Preparation method of L-phenylglycine methyl ester hydrochloride

Abstract

The invention provides a preparation method of L-phenylglycine methyl ester hydrochloride, and belongs to the technical field of pharmaceutical chemicals. The preparation method comprises the following steps: deoxidizing a reactor, adding methanol and L-phenylglycine, adding triphosgene in batches at the temperature of-5 to 10 DEG C, and heating to 60 to 70 DEG C for esterification reaction after the triphosgene is completely fed; when it is detected that the purity content of the L-phenylglycine methyl ester hydrochloride is 95% or above, the obtained L-phenylglycine methyl ester hydrochloride mother liquor is concentrated under reduced pressure to be dry; and adding pure water for dissolving, adjusting the pH value to 1.0-3.0, adjusting the temperature to below 20 DEG C, decolorizing, degassing and filtering to obtain an aqueous solution of the L-phenylglycine methyl ester hydrochloride. Compared with a thionyl chloride method for preparation, the method has remarkable advantages in the aspects of production storage, waste gas treatment and the like, the production cycle can be greatly shortened compared with a sulfuric acid method, and the method can be directly used for side chain enzymatic synthesis of beta-lactam antibiotics such as ampicillin, cefalexin and cefaclor.

Description

TECHNICAL FIELD

[0001] The application relates to a preparation method of levoglycyl methyl ester hydrochloride, and belongs to the technical field of medicines and chemical industry. BACKGROUND

[0002] Levoglycyl methyl ester hydrochloride (PGM . HCl) is an enzyme-synthesized side chain of ampicillin, cefalexin and cefaclor, etc. β-lactam antibiotics, has a wide range of uses, a large market demand, and is currently mainly prepared by a dichlorosulfur method, a hydrogen chloride catalysis method, etc.

[0003] CN 101277927A reports a method for synthesizing levoglycyl methyl ester hydrochloride, which comprises the following steps: taking levoglycyl as raw material, passing dry hydrogen chloride into a suspension of methanol and levoglycyl to synthesize levoglycyl hydrochloride, and continuously passing in excess of treated hydrogen chloride to catalyze esterification to synthesize levoglycyl methyl ester hydrochloride. The preparation of hydrogen chloride is complicated and difficult to control. Excess hydrogen chloride will react with methanol to form chloromethane, dimethyl ether and water, etc. by-products impurities, affecting the esterification effect.

[0004] In industry, levoglycyl methyl ester hydrochloride is usually prepared by taking dichlorosulfur as an acyl chloride reagent, dispersing levoglycyl in a methanol solution, adding dichlorosulfur for esterification, and obtaining levoglycyl methyl ester hydrochloride. Because dichlorosulfur is a liquid material, the production, use and storage are risky, and the waste gas generated in the reaction is a mixed gas of sulfur dioxide and hydrochloric acid, which must be treated as a mixed waste salt, and the environmental protection pressure is large.

[0005] CN 118878433A uses hydrogen chloride methanol solution and D(-) p-hydroxyphenylglycine as raw materials, and adds triphosgene in batches to prepare D(-) p-hydroxyphenylglycine methyl ester hydrochloride. The applicant found in subsequent research that the methanol hydrogen chloride solution is unstable at room temperature and needs to be absorbed at low temperature, which increases the energy consumption of the absorption system. And once the storage time is prolonged, the increase of dimethyl ether and water (methanol and hydrogen chloride react to generate dimethyl ether and water) is not conducive to the esterification reaction. To realize system circulation, water needs to be removed in a certain period. SUMMARY

[0006] Therefore, the application provides a preparation method of levoglycyl methyl ester hydrochloride, which takes levoglycyl as raw material and methanol as solvent. The method has simple process, short preparation period compared with the preparation of D-phenylglycine methyl sulfate, and the prepared D-phenylglycine methyl ester hydrochloride is directly used in the subsequent enzyme synthesis of β-lactam antibiotics. The hydrogen chloride generated in the reaction can also be absorbed by falling film to form hydrochloric acid by-product, which is used in the production process to realize material utilization.

