CN117843620B

CN117843620B - Purification preparation method of voronoi fumarate

Info

Publication number: CN117843620B
Application number: CN202311873815.6A
Authority: CN
Inventors: 隋海超; 聂胜维; 李跃东; 牛玉城; 王来庆; 薛富民
Original assignee: Shandong Chenghui Shuangda Pharmaceutical Co ltd
Current assignee: Shandong Chenghui Shuangda Pharmaceutical Co ltd
Filing date: 2023-12-31
Publication date: 2024-06-25
Anticipated expiration: 2043-12-31

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a purification preparation method of voronoi fumarate. The method comprises the following steps: s1: dissolving the crude product of the vonolamine free alkali by using methanol and water at a temperature, controlling Wen Dijia phosphoric acid, adjusting the pH value to 3.0-4.0, and cooling and crystallizing to obtain a wet product of the vonolamine phosphate; s2: directly adding the wet product of the voronoi phosphate into ethyl acetate and water, regulating to alkaline liquid with potassium carbonate, adding active carbon into an ethyl acetate layer for decolorization and filtration, concentrating to dryness, adding methanol and fumaric acid for heating to form salt, and cooling and filtering to obtain the voronoi fumarate. The method has the advantages of simple operation steps, low cost, less three wastes, environmental protection and high product purity, and is more suitable for industrial mass production.

Description

Purification preparation method of voronoi fumarate

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a purification preparation method of voronoi fumarate.

Background

Fumaric acid Fu Nuola is a novel oral gastric acid inhibitor, its chemical name: 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methyl methylamine fumarate, CAS No.: 1260141-27-2, molecular formula: c ₂₁H₂₀FN₃O₆ S, the structure is as follows:

Fumaric acid Fu Nuola is a novel calcium ion competitive acid blocker (P-CAB) and has the characteristics of full effect, quick effect and lasting acid inhibition. It can inhibit the resting or activated H+/K+ -ATPase and combine with cysteine molecule to form disulfide bond, acting on gastric wall cell for long term to inhibit gastric acid secretion. The latest guidelines for gastroesophageal reflux disease treatment in China have used P-CAB as one of the first-choice drugs for reflux esophagitis.

In CN116041326a, the free base of vonolamine is first prepared by adjusting ph=8 with 30% hydrochloric acid in methanol, then ethanol and fumaric acid are added, the mixture is heated to form salt, and after filtration, crude product of fumaric acid Fu Nuola is obtained, and then 50% of methanol water is used for dissolution, decolorization and recrystallization. The purification process needs to be repeatedly processed for three times, the product with the purity of more than 99.8 percent can be obtained through repeated crystallization and filtration, the yield is not high and is only 56 percent, the operation is very complicated, and the production efficiency is very low.

In patent CN116041326a, the hydrochloride of the vonolamine is prepared by using ethyl chloride solution of ethyl chloride under the mixed solvent of acetonitrile and ethyl acetate, after the hydrochloride is dissolved in water, the refined product of the vonolamine hydrochloride is separated out by adding sodium chloride aqueous solution through salting out, then the vonolamine free base is obtained again through the salting out of ethyl acetate and potassium carbonate, ethyl acetate, methanol and fumaric acid are added to form salt, after the crude product of the fumaric acid Fu Nuola is obtained, methanol is used: water=1:1, and cooling crystallization to obtain the final product with purity of 99.89%, and yield from Fu Nuola free alkali to Funula fumarate is 74.79%. The scheme repeatedly separates and purifies for 4 times, requires 4 times of filtration, is quite complex to operate, and generates a large amount of mixed solvent.

The patent CN114539219A reacts the prasugrel free base with di-tert-butyl dicarbonate in toluene to protect amino, the separation is carried out, then the acid is used for removing the protecting group to obtain the prasugrel free base, the prasugrel free base is salified with fumaric acid in toluene, and then methanol water is used for recrystallization, and the refining yield is 72.75%. The purification scheme needs four working procedures of protecting group reaction, protecting group removal, fumarate formation and recrystallization, is complex in operation, and the di-tert-butyl dicarbonate is expensive, so that the use cost for purification is too high.

