A synthesis process of tenofovir intermediate

Abstract

The invention discloses a synthesis technique for a tenofovir intermediate, 9-propylene adenine is synthesized by the imino group of an acetyl-protected adenine and propionaldehyde selective enamination reaction, and then the acetyl-protected tenofovir intermediate (R)-9-(2-hydroxypropyl) adenine is synthesized by the method for synthesizing a chiral group through S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine-induced oxidation. The invention has the beneficial effects of: the synthetic route of the present invention is simple to operate, process step is few, raw materials are easy to obtain, and reaction product is easy to process, and is suitable for industrial expansion production. The technical scheme of the present invention does not need to use expensive chiral reagents, and the reaction selectivity of the synthetic chiral group is high, so the yield yield and purity are higher, and the generation of by-products can be effectively reduced and the difficulty of by-product treatment can be reduced.

Description

Technical Field

[0001] The present invention relates to the technical field related to the synthesis of pharmaceutical intermediates, and in particular to a synthesis process of a tenofovir intermediate. Background Art

[0002] Tenofovir, chemically known as (R)-{[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}phosphonic acid, or (R)-9-(2-phosphonomethoxypropyl)adenine, has the following structural formula:

[0003]

[0004] (R)-(+)-9-(2-hydroxypropyl)adenine is a key intermediate in the synthesis of tenofovir. Due to the stereochemical factors in this compound, the desired product has a single configuration, making its synthesis relatively difficult. Currently, the methods for synthesizing (R)-(+)-9-(2-hydroxypropyl)adenine are mainly the following:

[0005] Synthesis Route 1

[0006] The document Collect Czech. Chem. Commun., 1995, 60, 1196 reports a method for preparing (R)-(+)-9-(2-hydroxypropyl)adenine using isobutyl lactate as a starting material through a five-step reaction. This method requires five steps, including protection and deprotection steps, and uses special red aluminum, resulting in high process costs and low industrial value.

[0007] Route 1

[0008]

[0009] Synthesis Route 2

[0010] Patent US5935946A1 protects a method for preparing (R)-(+)-9-(2-hydroxypropyl)adenine via a three-step reaction using (R)-cyclopropanol as a raw material. This method has a relatively short reaction process, but the raw material (R)-cyclopropanol is expensive and requires hydrogen reduction. This short synthetic route, however, has been shown in numerous experiments to inevitably racemize the reaction product of adenine and R-propylene carbonate under alkaline conditions, resulting in a final product with an optical purity of only 90%-94%, which falls short of clinical application requirements. Recrystallization is required to improve enantioselectivity to meet these requirements, but literature reports indicate unstable recrystallization yields, which increases costs to a certain extent. Furthermore, the reaction of adenine and R-propylene carbonate requires anhydrous and oxygen-free treatment, placing higher demands on instrumentation and equipment. This reduces its industrial value.

[0011] Route 2

[0012]

[0013] Synthesis Route 3

[0014] CN103374038B discloses a method for preparing tenofovir disoproxil fumarate. Specifically, the method uses adenine as a starting material and reacts it with (R)-propylene oxide under quaternary ammonium catalysis to obtain (R)-9-(2-hydroxypropyl)adenine through crystallization. Then, tenofovir is obtained through steps such as phosphorylation, hydrolysis, and acidification. The method discloses a method for quickly introducing a chiral alcohol at the 9-position of adenine. However, the method requires the use of a large amount of expensive chiral cyclopropane, resulting in high production costs and low reaction yields.

[0015] Route 3

[0016]

[0017] Synthesis Route 4

[0018] Chinese patent CN106632340A reports a method for synthesizing a tenofovir intermediate, wherein 9-formyl adenine with a primary amine protected by a Y acetyl group is subjected to a reflux reaction with ethyl formate under alkaline conditions to obtain 9-formyl adenine, which is then deprotected and subjected to a Witting reaction with ethyl triphenylphosphine in the presence of a base to obtain 9-propenyl adenine, which is then oxidized with tetramethylpiperidine nitrogen oxide under the induction of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl to selectively obtain the tenofovir chiral intermediate (R)-9-(2-hydroxypropyl) adenine. This scheme is simple to operate and has a high yield, but requires four steps and is prone to producing cis-trans isomers, resulting in a reduced yield. In addition, the waste generated by the ethyl triphenylphosphine after the reaction is difficult to handle.

