Preparation method of D-dihydrophenylglycine methyl ester hydrochloride

Abstract

The invention provides a preparation method of D-dihydrophenylglycine methyl ester hydrochloride, and belongs to the technical field of pharmaceutical chemicals. Deoxidizing the reactor, adding methanol and D-dihydrophenylglycine, and stirring and dispersing; adding triphosgene in batches under the conditions of nitrogen protection and-5 to 10 DEG C, and heating to 50 to 60 DEG C to carry out esterification reaction after the triphosgene is completely added; when it is detected that the conversion rate of D-dihydrophenylglycine reaches 96% or above, the esterification reaction is finished, and methanol is subjected to reduced pressure distillation until a dry solid is obtained; controlling the decompression temperature to be below 60 DEG C, adding a solvent sleeve to distill residual methanol, adding the solvent again to disperse and cool the solid, and cooling; and filtering and drying in vacuum to obtain the finished product D-dihydrophenylglycine methyl ester hydrochloride. The one-time yield of the method is greater than 90%, and the method can be used for the cefradine enzymatic side chain and has a great industrialization prospect.

Description

Technical Field

[0001] This application relates to a method for preparing D-dihydrophenylglycine methyl ester hydrochloride, belonging to the field of pharmaceutical and chemical technology. Background Technology

[0002] D-Dihydrophenylglycine methyl ester hydrochloride is a side chain used in the cefadroxil enzymatic process. It has a wide range of applications and a large market demand. Currently, the side chains used in the cefadroxil enzymatic process are mainly sulfation esterification and thionyl chloride esterification.

[0003] CN 101277927A reports a method for synthesizing amphiphilic phenylglycine methanesulfonate from D-phenylglycine or D-dihydrophenylglycine as raw materials, using dimethyl carbonate as the esterification reagent and solvent, and simultaneously adding methanesulfonic acid. The esterification time exceeds 24 hours, resulting in low production efficiency and complex post-processing. CN 106905174A reports a method for synthesizing D-dihydrophenylglycine methyl ester sulfate from dihydrophenylglycine as raw materials and methanol as the solvent under concentrated sulfuric acid catalysis. However, because the concentrated acid catalysis method produces water, the scheme uses azeotropic dehydration, which is time-consuming and the dehydration effect is not ideal. CN 105348121A reports a method for preparing D-dihydrophenylglycine methyl ester hydrochloride by suspending dihydrophenylglycine in a methanol solution and adding the acyl chloride reagent sulfoxide dropwise. However, due to the use of the acyl chloride reagent, sulfur dioxide gas and hydrogen chloride mixed waste gas are inevitably generated, causing significant environmental impact. CN 118878433A uses hydrogen chloride in methanol solution and D(-)-p-hydroxyphenylglycine as raw materials, adding triphosgene in batches to prepare D(-)-p-hydroxyphenylglycine methyl ester hydrochloride. The hydrogen chloride tail gas from the reaction is absorbed by methanol and recycled as a hydrogen chloride in methanol solution. However, subsequent research by the applicant revealed that the methanol-hydrogen chloride solution is unstable at room temperature and requires absorption at low temperatures, increasing the energy consumption of the absorption system. Furthermore, prolonged storage time leads to an increase in dimethyl ether and water (methanol reacts with hydrogen chloride to produce dimethyl ether and water), which is detrimental to the esterification reaction. To achieve system recycling, water removal is required periodically. Summary of the Invention

[0004] In view of this, this application provides a method for preparing D-dihydrophenylglycine methyl ester hydrochloride, which is not only simple in process and short in preparation cycle, but also allows the hydrogen chloride produced in the reaction to be absorbed by falling film to form hydrochloric acid byproduct, which can be used for subsequent dissolution of crude cefadroxil by enzymatic method, thus solving the storage problem and mixed waste gas problem caused by thionyl chloride.

[0005] Specifically, this application is implemented through the following scheme:

[0006] A method for preparing D-dihydrophenylglycine methyl ester hydrochloride, comprising the following steps:

[0007] Step 1: After deoxygenating the reactor, methanol and D-dihydrophenylglycine are added and stirred to disperse.

