CN101633614B - Synthesis method of D-(+)-2-chloropropionyl chloride - Google Patents
Synthesis method of D-(+)-2-chloropropionyl chloride Download PDFInfo
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- CN101633614B CN101633614B CN2009100180056A CN200910018005A CN101633614B CN 101633614 B CN101633614 B CN 101633614B CN 2009100180056 A CN2009100180056 A CN 2009100180056A CN 200910018005 A CN200910018005 A CN 200910018005A CN 101633614 B CN101633614 B CN 101633614B
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- propionyl chloride
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Abstract
The invention relates to a synthesis method of D-(+)-2-chloropropiony chloride as an organic synthesizing intermediate. In the method, food grade L-lactic acid and thionyl chloride are directly taken as raw materials in the presence of a catalyst to obtain the D-(+)-2-chloropropionyl chloride by a one-pot method. The synthesis method has simple process, high yield, low cost, cheap and available auxiliary raw materials, and applicability to industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of organic synthesis intermediate, relate in particular to the method that a kind of employing L-lactic acid and sulfur oxychloride single stage method prepare D-(+)-2-chloro propionyl 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 of medicine such as loxoprofen sodium.
Existing D-(+)-chlorpromazine chloride compound method mainly is to be raw material with L-ethyl lactate, L-methyl lactate; Under the effect of basic catalyst pyridine or picoline, obtain the D-2-chloropropionate, obtain D-(+)-2-chlorpromazine chloride by D-(+)-2-chloropropionate through hydrolysis, acidylate again.This method operational path is complicated, and yield is lower, and cost is high.
It is the compound method that catalyzer replaces pyridine that Chinese patent file CN101284772A (200810055056.1) discloses a kind of Calcium Fluoride (Fluorspan) that adopts; Though owing to used new catalyst Calcium Fluoride (Fluorspan); Improved yield; Reduced environmental pollution, but still continued former operational path, production cost is still higher.
In known technology; Alcohol generated chloro sulfite and hydrogenchloride before this with the sulfur oxychloride effect; Then the chloro sulfite decomposes; The Sauerstoffatom band the heterolytic fission of a pair of bonding electrons generation key of carbon-oxygen bond in this decomposition course, and the chlorine atom that at this moment has the part negative charge is positioned at the place ahead of electron deficiency carbon just and intramolecular nucleophilic substitution reaction takes place with it; When carbon chlorine key formed, SO was accomplished and emits in decomposition reaction
2, because the chlorine atom orientation of living in of nucleophillic attack and the SO that will leave away take place
2Be homonymy,, do not overturn so the alpha-carbon atom of alcohol is retention of configuration in reaction process.Again because there is not carbonium ion to generate in the reaction, so product does not have the racemization phenomenon yet.
In superincumbent reaction system, add pyridine or tertiary amine, can impel reaction to quicken, but the hydrochloric ether of configuration conversion is arranged in the product that obtains, this is owing to have in the reaction process by the SN2 mechanism shown in following and react the result who is caused:
Summary of the invention
In order to overcome the deficiency of prior art, solve D-(+)-2-chlorpromazine chloride complex synthetic route, yield is low, cost is high problem, the present invention provides the compound method of a kind of D-(+)-2-chlorpromazine chloride.
Technical scheme of the present invention is following:
The present invention directly adopts the L-lactic acid of food grade and sulfur oxychloride to obtain D-(+)-2-chloro propionyl chloride in next footwork prepared in reaction of catalyst, and reaction formula of the present invention is following:
L-lactic acid D-(+)-2-chloro propionyl chloride
The preparation method of D-of the present invention (+)-2-chloro propionyl chloride adopts the single stage method preparation, and step is following:
1) in reaction kettle, add sulfur oxychloride, cryosel is bathed cooling; Drip L-lactic acid, drip catalyzer simultaneously; The weight ratio of L-lactic acid and sulfur oxychloride is 1: 3.2～3.4, and the weight ratio of L-lactic acid and catalyzer is 1: 0.05～0.08.Dropwise under the cryosel bath condition stirring reaction 3-6 hour; Be warming up to 40-60 ℃, continued stirring reaction 2-4 hour;
2) reaction finishes and carries out rectification under vacuum after the cooling, and collecting optically-active is the cut between-4 °～-5 °, promptly gets D-(+)-2-chloro propionyl chloride.
After rectification under vacuum finished, the by product in the reaction kettle was POLYACTIC ACID and pyridine hydrochloride, can obtain the POLYACTIC ACID of different molecular weight through further underpressure distillation, carried out by-product and utilized.
Catalyzer in the inventive method is recyclable to be utilized again.