[0019] Route 4

[0020] Summary of the Invention

[0021] The present invention aims to address the deficiencies of the prior art and provide a synthesis process for a tenofovir intermediate. 9-Propyladenine is synthesized by selective enamination of the imino group of adenine with propionaldehyde, and then the tenofovir intermediate (R)-9-(2-hydroxypropyl)adenine is synthesized by a method of synthesizing a chiral group through S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine-induced oxidation. The method is simple to operate, has few steps, and the reaction product is easy to handle, with high yield and purity, and is suitable for industrial scale-up production. The synthesis route of the present invention is as follows:

[0022]

[0023] The technical solutions of the present invention are as follows:

[0024] A synthesis process of a tenofovir intermediate comprises the following steps:

[0025] In the first step, compound I is dissolved in an organic solvent, a dehydrating agent is added to the solution, and dried propionaldehyde is continuously added dropwise to the solution for reflux reaction. After the reaction is completed, the solution is cooled to room temperature, filtered, washed, dried, and recrystallized to obtain compound III.

[0026] In the second step, compound III obtained in the first step is added to a reaction flask filled with dichloromethane, an inducing agent is added, the mixture is stirred, and then an oxidant is added dropwise. The mixture is reacted at a constant temperature for 5 to 6 hours. After the reaction is completed, the reaction solution is washed with water and saturated sodium bicarbonate three times, the organic phase is separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized to obtain tenofovir intermediate compound IV.

[0027] Compound IV obtained in the second step was added with aqueous sodium hydroxide solution, stirred at 60-80° C. for 2 hours, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from petroleum ether to obtain the target compound V.

[0028] Furthermore, the solvent used in the first step reaction is one of diethyl ether, THF, and benzene, preferably diethyl ether.

[0029] Furthermore, the dehydrating agent used in the first step reaction is one of magnesium sulfate, potassium carbonate, and calcium oxide, preferably magnesium sulfate.

[0030] Furthermore, the molar ratio of reactant I, reactant II and dehydrating agent used in the first step reaction is 1:1:2.5-3.5, preferably 1:1:3.

[0031] Furthermore, the inducing agent used in the second step reaction is S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine.

[0032] Furthermore, the oxidant used in the second step reaction is a dichloromethane solution of tetramethylpiperidine nitrogen oxide.

[0033] Furthermore, in the second step reaction, the molar ratio of the reactant compound III, the oxidant and the inducer is 1:1.1-1.5:0.05-0.2, preferably 1:1.2:0.1.

[0034] Furthermore, the reaction temperature of the second step reaction is 10-20°C, preferably 15°C.

[0035] Furthermore, the recrystallization reagent used in the second step reaction is n-hexane / dichloromethane (volume ratio 10:1).

[0036] Furthermore, the concentration of the sodium hydroxide solution used in the third step reaction hydrolysis is 4 mol / L.

[0037] The beneficial effects of the present invention are: 1. The synthetic route of the present invention is simple to operate, has few process steps, and the raw materials are readily available, and the reaction products are easy to handle, making it suitable for industrial scale-up production; 2. The technical solution of the present invention does not require the use of expensive chiral reagents, and the reaction selectivity for synthesizing chiral groups is high, so the yield, yield and purity are high, which can effectively reduce the generation of by-products and reduce the difficulty of by-product treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 Schematic diagram of the reaction process of the present invention;

[0039] Figure 2 Schematic diagram of the reaction flow of route 1;

[0040] Figure 3 This is a schematic diagram of the reaction flow of Route 2;

[0041] Figure 4 Schematic diagram of the reaction flow of route three;

[0042] Figure 5 This is a schematic diagram of the reaction flow of route 4;

[0043] Figure 6 Schematic diagram of the chemical structure of tenofovir. DETAILED DESCRIPTION

[0044] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the embodiments of the present invention and the accompanying drawings. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0045]

[0046] Example 1

[0047] In the first step, 17.7 g (0.1 mol) of compound I was added to 200 ml of ether, 0.3 mol of magnesium sulfate as a dehydrating agent was added to the solution, and 5.8 g (0.1 mol) of dried propanal was added dropwise, and the mixture was stirred and refluxed for 4 to 5 hours. After the reaction was completed, it was cooled to room temperature, the solution was filtered, and the filtrate was washed with ether 2 to 3 times and combined with the filtrate. The solvent was evaporated, 50 ml of toluene and 50 ml of water were added, stirred to dissolve, and allowed to stand for stratification. The aqueous layer was extracted once with 50 ml of toluene, and the organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure, recrystallized with new toluene, filtered and dried to obtain 20.8 g of compound III with a yield of 95.9% and a purity of 99.1%.

