Preparation method of p-chlorophenylglycine

Abstract

The invention relates to the technical field of preparation of p-chlorophenylglycine, and provides a preparation method of p-chlorophenylglycine, which comprises the following steps: S1, mixing ammonia water and a sodium hydroxide solution, and introducing ammonia gas until saturation to obtain a mixed solution I; s2, adding p-chlorobenzaldehyde and a phase transfer catalyst into chloroform to obtain a mixed solution II; s3, adding the mixed solution II into the mixed solution I, adding ammonium bicarbonate, and stirring for reaction to obtain p-chlorophenylglycine; the phase transfer catalyst comprises tetrabutylammonium bromide and polyethylene glycol 400; the molar ratio of tetrabutylammonium bromide to polyethylene glycol 400 is 7: (1-7). By means of the technical scheme, the problem that the yield of the chlorophenylglycine is low in the prior art is solved.

Description

Technical Field

[0001] The invention relates to the technical field of p-chlorophenylglycine preparation, and specifically to a method for preparing p-chlorophenylglycine. Background Art

[0002] p-Chlorophenylglycine is an important organic intermediate with wide applications in the fields of medicine, pesticides and fine chemicals. In medicine, it is a key raw material for the synthesis of a variety of chiral drugs. For example, p-Chlorophenylglycine is a key intermediate for the synthesis of a variety of β-lactam antibiotics. It can be used as a raw material to synthesize cephalosporins with a specific antibacterial spectrum and antibacterial activity. It has a good inhibitory effect on both Gram-positive and Gram-negative bacteria and can be widely used in the clinic to treat various bacterial infectious diseases. In the field of pesticides, it can be used to prepare new pesticide varieties with high-efficiency weed control and insecticidal activity. In the research and development of some new pesticides, p-Chlorophenylglycine can be used as an intermediate to introduce specific active groups, so that the synthesized pesticides have stronger toxicity and selectivity to pests, improve the control effect of pesticides, and reduce toxicity to non-target organisms.

[0003] At present, the preparation method of p-chlorophenylglycine mainly includes chemical synthesis and biosynthesis. Although the biosynthesis method has the advantages of mild reaction conditions and environmental friendliness, it is also faced with many challenges. For example, the preparation and immobilization cost of the enzyme are high, the stability and activity of the enzyme are greatly affected by the reaction conditions, and the reaction system is complex, and it is difficult to achieve large-scale industrial production. The chemical synthesis method generally uses p-chlorobenzaldehyde, sodium cyanide and ammonium bicarbonate as raw materials, and p-chlorobenzene is prepared by Bucherer-Bergs reaction, and then alkaline hydrolysis is performed to obtain p-chlorophenylglycine. The method reaction steps are relatively simple, but using highly toxic sodium cyanide as raw material, there is a great safety hazard, and the reaction produces a large amount of cyanide-containing wastewater, which is difficult to handle, and the environmental pollution is serious, and the yield is low. Therefore, how to improve the yield of p-chlorophenylglycine is a problem that needs to be solved at present. Summary of the invention

[0004] The invention provides a method for preparing p-chlorophenylglycine, which solves the problem of low p-chlorophenylglycine yield in the related art.

[0005] The technical solution of the present invention is as follows: The present invention provides a method for preparing p-chlorophenylglycine, comprising the following steps: S1, after mixing ammonia water and sodium hydroxide solution, passing ammonia gas until saturated to obtain a mixed solution I; S2, adding p-chlorobenzaldehyde and a phase transfer catalyst into chloroform to obtain a mixed solution II; S3, adding the mixed solution II to the mixed solution I, adding ammonium bicarbonate, stirring for reaction, and obtaining p-chlorophenylglycine; The phase transfer catalyst includes tetrabutylammonium bromide and polyethylene glycol 400; the molar ratio of the tetrabutylammonium bromide to the polyethylene glycol 400 is 7:1-7.

[0006] As a further technical solution, the molar ratio of tetrabutylammonium bromide to polyethylene glycol 400 is 28:7-12.

[0007] In the present invention, the yield of p-chlorophenylglycine is further improved by limiting the molar ratio of tetrabutylammonium bromide to polyethylene glycol 400 to 28:7-12.

[0008] As a further technical solution, in step S3, after the stirring reaction, p-chlorophenylglycine is obtained by post-treatment, and the post-treatment sequentially includes concentration, acid adjustment, filtration, recrystallization, and drying.