[0008] Step 2: Under nitrogen protection and at -5 to 10°C, triphosgene (BTC) is added in batches. After the triphosgene is added, the temperature is raised to 50 to 60°C to carry out the esterification reaction.

[0009] Step 3: When the conversion rate of D-dihydrophenylglycine reaches 96% or more, the esterification reaction ends, and methanol is distilled under reduced pressure to obtain dry solid.

[0010] Step 4: Control the reduced pressure temperature to below 60°C, add solvent to distill the residual methanol, then add solvent again to disperse and cool the solid, and then cool down.

[0011] Step 5: Filtration and vacuum drying to obtain the final product, D-dihydrophenylglycine methyl ester hydrochloride, with a single-pass yield greater than 90%.

[0012] The entire process of steps two, three, and four above is under nitrogen protection.

[0013] Furthermore, as a preferred option:

[0014] In step one,

[0015] The weight ratio of methanol to D-dihydrophenylglycine is 1.0 to 5.0, w / w. More preferably, the weight ratio of methanol to D-dihydrophenylglycine is 2.0.

[0016] In step two,

[0017] The feed equivalent ratio of triphosgene to D-dihydrophenylglycine is 0.30 to 0.50, preferably 0.35.

[0018] The triphosgene is dissolved in dichloromethane, chloroform, toluene, xylene, or tetrahydrofuran and then added dropwise. In step four,

[0019] The solvent added during the double distillation is butyl acetate, dichloromethane, toluene, n-hexane, chloroform, or diethyl ether. More preferably, the solvent added during double distillation is butyl acetate or dichloromethane.

[0020] The solvent added to the dispersion cooling solid is butyl acetate, dichloromethane, toluene, n-hexane, chloroform, or diethyl ether. More preferably, the solvent added to the dispersion cooling solid is butyl acetate or dichloromethane.

[0021] Solid triphosgene (BTC, molecular formula CO(OCCl3), molecular weight 296.75, melting point 81-83℃, also known as trichloromethyl carbonate, CAS: 32315-10-9, white solid crystal) is safer to react when added in batches as an acyl chloride reagent.

[0022] The D-dihydrophenylglycine methyl ester hydrochloride synthesized by the above scheme exhibited high bio-enzyme catalytic efficiency and superior cefadroxil quality in subsequent cefadroxil enzyme synthesis experiments. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 This is a flowchart illustrating the process of this application;

[0025] Figure 2 A diagram showing the synthetic pathway of the side chain (D-dihydrophenylglycine methyl ester) of cefadroxil via enzymatic process;

[0026] Figure 3 This is a typical HPLC chromatogram of D-dihydrophenylglycine methyl ester hydrochloride in Example 5. Detailed Implementation

[0027] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without creative effort are within the scope of protection of this application.

[0028] In the implementation case, triphosgene (BTC) was sourced from Rudong Yichang Chemical Co., Ltd., D-dihydrophenylglycine was sourced from Heilongjiang Taina Technology Group Co., Ltd., and thionyl chloride was sourced from Shandong Kaisheng New Material Co., Ltd.

[0029]

[0030] Example 1

[0031] This embodiment provides a novel method for preparing D-dihydrobenzoic acid methyl ester hydrochloride, specifically as follows: Figure 1 As shown.

[0032] Step 1: After deoxygenating the reactor, add 100g of methanol and 50g of D-dihydrophenylglycine, and stir to disperse. Under nitrogen protection, add 48.46g (0.50 equivalent) of triphosgene (BTC) in 10 portions, and control the temperature at around 0℃.

[0033] Step 2: After the phosgene is added, the temperature is raised to 55°C. After 2 hours of esterification reaction, samples are taken to test D-dihydrophenylglycine. The conversion rate is calculated to be 98.2%, which is qualified. Nitrogen protection is maintained throughout the process.

[0034] Step 3: After the esterification reaction in the reactor is completed, distill the methanol under reduced pressure to dry solid, controlling the reduced pressure temperature below 60°C, and maintain nitrogen protection throughout the process.