[0048] In the second step, 10.9 g (0.05 mol) of compound III obtained in the first step was taken, 3.1 g (5 mmol) of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl was added to a reaction flask containing dichloromethane, the temperature was maintained at 15°C, and the mixture was stirred and mixed. Then, a dichloromethane solution of tetramethylpiperidine nitrogen oxide (containing 9.4 g of tetramethylpiperidine nitrogen oxide) was added dropwise. After the addition was completed, the temperature was maintained and the reaction was continued for 5 hours. The reaction solution was washed with water and saturated sodium bicarbonate three times, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from n-hexane / dichloromethane (volume ratio 10:1) to obtain 11.2 g of tenofovir intermediate compound IV with a yield of 94.9% and a purity of 98.3%.

[0049] 11.7 g (0.05 mol) of compound IV obtained in the second step reaction was added to 50 ml of 4 mol / L sodium hydroxide aqueous solution, stirred at 60 ° C for 2 hours, extracted twice with 50 ml * 2 of dichloromethane, and the organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure and recrystallized with petroleum ether, filtered and dried to obtain the target compound V, weighing 9.1 g, with a yield of 94.7% and a purity of 99.0%.

[0050] Example 2

[0051] In the first step, 17.7 g (0.1 mol) of compound I was added to 200 ml of benzene, 0.3 mol of magnesium sulfate as a dehydrating agent was added to the solution, and 5.8 g (0.1 mol) of dried propanal was added dropwise, and the mixture was stirred and refluxed for 4 to 5 hours. After the reaction was completed, it was cooled to room temperature, the solution was filtered, and the filtrate was washed with ether 2 to 3 times and combined with the filtrate. The solvent was evaporated, 50 ml of toluene and 50 ml of water were added, stirred to dissolve, and allowed to stand for stratification. The aqueous layer was extracted once with 50 ml of toluene, and the organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure, recrystallized with new toluene, filtered and dried to obtain 20.1 g of compound III with a yield of 92.6% and a purity of 98.5%.

[0052] Example 3

[0053] In the first step, 17.7 g (0.1 mol) of compound I was added to 200 ml of ether, 0.25 mol of magnesium sulfate as a dehydrating agent was added to the solution, and 5.8 g (0.1 mol) of dried propanal was added dropwise, and the mixture was stirred and refluxed for 4 to 5 hours. After the reaction was completed, it was cooled to room temperature, the solution was filtered, and the filtrate was washed with ether 2 to 3 times and combined with the filtrate. The solvent was evaporated, 50 ml of toluene and 50 ml of water were added, stirred to dissolve, and allowed to stand for stratification. The aqueous layer was extracted once with 50 ml of toluene, and the organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure, recrystallized with new toluene, filtered and dried to obtain 20.3 g of compound III with a yield of 93.5% and a purity of 99.1%.

[0054] Example 4

[0055] In the first step, 17.7 g (0.1 mol) of compound I was added to 200 ml of ether, 0.35 mol of magnesium sulfate as a dehydrating agent was added to the solution, and 5.8 g (0.1 mol) of dried propanal was added dropwise, and the mixture was stirred and refluxed for 4 to 5 hours. After the reaction was completed, it was cooled to room temperature, the solution was filtered, and the filtrate was washed with ether 2 to 3 times and combined with the filtrate. The solvent was evaporated, 50 ml of toluene and 50 ml of water were added, stirred to dissolve, and allowed to stand for stratification. The aqueous layer was extracted once with 50 ml of toluene, and the organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure, recrystallized with new toluene, filtered and dried to obtain 20.8 g of compound III with a yield of 96.5% and a purity of 98.8%.

[0056] Example 5

[0057] In the first step, 17.7 g (0.1 mol) of compound I was added to 200 ml of ether, 0.3 mol of potassium carbonate as a dehydrating agent was added to the solution, and 5.8 g (0.1 mol) of dried propanal was added dropwise, and the mixture was stirred and refluxed for 4 to 5 hours. After the reaction was completed, it was cooled to room temperature, the solution was filtered, and the filtrate was washed with ether 2 to 3 times and combined with the filtrate. The solvent was evaporated, 50 ml of toluene and 50 ml of water were added, stirred to dissolve, and allowed to stand for stratification. The aqueous layer was extracted once with 50 ml of toluene, and the organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure, recrystallized with new toluene, filtered and dried to obtain 20.0 g of compound III with a yield of 92.1% and a purity of 98.7%.

