CN109678737B - Preparation method of pregabalin - Google Patents
Preparation method of pregabalin Download PDFInfo
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- CN109678737B CN109678737B CN201910120352.3A CN201910120352A CN109678737B CN 109678737 B CN109678737 B CN 109678737B CN 201910120352 A CN201910120352 A CN 201910120352A CN 109678737 B CN109678737 B CN 109678737B
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Abstract
The invention relates to a preparation method of pregabalin, which comprises the following steps: carrying out Hofmann rearrangement reaction under the action of (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid and sodium hypochlorite in an alkaline solution, adding the reaction solution into an acid-organic solvent system after the rearrangement reaction is finished, extracting and combining organic phases, adding alkali for alkali precipitation, pulping and washing with water to obtain the high-purity pregabalin. The preparation method has the advantages of simple process route, high product yield and high product purity, can meet the medicinal quality standard without recrystallization, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmacy, and in particular relates to a preparation method of pregabalin.
Background
The pregabalin is used for treating partial epilepsy of adult patients, is approved by the U.S. Food and Drug Administration (FDA) for marketing in 6-menstrual period in 2005, is approved by 3-month in 2006, increases various new indications, has larger market demand, and becomes one of the global popular drugs.
At present, a plurality of patents report preparation and synthesis methods of pregabalin, and patent CN101500985A describes that (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid is subjected to hofmann rearrangement reaction under the action of sodium hydroxide and sodium hypochlorite, and then the pH is adjusted by hydrochloric acid to obtain pregabalin. However, when the proprietary method is reproduced, the product yield is low, unknown impurities which are difficult to remove are easily introduced, and the standard of pharmaceutical raw material medicines cannot be met.
Patent CN106748850A also reports that (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid undergoes a hofmann rearrangement reaction under the action of sodium hydroxide and sodium hypochlorite, and side reactions occur, resulting in impurity X and impurity Y, which are difficult to remove.
The impurity X and the impurity Y are used as key impurities in the preparation process of the pregabalin, and are difficult to remove in the subsequent product purification, so that the quality standard of the pregabalin product is directly influenced.
In view of the above problems, there is a need to find an improved method for optimizing pregabalin.
Disclosure of Invention
The invention aims to provide a preparation method of pregabalin. The preparation method can improve the yield and purity of the product, has simple process and is suitable for industrial production.
The technical problem to be solved by the invention is realized by adopting the following technical scheme.
The invention provides a preparation method of pregabalin, which comprises the following steps:
in alkaline solution, carrying out Hofmann rearrangement reaction on (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid and sodium hypochlorite to obtain reaction solution, adding the reaction solution into an acid-organic solvent system, extracting and combining organic phases, adding alkali for alkali precipitation, pulping and washing with water to obtain the high-purity pregabalin.
The invention has the beneficial effects that:
the invention provides a preparation method of pregabalin, which overcomes the defects of low yield, low purity and difficulty in meeting the medicinal quality standard in the existing pregabalin preparation process. The method comprises the steps of preparing pregabalin through Hofmann rearrangement reaction, after the rearrangement reaction is finished, adding reaction liquid after the Hofmann rearrangement reaction into an acid-organic solvent system, adjusting the pH value to be acidic, enabling a product to enter an organic system after salifying, enabling impurities generated by the reaction to be basically in a water phase, adding alkali into the organic system to perform alkali precipitation to free the pregabalin, and obtaining the high-purity pregabalin only by simple pulping after precipitation to remove a small amount of inorganic salt without recrystallization.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a liquid phase HPLC chromatogram of pregabalin prepared in example 10 described in CN101500985A,
FIG. 2 is a liquid phase HPLC chromatogram of pregabalin prepared in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The preparation method of pregabalin provided by the embodiment of the present invention is specifically described below.
The embodiment of the invention provides a preparation method of pregabalin, which comprises the following steps:
in alkaline solution, carrying out Hofmann rearrangement reaction on (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid and sodium hypochlorite to obtain reaction solution, adding the reaction solution into an acid-organic solvent system, extracting and combining organic phases, adding alkali for alkali precipitation, pulping and washing with water to obtain the high-purity pregabalin.
