Synthetic method of side chain alcohol

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of side chain alcohol. DMDO-Cl is adopted to react with anhydrous formic acid, triethylamine is added to neutralize HCl in the reaction process and promote right shift of reaction equilibrium to obtain formate, then alcoholysis is carried out under the catalytic action of hydrochloric acid, purification is carried out through a reduced pressure distillation method, and the target product DMDO-OH is generated. By optimizing the synthesis process of the side-chain alcohol and ingeniously selecting the types of catalysts, the yield and purity of the side-chain alcohol are effectively improved, the synthesis method is simple and easy to implement, the raw materials are cheap and easy to obtain, the reaction efficiency is relatively high, and industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing a side chain alcohol. Background Art

[0002] Azilsartan (Formula 1) is a potent and long-lasting angiotensin II receptor antagonist developed by Takeda Pharmaceuticals of Japan. It is a precursor drug of azilsartan and an angiotensin II receptor antagonist drug under development for the treatment of hypertension. It is mostly used to treat hypertension and is currently the only angiotensin II receptor antagonist (sartan) drug in the final stage of clinical trials. Compared with sartan drugs such as Olmesartan Medoxomil and Valsartan, azilsartan has a better blood pressure-lowering effect.

[0003]

[0004] Formula 1 4-(Hydroxymethyl)-5-methyl-[1,3]dioxol-2-one (side chain alcohol, DMDO-OH, Formula 2) is a key intermediate for the synthesis of drugs such as azilsartan medoxomil and olmesartan medoxomil. Therefore, it is crucial to provide a low-cost, high-purity and high-yield synthesis process of DMDO-OH.

[0005]

[0006] Formula 2 There are two main methods for preparing DMDO-OH: the first route is to use 4,5-dimethyl-1,3-dioxol-2-one (DMDO) as the starting material and obtain it under the action of selenium dioxide. The by-product in this route is a mixture of elemental selenium and selenium dioxide, and selenium dioxide is highly toxic and has a low yield of 60%. The second route is to use 4-chloromethyl-5-methyl-1,3-dioxol-2-one (DMDO-Cl) as the starting material, which is esterified with formic acid and then hydrolyzed with alcohol acid. The product obtained by this reaction route has many impurities and low purity, which is difficult to meet the large market demand.

[0007] The Chinese patent application with publication number CN113214215A discloses a method for preparing and purifying DMDO-OH, that is, preparing DMDO-OH by catalytic oxidation and purifying it by distillation, but the content of DMDO-OH can only reach 98.1%.

[0008] The Chinese patent application with publication number CN113912580A discloses a method for purifying DMDO-OH, wherein the crude product of 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one is subjected to vacuum distillation to improve its purity, wherein the vacuum distillation adopts a distillation column, the filler is a ceramic corrugated filler or a glass filler, the absolute vacuum of the distillation system of the vacuum distillation is controlled at 50-200 Pa, the internal temperature during distillation is controlled at 120-140°C, the reflux ratio of the distillation system is 1:1 or 2:1, and the length and diameter ratio of the distillation column used in the vacuum distillation is 10-30. This method can improve the purity of DMDO-OH to more than 98%. Summary of the invention

[0009] In order to solve the technical problems of low yield and poor purity existing in the related art, the purpose of the present invention is to provide a method for synthesizing side chain alcohols.

[0010] In order to achieve the above object, the technical solution of the present invention is as follows: A method for synthesizing a side chain alcohol comprises the following steps: S1: Add solvent and catalyst to the reaction bottle, stir evenly, add DMDO-Cl, stir at room temperature, cool to 0-5°C in an ice bath, add anhydrous formic acid, stir evenly and slowly add triethylamine dropwise, control the temperature of the reaction system to be less than 10°C; after the addition is complete, heat to 35-40°C, stir and react, stop the reaction when HPLC monitors that the content of DMDO-Cl is less than 0.2%, filter, and obtain filtrate I and filter cake; S2: washing the filter cake obtained in step S1 with a solvent for multiple times, combining the washing liquid and the filtrate I obtained in step S1, concentrating under reduced pressure, adding a solvent and water, stirring, and separating the phases to obtain an aqueous phase and an organic phase I; extracting the aqueous phase with a solvent to obtain an organic phase II; combining the organic phase I and the organic phase II, washing with water, a sodium thiosulfate solution, and a saturated brine in sequence, adding anhydrous magnesium sulfate, stirring, filtering, and concentrating under reduced pressure to obtain an oily substance; S3: Add methanol and concentrated hydrochloric acid to the oily substance obtained in step S2, stir and heat, react until HPLC monitors that the formate in the reaction system is less than 0.3%, add activated carbon, stir, filter, and obtain filtrate II and filter residue; wash the filter residue with methanol for multiple times, combine the washing liquid and filtrate II, and distill under reduced pressure to obtain a yellow liquid product.

