Synthesis method of alfasalone intermediate and synthesis method of alfasalone

Abstract

The invention discloses a synthetic method of an alfasalone intermediate and a synthetic method of alfasalone, the synthetic method of the alfasalone intermediate comprises the following steps: carrying out hydrogenation reaction on a compound IN-2 to obtain a compound I, the hydrogenation condition is that a solvent ethanol or acetic acid and palladium on carbon are added, and the addition volume of the ethanol or acetic acid is 10-80 times of the weight of the IN-2; the synthesis method of the alfasalone comprises the following steps: carrying out elimination reaction on a compound SM to obtain an intermediate IN-1; performing ketal protection reaction on the intermediate IN-1 to obtain an intermediate IN-2; carrying out hydrogenation reaction on the intermediate IN-2 to obtain a compound I; carrying out ketal removal protection reaction on the compound I to obtain an intermediate IN-3; the intermediate IN-3 is subjected to carbonyl reduction through an enzyme method to obtain alfasalone; by exploring the reaction raw materials, the reaction solvent, the solvent addition amount, the reaction time and the like in the synthesis process of the alfasalone, the obtained product is high in yield and purity, and the industrial production of the alfasalone is realized.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis process of active ingredients for pharmaceutical use, and specifically relates to a synthesis method of an alfaxalone intermediate and a synthesis method of alfaxalone. Background Art

[0002] Alfaxalone, chemical name is 3α-hydroxy-5α-prenan-11,20-dione. Alfaxalone was developed and marketed by GSK from the 1970s to the 1980s. It is a neurosteroid hypnotic used for induction and maintenance of anesthesia in dogs and cats. The synthesis of alfaxalone was reported in 1951 (J.Am.Chem.Soc.,1951,73,4765), but the source of its raw materials is relatively complex and has no synthetic value. The key to the synthesis of alfaxalone lies in the selection of raw materials with oxygen at position 11 and the construction method of 3α hydroxyl and 5α hydrogen.

[0003] The document "Helvetica Chimica Acta, 2011, 94, 98-104" describes a method for synthesizing alfaxalone, which uses the raw materials in Figure III to reduce the 5α-H product through a lithium-ammonia reduction reaction, and then selectively reduces the 3α-hydroxy alfaxalone. The first step reaction does not specify the yield of the reaction, and in general, the other two carbonyl groups will be reduced in the lithium-ammonia reduction reaction, and the reaction should be difficult to obtain the target product. The yield of the second step reaction is 78%, but it requires the use of an expensive reagent K-selectride. In addition, the raw materials are not readily available in industry.

[0004]

[0005] The document "Journal of Medicinal Chemistry, 2013, 56 (6), 2323-2336." describes the synthesis route of alfaxalone, see Route 2 in the figure below, but the yield of the second step hydrogenation reaction is only 41%, and the yield of the last step hydroxyl inversion reaction is only 56%. Both of them need to be separated by column chromatography, which is costly and not suitable for industrialization.

[0006]

[0007] The patent application document with patent publication number CN115215916A discloses the synthesis route of the key intermediate of alfaxalone, as shown in route 3, which moves the olefin to the 5-position through ketal protection, then synthesizes the 5α-H configuration through hydrogenation, and finally deprotects to obtain the triketone product. The problem with the reaction is that hydrogenation requires pressure, which is dangerous for industrial production.

[0008]

[0009] The patent application document with patent publication number CN115418385A discloses a synthetic route of alfaxalone, which uses the following triketone product as raw material and constructs 3α hydroxyl by enzymatic method. It is safe, environmentally friendly, has high yield and good purity, but the raw materials are expensive and the cost is relatively high.

[0010]

[0011] The patent application document with patent publication number CN112384525 A discloses neuroactive steroids and a preparation method. 11-hydroxyprogesterone is used as the raw material, 5α hydrogen is constructed by hydrogenation, then oxidized to obtain triketone, and finally selectively reduced to obtain 3α hydroxyl. The problem is that the configuration of the first step of direct hydrogenation will be mainly 5β.

[0012] The methods for synthesizing alfaxalone in the prior art all have certain defects or problems, which are not conducive to improving the yield and purity of the product, or affecting the industrialization process of alfaxalone. Therefore, it is necessary to further improve the synthesis method based on the prior art to realize the industrial production of alfaxalone. Summary of the invention

[0013] The technical problem to be solved by the present invention is to provide a method for synthesizing an alfaxalone intermediate and a method for synthesizing alfaxalone, which have high product yield and high purity and are suitable for industrial production.

