CN108084064B - Novel preparation method of D- (-) -tartaric acid - Google Patents
Novel preparation method of D- (-) -tartaric acid Download PDFInfo
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- CN108084064B CN108084064B CN201711399743.0A CN201711399743A CN108084064B CN 108084064 B CN108084064 B CN 108084064B CN 201711399743 A CN201711399743 A CN 201711399743A CN 108084064 B CN108084064 B CN 108084064B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
A new preparation method of D- (-) -tartaric acid relates to a preparation method of resolving agent D- (-) -tartaric acid which is widely applied in the field of medicine synthesis. The method sequentially comprises the following steps: the invention provides a new route for directly preparing chiral hydroxyl-protected D- (-) -tartaric acid ester through selective substitution reaction and then hydrolyzing to obtain a product, wherein the reaction conditions of each step are easy to operate, the process is simple, and the reactions of each step are relatively conventional operations.
Description
Technical Field
The invention relates to a preparation method of a resolving agent with wider application in the field of medicine synthesis, in particular to a method for preparing D- (-) -tartaric acid.
Background
Tartaric acid is widely used as an acidulant for beverages and other foods, and is typically present in the form of potassium salts in the fruits of a variety of plants. Tartaric acid can be complexed with various metal ions and can be used as a cleaning agent and a polishing agent for metal surfaces. Potassium sodium tartrate (Rochelle salt) can be used to formulate feline reagent, and can also be used in medicine as laxative and diuretic, and as an intermediate of cinchophene. The crystal has piezoelectric property and can be used in electronic industry. Used as chromatographic analysis reagent and masking agent, medicine resolving agent, food additive, biochemical reagent, etc.
In the known literature, more methods are used for preparing tartaric acid, and biological fermentation and catalytic oxidation methods are generally used for preparing tartaric acid, but the preparation method of D- (-) -tartaric acid is less, and fermentation thalli obtained by a fermentation method is generally used for a series of biological catalytic reactions to generate corresponding D- (-) -tartaric acid, but the method uses special strains, and the culture and use requirements of the strains are higher, so that the method is not favorable for large-scale production.
After a large number of relevant documents and patents at home and abroad are consulted, a new method is designed, and chiral hydroxyl protected D- (-) -tartaric acid ester is directly prepared by selective substitution reaction by adopting L- (+) -diethyl tartrate as a raw material, and then D- (-) -tartaric acid is obtained by hydrolysis reaction. The method effectively avoids high requirements of strain culture and use in biological methods, and is beneficial to market popularization.
Disclosure of Invention
The invention aims to provide a preparation method of resolving agent D- (-) -tartaric acid, which has the advantages of simple equipment, mild reaction conditions, convenient operation and wide application without damaging the environment. In order to achieve the purpose, a series of experiments are carried out, and a brand new synthetic route is provided.
The technical scheme for realizing the invention is as follows:
a preparation method of D- (-) -tartaric acid is characterized in that: d- (-) -tartaric acid represented by the formula (I) was obtained according to the following procedure:
preparation of diethyl (2R,3R) -2, 3-dimethylsulfonyloxy succinate (III)
Adding 1 time (weight ratio) of (2R,3R) -2, 3-dihydroxysuccinic acid diethyl ester, 5-10 times (weight ratio) of dichloromethane and 1.11-1.23 times (weight ratio) of methanesulfonyl chloride into a reactor, uniformly stirring, cooling to-10 ℃ by using an ice salt water bath, dropwise adding 0.98-0.99 time (weight ratio) of triethylamine, reacting for 4-6 hours at-10 ℃ under stirring, heating to room temperature after the reaction is finished, washing the reaction mixture with water, drying, and distilling under normal pressure to remove the solvent to obtain a liquid (2R,3R) -2, 3-dimethylsulfonyloxy succinic acid diethyl ester (III). Can be directly used for the next reaction.
Preparation of (2S,3S) -2, 3-diacetoxybutyric acid diethyl ester (II)
Adding 1 time (weight ratio) of (2R,3R) -2, 3-dimethyl sulfonyloxy diethyl succinate (III) and 8 times (weight ratio) of DMF4 into a reactor, adding 0.54-0.60 time (weight ratio) of potassium acetate in batches under the condition of stirring, heating to 80 ℃, continuing to stir for reaction for 6-10 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, evaporating under reduced pressure to remove most of solvent, pouring the residue into ice water, extracting with 5 times (weight ratio) of dichloromethane, separating liquid, drying an organic phase, concentrating and removing the solvent to obtain (2S,3S) -2, 3-diethyl diacetoxy succinate (II). Can be directly used for the next reaction.
