α-methyl acid dehydrogenase is: ; The structural formula of the tibolone intermediate is: .

[0010] Preferably, the orthomethyl ester is trimethyl orthoformate, trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthobutyrate, or trimethyl orthovalerate.

[0011] Preferably, the orthoacetic acid methyl ester is trimethyl orthoacetate.

[0012] Preferably, the catalyst is p-toluenesulfonic acid.

[0013] Preferably, the molar ratio of 7α-methyl acid dehydrogenase to orthocyanin methyl ester is 1:5~8.

[0014] Preferably, the mass ratio of 7α-methyl acid to methanol is 1:1 to 3.

[0015] Preferably, the molar ratio of the 7α-methyl acid desiccant to the catalyst is 1:0.1~0.2.

[0016] Preferably, 7α-methyl acid desulfurization, methyl orthocyanin, methanol and catalyst are mixed, and the reaction temperature is 0~65℃.

[0017] Preferably, in the hydrolysis reaction, the mass ratio of 7α-methyl acid to water is 1:0.05~0.2.

[0018] The reaction route of this invention is as follows: .

[0019] The beneficial effect of the present invention is that, using 7α-methyl acid dehydrogenase (7α-19-nor-4-androstenedione) as the starting material, under the action of orthocyanin methyl ester, methanol and acidic catalyst, a polyether is generated (both the 3 and 17 positions are etherified, and the double bond at the 4 and 5 positions is transferred to the 5 and 10 positions), and then the 17-position ether is selectively hydrolyzed to generate a substitute ether (7α-methyl-3,3-dimethoxy-5(10)-androstenedione-17-one).

[0020] This invention strictly controls the ratio of 7α-methyl acid desulfurization, orthocyanin methyl ester, methanol, and catalyst to obtain polyether compounds in which the double bonds at positions 4 and 5 are transferred to positions 5 and 10.

[0021] This invention strictly controls the amount of water added and the reaction temperature during the hydrolysis process to achieve selective hydrolysis of the 17-position ether, while the 3-position ether remains unhydrolyzed. Triethylamine is added after the reaction is complete to neutralize the acid in the system and prevent the 3-position ether from hydrolyzing during post-treatment.

[0022] The present invention has a short reaction route, which can prepare etherified compounds in one pot, increasing the overall yield to 90%. It overcomes the problems of large reaction byproducts, long synthesis routes, low yields and high production costs in the prior art, thereby improving the overall yield and reducing the production costs of enterprises. Attached Figure Description

[0023] Figure 1 This is the hydrogen spectrum of the etherified compound of Example 1 of the present invention.

[0024] Figure 2 This is the carbon spectrum of the etherified compound of Example 1 of the present invention. Detailed Implementation

[0025] Example 1 A method for preparing a tibolone intermediate includes the following steps: 1) Add 100g of 7α-methyl ester, 280g of trimethyl orthoacetate, and 200g of methanol to the reaction vessel and start stirring; after mixing, add 10g of p-toluenesulfonic acid monohydrate and react at 25°C until the reaction is complete as detected by TLC to obtain the polyether compound.

[0026] 2) Cool to 5°C, add 10g of water, and keep the reaction at this temperature until the polyether is completely hydrolyzed. After the reaction is complete, add 6g of triethylamine, cool to -10°C, and continue crystallization for 1 hour. Centrifuge, dry, and obtain 90g of the tebuconazole intermediate, with an HPLC purity of 99%.

[0027] The proton NMR spectrum of the etherified compound is as follows: Figure 1 As shown, the carbon spectrum of the etherified compound is as follows: Figure 2 As shown.

[0028] Example 2 A method for preparing a tibolone intermediate includes the following steps: 1) Add 100g of 7α-methyl ester, 280g of trimethyl orthoformate, and 200g of methanol to the reaction vessel and start stirring; after mixing, add 10g of p-toluenesulfonic acid monohydrate and react at 25°C until the reaction is complete as detected by TLC to obtain the polyether compound.

[0029] 2) Cool to 5°C, add 10g of water, and maintain the temperature until the polyether is completely hydrolyzed. After the reaction is complete, add 6g of triethylamine, cool to -10°C, continue crystallization for 1 hour, centrifuge, and dry to obtain 88g of the tebuconazole intermediate, with an HPLC purity of 99%.

[0030] Example 3 A method for preparing a tibolone intermediate includes the following steps: 1) Add 100g of 7α-methyl ester, 180g of trimethyl orthoformate, and 800g of methanol to the reaction vessel and start stirring; after mixing, add 7g of p-toluenesulfonic acid monohydrate and react at 25°C until the reaction is complete as detected by TLC to obtain the polyether compound.