In patent CN116621813a, fu Nuola free base and p-toluenesulfonic acid are refluxed in acetone and ethanol to form salt, then neutralized, mixed solvent of DMA and ethyl acetate is used to form Fu Nuola fumarate, and wet product is washed with absolute ethanol, thus obtaining high-purity vonolamine fumarate bulk drug. The purification method is also complex, two steps are needed to use mixed solvents, the generated waste liquid cannot be recycled, and the production cost is high.

Huang Kun et al in 2018,28 (2) 125-127 of Chinese J.pharmaceutical chemistry, use ethyl acetate and methanol mixed solvent to form fumarate, then use DMF + water mixed solvent to recrystalize, get filter cake to rinse with purified water, methanol beating and rinsing to get Fu Nuola crude fumaric acid, there are also problems that the waste liquid amount is large, the operation is complicated, and the solvent can not be recycled.

In CN115124506a, a free base oil of vonolamine is obtained, and then dissolved in a mixed solvent of isopropyl acetate and methanol, and then an aqueous solution of phosphoric acid or hydrobromic acid is added dropwise to form a salt, and the purity of the product is only about 98.6%. The obtained product is dried in vacuum, added into ethyl acetate and water, and then is subjected to alkali adjustment by ammonia water, and is washed by brine. And (3) forming fumarate in a mixed solvent of ethyl acetate and DMA/DMF, washing a filter cake twice, adding the wet product into the mixed solvent of methanol and water, and recrystallizing to obtain a fumaric acid Fu Nuola product, wherein the yield is only about 70%. According to the scheme, mixed solvents are needed to be used for forming salt for two times, DMF and DMA are high in price, more importantly, the DMF and the DMA are high in boiling point and difficult to recycle, separation and application are difficult, and because DMF is used as a universal solvent and is very high in polarity, a lost product in the purification process is difficult to recycle. And DMA and DMF are taken as second solvents, the residual solubility limit in pharmacopoeia is 1090ppm and 880ppm respectively, the boiling point is high, and the drying is difficult, so a large amount of low-boiling solvents are needed to rinse and wash DMF and DMA in order to ensure that the residual solubility is qualified, the operation steps are complicated, and the solvent consumption is large. The alkali adjusting step uses 25% ammonia water, and the generated ammonia nitrogen-containing wastewater is environment-friendly and cannot be treated. The final refining step uses mixed solvent methanol and water to recrystallize, the filter cake obtained needs to be leached again, and a great amount of mixed solvent is used for refining and purifying, and the steps of recrystallization, filtration, leaching, drying and the like are adopted for a plurality of times, so that the purity of the product is purified to more than 99.9 percent repeatedly. The multiple formulations of the vonolamine fumarate are incorporated into the 2020 edition of national medical insurance catalogue, and the product produced by analyzing the above aspects has no economic advantages in the aspects of raw material cost, production period and three-waste treatment.

The process steps of the patent CN113651798A and the patent CN115124506A are almost identical, and only the phosphoric acid/hydrobromic acid is adjusted to be L-malic acid or D-malic acid, so that the problems of high cost, long period and large three wastes are also caused. And malic acid as a usable acidulant is also more expensive than other mineral acids.

Disclosure of Invention

In order to solve the technical problems, the invention provides a purification preparation method of vonolamine fumarate. The method has the advantages of simple operation steps, low cost, less three wastes, environmental protection, high product yield and purity, and is more suitable for industrial mass production.

The invention is realized by the following technical scheme:

1. a purification preparation method of voronoi fumarate, comprising the following steps:

s1: dissolving the crude product of the vonolamine free alkali by using methanol and water at a temperature, controlling Wen Dijia phosphoric acid, adjusting the pH value to 3.0-4.0, and cooling and crystallizing to obtain a wet product of the vonolamine phosphate;

S2: directly adding the wet product of the voronoi phosphate into ethyl acetate and water, regulating to alkaline liquid with potassium carbonate, adding active carbon into an ethyl acetate layer for decolorization and filtration, concentrating to dryness, adding methanol and fumaric acid for heating to form salt, and cooling and filtering to obtain the voronoi fumarate.