Preparation of C.D- (-) -tartaric acid (I)
Adding 1 time (weight ratio) of (2S,3S) -2, 3-diacetoxy diethyl succinate (II) and 5-10 times (weight ratio) of 5% sodium hydroxide aqueous solution into a reactor, uniformly stirring, heating to 60 ℃, continuously stirring for reacting for 5-10 hours, cooling to room temperature after the reaction is finished, slowly adding 5% dilute hydrochloric acid while stirring to adjust the pH of the mixed solution to 2-3, filtering to remove insoluble substances, removing most of the solvent by reduced pressure distillation, adding a small amount of D- (-) -tartaric acid (I) seed crystals, stirring for crystallization, standing overnight, and filtering to collect precipitated crystals, namely D- (-) -tartaric acid (I).
The invention has the advantages that:
the route used by the invention avoids high requirements in the processes of strain culture and use in a biological method, and a corresponding chiral intermediate is directly obtained by selective substitution.
The reaction conditions of the invention are relatively mild, the reactions in each step are relatively conventional operations, and the product is obtained through two steps of reactions, thus being easy to control and needing no complex and special equipment.
Detailed Description
How this invention can be carried out is further illustrated by the following specific examples:
example 1
Preparation of diethyl (2R,3R) -2, 3-dimethylsulfonyloxy succinate (III)
Adding (2R,3R) -2, 3-dihydroxysuccinic acid diethyl ester (206g, 1.0mol), dichloromethane (2000g) and methanesulfonyl chloride (252g, 2.2mol) into a reactor, uniformly stirring, cooling to-10 ℃ by using an ice brine bath, dropwise adding triethylamine (202g), reacting for 6 hours at-10 ℃ under stirring, heating to room temperature, drying a reaction mixture after washing with water, and distilling under normal pressure to remove a solvent to obtain a liquid (2R,3R) -2, 3-dimethylsulfonyloxy succinic acid diethyl ester (III) with the yield of about 80.6 g. Can be directly used for the next reaction.
Preparation of (2S,3S) -2, 3-diacetoxybutyric acid diethyl ester (II)
Adding (2R,3R) -2, 3-dimethyl sulfonyloxy diethyl succinate (III) (362g, 1.0mol) and DMF (2850g) into a reactor, adding potassium acetate (215.6g, 2.2mol) in batches under stirring, heating to 80 ℃, continuing stirring for reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, evaporating under reduced pressure to remove most of solvent, pouring the residue into ice water, extracting with dichloromethane (1810g), separating liquid, drying an organic phase, concentrating and removing the solvent to obtain (2S,3S) -2, 3-diacetoxy diethyl succinate (II), wherein the yield is about 82.6 percent, and the content is 242.8 g. Can be directly used for the next reaction.
Preparation of C.D- (-) -tartaric acid (I)
Adding (2S,3S) -diethyl 2, 3-diacetoxy succinate (II) (290g, 1.0mol) and 5% sodium hydroxide aqueous solution (2900g) into a reactor, uniformly stirring, heating to 60 ℃, continuously stirring for reaction for 10 hours, cooling to room temperature after the reaction is finished, slowly adding 5% dilute hydrochloric acid while stirring to adjust the pH of the mixed solution to 2-3, filtering to remove insoluble substances, removing most of the solvent by reduced pressure distillation, adding a small amount of D- (-) -tartaric acid (I) seed crystals, stirring for crystallization, standing overnight, filtering to collect precipitated crystals, and drying to obtain D- (-) -tartaric acid (I) with the yield of 136.8g and the purity of about 91.2%, (using 0.5mol/L sodium hydroxide solution for titration) and the specific rotation [ α ]]D 25℃：-12.3°。
Example 2
The other steps are the same as example 1 except that diethyl (2R,3R) -2, 3-dimethylsulfonyloxy succinate (III) from step A is prepared as follows:
adding (2R,3R) -2, 3-dihydroxysuccinic acid diethyl ester (206g, 1.0mol), dichloromethane (1050g) and methanesulfonyl chloride (229g, 2.0mol) into a reactor, uniformly stirring, cooling to-10 ℃ by using an ice brine bath, dropwise adding triethylamine (202g), reacting for 4 hours at-10 ℃ under stirring, heating to room temperature, drying a reaction mixture after washing with water, and distilling under normal pressure to remove a solvent to obtain liquid (2R,3R) -2, 3-dimethylsulfonyloxy succinic acid diethyl ester (III), wherein the yield is 263.2g and is about 72.8%. Can be directly used for the next reaction.
