A preparation method of p-chlorophenylglycine

Abstract

The present invention relates to the technical field of p-chlorophenylglycine preparation, and proposes a method for preparing p-chlorophenylglycine, comprising the following steps: S1, mixing ammonia water and sodium hydroxide solution, and introducing ammonia gas until saturated to obtain a mixed solution I; S2, adding p-chlorobenzaldehyde and a phase transfer catalyst to chloroform to obtain a mixed solution II; S3, adding the mixed solution II to 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. The above technical solution solves the problem of low p-chlorophenylglycine yield in the related art.

Description

Technical Field

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

[0002] p-Chlorophenylglycine is an important organic intermediate with extensive applications in pharmaceuticals, pesticides, and fine chemicals. In pharmaceuticals, it is a key raw material for the synthesis of various chiral drugs. For example, p-Chlorophenylglycine is a key intermediate in the synthesis of numerous β-lactam antibiotics. It can be used as a raw material to synthesize cephalosporins with a specific antimicrobial spectrum and activity, exhibiting strong inhibitory effects against both Gram-positive and Gram-negative bacteria. It is widely used clinically to treat various bacterial infections. In the pesticide field, p-Chlorophenylglycine can be used to prepare new pesticides with highly effective herbicidal and insecticidal activity. In the development of some new pesticides, p-Chlorophenylglycine can be used as an intermediate to introduce specific active groups, making the resulting pesticides more potent and selective against pests, improving their effectiveness while reducing their toxicity to non-target organisms.

[0003] At present, the preparation method of 4-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 complicated, making it difficult to achieve large-scale industrial production. The chemical synthesis method generally uses 4-chlorobenzaldehyde, sodium cyanide and ammonium bicarbonate as raw materials, and 4-chlorophenyl hydroxylamine is prepared by Bucherer-Bergs reaction, and then alkaline hydrolysis is performed to obtain 4-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, has serious environmental pollution, and has a low yield. Therefore, how to improve the yield of 4-chlorophenylglycine is a problem that needs to be solved at present. Summary of the Invention

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

[0005] The technical solutions of the present invention are as follows:

[0006] The present invention provides a method for preparing p-chlorophenylglycine, comprising the following steps:

[0007] S1, after mixing ammonia water and sodium hydroxide solution, passing ammonia gas into it until saturated to obtain a mixed solution I;

[0008] S2, adding p-chlorobenzaldehyde and a phase transfer catalyst to chloroform to obtain a mixed solution II;

[0009] S3, adding the mixed solution II to the mixed solution I, adding ammonium bicarbonate, and stirring to react to obtain p-chlorophenylglycine;

[0010] 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.

[0011] As a further technical solution, the molar ratio of tetrabutylammonium bromide to polyethylene glycol 400 is 28:7-12.

[0012] 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.

[0013] 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.

[0014] As a further technical solution, the recrystallization solvent includes water, formic acid, and ethylene glycol.

[0015] In the present invention, 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.

[0016] As a further technical solution, the acid is adjusted to a pH value of 5-6.

[0017] As a further technical solution, the acid adjustment reagent is hydrochloric acid.

[0018] As a further technical solution, the volume ratio of water, ethylene glycol and formic acid is 10:40:0.5~1.

[0019] 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.

[0020] As a further technical solution, the recrystallization temperature is 50-60° C., and the recrystallization time is 2-3 hours.

[0021] 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%.

[0022] As a further technical solution, the volume ratio of the ammonia water to the sodium hydroxide solution is 1:2.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] The working principle and beneficial effects of the present invention are:

[0027] 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. 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 p-chlorophenylglycine yield. DETAILED DESCRIPTION

[0028] 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 embodiments described 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 making any creative efforts are within the scope of protection of the present invention.

[0029] Example 1

[0030] A method for preparing p-chlorophenylglycine comprises the following steps:

[0031] S1. After mixing 373 mL of aqueous ammonia and 746 mL of sodium hydroxide solution (30 wt %) at 0°C, ammonia gas was introduced into the mixture until saturation, while maintaining the temperature at 0°C, to obtain a mixed solution I;

[0032] S2. Add 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;

[0033] S3. Add the mixed solution II to the mixed solution I at -5°C, add 39.5 g of ammonium bicarbonate, stir and react at -5°C for 6 h, then raise the temperature to 45°C and continue the reaction for 15 h to obtain a p-chlorophenylglycine reaction solution;

[0034] S4. After concentrating the p-chlorophenylglycine reaction solution, hydrochloric acid was added to adjust the pH to 5. After filtering, the filter cake was added to the recrystallization solvent, heated to 50° C., stirred for 3 h, cooled to room temperature, filtered, washed, and dried to obtain 167.60 g of p-chlorophenylglycine with a purity of 93.5% and a yield of 90.3%;

[0035] The recrystallization solvent is obtained by mixing water and ethylene glycol in a volume ratio of 1:4.