[0035] Step 4: Add 50g of butyl acetate to distill the residual methanol. After that, add 100g of butyl acetate to disperse the solid, cool down, and keep the whole process under nitrogen protection.

[0036] Step 5: Filtration, vacuum drying of D-dihydrophenylglycine methyl ester hydrochloride to obtain 61.2 g of dry product, with a molar yield of 92.3%.

[0037] Example 2

[0038] Step 1: After deoxygenating the reactor, add 100g of methanol and 50g of D-dihydrophenylglycine, and stir to disperse. Under nitrogen protection, add 29.08g (0.30 equivalent) of triphosgene (BTC) in 10 portions, and control the temperature at around 0℃.

[0039] Step 2: After the phosgene is added, the temperature is raised to 55°C. After 4 hours of esterification reaction, samples are taken to test D-dihydrophenylglycine. The conversion rate is calculated to be 96.1%, which is qualified. Nitrogen protection is maintained throughout the process.

[0040] Step 3: After the esterification reaction in the reactor is completed, distill the methanol under reduced pressure to dry solid, controlling the reduced pressure temperature below 60°C, and maintain nitrogen protection throughout the process.

[0041] Step 4: Add 50g of butyl acetate to distill the residual methanol. After that, add 100g of butyl acetate to disperse the solid, cool down, and keep the whole process under nitrogen protection.

[0042] Step 5: Filtration, vacuum drying of D-dihydrophenylglycine methyl ester hydrochloride to obtain 60.0 g of dry product, with a molar yield of 90.2%.

[0043] Example 3

[0044] Step 1: After deoxygenating the reactor, add 100g of methanol and 50g of D-dihydrophenylglycine, and stir to disperse. Under nitrogen protection, add 48.46g (0.50 equivalent) of triphosgene (BTC) in 10 portions, and control the temperature at around 0℃.

[0045] Step 2: After the phosgene is added, the temperature is raised to 50°C. After 5 hours of esterification reaction, samples are taken to test D-dihydrophenylglycine. The conversion rate is calculated to be 96.1%, which is qualified. Nitrogen protection is maintained throughout the process.

[0046] Step 3: After the esterification reaction in the reactor is completed, distill the methanol under reduced pressure to dry solid, controlling the reduced pressure temperature below 60°C, and maintain nitrogen protection throughout the process.

[0047] Step 4: Add 50g of butyl acetate to distill the residual methanol. After that, add 100g of butyl acetate to disperse the solid, cool down, and keep the whole process under nitrogen protection.

[0048] Step 5: Filtration, vacuum drying of D-dihydrophenylglycine methyl ester hydrochloride to obtain 59.9 g of dry product, with a molar yield of 90.0%.

[0049] Example 4

[0050] Step 1: After deoxygenating the reactor, add 100g of methanol and 50g of D-dihydrophenylglycine, and stir to disperse. Under nitrogen protection, add 48.46g (0.50 equivalent) of triphosgene (BTC) in 10 portions, and control the temperature at around 0℃.

[0051] Step 2: After the phosgene is added, the temperature is raised to 60℃. After 2 hours of esterification reaction, samples are taken to test D-dihydrophenylglycine. The conversion rate is calculated to be 98.5%, which is qualified. Nitrogen protection is maintained throughout the process.

[0052] Step 3: After the esterification reaction in the reactor is completed, distill the methanol under reduced pressure to dry solid, controlling the reduced pressure temperature below 60°C, and maintain nitrogen protection throughout the process.

[0053] Step 4: Add 50g of butyl acetate to distill the residual methanol. After that, add 100g of butyl acetate to disperse the solid, cool down, and keep the whole process under nitrogen protection.

[0054] Step 5: Filtration, vacuum drying of D-dihydrophenylglycine methyl ester hydrochloride to obtain 62.7 g of dry product, with a molar yield of 94.3%.

[0055] The reaction results of Examples 1 to 4 are shown in Table 1.

