Synthesis of Trenbolone

Abstract

A synthesis method of trenbolone, the synthesis method comprising the following steps: 1) carbonyl reduction reaction, reacting compound I as a raw material to obtain compound II; 2) deprotection reaction, dissolving compound II obtained in step 1) in an organic solvent, adding dilute acid, reacting to obtain compound III; then extracting with toluene, drying the obtained organic phase and removing water to obtain a toluene solution of compound III; 3) one-pot Aldol condensation reaction and 11-hydroxylation reaction, adding an alcohol solvent to the toluene solution of compound III, maintaining the temperature of the reaction system at -20°C to 5°C, adding a base under the protection of an inert gas, stirring the reaction, and performing Aldol condensation reaction to obtain compound IV, dissolving compound V obtained in step 3) in a water-insoluble organic solvent, adding acid and stirring the reaction, performing 9,11 elimination reaction to obtain trenbolone, the reaction temperature is 10°C to 40°C, and obtaining product trenbolone.

Description

Technical Field

[0001] The present invention relates to a method for preparing a steroid compound, in particular to a method for synthesizing trenbolone. Background Art

[0002] Trenbolone is a 19-nor steroid that can greatly increase protein synthesis capacity and nitrogen storage in muscles, increase IGF-1 growth factor secretion, increase the number of red blood cells in the blood, improve food utilization and inhibit cortisol hormone. It is an extremely powerful steroid.

[0003] Pestovskii et al. (Chemistry of Natural Compounds, 1988, vol. 24, p. 263-264) reported a method for synthesizing trenbolone. The methyl ether was subjected to Birch reduction, hydrolysis, bromination elimination and dehydroxylation to obtain trenbolone. The specific route is as follows:

[0004]

[0005] This route uses a large amount of metallic lithium, ultra-low temperature and a large amount of acidic reagents, etc. It has high requirements on equipment and harsh conditions, making it difficult to produce on a large scale.

[0006] Patent document FR2125640 uses methyl diene ketone as raw material, protects the 3-carbonyl group, and obtains trenbolone through hydrolysis and DDQ dehydrogenation. The specific route is as follows:

[0007]

[0008] This route uses DDQ to dehydrogenate to form 11,12-double bonds. This method has obvious disadvantages, such as cumbersome post-processing, low product purification efficiency, large amount of wastewater and serious environmental pollution.

[0009] Other literature reports, such as patent documents WO2022106574, EP4001289, CN110437294, CN102399253, CN108017682, etc., all use the DDQ dehydrogenation method in the above patents. Problems such as cumbersome post-treatment, low product purification efficiency, large amount of wastewater and serious environmental pollution still exist. How to avoid the DDQ dehydrogenation process, reduce raw material costs, increase reaction yields, and make reaction conditions milder and suitable for industrial production has become an urgent problem to be solved in the existing trenbolone synthesis technology. Summary of the invention

[0010] In order to solve the above technical problems, the present invention provides a method for synthesizing trenbolone, which solves the problems of shortage of raw material resources, harsh reaction conditions, low purification yield, etc. in the prior art. The technical solution provided by the present invention is:

[0011] A method for synthesizing trenbolone, the method comprising the following steps:

[0012] 1) Carbonyl reduction reaction, the reaction formula is

[0013]

[0014] The operation method is as follows: after dissolving the compound I as a raw material in an organic solvent, a reducing agent is added in batches at 0°C to 30°C, wherein the organic solvent is methanol, ethanol and isopropanol; after the reaction is complete, water is added to the reaction system for water precipitation, and the precipitated product is filtered and dried to obtain compound II;

[0015] 2) Deprotection reaction, the reaction formula is

[0016] Compound II is treated with acid for deprotection to obtain compound III. The reaction formula is:

[0017]

[0018] The operation method is as follows: dissolving the compound II obtained in step 1) in an organic solvent, adding a dilute acid, and treating at a temperature of 10°C to 40°C until the reaction is complete to obtain the compound III; then adding a base to the reaction system for neutralization, concentrating under reduced pressure to remove the organic solvent, extracting with toluene, and drying the obtained organic phase to remove water to obtain a toluene solution of the compound III;

[0019] 3) One-pot Aldol condensation reaction and 11-hydroxylation reaction, the reaction formula is as follows

[0020]

