Production method of L-phenylglycine methyl ester hydrochloride

Abstract

The invention relates to the technical field of chemical production, and discloses a production method of L-phenylglycine methyl ester hydrochloride, which comprises the following steps: adding absolute methanol into an esterification kettle; introducing hydrogen chloride gas; l-phenylglycine is added into the mixture; preheating the dissolving solution to 67 DEG C and carrying out esterification reaction; concentrating under reduced pressure after the esterification reaction is complete; centrifugally separating the product; and discharging, packaging and warehousing, adopting hydrogen chloride gas, introducing the hydrogen chloride gas into hydrochloric acid containing red phosphorus or phosphorous acid, reducing to remove chlorine, cooling to remove organic matters, finally drying by concentrated sulfuric acid to obtain high-purity hydrogen chloride gas, and introducing the high-purity hydrogen chloride gas into the L-phenylglycine methanol suspension to form the L-phenylglycine hydrochloride. The preparation method comprises the following steps: firstly, taking L-phenylglycine as a raw material, heating and refluxing, esterifying and dehydrating with methanol under the catalysis of excessive hydrogen chloride to obtain L-phenylglycine methyl ester hydrochloride, dehydrating water-containing methanol generated by esterification through a continuous fractionating tower, and then recycling, thereby realizing environment-friendly and economic production of L-phenylglycine methyl ester hydrochloride.

Description

Technical Field

[0001] The invention relates to the technical field of chemical production, in particular to a method for producing L-phenylglycine methyl ester hydrochloride. Background Art

[0002] L-phenylglycine methyl ester hydrochloride is the raw material for the enzymatic synthesis of cephalexin and ampicillin. It is usually prepared by reacting L-phenylglycine with an acyl chlorinating agent to form an acyl chloride or a mixed anhydride, and then esterifying with methanol, such as: The thionyl chloride method has a high yield, but produces waste sulfur dioxide, which is difficult to handle and has environmental problems. The reaction formula is as follows: RCOOH +SOCl2 → RCOCl + HCl + SO2 RCOCl +CH3OH → RCOOC2 + HCl Acetyl chloride is used as an acyl chloride agent; the method using acetyl chloride as an acyl chloride agent has a high yield and is more environmentally friendly than the thionyl chloride method, but acetic acid must be recovered, which may contaminate the product. The reaction formula is as follows: RCOOH + AcCl2 → RCOOAc + HCl RCOOAc +CH3OH → RCOOCH2 + AcOH In view of this, we proposed a method for producing L-phenylglycine methyl ester hydrochloride. Summary of the invention

[0003] The object of the present invention is to provide a method for producing L-phenylglycine methyl ester hydrochloride to solve the problems raised in the above background technology.

[0004] To achieve the above object, the present invention provides the following technical solution: a method for producing L-phenylglycine methyl ester hydrochloride, the chemical reaction formula is:

[0005] The method comprises the following steps: S1. Add 5-10 times the equivalent of L-phenylglycine to an esterification reactor with anhydrous methanol; S2, introducing 1.0-1.1 equivalents of dried and purified hydrogen chloride gas of L-phenylglycine to make the concentration of hydrogen chloride in methanol 8-15%. Too much hydrogen chloride will cause waste, so the present invention adopts 1.05-1.1 equivalents; S3, adding 1 equivalent of L-phenylglycine, stirring to form a salt ester to dissolve, and obtaining a solution; S4, preheating the dissolved liquid to 67°C, pumping it into the top distributor of the esterification tower, reflux downward, and passing 68-75°C methanol steam through the tower kettle, and keeping the tower body at 68-72°C, so as to ensure that the methanol superheated steam takes away the water produced by esterification, so that the esterification is complete, and monitoring the endpoint by HPLC; S5, after the esterification reaction is complete, the mixture is concentrated under reduced pressure until crystals are precipitated, and then transferred to a crystallization kettle and slowly cooled for crystallization for 2 hours; S6, centrifuge the product, wash with a small amount of methanol, crush it, and dry it in a glass-lined vacuum dryer at 70°C until it reaches a constant weight; S7, unpack and package the prepared products for storage.

[0006] Optionally, in S2, the hydrogen chloride gas is subjected to temperature control treatment, and the treatment condition of the temperature control treatment is a temperature < 40 degrees Celsius.

