CN112479853A - Preparation method of D-2-chloropropionyl chloride and D-2-chloropropionyl chloride - Google Patents
Preparation method of D-2-chloropropionyl chloride and D-2-chloropropionyl chloride Download PDFInfo
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- CN112479853A CN112479853A CN202011307441.8A CN202011307441A CN112479853A CN 112479853 A CN112479853 A CN 112479853A CN 202011307441 A CN202011307441 A CN 202011307441A CN 112479853 A CN112479853 A CN 112479853A
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Abstract
The invention is suitable for the technical field of synthesis of medical intermediates, and provides a preparation method of D-2-chloropropionyl chloride and the D-2-chloropropionyl chloride, which comprise the following steps: adding L-ethyl lactate and a catalyst into a reaction container, dropwise adding thionyl chloride at-10 ℃, heating to 65-70 ℃ and carrying out heat preservation reaction; after the reaction is finished, cooling to 10-30 ℃, and carrying out treatments such as reduced pressure concentration and the like to obtain D-2-ethyl chloropropionate; adding resin, anhydrous formic acid and water, heating to 70-100 ℃, and reacting for 2-5 h; after the reaction is finished, cooling to 10-30 ℃, and carrying out filtration and distillation treatment to obtain D-2-chloropropionic acid; and then dropwise adding thionyl chloride at 0-5 ℃, heating to 45-65 ℃ for heat preservation reaction, and carrying out reduced pressure concentration and distillation treatment to obtain the product. The invention realizes the large-scale production of D-2-chloropropionyl chloride at the level of 10 kilograms, has high yield and high purity, can recycle the catalyst and does not need rectification equipment.
Description
Technical Field
The invention belongs to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of D-2-chloropropionyl chloride and the D-2-chloropropionyl chloride.
Background
D-2-chloropropionyl chloride is an important intermediate of alanyl glutamine, an important parenteral nutrition agent, and alanyl glutamine is a component of parenteral nutrition and is suitable for patients needing to be supplemented with glutamine, including patients in catabolic and hypermetabolic states. Meanwhile, the D-2-chloropropionyl chloride is also the starting material of the anti-inflammatory analgesic medicament loxoprofen sodium.
The existing synthesis method of D-2-chloropropionyl chloride mainly takes anhydrous L-lactic acid or L-lactic acid ester as a raw material; wherein, anhydrous L-lactic acid is used as a raw material, and is catalyzed by a chlorination reagent thionyl chloride in organic nitrogen alkali such as pyridine to synthesize D-2-chloropropionyl chloride in one step. The anhydrous L-lactic acid can be partially self-polymerized, the content of the raw materials of the polylactic acid is reduced, and a large amount of commercially available L-lactic acid is aqueous and cannot be used in a water-repellent reaction system such as thionyl chloride, so that the method limits large-scale production. Meanwhile, the method adopts a one-step method for synthesis, the amount of byproducts is large, and the subsequent rectification and separation difficulty is high.
In addition, in the prior art, D-2-chloropropionyl chloride is synthesized by adopting L-methyl lactate to replace anhydrous L-lactic acid as a raw material through three steps of chlorination, hydrolysis and chloric acylation. However, in the step of synthesizing D-2-chloropropionic acid by hydrolyzing the D-2-chloropropionic acid ethyl ester, a sodium hydroxide aqueous solution is used as a reaction system, the chloro group of the D-2-chloropropionic acid ethyl ester has hydrolysis risk, hydrochloric acid is needed for adjusting pH in post-treatment, chloroform is needed for multiple extraction, the operation is complex, and the yield is low. Meanwhile, the product D-2-chloropropionyl chloride prepared by the method needs rectification separation, so that the equipment and energy consumption cost of large-scale production are increased.
Therefore, the existing D-2-chloropropionyl chloride synthesis method has the problems of low yield, incapability of recycling reagents and high cost caused by the need of introducing rectification equipment.
Disclosure of Invention
The embodiment of the invention aims to provide a preparation method of D-2-chloropropionyl chloride, and aims to solve the problems of low yield, incapability of recycling reagents and high cost caused by the need of introducing rectification equipment in the conventional synthesis method of D-2-chloropropionyl chloride.