[0058] Example 6

[0059] In the second step, 10.9 g (0.05 mol) of compound III obtained in the first step was taken, 3.1 g (5 mmol) of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl was added to a reaction flask containing dichloromethane, the temperature was maintained at 10°C, the mixture was stirred and mixed, and then a dichloromethane solution of tetramethylpiperidine nitrogen oxide (containing 9.4 g of tetramethylpiperidine nitrogen oxide) was added dropwise. After the addition was completed, the temperature was maintained for 5 hours, sodium thiosulfate solution was added to quench the mixture, and the mixture was allowed to stand for stratification. The aqueous layer was extracted once with dichloromethane, the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolvated to dryness under reduced pressure, and recrystallized with n-hexane / dichloromethane (volume ratio 10:1), filtered and dried to obtain 10.8 g of tenofovir intermediate compound IV with a yield of 91.5% and a purity of 97.3%.

[0060] Example 7

[0061] In the second step, 10.9 g (0.05 mol) of compound III obtained in the first step was taken, and 3.1 g (5 mmol) of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl was added to a reaction flask containing dichloromethane, the temperature was maintained at 20°C, and the mixture was stirred and mixed. Then, a dichloromethane solution of tetramethylpiperidine nitrogen oxide (containing 9.4 g of tetramethylpiperidine nitrogen oxide) was added dropwise. After the addition was completed, the temperature was maintained for 5 hours, and sodium thiosulfate solution was added to quench the mixture. The mixture was allowed to stand for stratification, and the aqueous layer was extracted once with dichloromethane. The organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure and recrystallized with n-hexane / dichloromethane (volume ratio of 10:1). The mixture was filtered and dried to obtain 11.0 g of tenofovir intermediate compound IV with a yield of 93.2% and a purity of 97.8%.

[0062] Example 8

[0063] In the second step, 10.9 g (0.05 mol) of compound III obtained in the first step was taken, and 6.2 g (10 mmol) of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl was added to a reaction flask containing dichloromethane, the temperature was maintained at 15°C, and the mixture was stirred and mixed. Then, a dichloromethane solution of tetramethylpiperidine nitrogen oxide (containing 9.4 g of tetramethylpiperidine nitrogen oxide) was added dropwise. After the addition was completed, the temperature was maintained for 5 hours, and sodium thiosulfate solution was added to quench the mixture. The mixture was allowed to stand for stratification, and the aqueous layer was extracted once with dichloromethane. The organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure and recrystallized with n-hexane / dichloromethane (volume ratio 10:1). The mixture was filtered and dried to obtain 11.2 g of tenofovir intermediate compound IV with a yield of 94.0% and a purity of 98.3%.

[0064] Example 9

[0065] In the second step, 10.9 g (0.05 mol) of compound III obtained in the first step was taken, 1.5 g (2.5 mmol) of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl was added to a reaction flask containing dichloromethane, the temperature was maintained at 15°C, the mixture was stirred and mixed, and then a dichloromethane solution of tetramethylpiperidine nitrogen oxide (containing 9.4 g of tetramethylpiperidine nitrogen oxide) was added dropwise. After the addition was completed, the temperature was maintained for 5 hours, sodium thiosulfate solution was added to quench the reaction, the mixture was allowed to stand for stratification, the aqueous layer was extracted once with dichloromethane, the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolvated to dryness under reduced pressure, and recrystallized with n-hexane / dichloromethane (volume ratio 10:1), filtered and dried to obtain 10.5 g of tenofovir intermediate compound IV with a yield of 88.9% and a purity of 98.3%.

[0066] Example 10

[0067] In the second step, 10.9 g (0.05 mol) of compound III obtained in the first step was taken, and 3.1 g (5 mmol) of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl was added to a reaction flask containing dichloromethane, the temperature was maintained at 15°C, and the mixture was stirred and mixed. Then, a dichloromethane solution of tetramethylpiperidine nitrogen oxide (containing 8.6 g of tetramethylpiperidine nitrogen oxide) was added dropwise. After the addition was completed, the temperature was maintained for 5 hours, and sodium thiosulfate solution was added to quench the mixture. The mixture was allowed to stand for stratification, and the aqueous layer was extracted once with dichloromethane. The organic layers were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was desolvated to dryness under reduced pressure and recrystallized with n-hexane / dichloromethane (volume ratio 10:1). The mixture was filtered and dried to obtain 11.2 g of tenofovir intermediate compound IV with a yield of 94.9% and a purity of 98.5%.