Said step 1) cryosel is bathed and is cooled to below 0 ℃, and is preferred, and said step 1) cryosel is bathed and is cooled to 0 ℃～-5 ℃.
Preferably, said step 1) catalyzer is pyridine, picoline or tertiary amine organic bases, preferred pyridine;
Preferably, L-lactic acid and the sulfur oxychloride reaction times under cryosel bath condition is 4 hours in the said step 1); Be warming up to 50 ℃, continued stirring reaction 2.5 hours.
The present invention adopts the L-lactic acid of food grade and sulfur oxychloride single stage method to prepare D-(+)-2-chloro propionyl chloride; Under catalyst, make configuration conversion; Through the control reaction conditions, the method for treating different things alike has obtained D-(+)-2-chloro propionyl chloride, efficiently solves former operational path complicacy; And yield is lower, the difficult problem that cost is high.This method operational path is succinct, and yield is high, reaches more than 84%, and product purity is more than 97%.The inventive method cost is low, and supplementary material is cheap and easy to get, is fit to suitability for industrialized production.
Description of drawings
Fig. 1 is the infrared spectrogram of D-(+)-2-chloro propionyl chloride product of the embodiment of the invention 2 preparations.
Embodiment
Below in conjunction with embodiment and accompanying drawing the present invention is further specified, but be not limited thereto.
Embodiment 1:
Exsiccant has in the 500ml reaction flask of stirring and condensation, adds the 360g sulfur oxychloride, and cryosel is bathed and is cooled to-1.0 ℃, slowly drips 110g food grade L-lactic acid, drips pyridine 5.89g simultaneously, and the hierarchy of control dropwised below 0 ℃ in 2 hours.Cryosel is bathed down, and stirring reaction 3 hours is warming up to 45 ℃, and insulation reaction is 3 hours under this temperature.Stopped reaction, rectification under vacuum, collecting optically-active is the cut between-4 °～-5 °, is D-(+)-2-chloro propionyl chloride, and yield is 85.6%, and product purity is 98.3%, and optically-active is-4.6 °.
After rectification under vacuum finished, further underpressure distillation can obtain the POLYACTIC ACID of different molecular weight to the by product in the reaction kettle.Catalyst recovery is utilized again.
Embodiment 2:
Exsiccant has in the 500ml reaction flask of stirring and condensation, adds the 365g sulfur oxychloride, and cryosel is bathed and is cooled to-2.0 ℃, slowly drips 110g food grade L-lactic acid, drips pyridine 6.59g simultaneously, and the hierarchy of control dropwised below 0 ℃ in 2.5 hours.Cryosel is bathed down, and stirring reaction 4 hours is warming up to 50 ℃, and insulation reaction is 2.5 hours under this temperature.Stopped reaction, rectification under vacuum, collecting optically-active is the cut between-4 °～-5 °, is D-(+)-2-chloro propionyl chloride, and yield is 85.8%, and product purity is 98.5%, and optically-active is-4.8 °.
Ir spectra such as Fig. 1 of product D-(+)-2-chloro propionyl chloride, its characteristic peak data are following:
2900cm
-1About the absorption peak located be saturated C-H stretching vibration, showing in the compound has-CH
3Or-CH
2-, monomethyl is at 1380cm
-1There is unimodal appearance at the place, therefore proves in the compound have-CH
3
1800cm
-1The strong absorption peak at place is the stretching vibration charateristic avsorption band of C=O;
The stretching vibration absorption peak that replaces halogen atom is at 1000～500cm
-1The place, 700cm
-1The absorption peak at place is the stretching vibration peak of C-Cl;
1500cm
-1The absorption peak at place belongs to＞the asymmetric charateristic avsorption band of C-H.
Embodiment 3:
Exsiccant has in the 500ml reaction flask of stirring and condensation, adds the 370g sulfur oxychloride, and cryosel is bathed and is cooled to 0 ℃, slowly drips 110g food grade L-lactic acid, drips picoline 7.85g simultaneously, and the hierarchy of control dropwised below 0 ℃ in 4 hours.Cryosel is bathed down, and stirring reaction 5 hours is warming up to 60 ℃, and insulation reaction is 2 hours under this temperature; Stopped reaction, rectification under vacuum, collecting optically-active is the cut between-4 °～-5 °, is D-(+)-2-chloro propionyl chloride; Yield is 84.9%, and product purity is 97.8%, and optically-active is-4.5 °.
Comparative example:
Adopt the said method of patent CN101284772A (200810055056.1) to prepare D-(+)-2-chloro propionyl chloride, its reaction times, yield and product purity and the employing embodiment of the invention 1 gained result are more as follows:
Can be known by last table: the yield and the product purity of two kinds of method gained D-(+)-2-chloro propionyl chloride are more or less the same; But adopting the method production cycle of the present invention only is to adopt 1/3rd of Chinese patent CN200810055056.1 method; Therefore production cost is descended significantly; Adopting cheap food grade L-lactic acid simultaneously is raw material, makes production cost lower.