The embodiment of the invention is realized by a preparation method of D-2-chloropropionyl chloride, which comprises the following steps:
adding L-ethyl lactate and a catalyst into a reaction container, dropwise adding thionyl chloride at the temperature of-10 ℃, heating to 65-70 ℃ after the dropwise adding of the thionyl chloride is completed, and carrying out heat preservation reaction, wherein the weight ratio of the L-ethyl lactate to the catalyst is 1: 0.003-0.009, and the weight ratio of the L-ethyl lactate to the thionyl chloride is 1: 1.0-1.3;
after the heat preservation reaction is finished, reducing the temperature to 10-30 ℃, and performing reduced pressure concentration, washing, drying and filtering treatment to obtain D-2-ethyl chloropropionate;
adding resin, anhydrous formic acid and water into the D-2-ethyl chloropropionate, heating to 70-100 ℃, and reacting for 2-5 h, wherein the weight ratio of the D-2-ethyl chloropropionate to the anhydrous formic acid is 1: 0.8-1.3, and the water content of the system is 7-15%;
after the reaction is finished, cooling to 10-30 ℃, and carrying out filtration and distillation treatment to obtain D-2-chloropropionic acid;
dropwise adding thionyl chloride into the D-2-chloropropionic acid at the temperature of 0-5 ℃, and after the thionyl chloride is dropwise added, heating to 45-65 ℃ for heat preservation reaction, wherein the weight ratio of the D-2-chloropropionic acid to the thionyl chloride is 1: 1.1-1.4;
after the heat preservation reaction is finished, carrying out reduced pressure concentration and distillation treatment to obtain the D-2-chloropropionyl chloride.
Another object of an embodiment of the present invention is D-2-chloropropionyl chloride, which D-2-chloropropionyl chloride has been prepared by a process for the preparation of D-2-chloropropionyl chloride as claimed in any of claims 1 to 9.
According to the preparation method of the D-2-chloropropionyl chloride, the high-purity D-2-chloropropionyl chloride is prepared by using the L-ethyl lactate as a starting material through three-step parameter optimization of chlorination, hydrolysis, chloric acylation and the like and introduction of catalyst resin in the hydrolysis step, the single-step average yield verified by 10 kilograms reaches 93.4%, and the purity is 99.4%. On the other hand, the invention introduces a high-efficiency catalytic reaction system through the hydrolysis step and optimizes the parameters of the other steps, and can separate out the high-purity product D-2-chloropropionyl chloride by adopting conventional distillation, thereby saving the use of a rectifying tower during large-scale production and obviously reducing the production cost.
Drawings
FIG. 1 is a GC spectrum of a D-2-chloropropionyl chloride product provided in example 1 of the present invention;
FIG. 2 is a HNMR spectrum of a D-2-chloropropionyl chloride product provided in example 1 of the present invention;
FIG. 3 is a GC spectrum of a D-2-chloropropionyl chloride product provided in example 2 of the present invention;
FIG. 4 is a HNMR spectrum of a D-2-chloropropionyl chloride product provided in example 2 of the present invention;
FIG. 5 is a GC spectrum of a D-2-chloropropionyl chloride product provided in example 3 of the present invention;
FIG. 6 is a HNMR spectrum of a D-2-chloropropionyl chloride product provided in example 3 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention aims to solve the problems of low yield, incapability of recycling reagents and high cost caused by the need of introducing rectification equipment in the existing D-2-chloropropionyl chloride synthesis method, and provides a preparation method of D-2-chloropropionyl chloride, which adopts L-ethyl lactate as a starting material, prepares high-purity D-2-chloropropionyl chloride by three-step parameter optimization of chlorination, hydrolysis, chloric acylation and the like and introduction of catalyst resin in a hydrolysis step, has the single-step average yield of 93.4 percent and the purity of 99.4 percent verified by 10 kg, and compared with the prior art, on one hand, the invention adopts a resin/formic acid catalytic system in the hydrolysis step, optimizes the water content of the system, effectively inhibits the hydrolyzed impurities of ortho-chloro groups, and efficiently improves the yield and the purity of the intermediate D-2-chloropropionic acid, the resin/formic acid can be recycled, so that the material cost is effectively reduced; on the other hand, the invention introduces a high-efficiency catalytic reaction system through the hydrolysis step and optimizes the parameters of the other steps, and can separate out the high-purity product D-2-chloropropionyl chloride by adopting conventional distillation, thereby saving the use of a rectifying tower during large-scale production and obviously reducing the production cost.
In the embodiment of the invention, L-ethyl lactate is taken as a starting material, and D-2-chloropropionyl chloride is prepared by three steps of chlorination, hydrolysis and chloric acylation, wherein the reaction formula is as follows:
in an embodiment of the invention, the preparation method of the D-2-chloropropionyl chloride comprises the following steps:
step S101, adding L-ethyl lactate and a catalyst into a reaction container, dropwise adding thionyl chloride at the temperature of-10 ℃, and heating to 65-70 ℃ for heat preservation reaction after the completion of dropwise adding of the thionyl chloride; the weight ratio of the L-ethyl lactate to the catalyst is 1: 0.003-0.009, and the weight ratio of the L-ethyl lactate to the thionyl chloride is 1: 1.0-1.3.
In the embodiment of the invention, the catalyst is pyridine, N-dimethylformamide or other tertiary amine organic bases, and pyridine is preferred.
In a preferred embodiment of the present invention, the step of adding L-ethyl lactate and a catalyst into a reaction vessel, adding thionyl chloride dropwise at a temperature of-10 to 10 ℃, and after the addition of the thionyl chloride is completed, raising the temperature to 65 to 70 ℃ for a heat preservation reaction includes:
adding L-ethyl lactate and a catalyst into a reaction container, dropwise adding thionyl chloride at the temperature of-5 ℃, heating to 65-70 ℃ after the dropwise adding of the thionyl chloride is completed, carrying out heat preservation reaction, and carrying out heat preservation reaction for 3 hours.