Example 3
The other steps are the same as example 1 except that diethyl (2R,3R) -2, 3-dimethylsulfonyloxy succinate (III) from step A is prepared as follows:
diethyl (2R,3R) -2, 3-dihydroxysuccinate (206g, 1.0mol), dichloromethane (1500g) and methanesulfonyl chloride (240.5g, 2.1mol) were charged into a reactor, stirred uniformly, cooled to-10 ℃ with an ice-brine bath, triethylamine (202g) was added dropwise, the reaction was carried out at-10 ℃ for 5 hours with stirring, the reaction mixture was warmed to room temperature, washed with water and dried, and the solvent was removed by distillation under normal pressure to obtain 275.7g of (2R,3R) -2, 3-dimethylsulfonyloxy-succinic acid diethyl ester (iii) as a liquid with a yield of about 76.2%. Can be directly used for the next reaction.
Example 4
The procedure was otherwise the same as in example 1 except that diethyl (2S,3S) -2, 3-diacetoxybutyrate succinate (II) in step B was prepared as follows:
adding (2R,3R) -2, 3-dimethyl sulfonyloxy diethyl succinate (III) (362g, 1.0mol) and DMF (1450g) into a reactor, adding potassium acetate (196g, 2.0mol) in batches under stirring, heating to 80 ℃, continuing stirring for reaction for 6 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, evaporating under reduced pressure to remove most of solvent, pouring the residue into ice water, extracting with dichloromethane (1810g), separating liquid, drying an organic phase, concentrating and removing the solvent to obtain (2S,3S) -2, 3-diacetoxy diethyl succinate (II), wherein the yield is about 69.1%. Can be directly used for the next reaction.
Example 5
The procedure was otherwise the same as in example 1 except that diethyl (2S,3S) -2, 3-diacetoxybutyrate succinate (II) in step B was prepared as follows:
adding (2R,3R) -2, 3-dimethyl sulfonyloxy diethyl succinate (III) (362g, 1.0mol) and DMF (2150g) into a reactor, adding potassium acetate (205.8g, 2.1mol) in batches under stirring, heating to 80 ℃, continuing stirring for reacting for 8 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, evaporating under reduced pressure to remove most of solvent, pouring the residue into ice water, extracting with dichloromethane (1810g), separating liquid, drying the organic phase, concentrating and removing the solvent to obtain (2S,3S) -2, 3-diacetoxy diethyl succinate (II), wherein the yield is about 75.4% and the content is 218.8 g. Can be directly used for the next reaction.
Example 6
The other procedure was the same as in example 1 except that D- (-) -tartaric acid (I) of step C was prepared as follows:
adding (2S,3S) -diethyl 2, 3-diacetoxy succinate (II) (290g, 1.0mol) and 5% sodium hydroxide aqueous solution (1450g) into a reactor, stirring uniformly, heating to 60 ℃, continuing to stir for reaction for 5 hours, cooling to room temperature after the reaction is finished, slowly adding 5% dilute hydrochloric acid to adjust the pH of the mixed solution to 2-3 while stirring, filtering to remove insoluble substances, removing most of the solvent by reduced pressure distillation, adding a small amount of D- (-) -tartaric acid (I) seed crystals, stirring for crystallization, standing overnight, filtering to collect precipitated crystals, and drying to obtain D- (-) -tartaric acid (I) with the yield of 111.3g and the purity of about 74.2% (titration with 0.5mol/L sodium hydroxide solution) and the specific rotation [ α ]]D 25℃：-12.4°。
Example 7
The other procedure was the same as in example 1 except that D- (-) -tartaric acid (I) of step C was prepared as follows:
adding (2S,3S) -diethyl 2, 3-diacetoxy succinate (II) (290g, 1.0mol) and 5% sodium hydroxide aqueous solution (1600g) into a reactor, stirring uniformly, raising the temperature to 60 ℃, continuing to stir for reaction for 7 hours, cooling to room temperature after the reaction is finished, slowly adding 5% dilute hydrochloric acid while stirring to adjust the pH of the mixed solution to 2-3, filtering to remove insoluble substances, removing most of the solvent by reduced pressure distillation, adding a small amount of D- (-) -tartaric acid (I) seed crystals, stirring for crystallization, standing overnight, filtering to collect precipitated crystals, and drying to obtain D- (-) -tartaric acid (I) with the yield of 120.7g, the purity of 80.5 percent (titration by 0.5mol/L sodium hydroxide solution) and the specific optical rotation [ α ] D25 ℃ -12.2 ℃.
Example 8
The other procedure was the same as in example 1 except that D- (-) -tartaric acid (I) of step C was prepared as follows:
adding (2S,3S) -diethyl 2, 3-diacetoxy succinate (II) (290g, 1.0mol) and 5% sodium hydroxide aqueous solution (2500g) into a reactor, stirring uniformly, heating to 60 ℃, continuing to stir for reaction for 9 hours, cooling to room temperature after the reaction is finished, slowly adding 5% dilute hydrochloric acid while stirring to adjust the pH of the mixed solution to 2-3, filtering to remove insoluble substances, removing most of the solvent by reduced pressure distillation, adding a small amount of D- (-) -tartaric acid (I) seed crystals, stirring for crystallization, standing overnight, filtering to collect precipitated crystals, and drying to obtain D- (-) -tartaric acid (I) with the yield of 129.4g, about 86.3%, purity of 99.57% (titration with 0.5mol/L sodium hydroxide solution), and specific optical rotation [ α ] D25 ℃ -12.5 ℃.