[0007] Specifically, the application is realized by the following scheme:

[0008] A preparation method of a levoglycine methyl ester hydrochloride aqueous solution, steps as follows:

[0009] Step one, after the reactor is deoxygenated, methanol and levoglycine are added, and stirred and dispersed;

[0010] Step two, the temperature is controlled at -5-10℃, and solid triphosgene (BTC) is slowly added in batches;

[0011] Step three, after the triphosgene is completely added, the temperature is raised to 60-70℃, the esterification reaction is carried out for 4-6h, when the content of levoglycine methyl ester hydrochloride is detected to be not less than 95%, the esterification reaction is ended, and the methanol is distilled under reduced pressure until dry solid is obtained, and the reduced pressure temperature is controlled to be below 60℃;

[0012] Step four, pure water is added, stirred and dissolved, the pH is adjusted to 1.0-3.0, the temperature is adjusted to below 20℃, decolorization and degassing are carried out, and filtration is carried out, to obtain a levoglycine methyl ester hydrochloride aqueous solution which can be directly used for the enzymatic synthesis of a side chain of a β-lactam antibiotic.

[0013] Further, as preferred:

[0014] In step one,

[0015] The weight ratio of the methanol to levoglycine is 3.0-9.0 (w / w). More preferably, the weight ratio of the methanol to levoglycine is 5.0 (w / w).

[0016] In step two,

[0017] The equivalent ratio of the triphosgene to levoglycine is 0.30-0.40.

[0018] The triphosgene can be added in batches, or dissolved in dichloromethane, chloroform, tetrahydrofuran and then added dropwise, and is preferably added in batches.

[0019] In step three, the temperature is raised to 64℃ for esterification reaction.

[0020] In step four,

[0021] The pH is adjusted by using ammonia water, sodium hydroxide, sodium carbonate or sodium bicarbonate.

[0022] The decolorization and degassing are achieved by adding activated carbon.

[0023] The β-lactam antibiotic is any one of ampicillin, cefalexin and cefaclor.

[0024] In the above scheme, the triphosgene is replaced by diphosgene or oxalyl chloride. 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 when used as an acyl chloride reagent in batches.

[0025] In the above preparation process, only methanol as a single solvent can be recycled and reused. The synthesized aqueous solution of L-phenylglycine methyl ester hydrochloride can be directly used for the enzymatic synthesis of the side chain of ampicillin, cefalexin, cefaclor and other β-lactam antibiotics. Compared with the preparation method of thionyl chloride, it has obvious advantages in production and storage, waste gas treatment and other aspects; compared with the sulfuric acid method, the production cycle can be greatly shortened, the biocatalytic efficiency is high, and the quality of ampicillin, cefalexin and cefaclor is excellent. BRIEF DESCRIPTION OF DRAWINGS

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0027] Figure 1 The flowchart of the present application;

[0028] Figure 2 The control diagram of the synthesis of L-phenylglycine methyl ester hydrochloride by the present application and the thionyl chloride method;

[0029] Figure 3 The HPLC typical spectrum of L-phenylglycine methyl ester hydrochloride in Example 3;

[0030] Figure 4 The route diagram of the direct method of L-phenylglycine methyl ester hydrochloride obtained by the present application for the enzymatic synthesis of ampicillin;

[0031] Figure 5 The route diagram of the direct method of L-phenylglycine methyl ester hydrochloride obtained by the present application for the enzymatic synthesis of cefalexin;

[0032] Figure 6 The route diagram of the direct method of L-phenylglycine methyl ester hydrochloride obtained by the present application for the enzymatic synthesis of cefaclor;

[0033] Figure 7 The process flowchart of preparing hydrochloric acid by recycling hydrogen chloride from L-phenylglycine methyl ester hydrochloride obtained by the present application,