[0007] Optionally, the methanol vapor equivalent in S4 is 20-25.

[0008] Optionally, the monitoring result in S4 is: free L-phenylglycine content ≤ 0.6%, and the monitoring method of the HPLC monitoring endpoint is: C18 column, UV detector, wavelength 220NM, eluent flow rate 1.0ML / M, injection volume 20 microliters.

[0009] Optionally, the ambient temperature of the crystallization in S5 is 10 degrees Celsius.

[0010] Optionally, the constant weight treatment time in S6 is 8-12 hours.

[0011] Compared with the prior art, the present invention provides a method for producing L-phenylglycine methyl ester hydrochloride, which has the following beneficial effects: The method for producing L-phenylglycine methyl ester hydrochloride adopts hydrogen chloride gas, passes hydrogen chloride gas into hydrochloric acid containing red phosphorus or phosphorous acid, reduces and removes chlorine, then removes organic matter by ice cooling, and finally dries with concentrated sulfuric acid to obtain high-purity hydrogen chloride gas, which is passed into a suspension of L-phenylglycine methanol to form L-phenylglycine hydrochloride. The temperature is raised and refluxed, and esterification and dehydration with methanol are carried out under the catalysis of excess hydrogen chloride to obtain L-phenylglycine methyl ester hydrochloride, and the water produced by esterification is removed by adding excess methanol superheated steam (75 degrees Celsius) to complete the reaction. The water-containing methanol produced by esterification is dehydrated by a continuous distillation tower and then reused, thereby realizing both environmentally friendly and economical production of L-phenylglycine methyl ester hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 It is a schematic diagram of the process of the present invention; Figure 2 It is a reaction schematic diagram of the present invention. DETAILED DESCRIPTION

[0013] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments 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 creative work are within the scope of protection of the present invention. Example

[0014] like Figure 1-Figure 2 As shown, the present invention provides a technical solution: a method for producing L-phenylglycine methyl ester hydrochloride, the method comprising the following steps: In 10m 3 Add 1600 kg (5 equivalents) of anhydrous methanol to a glass-lined esterification reactor, stir and control the temperature (<40°C), introduce 383 kg (1.05 equivalents) of pure hydrogen chloride gas (10.5 Kmole) through a bubbler, then add 1510 kg (10 Kmole) of 1 equivalent of L-phenylglycine bag by bag, heat and reflux for 1 hour to partially esterify and dissolve it, control the temperature at 70-80°C, and keep warm for processing.

[0015] The esterification tower top distributor (Dn800×16000 glass-lined tower body, ceramic corrugated packing) is continuously pumped into the tower bottom (5m 3 ) 68-70℃ methanol superheated steam is introduced into the tower at 600kg / h, and the methanol steam containing water is discharged from the top of the tower directly into the methanol distillation tower 1 / 3 away from the bottom of the tower, and the anhydrous methanol steam is distilled out and preheated to 68-70℃, and then returned to the esterification tower kettle, thereby achieving continuous esterification and dehydration. After all esterification, transfer to the concentration kettle, reduce pressure and concentrate until crystals are precipitated, and transfer to the crystallization kettle. Stir and slowly cool down to crystallize, keep warm at 10℃ for crystallization for 2 hours, centrifuge, wash each centrifuge with 50 liters of anhydrous methanol, spin dry, crush the material into a rotary vacuum dryer, dry at 70℃ 0.09MPa vacuum for 10 hours, cool to 30℃, fill with nitrogen to vent the vacuum and discharge, and obtain 1916kg of L-phenylglycine methyl ester hydrochloride, with a yield of 95.02% and a content of 99.15 (HPLC). Example