[0011] In the present invention, DMDO-Cl is used as a reaction raw material, and an ester is generated under the catalytic action of a catalyst, and then an alcoholysis reaction occurs under the catalytic action of hydrochloric acid to generate DMDO-OH. It is worth mentioning that in the preparation method of the side chain alcohol provided by the present invention, the temperature of the reaction system is controlled to be 0-5°C before the addition of anhydrous formic acid and triethylamine, and the temperature of the reaction system is controlled to be less than 10°C during the addition of anhydrous formic acid and triethylamine, which effectively inhibits the occurrence of side reactions during the reaction and improves the yield; after the triethylamine is added dropwise, the reaction temperature of DMDO-Cl and anhydrous formic acid is controlled to be 35-40°C, and the reaction is carried out in this temperature range, which can effectively reduce the generation of ring-opening by-products such as acetic acid, acetaldehyde, and acetal, which is beneficial to improve the purity of DMDO-OH. In addition, in step S2, the prepared organic phase is washed with water, sodium thiosulfate solution and saturated brine in turn, which can not only wash away the water-soluble reagents in the organic phase, reduce and wash away the catalyst, but also effectively remove impurities in the organic phase, reduce the loss of the product dissolved in water, and further improve the yield and the purity of DMDO-OH.

[0012] Furthermore, the synthesis method of the side chain alcohol also includes the following steps: adding a mixture of ethyl acetate and cyclohexane to the yellow liquid product obtained in step S3, stirring and heating to 48-50°C, and then keeping the mixture warm for 1.5-2h, then performing reduced pressure distillation, and concentrating until no liquid flows out to obtain a high-purity side chain alcohol; the mixing mass ratio of ethyl acetate and cyclohexane is 3-5:8-11.

[0013] In the present invention, a mixture of ethyl acetate and cyclohexane is used to extract the obtained DMDO-OH, and then the DMDO-OH is purified by vacuum distillation, thereby effectively improving the purity of the DMDO-OH.

[0014] Furthermore, in step S1 of the synthesis method of the side chain alcohol, the solvent is one of acetonitrile, dichloromethane and dimethylacetamide.

[0015] Furthermore, in step S1 of the synthesis method of side chain alcohols, the catalyst consists of sodium iodide and ferric chloride in a mass ratio of 7-10:1-3.

[0016] In the reaction process of DMDO-Cl and anhydrous formic acid, sodium iodide can effectively promote the reaction. However, studies have found that using sodium iodide alone as a reaction catalyst will result in an excessively fast reaction rate and side reactions. Therefore, in the present invention, ferric chloride and sodium iodide are used together as reaction catalysts to effectively control the reaction rate, reduce the occurrence of side reactions, and improve the yield.

[0017] Furthermore, the mass fractions of the components in step S1 of the synthesis method of the side chain alcohol are: 90-100 parts of solvent, 18-22 parts of catalyst, 9-13 parts of DMDO-Cl, 6-10 parts of anhydrous formic acid, and 16-20 parts of triethylamine.

[0018] Furthermore, in step S1 of the synthesis method of the side chain alcohol, the room temperature stirring time is 50-60 minutes, and the stirring reaction time is 15-20 hours.

[0019] Furthermore, in step S2 of the synthesis method of the side chain alcohol, the solvent is one of dichloromethane, dimethylacetamide, and dimethyl sulfoxide.

[0020] Furthermore, in step S2 of the synthesis method of side chain alcohol, the amount of the solvent added is 45-50 parts, the amount of water added is 25-30 parts; the mass percentage of the sodium thiosulfate solution is 5-8%; and the amount of anhydrous magnesium sulfate added is 50-55 parts.