The embodiment of the invention provides a preparation method of pregabalin, which comprises the following steps: in alkaline solution, carrying out Hofmann rearrangement reaction on (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid and sodium hypochlorite to obtain reaction solution, adding the reaction solution into an acid-organic solvent system, extracting and combining organic phases, adding alkali for alkali precipitation, pulping and washing with water to obtain the high-purity pregabalin. The method overcomes the defects that after the traditional Hofmann rearrangement reaction is finished, acid is directly added to separate out solid in a water phase, isopropanol and water are needed for refining, impurities which are difficult to remove are contained in the product, and the product purity is low. According to the preparation method of the pregabalin provided by the embodiment of the invention, the pregabalin can meet the medicinal quality standard without recrystallization. The preparation method has the advantages of simple process route, high product yield and high product purity, and is suitable for industrial production.
In some embodiments, the preparation of pregabalin specifically comprises the steps of: in alkaline solution, carrying out Hofmann rearrangement reaction on (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid and sodium hypochlorite to obtain reaction solution, adding the reaction solution into an acid-organic solvent system, then regulating the pH for the first time, layering, extracting a water layer by using an organic solvent, combining organic phases, adding alkali into the organic phase, regulating the pH for the second time until pregabalin is separated out, pulping and washing with water to obtain the high-purity pregabalin.
At present, after the reaction is finished, acid is directly added to separate out solid in a water phase, isopropanol and water are needed for refining, and the product contains impurities which are difficult to remove.
According to the preparation method of the pregabalin provided by the embodiment of the invention, the separation and purification of the pregabalin comprise the following steps: after the Hofmann rearrangement reaction is finished, adding the reaction solution into an acid-organic solvent system, adjusting the pH value to acidity, enabling the product to enter an organic system after salification, enabling impurities generated by the reaction to be basically in a water phase, then extracting and combining organic phases, adding alkali into the organic phase to perform alkali precipitation to free pregabalin, removing a small amount of inorganic salt by simple pulping after precipitation, and obtaining the high-purity pregabalin without recrystallization of the product.
Specifically, the separation and purification of pregabalin provided by the embodiment of the invention comprises the following steps: the reaction liquid after the Hofmann rearrangement reaction is directly dripped into an acid-organic solvent system, most of pregabalin in the reaction liquid forms salt with acid and enters an organic solvent, impurities enter a water layer, so that the separation of a crude product and the impurities is effectively realized, and the crude product is subjected to simple post-treatment to obtain the high-purity pregabalin. Therefore, the separation and purification method in the embodiment of the invention well overcomes the defects that in the existing preparation process of pregabalin, acid is directly added into the reaction liquid to precipitate solid in a water phase, and the purity of the solid is low. The pregabalin solid obtained by the reaction is doped and wrapped with a large amount of impurities, the pregabalin and the impurities are not effectively separated from each other from the source, although isopropanol and water are used for refining, the impurities in the pregabalin solid cannot be effectively removed in the refining process, time and labor are wasted, the efficiency is low, and the purity of the obtained product is still low and cannot meet the requirements.
In some embodiments, (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid is added to the alkaline aqueous solution in portions, stirred and mixed uniformly to obtain a mixed solution, and an aqueous solution of sodium hypochlorite is added dropwise to the mixed solution to perform the Hofmann rearrangement reaction, wherein the reaction equation of the Hofmann rearrangement reaction is as follows:
the embodiment of the invention provides a preparation method of pregabalin, which comprises the following steps: in alkaline aqueous solution, (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid is subjected to Hofmann rearrangement reaction under the action of sodium hypochlorite. It can be seen that the preparation of pregabalin in the embodiments of the present invention involves hofmann degradation reaction, and the primary amine is generated by decarbonylation when the reaction raw material (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid is reacted with an alkaline solution of sodium hypochlorite. The reaction equation is as follows:
the reaction process is complex, and the reaction process is as follows:
And step 2, removing hydrogen chloride under the action of alkali to obtain an intermediate acylnitrene of an electron-deficient nitrogen atom (the outermost layer of the nitrogen atom has only six electrons). Acylazenes are very unstable and prone to rearrangement.
And 3, transferring the alkyl with a pair of electrons to an electron-deficient nitrogen atom to generate isocyanate, and removing carbon dioxide in the isocyanate at high temperature in an alkaline aqueous solution to generate primary amine.
Therefore, the Hofmann degradation reaction process is very complicated, and other side reactions and impurities are easily generated due to the obvious exothermic reaction of the reaction, and the temperature in the reaction process and the separation step of the crude product need to be controlled to obtain high-purity pregabalin.