[0036] Example 2

[0037] A method for preparing p-chlorophenylglycine comprises the following steps:

[0038] 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 maintaining the temperature at 0°C, to obtain a mixed solution I;

[0039] S2. Add 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;

[0040] 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;

[0041] S4. After concentrating the p-chlorophenylglycine reaction solution, hydrochloric acid was added to adjust the pH to 5. After filtering, the filter cake was added to the recrystallization solvent, heated to 50° C., stirred for 3 h, cooled to room temperature, filtered, washed, and dried to obtain 169.64 g of p-chlorophenylglycine with a purity of 92.8% and a yield of 91.4%;

[0042] The recrystallization solvent is obtained by mixing water and ethylene glycol in a volume ratio of 1:4.

[0043] Example 3

[0044] A method for preparing p-chlorophenylglycine comprises the following steps:

[0045] S1. After mixing 300 mL of aqueous ammonia and 600 mL of sodium hydroxide solution (40 wt %) at 0°C, ammonia gas was introduced into the mixture until saturation, while maintaining the temperature at 0°C, to obtain a mixed solution I;

[0046] S2. Add 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;

[0047] S3. Add the mixed solution II to the mixed solution I at 0°C, add 39.5 g of ammonium bicarbonate, stir and react at 0°C for 3 h, then raise the temperature to 50°C and continue the reaction for 10 h to obtain a p-chlorophenylglycine reaction solution;

[0048] S4. After concentrating the p-chlorophenylglycine reaction solution, hydrochloric acid was added to adjust the pH to 6. After filtering, the filter cake was added to the recrystallization solvent, heated to 60° C., stirred for 2 h, cooled to room temperature, filtered, washed, and dried to obtain 170.57 g of p-chlorophenylglycine with a purity of 92.3% and a yield of 91.9%;

[0049] The recrystallization solvent is obtained by mixing water and ethylene glycol in a volume ratio of 1:4.

[0050] Example 4

[0051] The only 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;

[0052] Results: 171.12 g of p-chlorophenylglycine was obtained with a purity of 93.4% and a yield of 92.2%.

[0053] Example 5

[0054] The only 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;

[0055] Results: 172.24 g of p-chlorophenylglycine was obtained with a purity of 93.7% and a yield of 92.8%.

[0056] Example 6

[0057] The only 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;

[0058] Results: 173.16 g of p-chlorophenylglycine was obtained with a purity of 93.1% and a yield of 93.3%.

[0059] Example 7

[0060] The only 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;

[0061] Results: 173.54 g of p-chlorophenylglycine was obtained with a purity of 95.2% and a yield of 93.5%.

[0062] Example 8

[0063] The only 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;

[0064] Results: 173.72 g of p-chlorophenylglycine was obtained with a purity of 95.9% and a yield of 93.6%.

[0065] Example 9

[0066] The only 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;

[0067] Results: 175.95 g of p-chlorophenylglycine was obtained with a purity of 97.1% and a yield of 94.8%.

[0068] Example 10

[0069] The only 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;

[0070] Results: 176.13 g of p-chlorophenylglycine was obtained with a purity of 97.3% and a yield of 94.9%.

[0071] Comparative Example 1

[0072] This comparative example is different from Example 1 only in that polyethylene glycol 400 is replaced with an equal amount of tetrabutylammonium bromide;

[0073] Results: 152.93 g of p-chlorophenylglycine was obtained with a purity of 90.4% and a yield of 82.4%.

[0074] Comparative Example 2

[0075] This comparative example differs from Example 1 only in that tetrabutylammonium bromide is replaced with an equal amount of polyethylene glycol 400;

[0076] Results: 148.67 g of p-chlorophenylglycine was obtained with a purity of 90.1% and a yield of 80.1%.

[0077] Compared with Comparative Example 1 and Comparative Example 2, the yield of p-chlorophenylglycine prepared in Example 1 is higher than that of Comparative Example 1 and Comparative Example 2, indicating that the use of tetrabutylammonium bromide and polyethylene glycol 400 as phase transfer can increase the yield of p-chlorophenylglycine.

[0078] 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 to polyethylene glycol 400 was 28:7 to 12, the yield of p-chlorophenylglycine could be further improved.

[0079] Compared with Example 6, formic acid was added to the recrystallization solvent in Examples 7 to 10. As a result, the purity of the p-chlorophenylglycine obtained in Examples 7 to 10 was higher than that in Example 6, indicating that the addition of formic acid during recrystallization can improve the purity of p-chlorophenylglycine. 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.

[0080] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection 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 into it until saturated to obtain a mixed solution I; S2, adding p-chlorobenzaldehyde and a phase transfer catalyst to chloroform to obtain a mixed solution II; S3, adding the mixed solution II to the mixed solution I, adding ammonium bicarbonate, and stirring to react to obtain p-chlorophenylglycine; The phase transfer catalyst is composed of tetrabutylammonium bromide and polyethylene glycol 400 in a molar ratio of 28:7-12; 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.

2. The method for preparing p-chlorophenylglycine according to claim 1, wherein 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.

3. The method for preparing p-chlorophenylglycine according to claim 2, wherein The recrystallization solvent includes water, ethylene glycol and formic acid.

4. The method for preparing p-chlorophenylglycine according to claim 3, wherein The volume ratio of water, ethylene glycol and formic acid is 10:40:0.5~1.

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

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

2.

7. The method for preparing p-chlorophenylglycine according to claim 1, wherein 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.

8. The method for preparing p-chlorophenylglycine according to claim 7, wherein: 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.