[0009] As a further technical solution, the recrystallization solvent includes water, formic acid, and ethylene glycol.

[0010] In the present invention, the crude p-chlorophenylglycine is purified by using a recrystallization solvent consisting of water, formic acid and ethylene glycol, thereby improving the purity of p-chlorophenylglycine.

[0011] As a further technical solution, the acid is adjusted to a pH value of 5-6.

[0012] As a further technical solution, the acid adjustment reagent is hydrochloric acid.

[0013] As a further technical solution, the volume ratio of water, ethylene glycol and formic acid is 10:40:0.5~1.

[0014] In the present invention, the purity of p-chlorophenylglycine is further improved by limiting the volume ratio of water, ethylene glycol and formic acid to 10:40:0.5-1.

[0015] As a further technical solution, the recrystallization temperature is 50-60° C., and the recrystallization time is 2-3 hours.

[0016] As a further technical solution, in step S1, the mixing temperature is 0°C; and the mass concentration of the sodium hydroxide solution is 30% to 40%.

[0017] As a further technical solution, the volume ratio of the ammonia water to the sodium hydroxide solution is 1:2.

[0018] As a further technical solution, the molar ratio of p-chlorobenzaldehyde, chloroform, phase transfer catalyst, sodium hydroxide and ammonium bicarbonate is 1:2:0.04~0.06:8~10:0.5.

[0019] As a further technical solution, in step S3, the stirring reaction includes a first stage stirring reaction and a second stage stirring reaction, and the temperatures of the first stage stirring reaction and the second stage stirring reaction are different.

[0020] As a further technical solution, the reaction temperature of the first stage stirring reaction is -5~0°C, and the reaction time of the first stage stirring reaction is 3~6h; the reaction temperature of the second stage stirring reaction is 45~50°C, and the reaction time of the second stage stirring reaction is 10~15h.

[0021] The working principle and beneficial effects of the present invention are: In the present invention, p-chlorobenzaldehyde is used as a raw material, and a phase transfer catalyst consisting of tetrabutylammonium bromide and polyethylene glycol 400 is added under the action of chloroform, sodium hydroxide and ammonia water, and the mass ratio of tetrabutylammonium bromide to polyethylene glycol 400 is limited to 8:1-8, so that the yield of p-chlorophenylglycine is increased to more than 90%, thereby solving the problem of low yield of p-chlorophenylglycine. DETAILED DESCRIPTION

[0022] The following will be combined with 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.

[0023] Example 1 A method for preparing p-chlorophenylglycine comprises the following steps: S1. After 373 mL of aqueous ammonia and 746 mL of sodium hydroxide solution (30 wt%) were mixed at 0° C., ammonia gas was introduced to saturation while maintaining the temperature at 0° C. to obtain a mixed solution I; S2, adding 140.6 g of p-chlorobenzaldehyde, 11.3 g of tetrabutylammonium bromide and 2 g of polyethylene glycol 400 to 238.8 g of chloroform to obtain a mixed solution II; S3, adding the mixed solution II to the mixed solution I at -5°C, adding 39.5 g of ammonium bicarbonate, stirring and reacting at -5°C for 6 hours, then raising the temperature to 45°C and continuing the reaction for 15 hours to obtain a p-chlorophenylglycine reaction solution; S4, after concentrating the p-chlorophenylglycine reaction solution, hydrochloric acid was added to adjust the pH to 5, and after filtering, the filter cake was added to the recrystallization solvent, heated to 50°C, stirred for 3h, cooled to room temperature, filtered, washed, and dried to obtain 167.60g of p-chlorophenylglycine with a purity of 93.5% and a yield of 90.3%; The recrystallization solvent is obtained by mixing water and ethylene glycol in a volume ratio of 1:4.