[0056] Table 1: Effect of different reaction conditions

[0057]

[0058]

[0059] Table 1 shows that a triphosgene feed equivalent of 0.30–0.50 can achieve a conversion rate of over 96% (calculated based on D-dihydrogen acid), with higher equivalents resulting in higher conversion rates. Esterification temperature also affects reaction time and conversion rate; higher esterification temperatures shorten esterification time and lead to higher conversion rates.

[0060] Taking all factors into consideration, the preferred triphosgene feed amount is 0.30–0.50; the preferred esterification temperature is 50–60°C, with 55°C being the optimal esterification temperature, at which point the molar yield of the product can be guaranteed to be greater than 90%.

[0061] Example 5

[0062] Step 1: After deoxygenating the reactor, add 100g of methanol and 50g of D-dihydrophenylglycine, and stir to disperse. Under nitrogen protection, add 48.46g (0.50 equivalent) of triphosgene (BTC) in 10 portions, and control the temperature at around 0℃.

[0063] Step 2: After the phosgene is added, the temperature is raised to 60℃. After 2 hours of esterification reaction, samples are taken to test D-dihydrophenylglycine. The conversion rate is calculated to be 98.4%, which is qualified. Nitrogen protection is maintained throughout the process.

[0064] Step 3: After the esterification reaction in the reactor is completed, distill the methanol under reduced pressure to dry solid, controlling the reduced pressure temperature below 60°C, and maintain nitrogen protection throughout the process.

[0065] Step 4: Add 50g of dichloromethane to distill the residual methanol. After that, add 100g of dichloromethane to disperse the solid, cool down, and keep the whole process under nitrogen protection.

[0066] Step 5: Filtration, vacuum drying of D-dihydrophenylglycine methyl ester hydrochloride to obtain 62.6 g of dry product, with a molar yield of 94.0%.

[0067] The main difference between Example 5 and Example 4 lies in the different solvents used in step four. The effects of the two examples are shown in Table 2.

[0068] Table 2: Effect of Solvent

[0069] Conversion rate % Product molar yield solvent Example 4 98.5％ 94.3％ Butyl acetate Example 5 98.4％ 94.0％ dichloromethane .

[0070] Table 2 shows that using dichloromethane as the co-distillation solvent for methanol and subsequent dispersion does not significantly differ from using butyl acetate in Example 4 in terms of product molar yield. Butyl acetate is a weakly polar solvent, and D-dihydrophenylglycine methyl ester hydrochloride has very low solubility in butyl acetate solvent, thus improving product yield. Dichloromethane was also used, and low temperature conditions had little effect on the yield. Furthermore, the co-distillation of methanol with butyl acetate and dichloromethane yields excellent results because they form an azeotropic system, and the low temperature further enhances the product yield.

[0071] Other solvents such as toluene, n-hexane, chloroform, and diethyl ether can also ensure yield, but they will not be elaborated on here.

[0072] Comparative Example 1

[0073] The preparation process of this comparative example is as follows:

[0074] Step 1: After deoxygenating the reactor, add 100g of methanol and 50g of D-dihydrophenylglycine, and stir to disperse. Under nitrogen protection, add 46.5g of thionyl chloride dropwise, and control the temperature at 0℃.

[0075] Step 2: After the addition is complete, heat to 60℃ and start sampling to test D-dihydrophenylglycine after 3 hours of esterification reaction. The conversion rate is calculated to be 98.5%, which is qualified. Nitrogen protection is maintained throughout the process.

[0076] Step 3: Add 1.5g of activated charcoal for decolorization, and filter while hot.

[0077] Step 4: Distill methanol under reduced pressure until dry solid, controlling the reduced pressure temperature below 60°C, with nitrogen protection throughout the process.

[0078] Step 5: Add 178g of dimethyl carbonate dispersion solid, cool down, and maintain nitrogen protection throughout the process.

[0079] Step 6: Filtration. Wash the filter cake with 35.5g of dimethyl carbonate to obtain D-dihydrophenylglycine methyl ester hydrochloride, which is then vacuum dried to obtain 62.1g of dry product, with a molar yield of 93.6%.