In the preparation process of the pregabalin provided by the embodiment of the invention, as the Hofmann rearrangement reaction has obvious heat release and the whole reaction process is very complex, in order to reduce the occurrence of side reactions and reduce the impurity content in the product, the addition sequence is controlled as follows: adding (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid into an alkaline aqueous solution in batches, stirring and mixing uniformly to obtain a mixed solution, and dropwise adding an aqueous solution of sodium hypochlorite into the mixed solution. The temperature in the reaction process can be controlled by controlling the addition sequence, which is beneficial to the rearrangement reaction and reduces the generation of side reaction and impurities.
In some embodiments, the hofmann rearrangement reaction comprises:
adding (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid into an alkaline aqueous solution in batches, stirring and mixing uniformly to obtain a mixed solution, dropwise adding an aqueous solution of sodium hypochlorite into the mixed solution, reacting at 0-10 ℃ for 0.5-1h, heating to 65-80 ℃ after dropwise adding of the aqueous solution of sodium hypochlorite is finished, and continuing to react for 1-2 h.
In some embodiments, the molar ratio of base to amount of (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid in the aqueous alkaline solution is 3.5 to 5.5:1, preferably 3.5 to 4.5:1,
the molar ratio of sodium hypochlorite to the useful amount of (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid is from 1.5 to 1.1:1, preferably 1.1: 1.
In some embodiments, the base in the aqueous alkaline solution is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide, the mass fraction of the aqueous alkaline solution is 20-30%, and the mass fraction of the aqueous sodium hypochlorite solution is 5-15%.
In the preparation process of the pregabalin in the embodiment of the invention, the use amount of the sodium hypochlorite aqueous solution is strictly controlled, so that the reaction degree and the reaction process of the pregabalin in the whole reaction process can be controlled.
In some embodiments, the organic phase comprises an organic solvent layer obtained after the separation and an extraction layer of an aqueous layer obtained after the separation, and preferably, the number of extractions of the aqueous layer is 3 to 4.
In the preparation process of the pregabalin provided by the embodiment of the invention, the reaction liquid obtained after the Hofmann rearrangement reaction is added into an acid-organic solvent system, and because the acid in the system is diluted by the organic solvent, the acidity of the system is mild and uniform, most of the pregabalin and the acid in the reaction liquid can form salt and enter the organic solvent, impurities enter a water layer, and a small amount of pregabalin also enters the water layer. Therefore, after the pH is adjusted for the first time, layering is carried out to obtain an organic solvent layer and a water layer, the water layer is extracted by using an organic solvent to obtain an organic solvent extraction layer of the water layer, the organic solvent layer obtained after layering and the extraction layer of the water layer obtained after layering are combined, preferably, the extraction solvent of the water layer is the same as or different from the organic solvent in an acid-organic solvent system, the extraction frequency of the water layer is 3-4 times, so that the pregabalin dissolved in the water layer is completely extracted into the organic solvent, then alkali is added into the combined organic phase, the pH is adjusted for the second time, at the moment, the salt of the pregabalin in the organic solvent is precipitated by the alkali, after precipitation, only a small amount of inorganic salt needs to be removed by simple beating, and the product can obtain the high-purity pregabalin without recrystallization.
In some embodiments, the acid is selected from at least one of an inorganic acid and an organic acid, preferably at least one of sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, and acetic acid,
the organic solvent is selected from at least one of C4 alcohol, C1-C6 aliphatic ketone, ethyl acetate and toluene, preferably at least one of n-butanol, isobutanol, butanone, ethyl acetate and toluene.
Preferably, the first pH is adjusted to 2-7, more preferably pH is adjusted to 2-5.
In some embodiments, layering specifically comprises the steps of: after the reaction solution is dripped, controlling the temperature within 25 ℃, regulating the pH value for the first time, heating to 25-30 ℃, standing and layering.
As can be seen from the foregoing reaction sequence: the Hoffman degradation reaction process is very complex, intermediate isocyanate is formed, the intermediate isocyanate can react with various substances such as water, alcohol, amine and the like, side reactions are easily caused, impurities which are difficult to purify appear, and the product generally has low yield and low purity and cannot meet the standards of medicinal raw material medicines.