Although the invention has been described and illustrated in some detail by the inventor, it should be understood that modifications and/or alterations to the above-described embodiments, or equivalent alterations thereto, will become apparent to those skilled in the art without departing from the spirit of the invention, and that no limitation to the invention is intended by the terms of the present invention as set forth herein is intended to be exhaustive or understood.
Claims (1)
1. A preparation method of D- (-) -tartaric acid is characterized in that: d- (-) -tartaric acid represented by the formula (I) was obtained according to the following procedure:
（Ⅲ）
（Ⅱ）（Ⅰ）
preparation of diethyl (2R,3R) -2, 3-dimethylsulfonyloxy succinate (III)
Adding 1 time of (2R,3R) -2, 3-dihydroxysuccinic acid diethyl ester, 5 to 10 times of dichloromethane and 1.11 to 1.23 times of methanesulfonyl chloride into a reactor in a weight ratio, uniformly stirring, cooling to-10 ℃ by using an ice salt water bath, dropwise adding 0.98 to 0.99 time of triethylamine in a weight ratio, reacting for 4 to 6 hours at the temperature of-10 ℃ under stirring, finishing the reaction, heating to room temperature, washing the reaction mixture with water, drying, distilling at normal pressure to remove the solvent, and obtaining a liquid (2R,3R) -2, 3-dimethylsulfonyloxy succinic acid diethyl ester (III); can be directly used for the next reaction;
preparation of (2S,3S) -2, 3-diacetoxybutyric acid diethyl ester (II)
Adding 1 time (2R,3R) -2, 3-dimethyl sulfonyloxy diethyl succinate (III) and 0.54-0.60 time DMF4-8 time DMF (dimethyl formamide) into a reactor by weight ratio, adding 0.54-0.60 time potassium acetate by weight ratio in batches under the stirring condition, heating to 80 ℃, continuing stirring for reaction for 6-10 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, evaporating under reduced pressure to remove most of solvent, pouring the residue into ice water, extracting by using 5 times dichloromethane by weight ratio, separating liquid, drying an organic phase, concentrating and removing the solvent to obtain (2S,3S) -2, 3-diethyl diacetoxy succinic acid (II); can be directly used for the next reaction;
preparation of C.D- (-) -tartaric acid (I)
Adding 1 time of (2S,3S) -2, 3-diacetoxy diethyl succinate (II) and 5-10 times of sodium hydroxide aqueous solution with the concentration of 5% into a reactor according to the weight ratio, uniformly stirring, heating to 60 ℃, continuously stirring for reaction for 5-10 hours, cooling to room temperature after the reaction is finished, slowly adding 5% dilute hydrochloric acid while stirring to adjust the pH of the mixed solution to 2-3, filtering to remove insoluble substances, removing most of the solvent by reduced pressure distillation, adding a small amount of D- (-) -tartaric acid (I) seed crystals, stirring for crystallization, standing overnight, and filtering to collect precipitated crystals, namely D- (-) -tartaric acid (I).
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| JP2012171927A (en) * | 2011-02-22 | 2012-09-10 | Tamagawa Gakuen | Method of producing d-tartaric acid or salts thereof |
| CN104592026A (en) * | 2013-11-01 | 2015-05-06 | 中国石油化工股份有限公司 | Compound, catalyst component and catalyst |
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2017
- 2017-12-22 CN CN201711399743.0A patent/CN108084064B/en active Active
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| JPS63245693A (en) * | 1987-04-01 | 1988-10-12 | Toray Ind Inc | Production of d-(-)-tartaric acid |
| JP2012171927A (en) * | 2011-02-22 | 2012-09-10 | Tamagawa Gakuen | Method of producing d-tartaric acid or salts thereof |
| CN102452932A (en) * | 2011-12-06 | 2012-05-16 | 浙江金伯士药业有限公司 | Preparation method for L-(+)-tartaric acid |
| CN104592026A (en) * | 2013-11-01 | 2015-05-06 | 中国石油化工股份有限公司 | Compound, catalyst component and catalyst |
| CN105087677A (en) * | 2014-04-21 | 2015-11-25 | 怀来县长城生物化学工程有限公司 | D-(-)-tartaric acid clean production process based on bipolar membrane electroosmosis technology |
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