[0016] A method for producing L-phenylglycine methyl ester hydrochloride, the method comprising the following steps: In 10m 31600 kg of anhydrous methanol was added to a glass-lined esterification kettle, and the temperature was controlled by stirring (<40°C). 401 kg of pure hydrogen chloride gas (11.0 kmole) was introduced through a bubbler, and then 1510 kg (10 Kmole) of L-phenylglycine was added bag by bag. The kettle temperature was controlled at 78-85°C, and the gas phase temperature was controlled at 68-70°C. Methanol was added dropwise while distilling. The amount of methanol added was 9000 kg, and 9180 kg of methanol was distilled out. The end point was measured by sampling. The residual L-phenylglycine content was <0.6%. Reduced pressure distillation was performed, and the vacuum was controlled at 0.08 MPa. The kettle was distilled until crystals precipitated. The kettle was transferred to a crystallization kettle and the temperature was lowered for crystallization. The mixture was stirred and slowly cooled to crystallize, and kept at 10°C for 2 hours. The mixture was centrifuged and washed with 50 liters of anhydrous methanol per centrifuge. After drying, the material was crushed and put into a rotary double cone vacuum dryer, and dried at 70°C and 0.09 MPa for 8 hours. The temperature was lowered to 30°C, and the vacuum was discharged after nitrogen was filled to obtain 1906 kg of L-phenylglycine methyl ester hydrochloride, with a yield of 94.82% and a content of 99.20% (HPLC).

[0017] Compared with Example 1, Example 2 saves 50% energy. Example

[0018] On the basis of Example 2, the initial amount of methanol was increased to 2240 kg (7 times equivalents, and other operations remained unchanged. As a result, 1907 kg of L-phenylglycine methyl ester hydrochloride was obtained with a yield of 94.88% and a content of 94.89%.

[0019] In summary, the present invention uses hydrogen chloride gas, passes hydrogen chloride gas into hydrochloric acid containing red phosphorus or phosphorous acid, reduces and removes chlorine, then removes organic matter by ice cooling, and finally dries with concentrated sulfuric acid to obtain high-purity hydrogen chloride gas, which is passed into a suspension of L-phenylglycine methanol to form L-phenylglycine hydrochloride. The temperature is raised and refluxed, and esterification and dehydration with methanol under the catalysis of excess hydrogen chloride are performed to obtain L-phenylglycine methyl ester hydrochloride, and the water produced by esterification is removed by adding excess methanol superheated steam to complete the reaction. The water-containing methanol produced by esterification is reused after dehydration in a continuous fractionation tower, thereby realizing both environmentally friendly and economical production of L-phenylglycine methyl ester hydrochloride.

[0020] The above generally describes the present invention in detail, but it is obvious to a person skilled in the art that some modifications or improvements can be made to the present invention. Therefore, modifications or improvements that do not depart from the spirit of the present invention are within the scope of protection of the present invention.

Claims

1. A method for producing L-phenylglycine methyl ester hydrochloride, characterized in that: The method comprises the following steps: S1. Add 5-10 times the equivalent of L-phenylglycine to an esterification reactor with anhydrous methanol; S2, introducing 1.0-1.1 equivalents of dried and purified hydrogen chloride gas of L-phenylglycine to make the concentration of hydrogen chloride in methanol 8-15%; S3, adding 1 equivalent of L-phenylglycine, stirring to form a salt ester to dissolve, and obtaining a solution; S4, preheating the dissolved liquid to 67°C, pumping it into the top distributor of the esterification tower, reflux downward, and passing 68-75°C methanol steam through the tower kettle, and keeping the tower body at 68-72°C. The superheated alcohol steam takes away the water produced by esterification, so that the esterification is complete, and the endpoint is monitored by HPLC; S5, after the esterification reaction is complete, the mixture is concentrated under reduced pressure until crystals are precipitated, and then transferred to a crystallization kettle and slowly cooled for crystallization for 2 hours; S6, centrifuge the product, wash with a small amount of methanol, crush it, and dry it in a glass-lined vacuum dryer at 70°C to constant weight; S7, unload materials, pack and store them.

2. A method for producing L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: In S2, the hydrogen chloride gas is subjected to temperature control treatment, and the treatment condition of the temperature control treatment is a temperature < 40 degrees Celsius.

3. A method for producing L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: The methanol vapor equivalent in S4 is 20-25.

4. A method for producing L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: The monitoring result in S4 is: the content of free L-phenylglycine is ≤0.6%, and the monitoring method of the HPLC monitoring endpoint is: C18 column, UV detector, wavelength 220NM, eluent flow rate 1.0ML / M, injection volume 20 microliters.

5. A method for producing L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: The ambient temperature of the crystallization in S5 is 10 degrees Celsius.

6. A method for producing L-phenylglycine methyl ester hydrochloride according to claim 1, characterized in that: The constant weight treatment time in S6 is 8-12 hours.

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