In a preferred embodiment of the present invention, the weight ratio of the ethyl L-lactate to the catalyst is preferably 1: 0.006; the weight ratio of the ethyl L-lactate to the thionyl chloride is preferably 1: 1.1.
And S102, after the heat preservation reaction is finished, reducing the temperature to 10-30 ℃, and carrying out reduced pressure concentration, washing, drying and filtering treatment to obtain the D-2-ethyl chloropropionate.
In the embodiment of the invention, the temperature in the reaction bottle is reduced to 10-30 ℃, the thionyl chloride and the acid gas are removed by decompression and concentration, the reaction bottle is washed by water, dried by anhydrous sodium sulfate and filtered to obtain the D-2-ethyl chloropropionate.
In the step S103, resin, anhydrous formic acid and water are added into the D-2-ethyl chloropropionate, the temperature is raised to 70-100 ℃, the reaction lasts for 2-5 hours, the weight ratio of the D-2-ethyl chloropropionate to the anhydrous formic acid is 1: 0.8-1.3, and the water content of the system is 7.9% -10.2%.
In the embodiment of the invention, the resin is 732 type cation exchange resin with sulfonic acid groups, and the resin can be recycled after being activated.
In a preferred embodiment of the invention, the weight ratio of ethyl D-2-chloropropionate to anhydrous formic acid is preferably 1:1.
In a preferred embodiment of the present invention, the water content of the system is preferably 8% to 10%.
And step S104, after the reaction is finished, cooling to 10-30 ℃, and carrying out filtration and distillation treatment to obtain the D-2-chloropropionic acid.
In a preferred embodiment of the invention, after the reaction is finished, the temperature is reduced to 10-30 ℃, and the step of filtering and distilling is performed to obtain the D-2-chloropropionic acid, which comprises the following steps:
and after the reaction is finished, cooling to 10-30 ℃, filtering the reaction liquid, distilling the filtrate at normal pressure to remove formic acid and byproduct ethanol, and then carrying out reduced pressure distillation, wherein the internal temperature is controlled to be less than or equal to 90 ℃, and the vacuum degree is controlled to be greater than or equal to 0.095Mpa to obtain the D-2-chloropropionic acid.
In the step S105, under the condition that the temperature is 0-5 ℃, thionyl chloride is dripped into the D-2-chloropropionic acid, after the thionyl chloride is dripped, the temperature is raised to 45-65 ℃ for heat preservation reaction, and the weight ratio of the D-2-chloropropionic acid to the thionyl chloride is 1: 1.1-1.4.
In a preferred embodiment of the invention, the weight ratio of D-2-chloropropionic acid to thionyl chloride is 1: 1.3.
In a preferred embodiment of the invention, the step of dropwise adding thionyl chloride into the D-2-chloropropionic acid at a temperature of 0-5 ℃, and after the completion of dropwise adding of the thionyl chloride, raising the temperature to 45-65 ℃ for a heat preservation reaction includes:
dropwise adding thionyl chloride into the D-2-chloropropionic acid at the temperature of 0-5 ℃, and after the thionyl chloride is dropwise added, heating to 50-55 ℃ for heat preservation reaction.
And step S106, after the heat preservation reaction is finished, carrying out reduced pressure concentration and distillation treatment to obtain the D-2-chloropropionyl chloride.
In a preferred embodiment of the present invention, the step of performing vacuum concentration and distillation treatment after the heat preservation reaction is finished to obtain D-2-chloropropionyl chloride comprises:
after the heat preservation reaction is finished, concentrating under reduced pressure to remove thionyl chloride and acid gas, distilling the product under normal pressure, controlling the temperature to be less than or equal to 115 ℃, and collecting fractions at the temperature of 102 ℃ and 113 ℃ to obtain D-2-chloropropionyl chloride.
In a preferred embodiment of the invention, the step of adding resin, anhydrous formic acid and water into the D-2-ethyl chloropropionate, heating to 70-100 ℃, and reacting for 2-5 hours comprises the following steps:
adding resin, anhydrous formic acid and water into the D-2-ethyl chloropropionate, heating to 85-90 ℃, and reacting for 3 hours.
The embodiment of the invention also provides D-2-chloropropionyl chloride, and the D-2-chloropropionyl chloride is prepared by the preparation method of the D-2-chloropropionyl chloride.
Examples of certain embodiments of the invention are given below, which are not intended to limit the scope of the invention.
In addition, it should be noted that the numerical values given in the following examples are as precise as possible, but those skilled in the art will understand that each numerical value should be understood as a divisor rather than an absolutely exact numerical value due to measurement errors and experimental operational problems that cannot be avoided. For example, it should be understood that the weight values of the respective raw materials for preparing D-2-chloropropionyl chloride with respect to the respective examples may have an error of ± 2 or ± 1 due to an error of a weighing instrument.