Content disclosed according to the present invention, those skilled in the art can use the present invention to greatest extent.Therefore, above-mentioned preferred embodiment only illustrates, but not limits scope of the present invention by any way.
Claims (3)
1.D-the preparation method of (+)-2-chloro propionyl chloride is characterized in that adopting the single stage method preparation, step is following:
1) in reaction kettle, add sulfur oxychloride, cryosel is bathed cooling; Drip L-lactic acid, drip catalyzer simultaneously; The weight ratio of L-lactic acid and sulfur oxychloride is 1: 3.2～3.4, and the weight ratio of L-lactic acid and catalyzer is 1: 0.05～0.08; Dropwise under the cryosel bath condition stirring reaction 3-6 hour; Be warming up to 40-60 ℃, continued stirring reaction 2-4 hour;
Said catalyzer is pyridine or picoline;
2) reaction finishes and carries out rectification under vacuum after the cooling, and collecting optically-active is the cut between-4 °～-5 °, promptly gets D-(+)-2-chloro propionyl chloride.
2. the preparation method of D-as claimed in claim 1 (+)-2-chloro propionyl chloride is characterized in that said step 1) cryosel bath is cooled to 0 ℃～-5 ℃.
3. the preparation method of D-as claimed in claim 1 (+)-2-chloro propionyl chloride is characterized in that L-lactic acid and the reaction times of sulfur oxychloride under cryosel bath condition are 4 hours in the said step 1); Be warming up to 50 ℃, continued stirring reaction 2.5 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102190574A (en) * | 2010-03-11 | 2011-09-21 | 通州市诚信氨基酸有限公司 | Method for preparing 2-chloropropionyl chloride with high optical activity |
| CN103910780A (en) * | 2014-04-09 | 2014-07-09 | 上海皓骏医药科技有限公司 | Preparation method of L-alanine-L-glutamine compound |
| CN107417516A (en) * | 2017-05-19 | 2017-12-01 | 武汉桀升生物科技有限公司 | One kind recycles the method that one kettle way prepares the vinasse of the chlorpromazine chlorides of D (+) 2 |
| 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 |
| CN113603582A (en) * | 2021-07-28 | 2021-11-05 | 苏州永诺泓泽生物科技有限公司 | Method for preparing D- (+) -2-chloropropionyl chloride by adopting micro-channel continuous flow reactor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1786019A (en) * | 2005-10-14 | 2006-06-14 | 邢将军 | Process for producing alanyl-glutamine dipeptide |
| CN101113141A (en) * | 2006-07-19 | 2008-01-30 | 南京圣和药业有限公司 | Optical active N-(alpha-mercapto radical propionyl group) aminoacetic acid |
| CN101284772A (en) * | 2008-06-11 | 2008-10-15 | 河北华晨药业有限公司 | Synthetic method of D-(+)-2-chloro-propanoyl chloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1786019A (en) * | 2005-10-14 | 2006-06-14 | 邢将军 | Process for producing alanyl-glutamine dipeptide |
| CN101113141A (en) * | 2006-07-19 | 2008-01-30 | 南京圣和药业有限公司 | Optical active N-(alpha-mercapto radical propionyl group) aminoacetic acid |
| CN101284772A (en) * | 2008-06-11 | 2008-10-15 | 河北华晨药业有限公司 | Synthetic method of D-(+)-2-chloro-propanoyl chloride |
Non-Patent Citations (1)
| Title |
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| SHOU-CHENG J.等.Influence of Optically Active Acyl Groups on the Enzymatic Hydrolysis of N-Acylated-L-amino Acids.《J. Am. Chem. Soc.》.1954,第76卷6054-6058. * |
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Address after: 272073 Shandong city of Jining province high tech Zone Shixian Road No. 1688 Patentee after: AMICOGEN (CHINA) BIOPHARM CO.,LTD. Address before: 272073 Shandong city of Jining province high tech Zone East Ring Road Lukang International Industrial Park Patentee before: SHANDONG LUKANG RECORD PHARMACEUTICALS Co.,Ltd. Address after: 272073 Shandong city of Jining province high tech Zone East Ring Road Lukang International Industrial Park Patentee after: SHANDONG LUKANG RECORD PHARMACEUTICALS Co.,Ltd. Address before: 272000 Shandong city of Jining province high tech Zone East Ring Road Lukang International Industrial Park Patentee before: Shandong Lukang Record Pharmaceutical Co.,Ltd. |