CN115784914B - Preparation method of o-chlorophenylglycine - Google Patents
Preparation method of o-chlorophenylglycine Download PDFInfo
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- CN115784914B CN115784914B CN202211649344.6A CN202211649344A CN115784914B CN 115784914 B CN115784914 B CN 115784914B CN 202211649344 A CN202211649344 A CN 202211649344A CN 115784914 B CN115784914 B CN 115784914B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to the technical field of pharmaceutical chemicals, and provides a preparation method of o-chlorophenylglycine, which comprises the following steps: s1, adding ammonia water, a sodium hydroxide solution, o-chlorobenzaldehyde, chloroform and a phase transfer catalyst into a reactor for reaction to obtain a reaction solution; s2, adding ammonium bicarbonate into the reaction solution for continuous reaction, and concentrating; s3, adding a decoloring agent to decolor; s4, crystallizing, suction filtering, washing and drying to obtain o-chlorophenylglycine; the phase transfer catalyst is a mixture of stearyl polyether-10, tetrabutylammonium bromide and tri-n-butyl tetradecylphosphine chloride. By the technical scheme, the problems that strict post-treatment is needed after the o-chlorophenylglycine in the prior art is prepared, the yield is low, and the production cost is increased are solved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of o-chlorophenylglycine.
Background
Clopidogrel is a novel and efficient anti-platelet aggregation drug, and compared with other anti-platelet drugs, clopidogrel has the advantages of good curative effect, low cost, small adverse reaction and the like. Clopidogrel was first marketed in the united states in 1998, and then in europe and countries such as canada, australia, singapore, etc., in 2001.
O-chlorophenylglycine is an intermediate of clopidogrel, and is mainly prepared from raw materials of O-chlorophenylglycine, sodium cyanide and ammonium bicarbonate at present. The process uses cyanide which is a highly toxic substance, and the industrial wastewater after production is subjected to strict treatment, so that the process has the advantages of high environmental pollution, low yield and increased production cost.
Disclosure of Invention
The invention provides a preparation method of o-chlorophenylglycine, which solves the problems that strict post-treatment is needed after the o-chlorophenylglycine is prepared in the related art, the yield is low, and the production cost is increased.
The technical scheme of the invention is as follows:
a preparation method of o-chlorophenylglycine comprises the following steps:
s1, adding ammonia water, a sodium hydroxide solution, o-chlorobenzaldehyde, chloroform and a phase transfer catalyst into a reactor to react to obtain a reaction solution;
s2, adding ammonium bicarbonate into the reaction solution for continuous reaction, and concentrating to obtain crude o-chlorophenylglycine;
s3, performing post-treatment on the crude o-chlorophenylglycine to obtain o-chlorophenylglycine;
the phase transfer catalyst is a mixture of stearyl polyether-10, tetrabutylammonium bromide and tri-n-butyl tetradecylphosphine chloride.
As a further technical scheme, the mass fraction of the sodium hydroxide solution in the S1 is 50%.
As a further technical scheme, the mass ratio of the sodium hydroxide solution to the o-chlorobenzaldehyde is (4-5.2): 1.
As a further technical scheme, the mass ratio of the stearyl alcohol polyether-10, the tetrabutylammonium bromide and the tri-n-butyl tetradecylphosphine chloride is (0.1-0.2) 1 (0.5-0.7).
As a further technical scheme, the molar ratio of the chloroform to the o-chlorobenzaldehyde is (1-3): 1.
As a further technical scheme, the phase transfer catalyst is 3-6% of the mass of the o-chlorobenzaldehyde.
As a further technical scheme, the reaction temperature in the S1 is-5-2 ℃ and the reaction time is 1.5-2h.
As a further technical scheme, the reaction temperature in the S2 is 40-50 ℃ and the reaction time is 10 hours.
As a further technical solution, the post-processing in S3 includes: and adding a decoloring agent into the crude o-chlorophenylglycine to decolor, and then crystallizing, filtering, washing and drying to obtain the o-chlorophenylglycine.
As a further technical scheme, the drying temperature is 75-85 ℃.
As a further technical scheme, the washing is sequentially performed by water, ethanol and diethyl ether. The working principle and the beneficial effects of the invention are as follows:
1. the invention does not use cyanide in the preparation of o-chlorophenylglycine, greatly reduces the difficulty of industrial wastewater treatment, reduces the pollution to the environment, reduces the production cost to a certain extent, and has the advantages of mild reaction conditions, stable reaction process and easy control.