[0021] Furthermore, in step S3 of the synthesis method of side chain alcohol, the amount of methanol added is 500-550 parts, the amount of concentrated hydrochloric acid added is 10-12 parts, and the stirring and heating to 50-55° C.; the amount of activated carbon added is 20-40 parts.

[0022] Furthermore, the HPLC conditions in step S1 and step S3 of the synthesis method of the side chain alcohol are: Chromatographic column: COSMOSIL C18 (4.6mm×150mm, 5um); flow rate: 1mL / min; wavelength: 210nm; column temperature: 30℃; time: 35min; injection volume: 10uL; mobile phase A: 0.1% H3PO4 solution, mobile phase B: acetonitrile; gradient elution:

[0024] Compared with the prior art, the synthesis method of the side chain alcohol provided by the present invention has the following technical advantages: (1) The yield of the synthesis method of the side chain alcohol provided by the present invention is above 98.5%, and the purity of the obtained side chain alcohol is above 98%; (2) The present invention optimizes the process of synthesizing side chain alcohols and skillfully selects the type of catalyst, thereby effectively improving the yield and purity of side chain alcohols; (3) The synthesis method of the side chain alcohol provided by the present invention is simple and easy, the raw materials are cheap and readily available, the reaction efficiency is high, and it is conducive to industrial production. DETAILED DESCRIPTION

[0025] The technical scheme of the present invention is clearly and completely described below in conjunction with specific embodiments. The specific embodiments described are only partial embodiments of the present invention, rather than limitations of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work belong to the protection scope of the present invention.

[0026] The HPLC conditions in step S1 and step S3 of the synthesis method of the side chain alcohol in this specific embodiment are: Chromatographic column: COSMOSIL C18 (4.6mm×150mm, 5um); flow rate: 1mL / min; wavelength: 210nm; column temperature: 30℃; time: 35min; injection volume: 10uL; mobile phase A: 0.1% H3PO4 solution, mobile phase B: acetonitrile; gradient elution:

[0028] Example 1 A method for synthesizing a side chain alcohol comprises the following steps: S1: Add 90 parts of acetonitrile and 18 parts of catalyst to a reaction bottle, stir evenly, add 9 parts of DMDO-Cl, stir at room temperature for 50 minutes, cool to 0°C in an ice bath, add 6 parts of anhydrous formic acid, stir evenly and slowly add 16 parts of triethylamine dropwise, and control the temperature of the reaction system to be less than 10°C; after the addition is complete, heat to 35°C, stir and react for 15 hours, stop the reaction when HPLC monitors that the content of DMDO-Cl is less than 0.2%, filter, and obtain filtrate I and filter cake; the catalyst is composed of sodium iodide and ferric chloride in a mass ratio of 7:1; S2: Wash the filter cake obtained in step S1 with dichloromethane three times, combine the washing liquid and the filtrate I obtained in step S1, concentrate under reduced pressure, add 45 parts of dichloromethane and 25 parts of water, stir, separate the phases, and obtain an aqueous phase and an organic phase I; extract the aqueous phase with dichloromethane to obtain an organic phase II; combine the organic phase I and the organic phase II, wash with water, a 5% by mass sodium thiosulfate solution, and saturated brine in sequence, add 50 parts of anhydrous magnesium sulfate, stir, filter, and concentrate under reduced pressure to obtain an oily substance; S3: Add 500 parts of methanol and 10 parts of concentrated hydrochloric acid to the oily substance obtained in step S2, heat to 50°C with stirring, and react until HPLC monitors that the formate in the reaction system is less than 0.3%, add 20 parts of activated carbon, stir, and filter to obtain filtrate II and filter residue; wash the filter residue with methanol for multiple times, combine the washing liquid and filtrate II, and distill under reduced pressure to obtain a yellow liquid product.

[0029] S4: Add a mixture of ethyl acetate and cyclohexane to the yellow liquid product obtained in step S3, heat to 48°C with stirring, and then keep the mixture warm for 1.5 hours, then perform vacuum distillation, and concentrate until no liquid flows out to obtain a high-purity side chain alcohol; the mass ratio of the ethyl acetate and cyclohexane is 3:8.