Example 1
Step a, preparation of D-2-ethyl chloropropionate
110g L-Ethyl lactate, 0.66g pyridine, was added to the reaction flask. The temperature was lowered to-5 ℃ and 132g of thionyl chloride started to be added dropwise. Controlling the reaction temperature to be below 0 ℃, after dropwise adding for 1.5h, raising the temperature in a reaction bottle to 69 ℃, preserving heat for reaction for 3h, after heat preservation, reducing the temperature in the reaction bottle to 25 ℃, removing thionyl chloride and acid gas under reduced pressure, washing with 20g of water, drying with anhydrous sodium sulfate, and filtering to obtain 126g D-ethyl 2-chloropropionate, wherein the yield is 98.9%, and the purity is 99.5%.
Step b, preparation of D-2-chloropropionic acid
50g of resin, 151g of anhydrous formic acid and 126g D-ethyl 2-chloropropionate are sequentially put into a reaction bottle, and a proper amount of purified water is added, so that the water content of a detection system is 7.6%. The temperature is increased to 84 ℃ and the reaction lasts for 3.5 h. After the reaction is finished, cooling to 21 ℃, filtering the reaction liquid, distilling the filtrate at normal pressure to remove formic acid and byproduct ethanol, then distilling at reduced pressure, controlling the internal temperature to be less than or equal to 90 ℃ and the vacuum degree to be more than or equal to 0.095Mpa, collecting fractions at 80-90 ℃ to obtain 88g D-2-chloropropionic acid, wherein the yield is 87.6%, and the purity is 99.4%.
Step c, preparation of D-2-chloropropionyl chloride
Adding 88g D-2-chloropropionic acid into a reaction bottle, reducing the temperature to 3 ℃, starting to slowly dropwise add 123g of thionyl chloride, controlling the reaction temperature to be below 5 ℃, after dropwise addition is finished within 1.5h, raising the temperature to 60 ℃, and carrying out heat preservation reaction for 3 h. After the reaction is finished, concentrating under reduced pressure to remove thionyl chloride and acid gas, distilling the product under normal pressure, controlling the temperature to be less than or equal to 115 ℃, and collecting the fraction at 102 ℃ and 113 ℃ to obtain 94g D-2-chloropropionyl chloride, wherein the yield is 91.3 percent, and the purity is 98.8 percent.
FIG. 1 is a GC spectrum of a D-2-chloropropionyl chloride product prepared in example 1 of the present invention: the retention time of the D-2-chloropropionyl chloride product is 8.69min, and the peak area content is 98.8%. The retention time of the maximum single impurity is 9.43min, and the peak area content is 0.46%.
FIG. 2 is a HNMR spectrogram of the D-2-chloropropionyl chloride product prepared in example 1 of the present invention: the D-2-chloropropionyl chloride product has 4 hydrogen atoms, and is detected in nuclear magnetic hydrogen spectrum detection. Wherein 1 hydrogen atom of the methine group shows a peak at a chemical shift δ of 4.63 to 4.68, and shows a quartet under the influence of the ortho-methyl group. 3 hydrogen atoms of the methyl group generate peaks at a chemical shift delta of 1.81-1.82, and the peaks are influenced by ortho-methine groups to form double peaks. The chemical shift δ is 7.26, which is the peak of deuterated chloroform solvent.
Example 2
Step a, preparation of D-2-ethyl chloropropionate
125g L-Ethyl lactate, 0.75g pyridine, was added to the reaction flask. The temperature was lowered to 0 ℃ and 138g of thionyl chloride were started dropwise. Controlling the reaction temperature to be below 5 ℃, after dropwise adding for 2 hours, raising the temperature in a reaction bottle to 66 ℃, preserving the heat for reaction for 3 hours, after finishing preserving the heat, reducing the temperature in the reaction bottle to 27 ℃, decompressing and pumping out thionyl chloride and acid gas, washing 25g of water, drying anhydrous sodium sulfate, and filtering to obtain 143g D-2-ethyl chloropropionate, wherein the yield is 99.1%, and the purity is 99.4%.
Step b, preparation of D-2-chloropropionic acid
57g of resin, 145g of anhydrous formic acid and 143g D-2-ethyl chloropropionate are sequentially added into a reaction bottle, and a proper amount of purified water is added, so that the water content of a detection system is 9.1%. The temperature is raised to 88 ℃ and the reaction lasts for 3 h. After the reaction is finished, cooling to 24 ℃, filtering the reaction liquid, distilling the filtrate at normal pressure to remove formic acid and byproduct ethanol, then distilling at reduced pressure, controlling the internal temperature to be less than or equal to 90 ℃ and the vacuum degree to be more than or equal to 0.095Mpa, collecting fractions at 80-90 ℃ to obtain 100g D-2-chloropropionic acid, wherein the yield is 88.3%, and the purity is 99.5%.