2. The invention adopts the phase transfer catalyst which consists of stearyl alcohol polyether-10, tetrabutylammonium bromide and tri-n-butyl tetradecylphosphine chloride, can enhance the activity of the catalytic reaction, increase the chance of mutual contact of two phases, lead the two-phase reaction to be easy to be carried out, and increase the product yield.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The preparation method of the o-chlorophenylglycine comprises the following steps:
s1, adding 100mL of 25% ammonia water and 640g of 50% sodium hydroxide solution, 140g of o-chlorobenzaldehyde, 238g of chloroform, 0.26g of stearyl polyether-10, 2.63g of tetrabutylammonium bromide and 1.31g of tri-n-butyl tetradecylphosphine chloride into a reaction kettle, and reacting for 2 hours at the temperature of minus 5 ℃ to obtain a reaction solution;
s2, adding 51.4g of ammonium bicarbonate into the reaction solution, reacting for 10 hours at 40 ℃, and carrying out distillation concentration;
s3, adding 2g of active carbon for decoloring;
s4, adjusting the pH value to 5, and crystallizing at 0 ℃; after crystallization, the mixture is subjected to suction filtration, washed by water, ethanol and diethyl ether in turn, and dried in an oven at 80 ℃ to obtain 130.3g of o-chlorophenylglycine, and the yield is 70.2%.
Example 2
The preparation method of the o-chlorophenylglycine comprises the following steps:
s1, adding 100mL of 25% ammonia water and 560g of 50% sodium hydroxide solution, 140g of o-chlorobenzaldehyde, 119g of chloroform, 0.74g of stearyl polyether-10, 3.68g of tetrabutylammonium bromide and 2.58g of tri-n-butyl tetradecylphosphine chloride into a reaction kettle, and reacting for 1.5 hours at 2 ℃ to obtain a reaction solution;
s2, adding 47.4g of ammonium bicarbonate into the reaction solution, reacting for 10 hours at 45 ℃, and carrying out distillation concentration;
s3, adding 2g of active carbon for decoloring;
s4, adjusting the pH value to 5, and crystallizing at 0 ℃; after crystallization, the mixture is subjected to suction filtration, washed by water, ethanol and diethyl ether in turn, and dried in a drying oven at 75 ℃ to obtain 127.5g of o-chlorophenylglycine, and the yield is 68.7%.
Example 3
The preparation method of the o-chlorophenylglycine comprises the following steps:
s1, adding 100mL of 25% ammonia water and 720g of 50% sodium hydroxide solution, 140g of o-chlorobenzaldehyde, 357g of chloroform, 0.49g of stearyl polyether-10, 4.94g of tetrabutylammonium bromide and 2.96g of tri-n-butyl tetradecylphosphine chloride into a reaction kettle, and reacting for 2 hours at 0 ℃ to obtain a reaction solution;
s2, adding 55.3g of ammonium bicarbonate into the reaction solution, reacting for 10 hours at 45 ℃, and carrying out distillation concentration;
s3, adding 2g of active carbon for decoloring;
s4, adjusting the pH value to 5, and crystallizing at 0 ℃; after crystallization, the mixture is subjected to suction filtration, washed by water, ethanol and diethyl ether in turn, and dried in an oven at 85 ℃ to obtain 129.0g of o-chlorophenylglycine, wherein the yield is 69.5%.
Comparative example 1
The preparation method of the o-chlorophenylglycine comprises the following steps:
s1, adding 100mL of 25% ammonia water, 640g of 50% sodium hydroxide solution, 140g of o-chlorobenzaldehyde, 238g of chloroform and 4.2g of tetrabutylammonium bromide into a reaction kettle, and reacting for 2 hours at-5 ℃ to obtain a reaction solution;
s2, adding 51.4g of ammonium bicarbonate into the reaction solution, reacting for 10 hours at 40 ℃, and carrying out distillation concentration;
s3, adding 2g of active carbon for decoloring;
s4, adjusting the pH value to 5, and crystallizing at 0 ℃; after crystallization, the mixture is subjected to suction filtration, washed by water, ethanol and diethyl ether in turn, and dried in an oven at 80 ℃ to obtain 115.8g of o-chlorophenylglycine, and the yield is 62.4%.
Comparative example 2
The preparation method of the o-chlorophenylglycine comprises the following steps:
s1, adding 100mL of 25% ammonia water, 640g of 50% sodium hydroxide solution, 140g of o-chlorobenzaldehyde, 238g of chloroform, 3.94g of tetrabutylammonium bromide and 0.26g of stearyl alcohol polyether-10 into a reaction kettle, and reacting for 2 hours at the temperature of minus 5 ℃ to obtain a reaction solution;
s2, adding 51.4g of ammonium bicarbonate into the reaction solution, reacting for 10 hours at 40 ℃, and carrying out distillation concentration;
s3, adding 2g of active carbon for decoloring;
s4, adjusting the pH value to 5, and crystallizing at 0 ℃; after crystallization, suction filtration, washing with water, ethanol and diethyl ether in turn, and drying in an oven at 80 ℃ to obtain 118.05g of o-chlorophenylglycine, wherein the yield is 63.6%.
Comparative example 3
The preparation method of the o-chlorophenylglycine comprises the following steps:
s1, adding 100mL of 25% ammonia water, 640g of 50% sodium hydroxide solution, 140g of o-chlorobenzaldehyde, 238g of chloroform, 2.89g of tetrabutylammonium bromide and 1.31g of tri-n-butyl tetradecylphosphine chloride into a reaction kettle, and reacting for 2 hours at-5 ℃ to obtain a reaction solution;
s2, adding 51.4g of ammonium bicarbonate into the reaction solution, reacting for 10 hours at 40 ℃, and carrying out distillation concentration;
s3, adding 2g of active carbon for decoloring;
s4, adjusting the pH value to 5, and crystallizing at 0 ℃; after crystallization, the mixture is subjected to suction filtration, washed by water, ethanol and diethyl ether in turn, and dried in an oven at 80 ℃ to obtain 117.3g of o-chlorophenylglycine, and the yield is 63.2%.