In the preparation process of the pregabalin provided by the embodiment of the invention, in the reaction liquid after the Hofmann rearrangement reaction, the reaction liquid is directly dripped into an acid-organic solvent system. The temperature in the adding process needs to be controlled in the adding process so as to avoid generating new side reactions and impurities, after the adding is finished, the temperature is controlled within 25 ℃, after the pH is adjusted for the first time, the temperature is increased to 25-30 ℃ (if the temperature is continuously increased, the pregabalin is likely to be separated out), standing and layering are carried out at the temperature, so that a water layer and an organic solvent layer can be fully separated, namely the pregabalin product enters an organic solvent after salifying, the impurities enter the water layer, and the effective separation of a crude product and the impurities is realized.
In some embodiments, the base used for the base precipitation is selected from at least one of organic bases and inorganic bases, preferably at least one of triethylamine, ammonia, sodium hydroxide, potassium carbonate and sodium bicarbonate,
preferably, the pH is adjusted to 6-8, more preferably to 7-8, for the second time.
In some embodiments, the caustic precipitation and slurrying water wash specifically comprises the steps of: adding alkali into the organic phase, adjusting pH for the second time, continuously heating to 75-85 deg.C, reacting for 0.5-1h, press filtering, cooling to 0-10 deg.C, precipitating for 3-5h, centrifuging, washing, pulping the solid with purified water, centrifuging, and drying.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
Adding 32kg (0.8mol) of sodium hydroxide into 80L of water, stirring and dissolving, cooling to 0-10 ℃, adding 40kg (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid in batches, controlling the temperature to 0-10 ℃, stirring for 10min after the addition is finished, dropwise adding a sodium hypochlorite solution (9.7% of 164kg), controlling the temperature to 0-10 ℃, keeping the temperature for reaction for 30min after the addition is finished, slowly heating to 80 ℃ for 1h, and cooling to room temperature for later use.
Adding 80L butanone and 50L sulfuric acid into a reaction kettle, cooling to about 15 ℃, dropwise adding the standby reaction liquid, controlling the temperature within 25 ℃, adjusting the pH to 2 after adding sulfuric acid, heating to 25-30 ℃, standing for layering, extracting a water layer with 40L 3 butanone, mixing organic layers, adjusting the pH to 8 by using ammonia water (the mixed organic layers comprise 80L butanone and 40L 3 butanone), heating to 85 ℃, stirring for 10min, filter-pressing into a crystallization kettle, cooling to 0-10 ℃, 3h, centrifuging, washing with 40ml ethanol, pulping the solid with 40L purified water for 1h, centrifuging, drying with 80 ℃ hot air for 2h to obtain 33kg of pregabalin with the yield of 97.1% and the purity of 99.99%.
Table 1 below is a table of peaks of pregabalin prepared in example 10 described in CN 101500985A:
TABLE 1 Peak Table
< Peak Table >
PDA Ch1 210nm
| Peak number | Name of Compound | Retention time | Area of | | Height | |
| 1 | Pregabalin | 7.987 | 3898243 | 99.134 | 335556 | |
| 2 | 12.750 | 23218 | 0.590 | 1466 | ||
| 3 | 33.528 | 3780 | 0.096 | 448 | ||
| 4 | 34.773 | 5345 | 0.136 | 780 | ||
| 5 | 39.579 | 1721 | 0.044 | 158 | ||
| Total of | 3932308 | 100.000 | 33848 |
The following table 2 is a table of peaks of pregabalin prepared in example 1 of the present invention:
TABLE 2 Peak Table
< Peak Table >
PDA Ch1 210nm
| Peak number | Name of Compound | Retention time | Area of | Height | Concentration of |
| 1 | Pregabalin | 7.990 | 4669852 | 394296 | 0.000 |
| Total of | 4669852 | 394296 |
Referring to fig. 1 and 2, fig. 1 is a liquid phase HPLC profile of pregabalin prepared in example 10 described in CN101500985A, and fig. 2 is a liquid phase HPLC profile of pregabalin prepared in example 1 of the present invention.
As can be seen from table 1 and fig. 1, the peak table 1 includes 4 peaks of other compounds in addition to the peak containing pregabalin, and occupies a larger peak area, which indicates that the purity of the compound is low, only about 99.1%, while as can be seen from table 2 and fig. 2, the peak table 2 includes only the peak containing pregabalin, and does not include the peak containing other substances, which indicates that the purity of the prepared pregabalin in example 1 of the present invention is very high, reaching 99.99%, and can completely meet the pharmaceutical raw material standards.