Step c, preparation of D-2-chloropropionyl chloride
Adding 100g D-2-chloropropionic acid into a reaction bottle, cooling to 0 ℃, starting to slowly dropwise add 130g thionyl chloride, controlling the reaction temperature to be below 5 ℃, after dropwise addition for 2h, heating to 54 ℃, and keeping the temperature for reaction for 3 h. After the reaction is finished, concentrating under reduced pressure to remove thionyl chloride and acid gas, distilling the product under normal pressure, controlling the temperature to be less than or equal to 115 ℃, and collecting the fraction at 102 ℃ and 113 ℃ to obtain 106g D-2-chloropropionyl chloride, wherein the yield is 90.4 percent, and the purity is 99.2 percent.
FIG. 3 is a GC spectrum of the D-2-chloropropionyl chloride product prepared in example 2 of the present invention: the retention time of the D-2-chloropropionyl chloride product is 8.69min, and the peak area content is 99.2%. The retention time of the maximum single impurity is 9.77min, and the peak area content is 0.28%.
FIG. 4 is a HNMR spectrogram of the D-2-chloropropionyl chloride product prepared in example 2 of the present invention: the D-2-chloropropionyl chloride product has 4 hydrogen atoms, and is detected in nuclear magnetic hydrogen spectrum detection. Wherein 1 hydrogen atom of the methine group shows a peak at a chemical shift δ of 4.63 to 4.68, and shows a quartet under the influence of the ortho-methyl group. 3 hydrogen atoms of the methyl group generate peaks at a chemical shift delta of 1.81-1.82, and the peaks are influenced by ortho-methine groups to form double peaks. The chemical shift δ is 7.26, which is the peak of deuterated chloroform solvent.
Example 3
Step a, preparation of D-2-ethyl chloropropionate
18.5Kg of L-ethyl lactate, 0.11Kg of pyridine were added to the reaction flask. The temperature is reduced to 0 ℃ and 20.4Kg of thionyl chloride is started to be added dropwise. Controlling the reaction temperature to be below 5 ℃, after dropwise adding is finished for 3.5 hours, raising the temperature in a reaction bottle to 65 ℃, preserving the heat for reaction for 3 hours, after the heat preservation is finished, lowering the temperature in the reaction bottle to 28 ℃, decompressing and pumping out thionyl chloride and acid gas, washing with 3.8Kg of water, drying with anhydrous sodium sulfate, and filtering to obtain 21.2Kg of D-2-ethyl chloropropionate, wherein the yield is 99.2%, and the purity is 99.6%.
Step b, preparation of D-2-chloropropionic acid
8.5Kg of resin, 21.3Kg of anhydrous formic acid and 21.2Kg of ethyl D-2-chloropropionate are put into a reaction bottle in sequence, and a proper amount of purified water is added, so that the water content of the detection system is 8.8 percent. The temperature is raised to 87 ℃ and the reaction lasts for 3 h. After the reaction is finished, cooling to 26 ℃, filtering the reaction liquid, distilling the filtrate at normal pressure to remove formic acid and byproduct ethanol, then distilling at reduced pressure, controlling the internal temperature to be less than or equal to 90 ℃ and the vacuum degree to be more than or equal to 0.095Mpa, collecting fractions at 80-90 ℃ to obtain 15.1Kg of D-2-chloropropionic acid, wherein the yield is 89.5%, and the purity is 99.5%.
Step c, preparation of D-2-chloropropionyl chloride
Adding 15.1Kg of D-2-chloropropionic acid into a reaction bottle, cooling to 2 ℃, starting to slowly dropwise add 19.6Kg of thionyl chloride, controlling the reaction temperature to be below 5 ℃, raising the temperature to 52 ℃ after dropwise addition is finished for 4 hours, and keeping the temperature for reaction for 3 hours. After the reaction is finished, concentrating under reduced pressure to remove thionyl chloride and acid gas, distilling the product under normal pressure, controlling the temperature to be less than or equal to 115 ℃, and collecting the fraction at 102-113 ℃ to obtain 16.2Kg of D-2-chloropropionyl chloride, wherein the yield is 91.9 percent, and the purity is 99.4 percent.
FIG. 5 is a GC spectrum of a D-2-chloropropionyl chloride product prepared in example 3 of the present invention: the retention time of the D-2-chloropropionyl chloride product is 8.79min, and the peak area content is 99.4%. The retention time of the maximum single impurity is 11.14min, and the peak area content is 0.17%.
FIG. 6 is a HNMR spectrum of a D-2-chloropropionyl chloride product prepared in example 3 of the present invention: the D-2-chloropropionyl chloride product has 4 hydrogen atoms, and is detected in nuclear magnetic hydrogen spectrum detection. Wherein 1 hydrogen atom of the methine group shows a peak at a chemical shift δ of 4.63 to 4.68, and shows a quartet under the influence of the ortho-methyl group. 3 hydrogen atoms of the methyl group generate peaks at a chemical shift delta of 1.81-1.83, and the peaks are influenced by ortho-methine groups to form double peaks. The chemical shift δ is 7.26, which is the peak of deuterated chloroform solvent.
