CN101284772B - Synthetic method of D-(+)-2-chloro-propanoyl chloride - Google Patents
Synthetic method of D-(+)-2-chloro-propanoyl chloride Download PDFInfo
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- CN101284772B CN101284772B CN2008100550561A CN200810055056A CN101284772B CN 101284772 B CN101284772 B CN 101284772B CN 2008100550561 A CN2008100550561 A CN 2008100550561A CN 200810055056 A CN200810055056 A CN 200810055056A CN 101284772 B CN101284772 B CN 101284772B
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Abstract
The invention relates to a method for synthesizing D-(+)-2-chloro-Propanoyl chloride, which is used for solving the problems that the product recovery rate of the prior synthetic method is low and the synthetic method is not suitable for industrial production. The method adopts the technical proposal that L-ethyl lactate and thionyl chloride react under the action of calcium fluoride catalyst to generate D-(+)-2-chloropropionic acid ethyl ester, D-(+)-2-chloropropionic acid ethyl ester is hydrolyzed under the action of caustic soda dissolving to generate D-(+)-2-chloropropionic acid, and D-(+)-2-chloropropionic acid reacts with the thionyl chloride to generate D-(+)-2-chloro-Propanoyl chloride. The method has the advantages that the method is novel, the process is simple, the product recovery rate is high, the cost of the catalyst is low, the catalyst is easy to obtain, the environment can not be affected, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic method of a kind of D-(+)-2-chloro propionyl chloride (being the D-2-chlorpromazine chloride).
Background technology
D-(+)-2-chloro propionyl chloride is the important intermediate of synthetic N (2)-L-alanyl-L-glutamine (power peptide), also is the starting raw material for medicines such as the main intermediate of medicines such as synthetic proglu-dipeptide and loxoprofen sodiums.Because L-glutaminate is the maximum amino acid of content in the blood of human body, have the important physical effect, but because the solubleness of L-glutaminate is little, poor heat stability, in the aqueous solution, easily be decomposed into Pyrrolidonecarboxylic acid and ammonia, harmful to human body, therefore limited L-glutaminate application clinically.And the solubleness height of N (2)-L-alanyl-L-glutamine in the aqueous solution, can tolerate high-temperature sterilization, good stability can be decomposed into L-glutaminate and L-L-Ala rapidly in human body, remedied the deficiency of L-glutaminate, therefore in the clinical substitute that is widely used as L-glutaminate.In known technology; existing D-(+)-2-chlorpromazine chloride synthetic method mainly is to be that L-ethyl lactate, L-methyl lactate are raw material with L-lactic acid; under the effect of basic catalyst pyridine or picoline, obtain the D-2-chloropropionate, obtain D-(+)-2-chlorpromazine chloride by D-(+)-2-chloropropionate direct hydrolysis, acidylate again.But because the amount of pyridine is a catalytic amount so that equimolar amount in the synthetic method of D-2-chloropropionate, but its yield is all lower, and the smell of pyridine influence environment, and the recycling of adding pyridine is handled and bothered, and suitability for industrialized production is brought very big inconvenience.
Summary of the invention
The present invention is used to solve the low problem of the synthetic method product yield of existing D-2-chlorpromazine chloride and provides that a kind of technology is easy, yield is high, supplementary material is cheap and easy to get, environmental protection, is suitable for D-(+)-2-chloro propionyl chloride synthetic method of suitability for industrialized production.
Addressing the above problem the technical scheme that is adopted is:
The synthetic method of-kind of D-(+)-2-chloro propionyl chloride, it adopts following steps:
A, L-ethyl lactate and thionyl chloride are reacted under the calcium fluoride catalyst effect, generate D-(+)-2-chloropropionate, temperature of reaction is 160 ℃～190 ℃, and the reaction times is 14～18 hours;
B, the hydrolysis under the sodium hydroxide solution effect of step a synthetic D-(+)-2-chloropropionate is obtained D-(+)-2-chloropropionic acid;
C, D-(+)-2-chloropropionic acid that step b is made obtain D-(+)-2-chloro propionyl chloride with the thionyl chloride reaction again.
The synthetic method of above-mentioned D-(+)-2-chloro propionyl chloride, L-ethyl lactate among the described step a: thionyl chloride: the mol ratio of Calcium Fluoride (Fluorspan) is 1.00: 1.02～1.07: 0.08～0.13.
The synthetic method of above-mentioned D-(+)-2-chloro propionyl chloride, D-2-chloropropionate in the hydrolysis reaction of D-2-chloropropionate under the sodium hydroxide solution effect among the described step b: the mol ratio of sodium hydroxide is 1.00: 1.10～1.18.
The synthetic method of above-mentioned D-(+)-2-chloro propionyl chloride, D-(+) among the described step b-hydrolysising reacting temperature of 2-chloropropionate under the sodium hydroxide solution effect is 45～60 ℃, the reaction times is 6～9 hours.
The synthetic method of above-mentioned D-(+)-2-chloro propionyl chloride, D-(+) among the described step C-2-chloropropionic acid: the mol ratio of thionyl chloride is 1.00: 1.18～1.23.