[0030] Example 2 A method for synthesizing a side chain alcohol comprises the following steps: S1: Add 100 parts of dimethylacetamide and 22 parts of catalyst to the reaction bottle, stir evenly, add 13 parts of DMDO-Cl, stir at room temperature for 60 minutes, cool to 5°C in an ice bath, add 10 parts of anhydrous formic acid, stir evenly and slowly add 20 parts of triethylamine, control the temperature of the reaction system to be less than 10°C; after the addition is completed, heat to 40°C, stir and react for 20 hours, stop the reaction when HPLC monitors that the content of DMDO-Cl is less than 0.2%, filter, and obtain filtrate I and filter cake; the catalyst is composed of sodium iodide and ferric chloride in a mass ratio of 10:3; S2: Wash the filter cake obtained in step S1 with dimethylacetamide three times, combine the washing liquid and the filtrate I obtained in step S1, concentrate under reduced pressure, add 50 parts of dimethylacetamide and 30 parts of water, stir, separate the phases, and obtain an aqueous phase and an organic phase I; extract the aqueous phase with dimethylacetamide to obtain an organic phase II; combine the organic phase I and the organic phase II, wash with water, 8% by mass sodium thiosulfate solution, and saturated brine in sequence, add 55 parts of anhydrous magnesium sulfate, stir, filter, and concentrate under reduced pressure to obtain an oily substance; S3: Add 550 parts of methanol and 12 parts of concentrated hydrochloric acid to the oily substance obtained in step S2, heat to 55°C with stirring, and react until HPLC monitors that the formate in the reaction system is less than 0.3%, add 40 parts of activated carbon, stir, and filter to obtain filtrate II and filter residue; wash the filter residue with methanol for multiple times, combine the washing liquid and filtrate II, and distill under reduced pressure to obtain a yellow liquid product.

[0031] S4: Add a mixture of ethyl acetate and cyclohexane to the yellow liquid product obtained in step S3, heat to 50°C with stirring, and then keep the mixture warm for 2 hours, then perform vacuum distillation, and concentrate until no liquid flows out to obtain a high-purity side chain alcohol; the mass ratio of the ethyl acetate to cyclohexane is 5:11.

[0032] Example 3 A method for synthesizing a side chain alcohol comprises the following steps: S1: Add 98 parts of dichloromethane and 20 parts of catalyst to the reaction bottle, stir evenly, add 11 parts of DMDO-Cl, stir at room temperature for 57 minutes, cool to 3°C in an ice bath, add 8 parts of anhydrous formic acid, stir evenly and slowly add 18 parts of triethylamine, control the temperature of the reaction system to be less than 10°C; after the addition is complete, heat to 38°C, stir and react for 17 hours, stop the reaction when HPLC monitors that the content of DMDO-Cl is less than 0.2%, filter, and obtain filtrate I and filter cake; the catalyst is composed of sodium iodide and ferric chloride in a mass ratio of 9:2; S2: Wash the filter cake obtained in step S1 with dimethyl sulfoxide three times, combine the washing liquid and the filtrate I obtained in step S1, concentrate under reduced pressure, add 48 parts of dimethyl sulfoxide and 28 parts of water, stir, separate the phases, and obtain an aqueous phase and an organic phase I; extract the aqueous phase with dimethyl sulfoxide to obtain an organic phase II; combine the organic phase I and the organic phase II, wash with water, a 7% by mass sodium thiosulfate solution, and saturated brine in sequence, add 53 parts of anhydrous magnesium sulfate, stir, filter, and concentrate under reduced pressure to obtain an oily substance; S3: Add 530 parts of methanol and 11 parts of concentrated hydrochloric acid to the oily substance obtained in step S2, heat to 53°C with stirring, and react until HPLC monitors that the formate in the reaction system is less than 0.3%, add 30 parts of activated carbon, stir, and filter to obtain filtrate II and filter residue; wash the filter residue with methanol for multiple times, combine the washing liquid and filtrate II, and distill under reduced pressure to obtain a yellow liquid product.