[0014] In one aspect, the present invention provides a method for synthesizing an alfaxalone intermediate, the method comprising:

[0015] Compound IN-2 is subjected to a hydrogenation reaction to obtain compound I;

[0016]

[0017] The hydrogenation reaction conditions are: adding solvent ethanol or acetic acid, palladium carbon, and reacting to obtain compound I, and the added volume of ethanol or acetic acid is 10-80 times the weight of compound IN-2.

[0018] The unit of the added volume of ethanol or acetic acid is mL, the unit of the weight of compound IN-2 is g, and the added volume of ethanol or acetic acid is 10-80 times the weight of compound IN-2, which means that if the weight of compound IN-2 is xg, then the added volume of ethanol or acetic acid is x*(10-80)mL.

[0019] Furthermore, when the added solvent is ethanol, the reaction time is 26-30 hours; when the added solvent is acetic acid, the reaction time is 14-18 hours.

[0020] Furthermore, the weight of the palladium carbon is 0.05 to 0.2 times the weight of compound IN-2, the palladium carbon contains 5-10% palladium, and the water content is 50-60%.

[0021] Another object of the present invention is to provide a method for synthesizing alfaxalone, comprising the steps of:

[0022] (1) Compound SM is subjected to elimination reaction to obtain intermediate IN-1;

[0023] (2) intermediate IN-1 is subjected to ketal protection reaction to obtain intermediate IN-2;

[0024] (3) intermediate IN-2 is prepared by the synthesis method according to any one of claims 1 to 3 to obtain compound I;

[0025] (4) Compound I is subjected to a deketalization reaction to obtain intermediate IN-3;

[0026] (5) The intermediate IN-3 is enzymatically reduced to give alfaxalone;

[0027] The specific synthetic route is as follows:

[0028]

[0029] Furthermore, in the deketalization protection reaction in step (4), dilute hydrochloric acid with a volume concentration of 2%-5% is added, and the volume of the dilute hydrochloric acid is 0.1-0.6 times the volume of the organic solvent in step (3).

[0030] Furthermore, the reaction conditions of step (1) are as follows: dissolving compound SM in pyridine, adding N-chlorosuccinimide and 4-dimethylaminopyridine, and dropping sulfur dioxide pyridine solution to react at -15°C to -40°C.

[0031] Furthermore, the weight of the N-chlorosuccinimide is 0.8-1 times the weight of the compound SM; the weight of the 4-dimethylaminopyridine is 1-2 times the weight of the compound SM; and the weight-to-volume ratio of the compound SM to the sulfur dioxide pyridine solution is 1:1.25-3.

[0032] Furthermore, the reaction conditions of the ketal protection reaction in step (2) are as follows: ethylene glycol, ortho acid triester and acid catalyst are added to the intermediate IN1 for reaction.

[0033] Furthermore, an organic solvent is added in step (2), and the organic solvent is one or more of dichloromethane, tetrahydrofuran, and ethyl acetate.

[0034] Furthermore, the ortho acid triester is one or more of trimethyl orthoformate, triethyl orthoformate, triethyl orthoacetate, and trimethyl orthoacetate; and the acid catalyst is one or more of p-toluenesulfonic acid, methanesulfonic acid, and sulfuric acid.

[0035] Beneficial effects of the present invention:

[0036] (1) In the synthesis step of the alfaxalone intermediate of the present invention, in the reaction of compound IN-2 synthesizing compound I, by selecting appropriate reaction compounds, reaction solvents, solvent addition amounts, reaction time and other conditions, the hydrogenation reaction can be carried out at room temperature and pressure, and the product yield and purity of this step of reaction are high, which are equivalent to the product yield and purity of the hydrogenation reaction under high temperature and high pressure, thus achieving the hydrogenation reaction at room temperature and pressure, which is conducive to the industrial production of alfaxalone;

[0037] (2) In the hydrogenation step of the present invention, a solvent effect is generated in the reaction system by adding a high ratio of ethanol or acetic acid solvent, thereby realizing a hydrogenation reaction at normal temperature and pressure; the catalyst is palladium carbon containing 10% palladium wetted with 55% water, and the reaction is safer;