The present invention has solved the problem that existing D-(+)-2-chloro propionyl chloride synthetic method product yield is low, be unsuitable for suitability for industrialized production effectively.Test shows, it compared with prior art, have catalysts novelty, feasible process, product yield height, supplementary material is cheap and easy to get, recycling is simple, do not influence environment, be suitable for advantages such as suitability for industrialized production, be to produce the synthetic method that D-(+)-2-chlorpromazine chloride product is new, made D-(+)-2-chloro propionyl chloride can be widely used as the intermediate and the raw material of medicines such as synthetic N (2)-L-alanyl-L-glutamine (power peptide), proglu-dipeptide, Chemicals.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail.
The present invention by a large amount of experiments, grope, screening, optimize reaction conditions, selected for use inorganic salt Calcium Fluoride (Fluorspan) cheap and easy to get as catalyzer, utilize configuration conversion synthetic route in the Calcium Fluoride (Fluorspan) catalysis SN2 substitution reaction.Its chemical reaction structural formula is:
Embodiment 1
Step a, synthetic D-(+)-2-chloropropionate
The four-hole reaction flask of mechanical stirring and hydrogen chloride absorption device is equipped with in setting, add 125 gram sulfur oxychlorides and 10 gram calcium fluoride catalysts, under room temperature (actual is 27 ℃) condition, drip 100 gram L-ethyl lactates, be warming up to 65-70 ℃ after dripping off, constant temperature stirred 2 hours, be warming up to 168 ℃ of back flow reaction 15 hours, stopped reaction, reaction solution is cooled to room temperature (actual is 27 ℃), enter into rectifying still and carry out rectifying and obtain D-(+)-2-chloropropionate, productive rate is 89.6%, and the purity of product reaches 99.5%, chirality GC analyzes optical purity and reaches 97.1%, and the specific rotation of product is at+19.2 degree.
Step b, synthetic D-(+)-2-chloropropionic acid
Churned mechanically four-hole reaction flask is equipped with in setting, the sodium hydroxide solution and the 70 gram distilled water that add 70 grams 30%, drip 63 gram D-(+)-2-chloropropionates under room temperature (actual the is 27 ℃) condition, be warmed up to 50-60 ℃ of insulation after dripping off, hydrolysis reaction stopped in 6 hours, was cooled to room temperature, after the concentrated hydrochloric acid acidifying, with ethyl acetate extraction three times (ethyl acetate is on the upper strata), merge organic phase, use anhydrous magnesium sulfate drying again, after filtration, precipitation, change over to and carry out rectifying in the still kettle, make D-(+)-2-chloropropionic acid, yield is 83.2%, the purity of product reaches 98.1%, and the specific rotation of product is at+14.5 degree.
Step C, synthetic D-(+)-2-chloro propionyl chloride
Churned mechanically four-hole reactor is equipped with in setting, add 118 gram sulfur oxychlorides earlier, under room temperature (actual is 27 ℃) condition, drip 100 gram D-(+)-2-chloropropionic acids, drip off the back and under the 65-70 degree, reacted 4 hours stopped reaction, after cooling, go into to carry out rectifying in the still kettle, obtain D-(+)-2-chloro propionyl chloride product, yield is 85.4%, the purity of product reaches 98.1%, and specific rotation is-4.5.
Embodiment 2
Step a, synthetic D-(+)-2-chloropropionate
Mechanical stirring is equipped with in setting, the reactor of hydrogen chloride absorption device, add 240 kilograms of sulfur oxychlorides and 10 kilograms of calcium fluoride catalysts, start and stir, under room temperature (actual is 25 ℃) condition, feed rate with 5 kg/minute, add 200 kilograms of L-ethyl lactates, add the L-ethyl lactate after, be warming up to 65-70 ℃ of constant temperature and stirred 3 hours, be warmed up to 170 ℃ of back flow reaction 15 hours again, stopped reaction is cooled to room temperature (actual is 25 ℃), enters into rectifying still and carries out rectifying and obtain D-(+)-2-chloropropionate product, productive rate is 79.7%, the purity of product reaches 99.5%, and chirality GC analyzes optical purity and reaches 97.1%, and the specific rotation of product is at+19.2 degree.
Step b, synthetic D-(+)-2-chloropropionic acid
Churned mechanically reactor is equipped with in setting, add 140 kilograms of 140 kilogram 30% sodium hydroxide solution and distilled water, start and stir, under room temperature (actual is 25 ℃) condition, with the feed rate of 4 kg/minute, add 126 kilograms of D-(+)-2-chloropropionate, be warmed up to 55-60 ℃ of insulation after adding, hydrolysis reaction stopped in 8 hours, was cooled to room temperature, use the concentrated hydrochloric acid acidifying, use ethyl acetate extraction three times (ethyl acetate is on the upper strata) again, merge organic phase, behind anhydrous magnesium sulfate drying, again after filtration, precipitation, change over to and carry out rectifying in the still kettle, obtain the D-2-chloropropionic acid, yield is 68.5%, the purity of product reaches 97.6%, and the specific rotation of product is at+14.5 degree.