[0024] Example 2 A method for preparing p-chlorophenylglycine comprises the following steps: S1. After mixing 420 mL of aqueous ammonia and 840 mL of sodium hydroxide solution (30 wt%) at 0° C., ammonia gas was introduced into the mixture until saturation, while the temperature was kept constant at 0° C., to obtain a mixed solution I; S2, adding 140.6 g of p-chlorobenzaldehyde, 14.1 g of tetrabutylammonium bromide and 2.5 g of polyethylene glycol 400 to 238.8 g of chloroform to obtain a mixed solution II; S3, adding the mixed solution II to the mixed solution I at -5°C, adding 39.5 g of ammonium bicarbonate, stirring and reacting at -5°C for 4 hours, then raising the temperature to 45°C and continuing the reaction for 15 hours to obtain a p-chlorophenylglycine reaction solution; S4, after concentrating the p-chlorophenylglycine reaction solution, add hydrochloric acid to adjust the pH to 5, filter, add the filter cake to the recrystallization solvent, heat to 50°C, stir for 3h, cool to room temperature, filter, wash and dry to obtain 169.64g p-chlorophenylglycine with a purity of 92.8% and a yield of 91.4%; The recrystallization solvent is obtained by mixing water and ethylene glycol in a volume ratio of 1:4.

[0025] Example 3 A method for preparing p-chlorophenylglycine comprises the following steps: S1. After 300 mL of aqueous ammonia and 600 mL of sodium hydroxide solution (40 wt%) are mixed at 0° C., ammonia gas is introduced to saturation while maintaining the temperature at 0° C. to obtain a mixed solution I; S2, adding 140.6 g of p-chlorobenzaldehyde, 16.9 g of tetrabutylammonium bromide and 3 g of polyethylene glycol 400 to 238.8 g of chloroform to obtain a mixed solution II; S3, adding the mixed solution II to the mixed solution I at 0°C, adding 39.5 g of ammonium bicarbonate, stirring and reacting at 0°C for 3 h, then raising the temperature to 50°C and continuing the reaction for 10 h to obtain a p-chlorophenylglycine reaction solution; S4, after concentrating the p-chlorophenylglycine reaction solution, hydrochloric acid was added to adjust the pH to 6, and after filtering, the filter cake was added to the recrystallization solvent, heated to 60°C, stirred for 2h, cooled to room temperature, filtered, washed, and dried to obtain 170.57g of p-chlorophenylglycine with a purity of 92.3% and a yield of 91.9%; The recrystallization solvent is obtained by mixing water and ethylene glycol in a volume ratio of 1:4.

[0026] Example 4 The difference between this embodiment and embodiment 1 is that the amount of tetrabutylammonium bromide added is 6.4 g and the amount of polyethylene glycol 400 added is 8 g; Result: 171.12 g of p-chlorophenylglycine was obtained with a purity of 93.4% and a yield of 92.2%.

[0027] Example 5 The difference between this embodiment and embodiment 1 is that the amount of tetrabutylammonium bromide added is 10.3 g, and the amount of polyethylene glycol 400 added is 3.2 g; Result: 172.24 g of p-chlorophenylglycine was obtained with a purity of 93.7% and a yield of 92.8%.

[0028] Example 6 The difference between this embodiment and embodiment 1 is that the amount of tetrabutylammonium bromide added is 9.0 g and the amount of polyethylene glycol 400 added is 4.8 g; Result: 173.16 g of p-chlorophenylglycine was obtained with a purity of 93.1% and a yield of 93.3%.

[0029] Example 7 The difference between this embodiment and embodiment 6 is that the recrystallization solvent is obtained by mixing water, ethylene glycol and formic acid in a mass ratio of 10:40:0.1; Result: 173.54 g of p-chlorophenylglycine was obtained with a purity of 95.2% and a yield of 93.5%.

[0030] Example 8 The difference between this embodiment and embodiment 6 is that the recrystallization solvent is obtained by mixing water, ethylene glycol and formic acid in a mass ratio of 10:40:2; Result: 173.72 g of p-chlorophenylglycine was obtained with a purity of 95.9% and a yield of 93.6%.

[0031] Example 9 The difference between this embodiment and embodiment 6 is that the recrystallization solvent is obtained by mixing water, ethylene glycol and formic acid in a mass ratio of 10:40:0.5; Result: 175.95 g of p-chlorophenylglycine was obtained with a purity of 97.1% and a yield of 94.8%.

[0032] Example 10 The difference between this embodiment and embodiment 6 is that the recrystallization solvent is obtained by mixing water, ethylene glycol and formic acid in a mass ratio of 10:40:1; Result: 176.13 g of p-chlorophenylglycine was obtained with a purity of 97.3% and a yield of 94.9%.

[0033] Comparative Example 1 The only difference between this comparative example and Example 1 is that polyethylene glycol 400 is replaced by an equal amount of tetrabutylammonium bromide; Result: 152.93 g of p-chlorophenylglycine was obtained with a purity of 90.4% and a yield of 82.4%.