[0038] (3) The present invention uses pregnane-4-ene-17α-hydroxy-3,11,20-trione (SM) as a raw material to prepare the target product alfaxalone through a 5-step reaction. The starting compound is relatively cheap and can be obtained from the market, and the source is convenient;

[0039] (4) In the synthesis step of the alfaxalone intermediate of the present invention, the problem of 18-methyl rearrangement in the synthesis of IN-1 by SM dehydration is solved. The addition of DMAP can largely avoid the generation of 18-methyl rearrangement byproducts, thereby improving the reaction yield and purity;

[0040] (5) The preparation method of the present invention has few by-products, high yields and high purity of intermediate products and target products, and some steps can be directly put into the next step reaction without purification. The operation is simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is the IN-3 H NMR spectrum;

[0042] Figure 2 This is the NMR carbon spectrum of IN-3;

[0043] Figure 3 is the H NMR spectrum of alfaxalone;

[0044] Figure 4 This is the carbon NMR spectrum of alfaxalone. DETAILED DESCRIPTION

[0045] Example 1

[0046] Synthesis of compound IN-1

[0047] Under nitrogen protection, add 125ml of pyridine to 25g of SM, add 40g of DMAP, stir to dissolve the system, cool to -20℃, add 21g of NCS at about -15℃ to -20℃, and then cool to -35℃. Take 43.75ml of 30% SO2 / pyridine solution, dilute with 100ml of pyridine, and drop the diluted SO2 / pyridine solution into the reaction system. Heat the system and control the internal temperature at -25~-40℃. Add the solution in about 1 hour. After the addition is complete, keep the temperature at -25~-35℃ for 20-30min, and detect by TLC until the reaction is complete. After the reaction is completed, pour the system into 112.5mL of hydrochloric acid-1500mL aqueous solution precooled to below 5℃, and a large amount of white solid will precipitate. Stir at 0~5℃ for 1 hour, filter, wash with water, press dry, and dry to obtain 23.5g of IN-1 white solid, with a yield of 99.1% and a purity of 97%.

[0048] Example 2

[0049] Synthesis of compound IN-2

[0050] 10g IN-1 obtained by the method of Example 1 was dissolved in 80ml dichloromethane, 15g ethylene glycol and 15g triethyl orthoformate were added, and then 0.25g p-toluenesulfonic acid was added. After stirring at room temperature for 18h, 1ml triethylamine was added to terminate the reaction. Washing with 50ml water was repeated once, and the mixture was dried, filtered, and concentrated under reduced pressure to remove the solvent. 20ml methanol was added, stirred and slurried to obtain a solid, and 10.2g of IN-2 as a white solid was obtained by suction filtration, with a yield of 80.3%.

[0051] Example 3

[0052] Synthesis of compound IN-2

[0053] 10g IN-1 obtained by the method of Example 1 was dissolved in 20g ethylene glycol, 15g trimethyl orthoformate was added, and then 0.3g p-toluenesulfonic acid was added. After stirring at 40°C for 6h, 1ml triethylamine was added to terminate the reaction. The reaction solution was added dropwise to 100mL water under stirring, stirred for 1h, filtered, the filter cake was washed with water, and dried to obtain 11.1g of product with a yield of 87.4%, which was directly used for the next step reaction.

[0054] Example 4

[0055] Synthesis of compound IN-3

[0056] Weigh 10g IN-2 obtained by the method of Example 3, add 200mL ethanol, then add 2g palladium carbon (10% palladium, containing 55% water), use hydrogen to replace air three times, place in a hydrogen atmosphere, react at room temperature and pressure for 28h, filter after the reaction, and wash the filter cake with 50mL dichloromethane, combine the organic phases, add 100mL dilute hydrochloric acid (4%), stir at room temperature for 6h, concentrate the solvent after the reaction, add 20mL methanol to pulp and filter, dry to obtain 6.8g product IN-3, yield 85.3%, purity 97.1%. The nuclear magnetic resonance spectrum of IN-3 is as follows, 1 H NMR(400MHz, CDCl3)δ2.88–2.70(m,2H),2.63(d,J=12.1Hz,1H),2.56–2.40(m,2H),2.36–2.20(m,3H),2.12(s,4H), 1.96–1.71(m,7H),1.51(ddd,J=17.7,8.9,4.0Hz,2H),1.37(td,J=11.1,10.1,3.3Hz,3H),1.23(s,3H),0.62(s,3H); 13 C NMR (101MHz,CDCl3)δ211.37,209.24,207.97,63.69,62.13,56.57,55.51,47.11,46.92,44.24,37.94,37.04,36.55,35.20,32.27,31.29,28.18,23.90,23.31,14.29,11.06; see Figure 1 , Figure 2 .