[0068] Example 11

[0069] In the second step, 10.9 g (0.05 mol) of compound III obtained in the first step was taken, 3.1 g (5 mmol) of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl was added to a reaction flask containing dichloromethane, the temperature was maintained at 15°C, the mixture was stirred and mixed, and then a dichloromethane solution of tetramethylpiperidine nitrogen oxide (containing 11.7 g of tetramethylpiperidine nitrogen oxide) was added dropwise. After the addition was completed, the temperature was maintained for 5 hours, sodium thiosulfate solution was added to quench the reaction, the mixture was allowed to stand for stratification, the aqueous layer was extracted once with dichloromethane, the organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, the organic layer was desolvated to dryness under reduced pressure, and recrystallized with n-hexane / dichloromethane (volume ratio 10:1), filtered and dried to obtain 11.1 g of tenofovir intermediate compound IV with a yield of 94.0% and a purity of 98.8%.

[0070] Example of comparative document (CN104710424A)

[0071] Example 1

[0072] To 6 mL of DMF (dimethylformamide, the same below) were added 1 mmol of 6-chloropurine and 3 mmol of potassium carbonate. The mixture was stirred in an ice bath for 10 minutes, followed by the addition of 0.168 mL (2 mmol) of bromoacetone. The mixture was allowed to react in an ice bath for 1 hour. An appropriate amount of water was added, and the mixture was extracted with ethyl acetate 3 to 5 times. The organic phase was dried over anhydrous sodium sulfate and separated by column chromatography to obtain 6-chloro-9-(acetonyl)purine with a yield of 96%. 5 mol% of the prolinol ligand and 1 mol% of the ruthenium catalyst were added to 0.5 mL of acetonitrile and stirred at room temperature for 1 hour. HCOONa·2H2O (1 mmol) was then added. After stirring for 10 minutes, 0.1 mol of 6-chloro-9-(acetonyl)purine was added. The mixture was allowed to react at room temperature for 24 hours. Purification by column chromatography afforded 6-chloro-9-(acetonyl)purine with a yield of 12% and an enantioselectivity of 98%. At 0°C, 0.5 mmol of 6-chloro-9-(acetonyl)purine was added to 50 ml of freshly prepared ammonia methanol solution, reacted at 60°C for 48 hours, and separated by column chromatography to obtain (R)-(+)-9-(2-hydroxypropyl)adenine in a yield of 76%.

[0073] In summary, the technical solution provided by the present invention is simpler to operate, more convenient to process the product, has better selectivity and higher yield than the prior art. Therefore, the present invention is a significant improvement over the prior art.

[0074] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be included therein. Any reference sign in a claim should not be construed as limiting the claim to which it relates.

[0075] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A synthesis process for a tenofovir intermediate, characterized in that: The following steps are involved: In the first step, compound I is dissolved in an organic solvent, a dehydrating agent is added to the solution, and dried propionaldehyde is added dropwise to the solution for reflux reaction. After the reaction is completed, the solution is cooled to room temperature, filtered, washed, dried, and recrystallized to obtain compound III. In the second step, compound III obtained in the first step is added to a reaction flask containing dichloromethane, an inducing agent is added, the mixture is stirred, and then an oxidant is added dropwise. The mixture is reacted at a constant temperature for 5 to 6 hours. After the reaction is completed, the reaction solution is washed with water and saturated sodium bicarbonate three times, the organic phase is separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized to obtain tenofovir intermediate compound IV; In the third step, compound IV obtained in the second step was added with aqueous sodium hydroxide solution, stirred at 60-80°C for 2 hours, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from petroleum ether to obtain the target compound V; The solvent used in the first step reaction is one of ether, THF and benzene; The dehydrating agent used in the first step reaction is one of magnesium sulfate, potassium carbonate and calcium oxide; The molar ratio of reactant I, reactant II and dehydrating agent used in the first step reaction is 1:1:2.5-3.5; The inducing agent used in the second step reaction is S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine; The oxidant used in the second step reaction is a dichloromethane solution of tetramethylpiperidine nitrogen oxide; In the second step, the molar ratio of the reactant compound III, the oxidant and the inducer is 1:1.1-1.5:0.05-0.2; The reaction temperature of the second step reaction is 10-20°C; The recrystallization reagent used in the second step reaction is a mixed solution of n-hexane and dichloromethane in a volume ratio of 10:1; The concentration of the sodium hydroxide solution used in the third step reaction hydrolysis is 4 mol / L.

Images