Production method of L-p-hydroxyphenylglycine methyl ester

Abstract

The invention relates to the technical field of chemical production, and discloses a production method of L-p-hydroxyphenylglycine methyl ester.The production method comprises the following steps that absolute methanol is added into an esterification kettle; introducing dried and purified hydrogen chloride gas; l-p-hydroxyphenylglycine is added into the mixture; carrying out temperature control treatment on the esterification kettle and then carrying out esterification dehydration; adding deionized water and a small amount of seed crystal, and carrying out cooling treatment; carrying out spin-drying and crushing treatment after centrifugal separation; according to the production method of the L-p-hydroxyphenylglycine methyl ester, the chlorinated paraffin byproduct hydrogen chloride is used as an acid catalysis and reaction agent, the L-p-hydroxyphenylglycine and methanol are esterified to form L-p-hydroxyphenylglycine methyl ester hydrochloride, then the free L-p-hydroxyphenylglycine methyl ester is neutralized with alkali, and the L-p-hydroxyphenylglycine methyl ester hydrochloride is obtained. The process is simple and safe, the cost is lowest, and the produced salt is good in quality and can be used for industry.

Description

Technical Field

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

[0002] The molecular formula of L-4-hydroxyphenylglycine methyl ester is C9H11NO3, the molecular weight is 181.19, the CAS number is 37763-23-8, and it is a white crystalline powder.

[0003] L-p-hydroxyphenylglycine methyl ester is the raw material for the enzymatic synthesis of amoxicillin. L-p-hydroxyphenylglycine is usually esterified with methanol under the catalysis of an acyl chloride dehydrating agent to obtain L-p-hydroxyphenylglycine hydrochloride, and then an alkali is added to neutralize the hydrogen chloride to obtain L-p-hydroxyphenylglycine methyl ester, see WO2011113486, WO2011161645, WO2021124269, WO2000044709, WO201819246 2. WO2013129879, WO2013033093, WO2012106448, CN112830852, CN104744281, CN103113250, CN108117502, JP2020111510, US6225311, US20030120073; This method produces sulfur dioxide and hydrogen chloride gas as by-products, which are very troublesome to handle and have environmental problems.

[0004] A few use sulfuric acid or sulfur trioxide to catalyze esterification, such as: CN111153821, CN112409199, CN103553949, CN101293868, CN109384485, CN108794341, WO2005085232, WO2011113486. The sulfuric acid produced by this method needs to be neutralized with alkali, because sodium sulfate has low solubility and is easy to precipitate at low temperature, which will affect the quality.

[0005] Some also use hydrochloric acid catalysis to prepare L-hydroxyphenylglycine methyl ester hydrochloride, see: WO9840056, WO9817639, WO2022091056, WO2022006023, WO2022006145, WO2020142450; however, due to the lack of a dehydrating agent, a large amount of methanol must be added to carry water for complete esterification. During neutralization, sodium chloride has a large solubility in water and is easy to separate and purify.

[0006] In view of this, we proposed a method for producing L-4-hydroxyphenylglycine methyl ester. Summary of the invention

[0007] The object of the present invention is to provide a method for producing L-4-hydroxyphenylglycine methyl ester to solve the problems raised in the above background technology.

[0008] To achieve the above object, the present invention provides the following technical solution: a method for producing L-parahydroxyphenylglycine methyl ester, the method comprising the following steps: S1. Add anhydrous methanol into the esterification kettle, with 7 times the equivalent being the best; S2, introducing dried and purified hydrogen chloride gas into the esterification kettle, and performing stirring and temperature control treatment; S3, adding 1 equivalent of L-hydroxyphenylglycine to the esterification kettle, and stirring to dissolve; S4, controlling the temperature of the esterification kettle, and dropping anhydrous methanol into the esterification kettle, while distilling methanol for esterification and dehydration; S5, adding deionized water and a small amount of seed crystals to the neutralization crystallization kettle, and cooling the mixture, while adding the esterification solution dropwise, neutralizing the mixture with 10% liquid alkali, controlling the pH value of the solution, and then adding liquid alkali dropwise to adjust the pH value; S6, crystallizing for 2 hours at a constant temperature, washing the chloride ions with deionized water after centrifugation, and then drying and crushing; S7, controlling the temperature to less than 30° C. in a rotary flash dryer, drying to constant weight, and obtaining a finished product.

[0009] Optionally, the anhydrous methanol added in S1 is 5 to 10 times the equivalent of L-parahydroxyphenylglycine.

[0010] Optionally, the hydrogen chloride gas added to S2 is 1.05-1.1 times the equivalent of L-parahydroxyphenylglycine.