[0034] Comparative Example 2 This comparative example is different from Example 1 in that tetrabutylammonium bromide is replaced with an equal amount of polyethylene glycol 400; Result: 148.67 g of p-chlorophenylglycine was obtained with a purity of 90.1% and a yield of 80.1%.

[0035] Compared with Comparative Examples 1 and 2, the yield of p-chlorophenylglycine prepared in Example 1 is higher than that of Comparative Examples 1 and 2, indicating that the use of tetrabutylammonium bromide and polyethylene glycol 400 as phase transfer can increase the yield of p-chlorophenylglycine.

[0036] Compared with Example 1, Examples 4 to 6 changed the molar ratio of tetrabutylammonium bromide and polyethylene glycol 400. As a result, the yield of p-chlorophenylglycine obtained in Examples 5 to 6 was higher than that in Example 1 and Example 4, indicating that when the molar ratio of tetrabutylammonium bromide and polyethylene glycol 400 was 28:7 to 12, the yield of p-chlorophenylglycine could be further improved.

[0037] Compared with Example 6, formic acid was added to the recrystallization solvent in Examples 7 to 10. As a result, the purity of p-chlorophenylglycine obtained in Examples 7 to 10 was higher than that in Example 6, indicating that the addition of formic acid in the recrystallization can improve the purity of p-chlorophenylglycine; by comparing Examples 7 to 10, it was found that the purity of p-chlorophenylglycine obtained in Examples 9 to 10 was higher than that in Examples 7 and 8, indicating that when the volume ratio of water, ethylene glycol and formic acid in the recrystallization solvent is 10:40:0.5 to 1, the purity of p-chlorophenylglycine can be further improved.

[0038] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing p-chlorophenylglycine, characterized in that: The following steps are involved: S1, after mixing ammonia water and sodium hydroxide solution, passing ammonia gas until saturated to obtain a mixed solution I; S2, adding p-chlorobenzaldehyde and a phase transfer catalyst into chloroform to obtain a mixed solution II; S3, adding the mixed solution II to the mixed solution I, adding ammonium bicarbonate, stirring for reaction, and obtaining p-chlorophenylglycine; The phase transfer catalyst includes tetrabutylammonium bromide and polyethylene glycol 400; the molar ratio of the tetrabutylammonium bromide to the polyethylene glycol 400 is 7:1-7.

2. The method for preparing p-chlorophenylglycine according to claim 1, characterized in that: The molar ratio of tetrabutylammonium bromide to polyethylene glycol 400 is 28:7-12.

3. The method for preparing p-chlorophenylglycine according to claim 1, characterized in that: In step S3, after the stirring reaction, p-chlorophenylglycine is obtained by post-treatment, and the post-treatment sequentially includes concentration, acid adjustment, filtration, recrystallization, and drying.

4. The method for preparing p-chlorophenylglycine according to claim 3, characterized in that: The recrystallization solvent includes water, ethylene glycol and formic acid.

5. The method for preparing p-chlorophenylglycine according to claim 4, characterized in that: The volume ratio of water, ethylene glycol and formic acid is 10:40:0.5-1.

6. The method for preparing p-chlorophenylglycine according to claim 1, characterized in that: In step S1, the mixing temperature is 0°C; and the mass concentration of the sodium hydroxide solution is 30% to 40%.

7. The method for preparing p-chlorophenylglycine according to claim 1, characterized in that: The volume ratio of the ammonia water to the sodium hydroxide solution is 1:

2.

8. The method for preparing p-chlorophenylglycine according to claim 1, characterized in that: The molar ratio of the p-chlorobenzaldehyde, chloroform, phase transfer catalyst, sodium hydroxide and ammonium bicarbonate is 1:2:0.04-0.06:8-10:0.

5.

9. The method for preparing p-chlorophenylglycine according to claim 1, characterized in that: Step S3, the stirring reaction includes a first stage stirring reaction and a second stage stirring reaction, and the temperatures of the first stage stirring reaction and the second stage stirring reaction are different.

10. The method for preparing p-chlorophenylglycine according to claim 9, characterized in that: The reaction temperature of the first stage stirring reaction is -5~0°C, and the reaction time of the first stage stirring reaction is 3~6h; the reaction temperature of the second stage stirring reaction is 45~50°C, and the reaction time of the second stage stirring reaction is 10~15h.