[0034] 1. Absorption liquid circulating tank 1; 2. First-stage circulating pump; 3. First-stage falling film absorber; 4. Absorption liquid circulating tank 2; 5. Second-stage circulating pump; 6. Second-stage falling film absorber; 7. Absorption liquid circulating tank 3; 8. Third-stage circulating pump; 9. Third-stage falling film absorber. DETAILED DESCRIPTION

[0035] In order to make the technical problems, technical solutions and beneficial effects of the present application clearer, the technical solutions in the embodiments of the present application will be further described in detail below with reference to the drawings in the embodiments of the present application. It should be understood that the specific embodiments described herein are only used to explain the present application and not used to limit the technical solutions of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0036] In the implementation case, the triphosgene (BTC) is from Ruiyichang Chemical Co., Ltd. and the levorotatory benzeneglycine is from Zhejiang Yuntao Biotechnology Co., Ltd.

[0037] Example 1

[0038] The present embodiment provides a new method for preparing an aqueous solution of levorotatory benzeneglycine methyl ester hydrochloride, and the flow chart is as shown in Figure 1

[0039] Step 1: After the reactor is deoxygenated, 168.3 g of methanol (w / w; 3.0), 56.1 g of levorotatory benzeneglycine, is added and stirred and dispersed; 33.03 g of triphosgene (BTC) (0.30 equivalent) is added in 10 times, the time is about 60 min, and the temperature is controlled at about 0℃.

[0040] Step 2: After the triphosgene is added, the temperature is increased to 64℃, the esterification reaction is started for 3 h, the content of levorotatory benzeneglycine hydrochloride is detected, and the content is calculated by area normalization method to be not less than 95%, which is qualified.

[0041] Step 3: After the esterification reaction in the reactor is completed, the methanol is distilled under reduced pressure until dry solid, and the reduced pressure temperature is controlled to be below 60℃.

[0042] Step 4: After pure water is added and stirred and dissolved, the pH is adjusted to 2.0 with ammonia water, 1 g of activated carbon is added, and the decolorization and degassing is performed for more than 60 min.

[0043] Step 5: Filtration is performed to obtain an aqueous solution of levorotatory benzeneglycine methyl ester hydrochloride.

[0044] Example 2

[0045] ​Step one, after the reactor deoxidation, add methanol 168.3g(w / w; 3.0), L-phenylglycine 56.1g, stirring dispersion; add triphosgene (BTC) 44.05g (0.40 equivalent) in 10 times, the temperature control near 0℃, time about 60min.

[0046] Step two, after the triphosgene is added, the temperature is raised to 64℃, and the esterification reaction is started for 3h. The content of L-phenylglycine hydrochloride is detected by area normalization method, and the content is not less than 95%, which is qualified.

[0047] Step three, after the esterification reaction in the reactor is completed, the methanol is distilled to dry solid under reduced pressure, and the reduced pressure temperature is controlled below 60℃.

[0048] Step four, add pure water, stir and dissolve, then adjust the pH to 2.0 with ammonia water, add 1g of activated carbon, and decolorize and degas for more than 60min.

[0049] Step five, filter, get L-phenylglycine methyl ester hydrochloride aqueous solution.

[0050] Example 3

[0051] Step one, after the reactor deoxidation, add methanol 168.3g(w / w; 3.0), L-phenylglycine 56.1g, stirring dispersion; add triphosgene (BTC) 44.05g (0.40 equivalent) in 10 times, the temperature control near 0℃, time about 60min.

[0052] Step two, after the triphosgene is added, the temperature is raised to 64℃, and the esterification reaction is started for 3h. The content of L-phenylglycine hydrochloride is detected by area normalization method, and the content is not less than 95%, which is qualified.

[0053] Step three, after the esterification reaction in the reactor is completed, the methanol is distilled to dry solid under reduced pressure, and the reduced pressure temperature is controlled below 60℃.

[0054] Step four, add pure water, stir and dissolve, then adjust the pH to 2.0 with ammonia water, add 1g of activated carbon, and decolorize and degas for more than 60min.

[0055] Step five, filter, get L-phenylglycine methyl ester hydrochloride aqueous solution.