[0033] S4: Add a mixture of ethyl acetate and cyclohexane to the yellow liquid product obtained in step S3, heat to 49°C with stirring, and then keep the mixture warm for 1.8 hours, then perform vacuum distillation, and concentrate until no liquid flows out to obtain a high-purity side chain alcohol; the mass ratio of the ethyl acetate and cyclohexane is 4:9.

[0034] Comparative Example 1 The synthesis method of the side chain alcohol in this comparative example is similar to that in Example 3. The difference between this comparative example and Example 3 is that the temperature of the ice cooling in step S1 of this comparative example is 8-12°C.

[0035] Comparative Example 2 The synthesis method of the side chain alcohol in this comparative example is similar to that in Example 3. The difference between this comparative example and Example 3 is that the temperature of the reaction system is controlled to be 14-18°C in step S1 of this comparative example.

[0036] Comparative Example 3 The synthesis method of the side chain alcohol in this comparative example is similar to that in Example 3. The difference between this comparative example and Example 3 is that the temperature is raised to 55° C. after the reaction in step S1 of this comparative example is completed.

[0037] Comparative Example 4 The synthesis method of the side chain alcohol in this comparative example is similar to that in Example 3. The difference between this comparative example and Example 3 is that an equal amount of water is used instead of the sodium thiosulfate solution in step S2 of this comparative example.

[0038] Comparative Example 5 The synthesis method of the side chain alcohol in this comparative example is similar to that in Example 3. The difference between this comparative example and Example 3 is that an equal amount of water is used instead of saturated brine in step S2 of this comparative example.

[0039] Comparative Example 6 The synthesis method of the side chain alcohol in this comparative example is similar to that in Example 3. The difference between this comparative example and Example 3 is that the synthesis method of the side chain alcohol in this comparative example does not perform step S4.

[0040] Comparative Example 7 The synthesis method of the side chain alcohol in this comparative example is similar to that in Example 3. The difference between this comparative example and Example 3 is that the mixing mass ratio of ethyl acetate and cyclohexane in step S4 of this comparative example is 9:4.

[0041] Comparative Example 8 The synthesis method of the side chain alcohol in this comparative example is similar to that in Example 3. The difference between this comparative example and Example 3 is that the catalyst in step S1 of this comparative example is composed of sodium iodide and ferric chloride in a mass ratio of 2:9.

[0042] Test example This test example calculated the yields of the side chain alcohols obtained in Example 1 to Example 3 and Comparative Example 1 to Comparative Example 8, and used HPLC to test the purity of the obtained side chain alcohols. The test results are shown in Table 1.

[0043] Table 1 Test results

[0044] As can be seen from Table 1, the yield of the side chain alcohol in the synthesis method of the side chain alcohol provided by the present invention is 98.5%-99.2%, and the purity of the synthesized side chain alcohol is 98.1%-99.4%. Among them, Example 3 has the highest yield and purity, which is the best embodiment of the present invention.

[0045] Compared with Example 3, in step S1 of comparative example 1, the temperature of the reaction system before the addition of anhydrous formic acid and triethylamine was changed, and in step S1 of comparative example 2, the temperature of the reaction system during the addition of anhydrous formic acid and triethylamine was changed, but the yield of the obtained side chain alcohol was increased, which indicates that low temperature can effectively inhibit the by-products in the reaction process; in step S1 of comparative example 3, the reaction temperature of DMDO-Cl and anhydrous formic acid was changed, but the purity of the obtained coarse quail was reduced, which indicates that the generation of reaction by-products can be effectively reduced within the reaction temperature range provided by the present invention, which is beneficial to improve the purity of the side chain alcohol; in step S2 of comparative example 4, an equal amount of water was used instead of the sodium thiosulfate solution, in step S2 of comparative example 5, an equal amount of water was used instead of the saturated salt water, and in step S2 of comparative example 6, an equal amount of water was used instead of the saturated salt water. Step S4 is not performed in the comparative example 7, but the purity of the obtained side chain alcohol is reduced, which shows that the washing with water, sodium thiosulfate solution and saturated brine in the present invention can not only wash away the water-soluble reagents in the organic phase, reduce and wash away the catalyst, but also effectively remove impurities in the organic phase, reduce the loss of the product dissolved in water, and further improve the purity of the side chain alcohol; comparative example 7 changes the mixing mass ratio of ethyl acetate and cyclohexane in step S4, but the purity of the obtained side chain alcohol is reduced, which shows that the mixing mass ratio of ethyl acetate and cyclohexane is one of the key factors affecting the purity of the side chain alcohol; comparative example 8 changes the mass ratio of the catalyst in step S1, but the yield and purity of the side chain alcohol are reduced, which shows that the amount ratio of the catalyst in the present invention has been optimized.