Step C, synthetic D-(+)-2-chloro propionyl chloride
Churned mechanically reactor is equipped with in setting, adds 236 kilograms of sulfur oxychlorides, starts to stir, under room temperature (actual is 25 ℃) condition,, add 200 kilograms of D-(+)-2-chloropropionic acid with the feed rate of 5 kg/minute, add the back under 65-70 degree condition, stirring reaction 4 hours after cooling, is gone into and is carried out rectifying in the still kettle again, obtain D-(+)-2-chloro propionyl chloride product, yield is 84.7%, and the purity of product reaches 97.8%, and specific rotation is-4.5.
Claims (5)
1. the synthetic method of a D-(+)-2-chloro propionyl chloride is characterized in that it comprises the steps:
A, L-ethyl lactate and thionyl chloride are reacted under the calcium fluoride catalyst effect, generate D-(+)-2-chloropropionate, temperature of reaction is 160 ℃～190 ℃, and the reaction times is 14～18 hours;
B, the hydrolysis under the sodium hydroxide solution effect of D-(+)-2-chloropropionate is obtained D-(+)-2-chloropropionic acid;
C, the reaction of D-(+)-2-chloropropionic acid and thionyl chloride is obtained D-(+)-2-chloro propionyl chloride.
2. according to the synthetic method of the described D-of claim 1 (+)-2-chloro propionyl chloride, it is characterized in that the L-ethyl lactate among the described step a: thionyl chloride: the mol ratio of Calcium Fluoride (Fluorspan) is 1.00: 1.02～1.07: 0.08～0.13.
3. according to the synthetic method of the described D-of claim 2 (+)-2-chloro propionyl chloride, it is characterized in that D-(+)-2-chloropropionate in D-(+) among the described step b-hydrolysis reaction of 2-chloropropionate under the sodium hydroxide solution effect: the mol ratio of sodium hydroxide is 1.00: 1.10～1.18.
4. according to the synthetic method of the described D-of claim 3 (+)-2-chloro propionyl chloride, it is characterized in that D-(+) among the described step b-hydrolysising reacting temperature of 2-chloropropionate under the sodium hydroxide solution effect is 45-60 ℃, the reaction times is 6～9 hours.
5. the synthetic method of D-according to claim 4 (+)-2-chloro propionyl chloride is characterized in that, D-(+) among the step C-2-chloropropionic acid: the mol ratio of thionyl chloride is 1.00: 1.18～1.23.
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101633614B (en) * | 2009-08-18 | 2012-07-18 | 山东鲁抗立科药物化学有限公司 | Synthesis method of D-(+)-2-chloropropionyl chloride |
| CN101935273A (en) * | 2010-09-07 | 2011-01-05 | 南通诚信氨基酸有限公司 | Method for preparing high-purity S-2-chloropropionic acid |
| CN103030574B (en) * | 2013-01-04 | 2014-10-01 | 中国农业大学 | Cyano acidamide compound, and synthetic method and application of compound |
| CN103435469B (en) * | 2013-08-29 | 2015-05-20 | 张家港市三联化工科技有限公司 | Method for preparing high-optical purity R-(+)-2-chloropropionic acid |
| CN103408416B (en) * | 2013-08-30 | 2015-04-29 | 山东金城医药化工股份有限公司 | Synthesis method of high-purity D-2-chloropropionyl chloride |
| CN103467334B (en) * | 2013-09-03 | 2015-07-08 | 重庆工商大学 | Synthesis method of N-(2-chloride)-propionyl-glutamine |
| CN110590517A (en) * | 2019-09-24 | 2019-12-20 | 武汉嘉诺康医药技术有限公司 | Preparation method of 3, 4-dihydroxy-2' -chloroacetophenone |
| CN112479853B (en) * | 2020-11-19 | 2023-05-02 | 四川新迪医药化工有限公司 | Preparation method of D-2-chloropropionyl chloride and D-2-chloropropionyl chloride |
| CN113773190A (en) * | 2021-07-28 | 2021-12-10 | 苏州永诺泓泽生物科技有限公司 | Preparation method of D- (+) -2-chloropropionyl chloride |
Citations (3)
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| US4770821A (en) * | 1985-06-05 | 1988-09-13 | Ihara Nikkei Chemical Industry Co., Ltd. | Method for preparing β-chloropivaloyl chloride |
| CN1740132A (en) * | 2005-08-29 | 2006-03-01 | 上海华谊丙烯酸有限公司 | Synthesis and purification process of (2-methyl)-3-chloropropionyl chloride |
| CN1786019A (en) * | 2005-10-14 | 2006-06-14 | 邢将军 | Manufacturing method of proglu-dipeptide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4770821A (en) * | 1985-06-05 | 1988-09-13 | Ihara Nikkei Chemical Industry Co., Ltd. | Method for preparing β-chloropivaloyl chloride |
| CN1740132A (en) * | 2005-08-29 | 2006-03-01 | 上海华谊丙烯酸有限公司 | Synthesis and purification process of (2-methyl)-3-chloropropionyl chloride |
| CN1786019A (en) * | 2005-10-14 | 2006-06-14 | 邢将军 | Manufacturing method of proglu-dipeptide |
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