In the embodiment of the invention, relevant optimization experimental design is carried out on each process parameter of the preparation method of the D-2-chloropropionyl chloride in the early research and development process, wherein the usage amount of the catalyst, the usage amount of the thionyl chloride and the dropping temperature of the thionyl chloride in the preparation process of the D-2-chloropropionyl chloride are optimized, and the following experimental groups 1 to 14 are provided.
Experimental groups 1-5: the use amount of pyridine: the purity and yield of ethyl D-2-chloropropionate as an intermediate are shown in Table 1, when the weight ratio of ethyl L-lactate to pyridine is 1:0.001, 1:0.003, 1:0.006, 1:0.009, and 1:0.012, respectively.
The specific experimental process is as follows: adding L-ethyl lactate and pyridine into the reaction flask, wherein the weight ratio of the L-ethyl lactate to the pyridine in the five experiments is 1:0.001, 1:0.003, 1:0.006, 1:0.009 and 1:0.012 respectively. And (3) cooling to 5 ℃, beginning to dropwise add thionyl chloride, controlling the temperature to be 5-10 ℃, and controlling the weight ratio of the L-ethyl lactate to the thionyl chloride to be 1: 1.3. And after the dropwise addition, raising the temperature in the reaction bottle to 65 ℃, preserving the heat for reaction for 3 hours, after the heat preservation is finished, reducing the temperature in the reaction bottle to 23 ℃, decompressing and concentrating to remove thionyl chloride and acid gas, washing with water, drying with anhydrous sodium sulfate, and filtering to obtain the D-2-chloropropionic acid ethyl ester.
TABLE 1
Experimental groups 6-11: the usage amount of thionyl chloride: the purity and yield of the intermediate D-2-ethyl chloropropionate corresponding to the weight ratio of L-ethyl lactate to thionyl chloride of 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3 and 1:1.4 are shown in Table 2.
The specific experimental process is as follows: adding L-ethyl lactate and pyridine into a reaction bottle, wherein the weight ratio of the L-ethyl lactate to the pyridine is 1: 0.006. And (3) dropping thionyl chloride when the temperature is reduced to 7 ℃, controlling the temperature to be 5-10 ℃, wherein the weight ratios of the L-ethyl lactate to the thionyl chloride in six groups of experiments are 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3 and 1:1.4 respectively. And after the dropwise addition, raising the temperature in the reaction bottle to 70 ℃, preserving the heat for reaction for 3.5 hours, after the heat preservation is finished, reducing the temperature in the reaction bottle to 21 ℃, decompressing and concentrating to remove thionyl chloride and acid gas, washing with water, drying with anhydrous sodium sulfate, and filtering to obtain the D-2-chloropropionic acid ethyl ester.
TABLE 2
Experimental groups 12-14: temperature of thionyl chloride addition: the purity and yield of the intermediate D-2-ethyl chloropropionate corresponding to the temperature of-10 to-5 ℃, the temperature of-5 to 5 ℃ and the temperature of 5 to 10 ℃ are shown in Table 3.
The specific experimental process is as follows: adding L-ethyl lactate and pyridine into a reaction bottle, wherein the weight ratio of the L-ethyl lactate to the pyridine is 1: 0.006. Dropping the temperature to-10 ℃, starting to drop thionyl chloride, controlling the dropping temperatures of three groups of experiments to be-10-5 ℃, 5-5 ℃ and 5-10 ℃ respectively, and controlling the weight ratio of the L-ethyl lactate to the thionyl chloride to be 1: 1.3. And after the dropwise addition, raising the temperature in the reaction bottle to 70 ℃, preserving the heat for reaction for 3 hours, after the heat preservation is finished, reducing the temperature in the reaction bottle to 25 ℃, decompressing and concentrating to remove thionyl chloride and acid gas, washing with water, drying with anhydrous sodium sulfate, and filtering to obtain the D-2-chloropropionic acid ethyl ester.
TABLE 3
| Experimental group | Temperature of dropping thionyl chloride | Purity of intermediate D-2-ethyl chloropropionate | Yield of |
| 12 | -10～-5℃ | 98.96％ | 97.9％ |
| 13 | -5～5℃ | 99.04％ | 98.2％ |
| 14 | 5～10℃ | 98.83％ | 97.4％ |
Wherein, the using amount of the anhydrous formic acid and the water content of the reaction system in the preparation process of the D-2-chloropropionic acid are optimized, and the specific details are shown in the following experimental groups 15-25.
Experimental groups 15-19: the use amount of the anhydrous formic acid is as follows: the purity and yield of the intermediate D-2-ethyl chloropropionate corresponding to the weight ratio of D-2-ethyl chloropropionate to anhydrous formic acid of 1:0.6, 1:0.8, 1:1, 1:1.3 and 1:1.5 are shown in Table 4.