[0011] Optionally, the temperature control temperature of the stirring temperature control treatment is <40 degrees Celsius.

[0012] Optionally, the cooling treatment reduces the temperature to 15 degrees Celsius.

[0013] Optionally, in S5, the pH of the solution is first controlled to be less than 7, and then liquid alkali is added dropwise to adjust the pH value to 8.3.

[0014] Optionally, the drying treatment time in S7 is 8-10 hours.

[0015] Compared with the prior art, the present invention provides a method for producing L-parahydroxyphenylglycine methyl ester, which has the following beneficial effects: The method for producing L-parahydroxyphenylglycine methyl ester adopts hydrogen chloride produced as a byproduct of chlorinated paraffin as an acid catalyst and a reactant to esterify L-parahydroxyphenylglycine with methanol to form L-parahydroxyphenylglycine methyl ester hydrochloride, and then neutralizes the free L-parahydroxyphenylglycine methyl ester with an alkali, thereby achieving separation and purification from sodium chloride. The process is simple and safe, the cost is the lowest, and the salt produced is of good quality and can be used for industrial purposes. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is the esterification reaction diagram of the existing L-hydroxyphenylglycine and methanol under the catalysis of acyl chloride dehydrating agent; Figure 2 The existing esterification reaction diagram is catalyzed by sulfuric acid or sulfur trioxide; Figure 3 This is the reaction diagram of preparing L-hydroxyphenylglycine methyl ester hydrochloride by hydrochloric acid catalysis; Figure 4 It is a schematic diagram of the process of the present invention. DETAILED DESCRIPTION

[0017] 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

[0018] like Figure 1-4 As shown, at 10m 3 Add 70 Kmole 2240 kg of anhydrous methanol to a glass-lined esterification reactor, stir and control the temperature (<40°C), introduce 10.5 Kmole 383 kg of pure hydrogen chloride gas (slightly in excess of L-hydroxyphenylglycine) through a bubbler, then add 1671.6 kg (10 Kmole) of L-hydroxyphenylglycine bag by bag, heat and reflux for 1 hour to dissolve it by esterification, control the temperature at 70-75°C, and keep warm for processing.

[0019] The solution was continuously pumped into the esterification tower top distributor (Dn800×16000 glass-lined tower kettle, ceramic corrugated packing) at a flow rate of 200L / h. 3 ) 68-75℃ methanol superheated steam is introduced at a flow rate of 600kg / h. The water-containing methanol distilled from the top of the tower directly enters the 1 / 3 of the methanol distillation tower kettle, and the anhydrous methanol steam is continuously distilled and preheated to 68-70℃, and then returns to the esterification tower kettle with water, thereby achieving continuous esterification. When the whole batch of materials is fed into the tower and esterification is completed, it is transferred to the cooling kettle and cooled to 30℃ for standby use.

[0020] In 10m 3Add 500kg of deionized water to the neutralization crystallization kettle, add 20kg of left-handed p-hydroxyphenylglycine methyl ester as seed crystals under stirring, pass ice brine into the jacket to keep the neutralization kettle temperature at 10-20°C, and simultaneously drip esterification liquid and 10% sodium hydroxide solution, control PH <7, after dripping the esterification liquid, continue to drip liquid alkali to adjust PH to 8.3, crystallize at about 15°C for 2 hours, centrifuge the product, wash the crystals with deionized water until there is no chloride ion, spin dry, discharge, and put the material into a rotary flash dryer, control <30°C for drying, discharge, and obtain 1726.5kg of finished product, with a yield of 95.3% and a content of 99.12% (HPLC). This method saves 50% energy compared to Example 2. Example

[0021] In 10m 3 Add 100 Kmole 3200kg of anhydrous methanol to the glass-lined esterification reactor, stir and control the temperature (<40℃), introduce 10.8 kmole 394kg of pure hydrogen chloride gas through a bubbler, then add 1672kg (10 Kmole) of L-hydroxyphenylglycine bag by bag, heat up to dissolve and distill, and when the bottom temperature reaches 78~82℃, add anhydrous methanol while distilling. The distilled methanol (containing trace amounts of hydrogen chloride and water) is neutralized with alkali and then distilled to anhydrous methanol. A total of about 9000kg of methanol is used. The reaction endpoint is detected by HPLC (the residual L-hydroxyphenylglycine content is <0.5%), and then concentrated to a volume of 5000L, cooled to 30℃ for use. At 10m 3 Add 500kg of deionized water to the crystallization kettle, add 20kg of L-hydroxyphenylglycine methyl ester as seed crystals, stir and slowly cool to 10-15°C, add esterification liquid and 10% liquid alkali to neutralize, make the pH of the neutralization liquid <7, after the esterification liquid is added, continue to add liquid alkali to adjust the pH to 8.3, crystallize at about 15°C for 2 hours, centrifuge, wash with deionized water until there is almost no chloride ion, spin dry, put the material into a rotary flash dryer, control the temperature <30°C to dry, discharge, package, and obtain 1705kg of finished product, with a yield of 94.12% and a content of 98.8% (HPLC). See HG / T6250-2023 and HG / T5804-2021 for the detection method.