Example 2
Adding 32kg (0.8mol) of sodium hydroxide into 80L of water, stirring and dissolving, cooling to 0 ℃, adding 40kg (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid in batches, controlling the temperature to be 0-10 ℃, stirring for 10min after the addition is finished, dropwise adding a sodium hypochlorite solution (9.7% of 164kg), controlling the temperature to be 0-10 ℃, keeping the temperature for reaction for 30min after the addition is finished, slowly heating to 80 ℃ for 1h, and cooling to room temperature for later use.
Adding 80L of toluene and sulfuric acid into a reaction kettle, cooling to about 15 ℃, dropwise adding the standby reaction solution, controlling the temperature within 25 ℃, adjusting the pH to 3 after adding sulfuric acid, heating to 25-30 ℃, standing for layering, extracting a water layer with 40L of 3 toluene, mixing organic layers (the mixed organic layers comprise 80L of toluene and 40L of 3 toluene), adjusting the pH to 7.5 with ammonia water, heating to 85 ℃, stirring for 10min, filter-pressing into a crystallization kettle, cooling to 0-10 ℃, 4h, centrifuging, washing with 40ml of ethanol, pulping the solid with 40L of purified water for 1h, centrifuging, drying with 50 ℃ hot air for 3h to obtain 31kg of pregabalin, the yield is 95.1%, and the purity is 99.99%.
Example 3
Adding 32kg (0.8mol) of sodium hydroxide into 80L of water, stirring and dissolving, cooling to 0-10 ℃, adding 40kg (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid in batches, controlling the temperature to 0-10 ℃, stirring for 10min after the addition is finished, dropwise adding a sodium hypochlorite solution (9.7% of 164kg), controlling the temperature to 0-10 ℃, keeping the temperature for reaction for 30min after the addition is finished, slowly heating to 75 ℃ for 1h, and cooling to room temperature for later use.
Adding 80L of n-butanol and hydrochloric acid into a reaction kettle, cooling to about 15 ℃, dropwise adding the standby reaction solution, controlling the temperature within 25 ℃, adjusting the pH to 4 after adding hydrochloric acid, heating to 25-30 ℃, standing for layering, extracting a water layer with 40L of 3 n-butanol, mixing organic layers (the mixed organic layers comprise 80L of n-butanol and 40L of 3 n-butanol), adjusting the pH to 7 with ammonia water, heating to 85 ℃, stirring for 10min, filter-pressing into a crystallization kettle, cooling to 0-10 ℃, 5h, centrifuging, washing with 40ml of isopropanol, pulping a solid with 40L of purified water for 1h, centrifuging, drying with 50 ℃ hot air for 3h to obtain 32.2kg of pregabalin, wherein the yield is 97.7%, and the purity is 99.99%.
Example 4
Adding 32kg (0.8mol) of sodium hydroxide into 80L of water, stirring and dissolving, cooling to 0-10 ℃, adding 40kg (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid in batches, controlling the temperature to 0-10 ℃, stirring for 10min after the addition is finished, dropwise adding a sodium hypochlorite solution (9.7% 153kg), controlling the temperature to 0-10 ℃, keeping the temperature for reaction for 30min after the addition is finished, slowly heating to 65 ℃ for 1h, and cooling to room temperature for later use.
Adding 80L ethyl acetate and formic acid into a reaction kettle, cooling to about 15 ℃, dropwise adding the standby reaction solution, controlling the temperature within 25 ℃, adjusting the pH to 5 after adding formic acid, heating to 25-30 ℃, standing for layering, extracting a water layer by 40L 3 n-butyl alcohol, mixing organic layers, adjusting the pH to 7 by ammonia water (the mixed organic layers comprise 80L ethyl acetate and 40L 3 n-butyl alcohol), heating to 85 ℃, stirring for 10min, filter-pressing into a crystallization kettle, cooling to 0-10 ℃, 3h, centrifuging, washing by 40ml isopropanol, pulping the solid by 40L purified water for 1h, centrifuging, drying by hot air at 50 ℃ for 3h to obtain 29.8kg of pregabalin with the yield of 94.6% and the purity of 99.99%.