[0057] Example 5

[0058] Synthesis of compound IN-3

[0059] Weigh 10g of IN-2 obtained by the method of Example 3, add 100mL of acetic acid, then add 2g of palladium carbon (10% palladium, containing 55% water), use hydrogen to replace the air three times, place under a hydrogen atmosphere, react at room temperature and pressure for 16h, filter after the reaction, and wash the filter cake with 10mL of acetic acid, combine the organic phases, add 50mL of dilute hydrochloric acid (4%), stir at room temperature for 6h, concentrate the solvent after the reaction, add 20mL of methanol for pulping, filter after suction, and dry to obtain 6.6g of product with a yield of 82.8% and a purity of 96.5%.

[0060] Example 6

[0061] Synthesis of compound IN-3

[0062] Weigh 10g IN2 obtained by the method of Example 3, add 500mL of acetic acid, then add 2g of palladium carbon (10% palladium content, containing 55% water), use hydrogen to replace air three times, place under a hydrogen atmosphere, react at normal temperature and pressure for 16h, filter after completion of the reaction, and wash the filter cake with 10mL of acetic acid, merge the organic phases, add 50mL of dilute hydrochloric acid (4%), stir at room temperature for 6h, concentrate the solvent after completion of the reaction, add 20mL of methanol to pulp and filter, and dry to obtain 6.8g of product, with a yield of 85.3% and a purity of 96.8%.

[0063] Example 7

[0064] Synthesis of Alfaxalone

[0065] Take a 500ml three-necked reaction bottle, stir, add 4.5g of IN-3 compound, add 20.9g of glucose, 135ml of tert-butanol, 135ml of water, add 13.5ml of enzyme B (XE-4 homogenized solution), 13.5ml of 3α reductase, and finally add 0.0025g of NAD+, stir in a 31℃ water bath, and use 15% sodium carbonate solution to adjust the pH to maintain pH6.8-7.3 during the reaction. After 18h, the reaction is complete, and the tert-butanol is concentrated at 60℃ under reduced pressure to destroy the enzyme, and the filter cake is obtained by suction filtration. The filter cake is scraped out and 100ml of dichloromethane is added, stirred for 2.0h, and suction filtered. The filtrate is concentrated under reduced pressure, and the obtained solid is slurried with isopropyl ether, suction filtered, and dried to obtain 4.38g of the product, with a yield of 96.7%. The liquid phase purity is 94.20%. 1H NMR (400MHz, CDCl3) δ4.03(t,J=2.6Hz,1H),2.71(t,J=8.9Hz,1H),2.51(q,J=11.9Hz,2H),2.28–2.15(m, 2H),2.08(s,3H),1.86–1.64(m,7H),1.60–1.46(m,4H),1.43–1.08(m,7H),0.98(s,3H),0.55(s,3H).13C NMR (101MHz,CDCl3)δ209.99,208.34,66.34,64.34,62.31,56.86,55.96,47.33,39.02,36.72,35.84,35.35,32.70,31.45,30.96,28.95,27.91,23.93,23.34,14.39,10.99; see Figure 3 , Figure 4 .

[0066] Example 8

[0067] Synthesis of Alfaxalone

[0068] Take a 500ml three-necked reaction flask, stir, add 4.5g of IN-3 compound, add 20.9g of glucose, 70ml of isopropanol, 135ml of water, add 13.5ml of enzyme B (XE-4 homogenized solution), 13.5ml of 3α-reductase, and finally add 0.0025g of NAD+, stir in a 31°C water bath, and adjust the pH to maintain at pH 6.8-7.3 with 15% sodium carbonate solution during the reaction. After 24 hours, the reaction is complete, and the tert-butanol is concentrated at 60°C under reduced pressure to destroy the enzyme, and the filter cake is obtained by suction filtration. The filter cake is scraped out and 100ml of dichloromethane is added, stirred for 2.0 hours, and suction filtered. The filtrate is concentrated under reduced pressure, and the obtained solid is slurried with isopropyl ether, suction filtered, and dried to obtain 4.30g of the product with a yield of 94.9%.