[0056] Example 4

[0057] Step one, after the reactor deoxidation, add methanol 168.3g(w / w; 3.0), L-phenylglycine 56.1g, stirring dispersion; add triphosgene (BTC) 44.05g (0.40 equivalent) in 10 times, the temperature control near 0℃, time about 60min.

[0058] Step two, after the completion of the addition of the triphosgene, the temperature was raised to 64°C, and the esterification reaction was allowed to proceed for 3 hours. The sample was then taken for the determination of the content of the L-phenylglycine hydrochloride. The content was calculated by the area normalization method, and the content was not less than 95%, which was qualified.

[0059] Step three, after the completion of the esterification reaction in the reactor, the methanol was distilled under reduced pressure until the solid was dry. The temperature was controlled to be below 60°C, and the whole process was protected by nitrogen.

[0060] Step four, after the addition of pure water and the stirring and dissolution, the pH was adjusted to 2.0 by using ammonia water. Then, 1 g of activated carbon was added, and the decolorization and degassing were carried out for more than 60 minutes.

[0061] Step five, filtration was carried out to obtain the aqueous solution of the L-phenylglycine methyl ester hydrochloride.

[0062] The reaction results of Examples 1 to 4 are shown in Table 1.

[0063] Table 1: Influence of different feeding ratios

[0064] BTC charge amount Methanol amount (w / w) L-phenylglycine methyl ester hydrochloride content Example 1 0.30 equivalents 3 95.51％ Example 2 0.40 equivalents 3 95.60％ Example 3 0.50 equivalents 5 96.21％ Example 4 0.30 equivalents 9 96.33％ .

[0065] The results in Table 1 show that:

[0066] Under the same reaction conditions (esterification temperature 64°C, esterification time 240 minutes), the triphosgene feeding equivalent of 0.30 to 0.50 can meet the content of more than 95% of the L-phenylglycine methyl ester hydrochloride. The higher the equivalent, the higher the conversion rate, but it is not obvious. The excessive triphosgene will increase the pressure of the post-treatment, and therefore, the triphosgene feeding equivalent of 0.30 to 0.50 is preferred.

[0067] The amount of methanol feeding also has an influence on the esterification reaction. The content of the L-phenylglycine methyl ester hydrochloride increases with the increase of the amount of methanol feeding, but the content of the L-phenylglycine methyl ester hydrochloride does not increase significantly when the amount of methanol feeding is 5 times the weight or 9 times the weight. Therefore, the amount of methanol feeding is preferably 5 times the weight.

[0068] The applicant also made the implementation cases of the esterification conditions. Considering the boiling point of methanol, the esterification temperature is preferably controlled to be 64°C.

[0069] The degassing in the decolorization process is helpful to remove the potential chloromethane, dimethyl ether and other low-boiling-point impurities, which is helpful to the next step of the enzyme synthesis application.

[0070] The following is represented by Example 3 (the spectrum comparison of the raw material and the product is shown in Figure 3 ), and the application examples are described.

[0071] Application Example 1

[0072] The application example uses the water solution of L-phenylglycine methyl ester hydrochloride obtained in Example 3 directly for the synthesis of ampicillin by the straight-through method, and the route is shown in Figure 4 .

[0073] 1) 6-APA 20g, add pure water 80g, cool to below 10°C (but not lower than 5°C), and adjust pH to 7.5 with ammonia water.

[0074] 2) Put immobilized penicillin acylase (PGA) 24g and pure water 80g into the reaction bottle.

[0075] 3) At the same time, drop the 6-APA solution prepared in step 2) and the water solution of L-phenylglycine methyl ester hydrochloride prepared in Example 3, and maintain pH at about 7.0 and temperature at about 10°C.

[0076] 4) After 90 minutes of reaction, take samples for detection of 6-APA residue, and control the conversion rate of 6-APA to be more than 98%, which is qualified.