[0021] Add an alcohol solvent to the toluene solution of compound III, keep the temperature of the reaction system at -20°C to 5°C, add a base under the protection of an inert gas, stir the reaction, and perform an Aldol condensation reaction to obtain compound IV. After the reaction is complete, add water to the reaction system, and at the same time introduce oxygen, stir the reaction, so that the 11-position hydroxylation of compound IV is obtained to obtain compound V. After the reaction is completed, add dilute acid to neutralize, stand and separate, collect the organic phase, wash the aqueous phase with toluene, combine the organic phases, dry and concentrate to obtain the compound V product; 4) Elimination reaction, the reaction formula is as follows

[0022]

[0023] Step 3) The obtained compound V is dissolved in a water-insoluble organic solvent, an acid is added and stirred for reaction, and a 9,11 elimination reaction is performed to obtain trenbolone. The reaction temperature is 10°C to 40°C. After the reaction is completed, an alkaline solution is added for neutralization, the mixture is allowed to stand for separation, the organic phase is collected, the aqueous phase is extracted with the water-insoluble organic solvent, and the organic phases are combined, and the organic phases are washed with water and saturated brine in sequence, and the organic phase is concentrated until a solid is precipitated, and a refining solvent is added to continue to concentrate until the water-insoluble organic solvent is distilled out, the temperature is reduced for crystallization, and the mixture is filtered and dried to obtain the product trenbolone.

[0024] The synthetic method of trenbolone, further, in step 1), the organic solvent is selected from methanol, ethanol or isopropanol, the volume weight ratio of the organic solvent to the raw material is 3 to 10; the reaction temperature is 0 to 30°C. The reducing agent used is sodium borohydride or potassium borohydride, and the molar ratio of the reducing agent to compound I is 0.5 to 2.0.

[0025] The synthetic method of trenbolone, further, the organic solvent in step 1) is preferably methanol, the volume weight ratio of the organic solvent to the raw material is preferably 5, the reaction temperature is preferably 0-5°C, the reducing agent is preferably sodium borohydride, and the molar ratio of the reducing agent to compound I is preferably 0.73-0.77.

[0026] The synthetic method of trenbolone is further characterized in that the dilute acid in step 2) is dilute hydrochloric acid or dilute sulfuric acid, and the organic solvent is methanol or acetone.

[0027] The synthetic method of trenbolone is further characterized in that the dilute acid in step 2) is sulfuric acid with a mass percentage concentration of 4% to 7%, the organic solvent is preferably acetone, the mass ratio of acetone to compound II is 1.5 to 3, and the reaction temperature is 25°C to 30°C.

[0028] The synthesis method of trenbolone, further, in the step 3), the base is potassium hydroxide or potassium tert-butoxide, and the molar ratio of the base to compound I is 1.5 to 2.5:1; the alcohol solvent is methanol or tert-butanol, and the molar ratio of the added water to compound I is 2 to 5

[0029] The synthesis method of trenbolone, further, in the step 3), the base is potassium tert-butoxide, the alcohol solvent is tert-butanol; the molar ratio of potassium tert-butoxide to compound I is 1.9-2.1, the mass ratio of tert-butanol to tert-butyl potassium is 0.8-1.2, the molar ratio of the added water to compound I is 2-3, and the reaction temperature is maintained at -6°C to 0°C;

[0030] The synthetic method of trenbolone, further, in step 4), the water-insoluble organic solvent is chloroform; the acid is hydrochloric acid or p-toluenesulfonic acid monohydrate,

[0031] The synthetic method of trenbolone is further characterized in that in the step 4), the acid is p-toluenesulfonic acid monohydrate, the volume mass ratio of chloroform to compound V during the reaction is 7-15, the molar ratio of p-toluenesulfonic acid monohydrate to compound V is 1-1.5, the refining solvent is ethyl acetate, ethyl acetate is added and concentrated until the chloroform is distilled off, all the solvent is evaporated, and then ethyl acetate is added at a volume mass ratio of 1.5-2.5 to compound V, heated to reflux, cooled to 0°C-10°C for crystallization, filtered and dried to obtain the product trenbolone.

[0032] The trenbolone synthesis method provided by the present invention utilizes simple and readily available raw materials to selectively allylate in oxygen to obtain an intermediate product, and trenbolone can be quickly synthesized through a simple elimination reaction, thereby avoiding the use of DDQ and achieving the purpose of reducing costs, energy consumption and three wastes. DETAILED DESCRIPTION

[0033] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0034] Example 1 Carbonyl reduction reaction, the reaction formula is as follows:

[0035]

[0036] The specific steps are:

[0037] In a 250 ml reaction bottle, compound I (10.0 g, 26.7 mmol, HPLC content 99.5%) and methanol (50 mL) were added to dissolve and cooled to 0-5°C, sodium borohydride (0.76 g, 20.1 mmol) was added in batches, the reaction system was maintained at 0-5°C with stirring, TLC detected that the raw materials reacted completely, 250 ml of water was added dropwise to the reaction system, a white solid precipitated, and stirring was continued for 1 hour. Filtered to obtain a white solid (9.8 g), dried with a yield of 97%, and used directly in the next step.