[0080] Comparative Example 2

[0081] The preparation process of this comparative example is as follows:

[0082] Step 1: After deoxygenating the reactor, add 100g of methanol and 50g of D-dihydrophenylglycine, and stir to disperse. Under nitrogen protection, add 39.14g (1.2 equivalents) of concentrated sulfuric acid dropwise, and control the temperature at 0℃.

[0083] Step 2: After the addition is complete, heat to 60°C and allow the esterification reaction to proceed for 3 hours.

[0084] Step 3: Concentrate under reduced pressure until oily, add 100g of methanol and continue heating to 60℃ for esterification for 3 hours;

[0085] Repeat steps two and three until D-dihydrophenylglycine is sampled and tested. The conversion rate is calculated to be 98.5%. Generally, four iterations are required.

[0086] Qualified, nitrogen protection throughout, total duration approximately 24 hours.

[0087] Step 4: Concentrate methanol under reduced pressure until it becomes oily, add 200g of purified water, stir to disperse, and adjust the pH to 1.0-3.0 with ammonia.

[0088] Step 5: Add 1.5g of activated charcoal for decolorization and filter.

[0089] Step six yields a D-dihydrophenylglycine methyl ester hydrochloride solution, with a molar yield of 91.6% based on D-dihydrophenylglycine methyl ester.

[0090] Table 3: Effects of different acyl chloride reagents on the reaction effect (normalization method)

[0091] D-Dihydrophenylglycine Phenylglycine methyl ester dihydrophenylglycine methyl ester Tetrahydrophenylglycine methyl ester Example 5 3.8％ 4.26％ 89.6％ 1.85％ Comparative Example 1 4.0％ 4.75％ 89.8％ 1.82％ Comparative Example 2 4.0％ 6.5％ 87.1％ 2.0％ .

[0092] Table 3 shows that, compared with the D-dihydrophenylglycine methyl ester hydrochloride prepared by the sulfoxide method in Comparative Example 1, its main quality indicators are basically consistent with those of the triphosgene (BTC) method of this application: the content of D-dihydrophenylglycine is 3.8%, and the yield of dihydrophenylglycine methyl ester can reach 89.6%; the key side reaction impurities are 4.26% phenylglycine methyl ester and 1.85% tetrahydrophenylglycine methyl ester. In Comparative Example 1, the content of D-dihydrophenylglycine is 4.0%, the yield of dihydrophenylglycine methyl ester is 89.8%, and the key side reaction impurities are 4.75% phenylglycine methyl ester and 1.82% tetrahydrophenylglycine methyl ester.

[0093] Compared to the D-dihydrophenylglycine methyl ester prepared by the sulfation method in Comparative Case 2, its main quality indicators are inferior to those of the triphosgene (BTC) method of this application: the content of D-dihydroacid is 4.0%, and the content of dihydrophenylglycine methyl ester is 87.1%; the key side reaction impurities are 4.0% phenylglycine methyl ester and 2.0% tetrahydrophenylglycine methyl ester; due to the oxidizing properties of concentrated sulfuric acid, the content of phenylglycine methyl ester impurities will increase, and the method produces a dihydrophenylglycine methyl ester solution in a one-pot process; it does not have the function of removing key side reaction impurities, especially the quality indicators of tetrahydrocephalosporin, which is strictly controlled downstream.

[0094] Combination Figure 2 Currently, the side chains used in the cefadroxil enzymatic process mainly include sulfation esterification (adding concentrated sulfuric acid and CH3OH) and thionyl chloride esterification (adding thionyl chloride and CH3OH). This application uses the triphosgene method (adding triphosgene and CH3OH). Phenylglycine methyl hydrochloride is produced by the esterification of phenylglycine, an impurity in the starting material D-dihydrophenylglycine; tetrahydrophenylglycine methyl hydrochloride is also produced by the esterification of tetrahydrophenylglycine, an impurity in the starting material D-dihydrophenylglycine, representing a derivatization reaction after the introduction of raw materials. Since both the thionyl chloride method and the BTC method can yield solid dihydrophenylglycine methyl hydrochloride, and the process includes filtration and impurity removal steps, the acyl chloride method significantly shortens the preparation time compared to the concentrated sulfuric acid catalytic method, making it superior to the sulfation esterification method in this regard.