[0077] We continuously repeated 3 batches of reactions, and the reaction time was 180 minutes. The conversion rates of 6-APA were 98.6%, 99.1%, and 98.9%, which met the control standard. The molar ratio of L-phenylglycine to 6-APA was 1.13, which proved the feasibility of the application.

[0078] The obtained enzyme reaction liquid (ampicillin crude product and enzyme) was separated to obtain ampicillin crude product slurry. After dissolution with new hydrochloric acid or falling film absorption of hydrochloric acid, filtration, and crystallization with ammonia water, ampicillin wet product was obtained, and the finished product was obtained after drying.

[0079] The detection results are shown in Table 2.

[0080] Table 2: Control table of finished products of different batches

[0081]

[0082] From the quality analysis of the three batches of finished products, the product quality obtained by this route is better than the pharmacopoeia standard, and the product quality of ampicillin obtained by using new hydrochloric acid and falling film absorption of hydrochloric acid is basically the same.

[0083] Application Example 2

[0084] The application example uses the water solution of L-phenylglycine methyl ester hydrochloride obtained in Example 3 directly for the synthesis of ampicillin by the straight-through method, and the route is shown in Figure 5 .

[0085] 1) 7-ADCA 20g, add pure water 80g, cool to about 15°C, and adjust pH to 7.0 with ammonia water.

[0086] 2) Put in immobilized penicillin acylase (PGA) 24 g.

[0087] 3) Drop in the aqueous solution of L-phenylglycine methyl ester hydrochloride prepared in Example 3, maintain pH about 7.0, temperature about 15°C.

[0088] 4) Start sampling to detect 7-ADCA residue after 360 min reaction, control 7-ADCA conversion rate above 98%, qualified.

[0089] We continuously repeated 3 batches of reaction, reaction time 240 min, 7-ADCA conversion rate 98.3%, 98.6%, 99.1%, in line with control standards, calculated with L-phenylglycine, molar ratio with 7-ADCA 1.12, proved the feasibility of application.

[0090] Separate the obtained enzyme reaction liquid (cephalexin crude product and enzyme), obtain cephalexin crude product slurry, dissolve with new hydrochloric acid or falling film absorption of hydrochloric acid, filter, then crystallize with ammonia water, obtain cephalexin wet product, wash and dry to obtain finished product. Test it, the results are shown in Table 3.

[0091] Table 3: Control table of different batches of finished products

[0092]

[0093]

[0094] From the quality analysis of three batches of finished products, the product quality obtained by this route is better than the pharmacopoeia standard, and the quality of cephalexin obtained by using new hydrochloric acid and falling film absorption of hydrochloric acid is basically the same.

[0095] Application Example 3

[0096] This application example uses the aqueous solution of L-phenylglycine methyl ester hydrochloride obtained in Example 3 directly for the synthesis of cefaclor, the route is shown in Figure 6 .

[0097] 1) 7-ACCA 20 g, add pure water 80 g, cool to 15°C, adjust pH to 7.0 with ammonia water.

[0098] 2) Put in immobilized penicillin acylase (PGA) 24 g.

[0099] 3) Drop in the aqueous solution of L-phenylglycine methyl ester hydrochloride prepared in Example 3, maintain pH 7.0, temperature about 15°C.

[0100] 4) Start sampling to detect 7-ACCA residue after 360 min reaction, control 7-ACCA conversion rate above 98%, qualified.

[0101] We repeated the reaction three times consecutively, with a reaction time of 360 min. The conversion rates of 7-ACCA were 98.5%, 99.6%, and 99.0%, respectively, which met the control standards. The molar ratio of L-phenylglycine to 7-ACCA was 1.18, which proved the feasibility of the application.

[0102] The obtained enzyme reaction solution (crude cefaclor and enzyme) was separated to obtain a crude cefaclor slurry. This slurry was dissolved in fresh hydrochloric acid or by falling membrane absorption, filtered, and then crystallized with ammonia to obtain a wet cefaclor product. After washing and drying, the final product was obtained. The results of the tests are shown in Table 4.