[0046] The above embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any person skilled in the art shall not modify the above embodiments without violating the spirit and scope of the present invention. Therefore, any modification, equivalent substitution and improvement made by those skilled in the art under the technical concept of the present invention shall still be covered by the claims of the present invention.

Claims

1. A method for synthesizing a side chain alcohol, characterized in that: The following steps are involved: S1: Add solvent and catalyst to the reaction bottle, stir evenly, add DMDO-Cl, stir at room temperature, cool to 0-5°C in an ice bath, add anhydrous formic acid, stir evenly and slowly add triethylamine dropwise, control the temperature of the reaction system to be less than 10°C; after the addition is complete, heat to 35-40°C, stir and react, stop the reaction when HPLC monitors that the content of DMDO-Cl is less than 0.2%, filter, and obtain filtrate I and filter cake; S2: washing the filter cake obtained in step S1 with a solvent for multiple times, combining the washing liquid and the filtrate I obtained in step S1, concentrating under reduced pressure, adding a solvent and water, stirring, and separating the phases to obtain an aqueous phase and an organic phase I; extracting the aqueous phase with a solvent to obtain an organic phase II; combining the organic phase I and the organic phase II, washing with water, a sodium thiosulfate solution, and a saturated brine in sequence, adding anhydrous magnesium sulfate, stirring, filtering, and concentrating under reduced pressure to obtain an oily substance; S3: Add methanol and concentrated hydrochloric acid to the oily substance obtained in step S2, stir and heat, react until HPLC monitors that the formate in the reaction system is less than 0.3%, add activated carbon, stir, filter, and obtain filtrate II and filter residue; wash the filter residue with methanol for multiple times, combine the washing liquid and filtrate II, and distill under reduced pressure to obtain a yellow liquid product.

2. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: The following steps are also included: A mixture of ethyl acetate and cyclohexane is added to the yellow liquid product obtained in step S3, and the mixture is heated to 48-50° C. with stirring, and then kept warm for reaction for 1.5-2 hours, and then distilled under reduced pressure and concentrated until no liquid flows out to obtain a high-purity side chain alcohol; the mixing mass ratio of ethyl acetate and cyclohexane is 3-5:8-11.

3. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: The solvent in step S1 is one of acetonitrile, dichloromethane and dimethylacetamide.

4. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: The catalyst in step S1 is composed of sodium iodide and ferric chloride in a mass ratio of 7-10:1-3.

5. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: The mass fractions of the components in step S1 are: 90-100 parts of solvent, 18-22 parts of catalyst, 9-13 parts of DMDO-Cl, 6-10 parts of anhydrous formic acid, and 16-20 parts of triethylamine.

6. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: The stirring time at room temperature in step S1 is 50-60 min, and the stirring reaction time is 15-20 h.

7. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: The solvent in step S2 is one of dichloromethane, dimethylacetamide and dimethyl sulfoxide.

8. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: In step S2, the amount of the solvent added is 45-50 parts, the amount of water added is 25-30 parts; the mass percentage of the sodium thiosulfate solution is 5-8%; and the amount of anhydrous magnesium sulfate added is 50-55 parts.

9. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: In step S3, the amount of methanol added is 500-550 parts, the amount of concentrated hydrochloric acid added is 10-12 parts, and the stirring and heating to 50-55° C.; the amount of activated carbon added is 20-40 parts.

10. The method for synthesizing a side chain alcohol according to claim 1, characterized in that: The HPLC conditions in step S1 and step S3 are as follows: chromatographic column: COSMOSIL C18 (4.6 mm×150 mm, 5 um); flow rate: 1 mL / min; Wavelength: 210nm; Column temperature: 30℃; Time: 35min; Injection volume: 10uL; Mobile phase A: 0.1% H3PO4 solution, Mobile phase B: acetonitrile; Gradient elution: 。

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