[0038] Example 2 Deprotection reaction, the reaction formula is as follows:

[0039]

[0040] The specific steps are as follows: concentrated sulfuric acid (0.50 g) is dissolved in water (10 g), cooled to room temperature, added to the system of compound II (9.8 g, 26.0 mmol) and acetone (16 g) obtained in Example 1, reacted at 25°C to 30°C for 2.5 hours, and TLC detected that the raw material reacted completely. Sodium carbonate (521 mg) was added to the reaction system for neutralization, concentrated at 40°C to remove acetone, extracted three times with toluene (30 mL×3), and the toluene solution of compound III obtained after drying and removing water from the organic phase was directly used in the next step.

[0041] Example 3 One-pot Aldol condensation reaction and allylic hydroxylation reaction:

[0042]

[0043] Add tert-butyl alcohol (5.8 g) to the toluene solution of compound III obtained in Example 2, cool to -6°C to 0°C under nitrogen protection, add potassium tert-butylate (5.8 g, 51.7 mmol), react for 3 hours, and TLC detects that the raw material is completely converted to obtain compound IV. Slowly add 1.4 grams of water to the reaction system, while passing oxygen, maintain stirring at -6 to 0°C, and detect the reaction by TLC until it is complete. Adjust the pH to 7 to 8 with 1.25% acetic acid aqueous solution at no more than 10°C, stand and separate, extract the aqueous phase twice with toluene (30 mL×2), combine the organic phases, dry, and concentrate to obtain compound V (7.1 g), and the molar yield of the combined steps of Example 2 and Example 3 is 95%.

[0044] Embodiment 4 elimination reaction:

[0045]

[0046] The compound V (7.1 g, 24.6 mmol) prepared in Example 3 was dissolved in chloroform (71 mL), and p-toluenesulfonic acid monohydrate (4.73 g, 24.9 mmol) was added. The mixture was reacted at 25-30°C for 1.5 hours. The reaction was complete after TLC detection. The mixture was neutralized with saturated sodium bicarbonate aqueous solution, separated, and the aqueous phase was extracted twice with chloroform (71 mL×2). The organic phases were combined, washed once with water (50 mL), washed once with saturated brine (50 mL), dried, concentrated until solids were precipitated, and ethyl acetate was added to continue concentrating with chloroform. Ethyl acetate was added repeatedly until the distillate was free of chloroform. After all the solvents were evaporated, ethyl acetate (14 mL) was added, heated to reflux for 10 minutes, cooled to 5°C for crystallization, filtered, and dried to obtain 6.32 g of a light yellow final product, namely trenbolone, with a content of 99.1% and a molar yield of 95% detected by HPLC. The total molar yield of trenbolone from compound I was 88%.

[0047] The NMR spectrum data of trenbolone obtained are as follows (hydrogen spectrum)

[0048] 1 H NMR (400 MHz, CDCl 3):δ(ppm)6.50-6.38(m,2H),5.80-5.75(s,1H),3.93-3.84(m,1H),2.89-2.73(m,2H),2.63-2.36(m,5H),2.23-2.12(m,1H),1.93-1.84(m,1H),1.75-1.60(m,4H),1.60-1.22(m,5H),0.91(s,3H)。