[0095] The exhaust gas composition differs: using thionyl chloride produces a large amount of sulfur dioxide, a strong acid gas, causing severe pollution. In contrast, the exhaust gas generated by this application consists of carbon dioxide and hydrogen chloride. The hydrogen chloride is recovered as a hydrochloric acid byproduct through falling membrane absorption, achieving zero emissions. This is clarified here. Figure 2 By comparing the results, we can illustrate the advantages of this case.

[0096] In summary, the triphosgene (BTC) method is a superior approach for the preparation of cefadroxil enzyme side chains. We were pleasantly surprised to find that the bio-enzyme catalytic efficiency was high in subsequent cefadroxil enzyme synthesis experiments, further demonstrating the advantages of the process route.

[0097] Application examples:

[0098] 1) 7-ADCA 15g, pure water 60g, stir to adjust pH to 7.0, add immobilized penicillin acylase 15g, and control the temperature at 20±1℃.

[0099] 2) Weigh 16.86g (1.10 equivalents, calculated as 7-ADCA) of D-dihydrophenylglycine methyl ester hydrochloride prepared in Case 5, add 25.30g of pure water and stir to dissolve.

[0100] 3) Add the D-dihydrophenylglycine methyl ester hydrochloride solution prepared in 2) dropwise, with the injection pump controlling the time at 180 min and the temperature at 20±1℃; pH 7.0; nitrogen protection throughout the process, starting the timer from the start of the dropwise addition.

[0101] 4) After dripping, start sampling to test for 7-ADCA residue and calculate the 7-ADCA conversion rate. A rate of not less than 98% is acceptable.

[0102] We repeated the experiment three times, with an enzyme reaction time of 240 min, and the conversion rates were 98.5%, 99.1%, and 98.9% respectively, proving the feasibility of the application.

Claims

1. A method for preparing D-dihydrophenylglycine methyl ester hydrochloride, characterized in that, The steps are as follows: Step 1: After deoxygenating the reactor, methanol and D-dihydrophenylglycine are added and stirred to disperse. Step 2: Under nitrogen protection, triphosgene is added in batches at -5~10℃. After the triphosgene is added, the temperature is raised to 50~60℃ to carry out the esterification reaction. Step 3: When the conversion rate of D-dihydrophenylglycine reaches 96% or more, the esterification reaction ends, and methanol is distilled under reduced pressure to obtain dry solid. Step 4: Control the reduced pressure temperature to below 60°C, add solvent to distill the residual methanol, then add solvent again to disperse and cool the solid, and then cool down. Step 5: Filter and vacuum dry to obtain the final product, D-dihydrophenylglycine methyl ester hydrochloride. The entire process of steps two, three, and four above is under nitrogen protection.

2. The method for preparing D-dihydrophenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step one, the weight ratio of methanol to D-dihydrophenylglycine is 1.0 to 5.

0.

3. The method for preparing D-dihydrophenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step two, the feed equivalent ratio of triphosgene to D-dihydrophenylglycine is 0.30~0.

50.

4. The method for preparing D-dihydrophenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step two, triphosgene is dissolved in dichloromethane, chloroform, toluene, xylene, or tetrahydrofuran and then added dropwise.

5. The method for preparing D-dihydrophenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step four, the solvent added during distillation is butyl acetate, dichloromethane, toluene, n-hexane, chloroform, or diethyl ether.

6. The method for preparing D-dihydrophenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step four, the solvent added to disperse the cooled solid is butyl acetate, dichloromethane, toluene, n-hexane, chloroform, or diethyl ether.

7. The method for preparing D-dihydrophenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step four, the solvent added during distillation is butyl acetate or dichloromethane, and the solvent added during dispersion and cooling of the solid is butyl acetate or dichloromethane.

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