The specific experimental process is as follows: resin, anhydrous formic acid, a proper amount of purified water and D-2-ethyl chloropropionate are sequentially added into a reaction bottle, the weight ratio of the D-2-ethyl chloropropionate to the resin is 1:0.4, the weight ratios of the D-2-ethyl chloropropionate to the anhydrous formic acid in five experiments are respectively 1:0.6, 1:0.8, 1:1, 1:1.3 and 1:1.5, and the water content of the system is 7.1 percent. The temperature is raised to 83 ℃ and the reaction is carried out for 4.5 h. After the reaction is finished, cooling to 24 ℃, filtering the reaction liquid, distilling the filtrate at normal pressure to remove formic acid and byproduct ethanol, then distilling at reduced pressure, controlling the internal temperature to be less than or equal to 90 ℃ and the vacuum degree to be more than or equal to 0.095Mpa, and obtaining the D-2-chloropropionic acid.
TABLE 4
Experimental groups 20-25: the purity and yield of intermediate D-2-chloropropionic acid ethyl ester with the water content of 6.1%, 6.8%, 7.9%, 10.2%, 15.1% and 15.9% in the reaction system are shown in Table 5.
The specific experimental process is as follows: resin, anhydrous formic acid, a proper amount of purified water and D-2-ethyl chloropropionate are sequentially added into a reaction bottle, the weight ratio of the D-2-ethyl chloropropionate to the resin is 1:0.4, the weight ratio of the D-2-ethyl chloropropionate to the anhydrous formic acid is 1:1, and the water contents of six experimental systems are respectively 6.7%, 6.8%, 7.9%, 10.2%, 15.1% and 15.2%. The temperature is increased to 90 ℃ and the reaction is carried out for 5 h. After the reaction is finished, cooling to 25 ℃, filtering the reaction liquid, distilling the filtrate at normal pressure to remove formic acid and byproduct ethanol, then distilling at reduced pressure, controlling the internal temperature to be less than or equal to 90 ℃ and the vacuum degree to be more than or equal to 0.095Mpa, and obtaining the D-2-chloropropionic acid.
TABLE 5
| Experimental group | Water content of system | Purity of intermediate D-2-chloropropionic acid | Yield of |
| 20 | 6.7％ | 96.99％ | 83.9％ |
| 21 | 6.8％ | 97.79％ | 87.8％ |
| 22 | 7.9％ | 99.30％ | 89.6％ |
| 23 | 10.2％ | 99.35％ | 90.2％ |
| 24 | 15.1％ | 98.33％ | 87.5％ |
| 25 | 15.2％ | 95.02％ | 82.6％ |
The usage amount of thionyl chloride in the preparation process of D-2-chloropropionyl chloride is optimized, and the optimization method is shown in the following experimental groups 26-31.
Experimental groups 26-31: the usage amount of thionyl chloride: the purity and yield of intermediate D-ethyl 2-chloropropionate corresponding to 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4 and 1:1.5 are shown in table 6.
The specific experimental process is as follows: adding D-2-chloropropionic acid into a reaction bottle, cooling to 2 ℃, and starting to slowly dropwise add thionyl chloride, wherein the weight ratio of the D-2-chloropropionic acid to the thionyl chloride in six experiments is 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4 and 1:1.5 respectively. After the dropwise addition, the temperature is raised to 59 ℃ and the reaction is carried out for 3 hours under the condition of heat preservation. After the reaction is finished, concentrating under reduced pressure to remove thionyl chloride and acid gas, distilling the product under normal pressure, controlling the temperature to be less than or equal to 115 ℃, and collecting fractions at 102 ℃ and 113 ℃ to obtain D-2-chloropropionyl chloride.