Claims

1. A method for synthesizing trenbolone, the method comprising the following steps: 1) Carbonyl reduction reaction, the reaction formula is The operation method is as follows: after dissolving the compound I as a raw material in an organic solvent, a reducing agent is added in batches at 0°C to 30°C, wherein the organic solvent is methanol, ethanol and isopropanol; after the reaction is complete, water is added to the reaction system for water precipitation, and the precipitated product is filtered and dried to obtain compound II; 2) Deprotection reaction, the reaction formula is Compound II is treated with acid for deprotection to obtain compound III. The reaction formula is: The operation method is as follows: dissolving the compound II obtained in step 1) in an organic solvent, adding a dilute acid, and treating at a temperature of 10°C to 40°C until the reaction is complete to obtain the compound III; then adding a base to the reaction system for neutralization, concentrating under reduced pressure to remove the organic solvent, extracting with toluene, and drying the obtained organic phase to remove water to obtain a toluene solution of the compound III; 3) One-pot Aldol condensation reaction and 11-hydroxylation reaction, the reaction formula is as follows Add an alcohol solvent to the toluene solution of compound III, keep the temperature of the reaction system at -20°C to 5°C, add a base under the protection of an inert gas, stir the reaction, and perform an Aldol condensation reaction to obtain compound IV. After the reaction is complete, add water to the reaction system, and introduce oxygen at the same time, stir the reaction, so that the 11-position hydroxylation of compound IV is obtained to obtain compound V. After the reaction is completed, add dilute acid to neutralize, stand and separate, collect the organic phase, wash the aqueous phase with toluene, combine the organic phases, dry and concentrate to obtain the compound V product; 4) Elimination reaction, the reaction formula is as follows Step 3) The obtained compound V is dissolved in a water-insoluble organic solvent, an acid is added and stirred for reaction, and a 9,11 elimination reaction is performed to obtain trenbolone. The reaction temperature is 10°C to 40°C. After the reaction is completed, an alkaline solution is added for neutralization, the mixture is allowed to stand for separation, the organic phase is collected, the aqueous phase is extracted with the water-insoluble organic solvent, and the organic phases are combined, and the organic phases are washed with water and saturated brine in sequence, and the organic phase is concentrated until a solid is precipitated, and a refining solvent is added to continue to concentrate until the water-insoluble organic solvent is distilled out, the temperature is reduced for crystallization, and the mixture is filtered and dried to obtain the product trenbolone.

2. A method for synthesizing trenbolone as claimed in claim 1, characterized in that: In the step 1), the organic solvent is selected from methanol, ethanol or isopropanol, and the volume weight ratio of the organic solvent to the raw material is 3 to 10; the reaction temperature is 0 to 30° C., the reducing agent used is sodium borohydride or potassium borohydride, and the molar ratio of the reducing agent to compound I is 0.5 to 2.

0.

3. A method for synthesizing trenbolone as claimed in claim 2, characterized in that: The organic solvent in step 1) is preferably methanol, the volume weight ratio of the organic solvent to the raw material is preferably 5, the reaction temperature is preferably 0-5°C, the reducing agent is preferably sodium borohydride, and the molar ratio of the reducing agent to compound I is preferably 0.73-0.

77.

4. A method for synthesizing trenbolone as claimed in claim 1, characterized in that: In the step 2), the dilute acid is dilute hydrochloric acid or dilute sulfuric acid, and the organic solvent is methanol or acetone.

5. A method for synthesizing trenbolone as claimed in claim 4, characterized in that: In the step 2), the dilute acid is sulfuric acid with a mass percentage concentration of 4% to 7%, the organic solvent is preferably acetone, the mass ratio of acetone to compound II is 1.5 to 3, and the reaction temperature is 25° C. to 30° C.

6. A method for synthesizing trenbolone as claimed in claim 1, characterized in that: In the step 3), the base is potassium hydroxide or potassium tert-butoxide, and the molar ratio of the base to compound I is 1.5-2.5:1; the alcohol solvent is methanol or tert-butanol, and the molar ratio of the added water to compound I is 2-5.

7. A method for synthesizing trenbolone as claimed in claim 6, characterized in that: In the step 3), the base is potassium tert-butoxide, the alcohol solvent is tert-butanol; the molar ratio of potassium tert-butoxide to compound I is 1.9-2.1, the mass ratio of tert-butanol to potassium tert-butoxide is 0.8-1.2, the molar ratio of the added water to compound I is 2-3, and the reaction temperature is maintained at -6°C to 0°C.

8. The method for synthesizing trenbolone according to claim 1, further, in step 4), the water-insoluble organic solvent is chloroform; and the acid is hydrochloric acid or p-toluenesulfonic acid monohydrate.

9. A method for synthesizing trenbolone as claimed in claim 8, further, the acid in step 4) is p-toluenesulfonic acid monohydrate, the molar ratio of p-toluenesulfonic acid monohydrate to compound V is 1-1.5, the volume mass ratio of chloroform to compound V during the reaction is 7-15, the refining solvent is ethyl acetate, ethyl acetate is added and concentrated until chloroform is distilled off, all the solvent is evaporated, and then ethyl acetate is added in a volume mass ratio of 1.5-2.5 to compound V, heated to reflux, cooled to 0°C-10°C for crystallization, filtered and dried to obtain the product trenbolone.

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