Comparative example 4
The preparation method of the o-chlorophenylglycine comprises the following steps:
s1, adding 100mL of 25% ammonia water and 640g of 50% sodium hydroxide solution, 140g of o-chlorobenzaldehyde, 238g of chloroform, 1.56g of stearyl polyether-10 and 2.64g of tri-n-butyl tetradecylphosphine chloride into a reaction kettle, and reacting for 2 hours at the temperature of minus 5 ℃ to obtain a reaction solution;
s2, adding 51.4g of ammonium bicarbonate into the reaction solution, reacting for 10 hours at 40 ℃, and carrying out distillation concentration;
s3, adding 2g of active carbon for decoloring;
s4, adjusting the pH value to 5, and crystallizing at 0 ℃; after crystallization, the mixture is subjected to suction filtration, washed by water, ethanol and diethyl ether in turn, and dried in an oven at 80 ℃ to obtain 114.3g of o-chlorophenylglycine with the yield of 61.6%.
The yields of examples 1-3 of the present invention were 70.2% -68.7%, and the phase transfer catalyst of comparative example 1 was added with tetrabutylammonium bromide alone, resulting in a lower yield of comparative example 1 than example 1. The comparative example 2 phase transfer catalyst was tetrabutylammonium bromide, stearyl polyether-10, the comparative example 3 phase transfer catalyst was tetrabutylammonium bromide, tri-n-butyltetradecylphosphine chloride, the comparative example 4 phase transfer catalyst was stearyl polyether-10, tri-n-butyltetradecylphosphine chloride, and as a result, the yields of comparative examples 1-4 were all lower than those of example 1, indicating that the highest yields were obtained only when stearyl polyether-10, tri-n-butyltetradecylphosphine chloride, tetrabutylammonium bromide were used as the catalyst.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (8)
1. The preparation method of the o-chlorophenylglycine is characterized by comprising the following steps of:
s1, adding ammonia water, a sodium hydroxide solution, o-chlorobenzaldehyde, chloroform and a phase transfer catalyst into a reactor to react to obtain a reaction solution;
s2, adding ammonium bicarbonate into the reaction solution for continuous reaction, and concentrating to obtain crude o-chlorophenylglycine;
s3, performing post-treatment on the crude o-chlorophenylglycine to obtain o-chlorophenylglycine;
the phase transfer catalyst is a mixture of stearyl polyether-10, tetrabutylammonium bromide and tri-n-butyl tetradecylphosphine chloride;
the mass ratio of the stearyl alcohol polyether-10 to the tetrabutylammonium bromide to the tri-n-butyltetradecylphosphine chloride is (0.1-0.2) 1 (0.5-0.7);
the phase transfer catalyst accounts for 3-6% of the mass of the o-chlorobenzaldehyde.
2. The method for preparing o-chlorophenylglycine according to claim 1, wherein the mass fraction of the sodium hydroxide solution in the S1 is 50%.
3. The method for producing o-chlorobenzeneglycine according to claim 1, wherein the molar ratio of chloroform to o-chlorobenzaldehyde is (1-3): 1.
4. The method for preparing o-chlorophenylglycine according to claim 1, wherein the reaction temperature in the step S1 is-5-2 ℃ and the reaction time is 1.5-2h.
5. The method for preparing o-chlorophenylglycine according to claim 1, wherein the reaction temperature in the step S2 is 40-50 ℃ and the reaction time is 10 hours.
6. The method for preparing o-chlorophenylglycine according to claim 1, wherein the post-treatment in S3 comprises: and adding a decoloring agent into the crude o-chlorophenylglycine to decolor, and then crystallizing, filtering, washing and drying to obtain the o-chlorophenylglycine.
7. The method for preparing o-chlorophenylglycine according to claim 6, wherein the drying temperature is 75-85 ℃.
8. The method for preparing o-chlorophenylglycine according to claim 6, wherein the washing is sequentially performed by water, ethanol and diethyl ether.
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| FR2760456B1 (en) * | 1997-03-05 | 2000-05-12 | Sanofi Sa | PROCESS FOR THE PREPARATION OF 2-THIENYL-ETHYLAMINE DERIVATIVES |
| CN103172527A (en) * | 2011-12-26 | 2013-06-26 | 湖北德洲科技发展有限公司 | Method for preparing clopidogrel synthetic intermediate-L-2-chlorophenylglycine methyl ester |
| CN111470994A (en) * | 2019-10-31 | 2020-07-31 | 上海开荣化工科技有限公司 | Preparation method of p-chlorobenzene glycine |
| CN114685300A (en) * | 2020-12-31 | 2022-07-01 | 抚顺顺能化工有限公司 | Preparation method of o-chlorophenylglycine |
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