[0069] Comparative Example 1

[0070] Synthesis of compound IN-3

[0071] Weigh 10 g of IN-2 obtained by the method of Example 3, add 100 mL of tetrahydrofuran, then add 2 g of palladium carbon (10% palladium, containing 55% water), use hydrogen to replace the air three times, place it in a hydrogen atmosphere, and react at room temperature and pressure for 16 hours. TLC shows that the raw material is basically converted, but there is only a small amount of product, one of the two olefins is reduced, and no product can be obtained after hydrolysis of the ketal with hydrochloric acid.

[0072] Comparative Example 2

[0073] Synthesis of compound IN-3

[0074] Weigh 10 g of IN-2 obtained by the method of Example 3, add 50 mL of ethanol, then add 2 g of palladium carbon (10% palladium, containing 55% water), use hydrogen to replace the air three times, place under a hydrogen atmosphere, react at room temperature and pressure for 28 h, filter after the reaction, wash the filter cake with 50 mL of dichloromethane, combine the organic phases, add 20 mL of dilute hydrochloric acid (4%), stir at room temperature for 6 h, after the reaction is completed, TLC shows that there are still many olefin impurities that have not been hydrogenated.

[0075] Comparative Example 3

[0076] Synthesis of compound IN-3

[0077] Weigh 10g of IN-2 obtained by the method of Example 3, add 100mL of methanol, then add 2g of palladium carbon (10% palladium, containing 55% water), use hydrogen to replace air three times, place under hydrogen atmosphere, react at room temperature and pressure for 28h, filter after the reaction, wash the filter cake with 50mL of dilute hydrochloric acid (4%), combine the organic phases, add 50mL of dilute hydrochloric acid (4%), stir at room temperature for 6h, concentrate the solvent after the reaction, add 20mL of methanol for pulping, filter after suction, and dry to obtain 6.3g of product, with a yield of 79%, but the product has a small amount of impurities of olefins that have not been hydrogenated, and the purity is 82%.

[0078] Comparative Example 4

[0079] Weigh 10 g of IN-2 obtained by the method of Example 3, add 100 mL of isopropanol, then add 2 g of palladium carbon (10% palladium, containing 55% water), use hydrogen to replace the air three times, place under a hydrogen atmosphere, react at room temperature and pressure for 28 h, filter after the reaction, wash the filter cake with 50 mL of dichloromethane, combine the organic phases, add 50 mL of dilute hydrochloric acid (4%), stir at room temperature for 6 h, after the reaction is completed, TLC shows that there are still many impurities of olefins that have not been hydrogenated.

[0080] Comparative Example 5

[0081] Synthesis of compound IN-3

[0082] Weigh 10g IN-2 obtained by the method of Example 3, add 200mL ethanol, then add 2g palladium carbon (10% palladium, containing 55% water), use nitrogen to replace air three times, hydrogenate to 3 kg pressure, stir, react for 28h, filter after the reaction, and wash the filter cake with 50mL dichloromethane, combine the organic phases, add 100mL dilute hydrochloric acid (4%), stir at room temperature for 6h, concentrate the solvent after the reaction, add 20mL methanol to pulp and filter, dry to obtain 6.7g product, yield 84%, purity 97.9%.

[0083] Comparative Example 6

[0084] Synthesis of compound IN-3

[0085] Weigh 10g of IN-2 obtained by the method of Example 3, add 50mL of ethanol, 50mL of methanol, and then add 2g of palladium carbon (10% palladium, containing 55% water), use hydrogen to replace air three times, place under a hydrogen atmosphere, react at room temperature and pressure for 28h, filter after the reaction, and wash the filter cake with 50mL of dichloromethane, combine the organic phases, add 100mL of dilute hydrochloric acid (4%), stir at room temperature for 6h, concentrate the solvent after the reaction, add 20mL of methanol for pulping, filter after suction, and dry to obtain 6.7g of product, with a yield of 84%, but the product has a small amount of impurities that are not completely hydrogenated from olefins, and the purity is 81.1%.