In summary, the present invention provides a preparation method of pregabalin, which comprises the following steps: the (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid is subjected to Hofmann rearrangement reaction under the action of sodium hydroxide and sodium hypochlorite, after the rearrangement reaction is finished, the reaction solution is added into an acid-organic solvent system, alkali is added after organic phases are combined for alkali precipitation, and the pregabalin with high purity is prepared by pulping and washing with water, and can meet the medicinal quality standard without recrystallization. Meanwhile, as can be seen from the tests in examples 1-4, the pregabalin prepared by the method has high yield and purity of 99.99%, and can completely meet the standards of pharmaceutical raw material medicines. The preparation method has the advantages of simple process route, high product yield and high product purity, and is suitable for industrial production.
Compared with the prior art, the embodiment of the invention has the following effective effects:
1. at present, after the reaction is finished, acid is directly added to separate out solid in a water phase, the solid needs to be refined by isopropanol and water, and the product contains impurities which are difficult to remove.
2. The separation and purification of the pregabalin in the embodiment of the invention is to directly add an acid-organic solvent system into a reaction system after the reaction is finished, adjust the pH value to acidity, enter a product into an organic system after salifying, basically separate free pregabalin by alkali precipitation, remove a small amount of inorganic salt by simple pulping after the separation, and obtain the high-purity pregabalin without recrystallization.
3. The preparation of pregabalin in the embodiment of the invention has the advantages of mild reaction conditions, high reaction yield and high product purity, and the product can meet the medical quality standard once and is suitable for industrial production.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (8)
1. A preparation method of pregabalin is characterized by comprising the following steps:
carrying out Hofmann rearrangement reaction on (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid and sodium hypochlorite in an alkaline solution to obtain a reaction solution, adding the reaction solution into an acid-organic solvent system, then regulating the pH for the first time, layering, extracting a water layer by using an organic solvent, combining organic phases, adding alkali into the organic phase, regulating the pH for the second time until pregabalin is separated out, pulping and washing with water to obtain high-purity pregabalin;
the acid is at least one of sulfuric acid, hydrochloric acid, phosphoric acid, formic acid and acetic acid,
the organic solvent is selected from the group consisting of n-butanol,
the pH is adjusted to 2-5 for the first time.
2. The method for preparing pregabalin according to claim 1, wherein the hofmann rearrangement reaction comprises the following steps:
adding (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid into an alkaline aqueous solution in batches, stirring and uniformly mixing to obtain a mixed solution, dropwise adding an aqueous solution of sodium hypochlorite into the mixed solution, and carrying out Hofmann rearrangement reaction, wherein the reaction equation of the Hofmann rearrangement reaction is as follows:
3. the method for preparing pregabalin according to claim 2, wherein the hofmann rearrangement reaction comprises:
adding (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid into an alkaline aqueous solution in batches, stirring and mixing uniformly to obtain a mixed solution, dropwise adding an aqueous solution of sodium hypochlorite into the mixed solution, reacting at 0-10 ℃ for 0.5-1h, heating to 65-80 ℃ after dropwise adding of the aqueous solution of sodium hypochlorite is finished, and continuing to react for 1-2 h.
4. The method for preparing pregabalin of claim 3, wherein the molar ratio of the base in the basic aqueous solution to the (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid is 3.5-5.5:1,
the molar ratio of the sodium hypochlorite to the (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid is 1.5-1.1:1,
the alkali in the alkaline aqueous solution is selected from sodium hydroxide or potassium hydroxide, the mass fraction of the alkaline aqueous solution is 20-30%,
the mass fraction of the sodium hypochlorite aqueous solution is 5-15%.
5. The method for producing pregabalin of claim 1, wherein the organic phase comprises an organic solvent layer obtained after the layering and an extraction layer of an aqueous layer obtained after the layering, and the number of times of extraction of the aqueous layer is 3 to 4.
6. The method for preparing pregabalin according to claim 1, wherein the layering specifically comprises the following steps: after the reaction solution is dripped, controlling the temperature within 25 ℃, regulating the pH value for the first time, heating to 25-30 ℃, standing and layering.
7. The process for producing pregabalin of claim 1, wherein the base used for the base precipitation is at least one selected from triethylamine, aqueous ammonia, sodium hydroxide, potassium carbonate, and sodium bicarbonate, and the pH is secondarily adjusted to 7 to 8.
8. The method for preparing pregabalin according to claim 1, wherein the alkali separation and beating water washing specifically comprises the steps of: adding alkali into the organic phase, adjusting pH for the second time, continuously heating to 75-85 deg.C, reacting for 0.5-1h, press filtering, cooling to 0-10 deg.C, precipitating for 3-5h, centrifuging, washing, pulping the solid with purified water, centrifuging, and drying.
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