[0103] Table 4: Comparison of Finished Products from Different Batches

[0104]

[0105] Analysis of the quality of three batches of finished products showed that the product quality obtained by this route was better than the pharmacopoeia standard, and the quality of cefaclor obtained by using new hydrochloric acid and by absorbing hydrochloric acid through the membrane was basically the same.

[0106] Triphosgene is easier to store and manage compared to other products. Figure 2 As can be seen from the thionyl chloride route, this application can effectively avoid the drawbacks of producing mixed tail gas of sulfur dioxide and hydrogen chloride when using thionyl chloride; the hydrogen chloride produced by the use of triphosgene can be absorbed by a membrane as a hydrochloric acid byproduct with high purity, which can be used for subsequent crude product purification and dissolution. The hydrogen chloride absorption system in the tail gas is as follows: Figure 7 As shown.

[0107] according to Figure 7 In the process flow of L-phenylglycine methyl ester hydrochloride preparation, hydrochloric acid (hydrogen chloride) is generated as a byproduct during the esterification reaction and vacuum concentration steps. The methanol concentration in the exhaust gas is reduced by setting up a two-stage condenser (7°C ± 20°C) before the pump and a three-stage condenser (two stages of 7°C water ± 20°C condensation) after the pump. The exhaust gas from the workshop is then subjected to a three-stage falling film absorption process for hydrochloric acid (including circulating cooling). Figure 7 The device (3-stage falling film absorber, 6-stage falling film absorber, and 9-stage falling film absorber) produces 20% hydrochloric acid as a byproduct. The concentration of hydrochloric acid can reach 20% or even higher, which is used for subsequent crude product dissolution.

[0108] The above embodiments confirm that the triphosgene (BTC) method provided in this application is a superior new technology applied to the preparation of L-phenylglycine methyl ester hydrochloride and the corresponding aqueous solution. The resulting aqueous solution can be used directly for the side chains of β-lactam antibiotics such as ampicillin, cephalexin, and cefaclor.

[0109] The above-described embodiments only express several possible implementation manners of the present application, the description is relatively specific and detailed, but it cannot be understood as the limitation of the patent scope of the present application, and the embodiments are not used to limit the protection scope in the claims of the present application. For ordinary skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, and any equivalent implementation or change made without departing from the present application shall be included in the present application.

Claims

1. A method for preparing an aqueous solution of L-phenylglycine methyl ester hydrochloride, characterized in that, The steps are as follows: Step 1: After deoxygenating the reactor, methanol and L-phenylglycine are added and stirred to disperse. Step 2: Control the temperature at -5~10℃ and add triphosgene in batches; Step 3: After the phosgene is fed in, raise the temperature to 60~70℃ and carry out the esterification reaction for 4~6 hours. When the content of L-phenylglycine methyl ester hydrochloride is not less than 95%, the esterification reaction ends. Distill methanol under reduced pressure to obtain dry solid, and control the reduced pressure temperature to below 60℃. Step 4: Add pure water and stir to dissolve, adjust pH to 1.0~3.0 and temperature to below 20℃, decolorize and degas, filter, and obtain an aqueous solution of L-phenylglycine methyl ester hydrochloride, which can be directly used for the enzymatic synthesis of the side chain of β-lactam antibiotics.

2. The method for preparing an aqueous solution of L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step one, the weight ratio of methanol to L-phenylglycine is 3.0 to 9.

0.

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

50.

4. The method for preparing an aqueous solution of L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step two, triphosgene is dissolved in dichloromethane, chloroform, or tetrahydrofuran and then added dropwise.

5. The method for preparing an aqueous solution of L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step four, the pH is adjusted using ammonia, sodium hydroxide, sodium carbonate, or sodium bicarbonate.

6. The method for preparing an aqueous solution of L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step four, activated carbon is added for decolorization and degassing.

7. The method for preparing an aqueous solution of L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In step four, the β-lactam antibiotic is any one of ampicillin, cephalexin, or cefaclor.

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