[0086] Comparative Example 7

[0087] Synthesis of compound IN-1

[0088] Under nitrogen protection, add 125ml of pyridine to 25g of SM, stir to dissolve the system, cool to -20℃, add 21g of NCS at about -15℃ to -20℃, and then cool to -35℃. Take 43.75ml of 30% SO2 / pyridine solution, dilute with 100ml of pyridine, drop the diluted SO2 / pyridine solution into the reaction system, heat the system, control the internal temperature at -25~-40℃, drip it in about 1 hour, keep it at -25~-35℃ for 20-30min, and detect by TLC until the reaction is complete. After the reaction is completed, pour the system into 112.5mL of hydrochloric acid-1500mL aqueous solution precooled to below 5°, precipitate a large amount of white solid, stir at 0~5℃ for 1 hour, filter, wash with water, press dry, and dry to obtain 23.3g of white solid, with a yield of 98.3% and a purity of 92%.

[0089] A person skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of protection of the present application is limited to these examples. In line with the concept of the present application, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of simplicity.

[0090] One or more embodiments of the present application are intended to cover all such substitutions, modifications and variations that fall within the broad scope of the present application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the protection scope of the present application.

Claims

1. A method for synthesizing an alfaxalone intermediate, characterized in that: The synthesis method comprises: Compound IN-2 is subjected to a hydrogenation reaction to obtain compound I; The hydrogenation reaction conditions are: adding solvent ethanol or acetic acid, palladium carbon, and reacting to obtain compound I, and the added volume of ethanol or acetic acid is 10-80 times the weight of compound IN-2.

2. The method for synthesizing the intermediate of alfaxalone according to claim 1, characterized in that: When the added solvent is ethanol, the reaction time is 26-30 hours; when the added solvent is acetic acid, the reaction time is 14-18 hours.

3. The method for synthesizing the alfaxalone intermediate according to claim 1 or 2, characterized in that: The weight of the palladium carbon is 0.05 to 0.2 times the weight of compound IN-2, the palladium carbon contains 5-10% palladium, and the water content is 50-60%.

4. A method for synthesizing alfaxalone, characterized in that: The steps include: (1) Compound SM is subjected to elimination reaction to obtain intermediate IN-1; (2) intermediate IN-1 is subjected to ketal protection reaction to obtain intermediate IN-2; (3) intermediate IN-2 is prepared by the synthesis method according to any one of claims 1 to 3 to obtain compound I; (4) Compound I is subjected to a deketalization reaction to obtain intermediate IN-3; (5) The intermediate IN-3 is enzymatically reduced to give alfaxalone; The specific synthetic route is as follows:

5. The method for synthesizing alfaxalone as claimed in claim 4, characterized in that: In the deketalization protection reaction in step (4), dilute hydrochloric acid with a volume concentration of 2%-5% is added, and the volume of the dilute hydrochloric acid is 0.1-0.6 times the volume of the organic solvent in step (3).

6. The method for synthesizing alfaxalone as claimed in claim 4, characterized in that: The reaction conditions of step (1) are as follows: dissolving compound SM in pyridine, adding N-chlorosuccinimide and 4-dimethylaminopyridine, and dropping sulfur dioxide pyridine solution to react at -15°C to -40°C.

7. The method for synthesizing alfaxalone as claimed in claim 6, characterized in that: The weight of the N-chlorosuccinimide is 0.8-1 times the weight of the compound SM; the weight of the 4-dimethylaminopyridine is 1-2 times the weight of the compound SM; the weight-to-volume ratio of the compound SM to the sulfur dioxide pyridine solution is 1:1.25-3.

8. The method for synthesizing alfaxalone as claimed in claim 4, characterized in that: The reaction conditions of the ketal protection reaction in step (2) are as follows: ethylene glycol, ortho acid triester and acid catalyst are added to the intermediate IN1 for reaction.

9. The method for synthesizing alfaxalone as claimed in claim 4, characterized in that: In the step (2), an organic solvent is further added, and the organic solvent is one or more of dichloromethane, tetrahydrofuran, and ethyl acetate.

10. The method for synthesizing alfaxalone according to claim 8 or 9, characterized in that: The ortho acid triester is one or more of trimethyl orthoformate, triethyl orthoformate, triethyl orthoacetate, and trimethyl orthoacetate; the acid catalyst is one or more of p-toluenesulfonic acid, methanesulfonic acid, and sulfuric acid.

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