TABLE 6
| Experimental group | Weight ratio of D-2-chloropropionic acid to thionyl chloride | Purity of D-2-chloropropionyl chloride | Yield of |
| 26 | 1:1.0 | 92.16％ | 80.3％ |
| 27 | 1:1.1 | 98.57％ | 87.2％ |
| 28 | 1:1.2 | 99.02％ | 90.5％ |
| 29 | 1:1.3 | 99.11％ | 90.7％ |
| 30 | 1:1.4 | 98.81％ | 89.6％ |
| 31 | 1:1.5 | 93.88％ | 81.9％ |
To sum up, according to the preparation method of D-2-chloropropionyl chloride provided by the embodiment of the invention, L-ethyl lactate is used as a starting material, and through parameter optimization of three steps of chlorination, hydrolysis, chloric acylation and the like and introduction of catalyst resin in the hydrolysis step, high-purity D-2-chloropropionyl chloride is prepared, the single-step average yield verified by 10 kg reaches 93.4%, and the purity is 99.4%. On the other hand, the invention introduces a high-efficiency catalytic reaction system through the hydrolysis step and optimizes the parameters of the other steps, and can separate out the high-purity product D-2-chloropropionyl chloride by adopting conventional distillation, thereby saving the use of a rectifying tower during large-scale production and obviously reducing the production cost.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A preparation method of D-2-chloropropionyl chloride is characterized by comprising the following steps:
adding L-ethyl lactate and a catalyst into a reaction container, dropwise adding thionyl chloride at the temperature of-10 ℃, heating to 65-70 ℃ after the dropwise adding of the thionyl chloride is completed, and carrying out heat preservation reaction, wherein the weight ratio of the L-ethyl lactate to the catalyst is 1: 0.003-0.009, and the weight ratio of the L-ethyl lactate to the thionyl chloride is 1: 1.0-1.3;
after the heat preservation reaction is finished, reducing the temperature to 10-30 ℃, and performing reduced pressure concentration, washing, drying and filtering treatment to obtain D-2-ethyl chloropropionate;
adding resin, anhydrous formic acid and water into the D-2-ethyl chloropropionate, heating to 70-100 ℃, and reacting for 2-5 h, wherein the weight ratio of the D-2-ethyl chloropropionate to the anhydrous formic acid is 1: 0.8-1.3, and the water content of the system is 7-15%;
after the reaction is finished, cooling to 10-30 ℃, and carrying out filtration and distillation treatment to obtain D-2-chloropropionic acid;
dropwise adding thionyl chloride into the D-2-chloropropionic acid at the temperature of 0-5 ℃, and after the thionyl chloride is dropwise added, heating to 45-65 ℃ for heat preservation reaction, wherein the weight ratio of the D-2-chloropropionic acid to the thionyl chloride is 1: 1.1-1.4;
after the heat preservation reaction is finished, carrying out reduced pressure concentration and distillation treatment to obtain the D-2-chloropropionyl chloride.
2. The process for the preparation of D-2-chloropropionyl chloride according to claim 1, characterized in that the catalyst is pyridine, N-dimethylformamide or a tertiary amine organic base.
3. The preparation method of D-2-chloropropionyl chloride according to claim 1, characterized in that the step of adding L-ethyl lactate and a catalyst into a reaction vessel, dropwise adding thionyl chloride at a temperature of-10 to 10 ℃, and after the completion of dropwise adding of thionyl chloride, raising the temperature to 65 to 70 ℃ for heat preservation reaction comprises:
adding L-ethyl lactate and a catalyst into a reaction container, dropwise adding thionyl chloride at the temperature of-5 ℃, heating to 65-70 ℃ after the dropwise adding of the thionyl chloride is completed, carrying out heat preservation reaction, and carrying out heat preservation reaction for 3 hours.
4. The process for the preparation of D-2-chloropropionyl chloride according to claim 1, characterized in that the weight ratio of the L-ethyl lactate to the catalyst is 1: 0.006; the weight ratio of the L-ethyl lactate to the thionyl chloride is 1: 1.1; the weight ratio of the D-2-chloropropionic acid to the thionyl chloride is 1: 1.3.
5. The process for the preparation of D-2-chloropropionyl chloride according to claim 1, characterized in that the weight ratio of ethyl D-2-chloropropionate to resin is 1: 0.4; the resin is 732 type cation exchange resin with sulfonic acid groups.
6. The process for the preparation of D-2-chloropropionyl chloride according to claim 1, characterized in that the weight ratio of ethyl D-2-chloropropionate to anhydrous formic acid is 1: 1; the water content of the system is 7.9-10.2%.
7. The preparation method of D-2-chloropropionyl chloride according to claim 1, characterized in that after the reaction is finished, the temperature is reduced to 10-30 ℃, and the D-2-chloropropionyl chloride is obtained by filtration and distillation, and comprises the following steps:
and after the reaction is finished, cooling to 10-30 ℃, filtering the reaction liquid, distilling the filtrate at normal pressure to remove formic acid and byproduct ethanol, and then carrying out reduced pressure distillation, wherein the internal temperature is controlled to be less than or equal to 90 ℃, and the vacuum degree is controlled to be greater than or equal to 0.095Mpa to obtain the D-2-chloropropionic acid.
8. The preparation method of D-2-chloropropionyl chloride according to claim 1, characterized in that the step of performing reduced pressure concentration and distillation treatment after the heat preservation reaction is finished to obtain D-2-chloropropionyl chloride comprises the following steps:
after the heat preservation reaction is finished, concentrating under reduced pressure to remove thionyl chloride and acid gas, distilling the product under normal pressure, controlling the temperature to be less than or equal to 115 ℃, and collecting fractions at the temperature of 102 ℃ and 113 ℃ to obtain D-2-chloropropionyl chloride.
9. The preparation method of D-2-chloropropionyl chloride according to claim 1, characterized in that the step of adding resin, anhydrous formic acid and water into the ethyl D-2-chloropropionate, heating to 70-100 ℃ and reacting for 2-5 h comprises the following steps:
adding resin, anhydrous formic acid and water into the D-2-ethyl chloropropionate, heating to 85-90 ℃, and reacting for 3 hours.
10. D-2-chloropropionyl chloride, characterized in that the D-2-chloropropionyl chloride is prepared by a process for the preparation of D-2-chloropropionyl chloride as claimed in any of claims 1 to 9.
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