[0031] 2) Cool to 5°C, add 10g of water, and keep the reaction at this temperature until the polyether is completely hydrolyzed. After the reaction is complete, add 6g of triethylamine, cool to -10°C, and continue crystallization for 1 hour. Centrifuge, dry, and obtain 89g of the tebuconazole intermediate, with an HPLC purity of 99%.

[0032] Example 4 A method for preparing a tibolone intermediate includes the following steps: 1) Add 100g of 7α-methyl ester, 280g of trimethyl orthoacetate, and 200g of methanol to the reaction vessel and start stirring; after mixing, add 10g of p-toluenesulfonic acid monohydrate and react at 25°C until the reaction is complete as detected by TLC to obtain the polyether compound.

[0033] 2) Cool to 5℃, add 50g of water, and keep the reaction at this temperature until the polyether is completely hydrolyzed. After the reaction is complete, add 6g of triethylamine, cool to -10℃, continue crystallization for 1 hour, centrifuge, and dry to obtain 80g of the tebuconazole intermediate, with an HPLC purity of 90%.

[0034] Comparative Example 1 A method for preparing a tibolone intermediate includes the following steps: 1) Add 100g of 7α-methyl ester, 100g of trimethyl orthoacetate, and 1000g of methanol to the reaction vessel and start stirring; after mixing, add 2g of p-toluenesulfonic acid monohydrate and react at 25°C until the reaction is complete as detected by TLC.

[0035] 2) Cool to 5°C, add 10g of water, and maintain the temperature until hydrolysis is complete. After the reaction is complete, add 6g of triethylamine, cool to -10°C, continue crystallization for 1 hour, centrifuge, and dry to obtain 80g of the tebolone intermediate, with an HPLC purity of 50%. The reaction product in step 1) contains a large amount of 3-monoether and diether, resulting in a lower purity of the final product.

[0036] Comparative Example 2 A method for preparing a tibolone intermediate includes the following steps: 1) Add 100g of 7α-methyl ester, 280g of trimethyl orthoacetate, and 200g of methanol to the reaction vessel and start stirring; after mixing, add 10g of p-toluenesulfonic acid monohydrate and react at 25°C until the reaction is complete as detected by TLC to obtain the polyether compound.

[0037] 2) Add 10g of water and keep the reaction at the specified temperature until the polyether is completely hydrolyzed. After the reaction is complete, add 6g of triethylamine, cool to -10℃, continue crystallization for 1 hour, centrifuge, dry, and obtain 70g of the tebuconazole intermediate with HPLC purity of 99%.

[0038] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of protection of this application is limited to these examples; within the framework of this application, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of one or more embodiments of this application as described above, which are not provided in detail for the sake of brevity.

[0039] One or more embodiments in this application are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of one or more embodiments in this application should be included within the protection scope of this application.

Claims

1. A method for preparing a tibolone intermediate, characterized in that, Includes the following steps: 7α-methyl acid desulfate, orthocyanin methyl ester, methanol, and catalyst are mixed and reacted to obtain a polyether compound. The catalyst is p-toluenesulfonic acid or methanesulfonic acid. The molar ratio of 7α-methyl acid desulfate to orthocyanin methyl ester is 1:4~10, the mass ratio of 7α-methyl acid desulfate to methanol is 1:1~8, and the molar ratio of 7α-methyl acid desulfate to catalyst is 1:0.1~0.

5. Then water is added, and the mass ratio of 7α-methyl acid to water is 1:0.05~0.

5. The temperature is controlled at 0~15℃ for hydrolysis. After hydrolysis is completed, the reaction is terminated and processed to obtain tibolone intermediate. The structural formula of the 7α-methyl acid dehydrogenase is: ; The structural formula of the tibolone intermediate is: .

2. The preparation method according to claim 1, characterized in that, The orthomethyl ester is trimethyl orthoformate, trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthobutyrate, or trimethyl orthovalerate.

3. The preparation method according to claim 2, characterized in that, The orthoacetic acid methyl ester is trimethyl orthoacetate.

4. The preparation method according to claim 1, characterized in that, The catalyst is p-toluenesulfonic acid.

5. The preparation method according to claim 1, characterized in that, The molar ratio of 7α-methyl acid dehydrogenase to orthocyanin methyl ester is 1:5~8.

6. The preparation method according to claim 1, characterized in that, The mass ratio of 7α-methyl acid to methanol is 1:1~3.

7. The preparation method according to claim 1, characterized in that, The molar ratio of the 7α-methyl acid decontamination catalyst is 1: 0.1~0.

2.

8. The preparation method according to claim 1, characterized in that, The mixture of 7α-methyl acid, methyl orthocyanin, methanol, and catalyst is reacted at a temperature of 0–65 °C.

9. The preparation method according to claim 1, characterized in that, In the hydrolysis reaction, the mass ratio of 7α-methyl acid to water is 1:0.05~0.2.

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