[0022] Reference for detection method of L-hydroxyphenylglycine: HG / T5804-2021; HG / T 5804-2021 Page 25. (HPLC) Detector UV detector Chromatographic columns Crownpak CR(-1) Chiral Column C4.0nm×150mm, 5 microns Column temperature 25℃ Detection wavelength 220nm Flow rate (ml / min) 0.8 Injection volume 5 μl 4-Hydroxyphenylglycine methyl ester detection reference: HG / T6250-2023; Detector UV detector Chromatographic columns C18 column (inner diameter 4.6 mm × 250 mm, particle size 5 μm Column temperature 25℃ Detection wavelength 226nm Flow rate (ml / min) 1.0 Injection volume 20 μl Example

[0023] On the basis of Example 1, the amount of methanol was reduced to 50KMole1600KG, and the results were almost the same under the same operation. However, if the amount was further reduced, insoluble solids were found. Example

[0024] On the basis of Example 1, the amount of hydrogen chloride was increased to 1.1 times the equivalent, and the operation was carried out according to Example 1, and the results were the same, which shows that increasing the amount of hydrogen chloride is just a waste.

[0025] In summary, the production method of L-parahydroxyphenylglycine methyl ester proposed by the present invention uses hydrogen chloride produced as a by-product of chlorinated paraffin as an acid catalyst and reactant to esterify L-parahydroxyphenylglycine with methanol to form L-parahydroxyphenylglycine methyl ester hydrochloride, and then neutralizes the free p-hydroxyphenylglycine methyl ester with an alkali, thereby achieving separation and purification from sodium chloride. The process is simple and safe, the cost is lowest, and the salt produced is of good quality and can be used for industrial purposes.

[0026] 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-hydroxyphenylglycine methyl ester, characterized in that: The method comprises the following steps: S1. Add anhydrous methanol into the esterification kettle; S2, introducing dried and purified hydrogen chloride gas into the esterification kettle, and performing stirring and temperature control treatment; S3, adding 1 equivalent of L-hydroxyphenylglycine to the esterification kettle, and stirring to dissolve; S4, controlling the temperature of the esterification kettle, and dropping anhydrous methanol into the esterification kettle, while distilling methanol for esterification and dehydration; S5, adding deionized water and a small amount of seed crystals to the neutralization crystallization kettle, and cooling the mixture, while adding the esterification solution dropwise, neutralizing the mixture with 10% liquid alkali, controlling the pH value of the solution, and then adding liquid alkali dropwise to adjust the pH value; S6, crystallizing for 2 hours at a constant temperature, washing the chloride ions with deionized water after centrifugation, and then drying and crushing; S7, controlling the temperature to less than 30° C. in a rotary flash dryer, drying to constant weight, and obtaining a finished product.

2. The method for producing L-4-hydroxyphenylglycine methyl ester according to claim 1, characterized in that: The anhydrous methanol added to the S1 is 5 to 10 times the equivalent of L-parahydroxyphenylglycine.

3. The method for producing L-parahydroxyphenylglycine methyl ester according to claim 1, characterized in that: The hydrogen chloride gas added to S2 is 1.05-1.1 times the equivalent of L-parahydroxyphenylglycine.

4. The method for producing L-4-hydroxyphenylglycine methyl ester according to claim 1, characterized in that: The temperature control temperature of the stirring temperature control treatment is less than 40 degrees Celsius.

5. The method for producing L-parahydroxyphenylglycine methyl ester according to claim 1, characterized in that: The cooling treatment lowers the temperature to 15 degrees Celsius.

6. The method for producing L-parahydroxyphenylglycine methyl ester according to claim 1, characterized in that: In S5, the pH of the solution is first controlled to be less than 7, and then liquid alkali is added dropwise to adjust the pH value to 8.

3.

7. The method for producing L-parahydroxyphenylglycine methyl ester according to claim 1, characterized in that: The drying time in S7 is 8-10 hours.

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