The preparation method has the following reaction formula:

In the purification preparation method of the vonolamine fumarate, the mass ratio of the vonolamine free base to the phosphoric acid in the step S1 is 0.2-1.0: 1, preferably 0.25 to 0.35:1.

The pH value in the step S1 ranges from 3.5 to 3.8.

In the step S1, the mass ratio of the methanol to the water is 1.0-8.0: 1, preferably 3.0 to 5.0:1.

The temperature of Wen Di plus phosphoric acid in the step S1 is controlled to be 40-60 ℃.

In the step S2, the mass ratio of the ethyl acetate to Fu Nuola raw free alkali is 5.0-8.0: 1, wherein the mass ratio of the ethyl acetate to the water is 4-7:1.

In the step S2, the mass ratio of the methanol to the vonolamine free alkali is 3.0-20.0: 1, preferably 5.0 to 10.0:1.

In the step S2, fumaric acid is added, and the temperature for heating to form salt is 30-50 ℃.

Preferably, the purification preparation method of the voronoi fumarate comprises the following steps:

s1: dissolving the crude product of the vonolamine free alkali by using methanol and water at a temperature of 40-50 ℃, dropwise adding phosphoric acid, adjusting the pH value to 3.0-4.0, cooling to 0-10 ℃ and crystallizing for 1-3 hours to obtain a wet product of the vonolamine phosphate;

S2: directly adding the voronoi phosphate wet product into ethyl acetate and water, regulating the pH value to 8-9 by using potassium carbonate, decoloring and filtering an ethyl acetate layer by adding active carbon, concentrating to dryness, adding methanol and fumaric acid, heating to 30-40 ℃ for reacting for 0.5-2 h, cooling to 0-5 ℃, crystallizing and filtering to obtain the voronoi fumarate.

In the technical scheme of the invention, the phosphoric acid is 85% phosphoric acid by mass percent.

The 10% potassium carbonate is a 10% potassium carbonate solution.

The invention has the beneficial effects that:

1. According to the purification preparation method of the voronoi fumarate, phosphoric acid is used for salifying with Fu Nuola raw free base in methanol and water. Phosphoric acid is a ternary weak acid, a medium strong acid with almost no oxidizing property and an acidity coefficient of 2.12 (primary ionization). In most of the presently disclosed fumaric acid Fu Nuola- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-formaldehyde is taken as a raw material, and reacts with methylamine to generate Schiff base, and then is reduced. The unavoidable impurities a and B are extremely difficult to remove in the work-up, and both of these impurities structurally have a tertiary amine structure, while the group in the position of vonolamine is a secondary amine. The lone pair electron on the nitrogen atom in the amine molecule can receive the proton to be alkaline, and the result of the combined action of the electron effect and the solvation effect makes the alkalinity of the secondary amine strongest in the three aliphatic amines. It is therefore theoretically possible to salt out only with the vonolamine free base containing the secondary amine structure by using an acid of suitable acidity, while other impurities not containing the secondary amine structure remain in the mother liquor. The invention uses phosphoric acid and Fu Nuola raw free alkali to form salt, and strictly controls the addition amount of acid and the pH value of the system in the salt forming process, and has high impurity removal rate, short operation steps and low cost.

2. According to the purification preparation method of the voronoi fumarate, only three solvents including methanol, water and ethyl acetate are used, and in other schemes, 5-6 organic solvents are used, such as: acetone, toluene, methylene chloride, ethyl acetate, methanol, ethanol, DMAC, DMF, tetrahydrofuran, etc., and most of them are recrystallized from mixed solvents, a large amount of waste liquid is generated and it is difficult to recycle. The methanol and the water in the application can be directly used without separation after distillation, and the ethyl acetate can also be directly used after distillation. The three wastes are less, the method is more environment-friendly, the cost is lower, and the method is more suitable for industrial continuous production.

3. According to the purification preparation method of the voronoi fumarate, after the obtained voronoi fumarate is centrifuged, operations such as pulping, leaching, drying and the like are not needed, wet products can be directly added with water and ethyl acetate to regulate alkali, then the voronoi fumarate free alkali is extracted into ethyl acetate in a liquid separation mode, and after the voronoi fumarate free alkali is concentrated to be dry, methanol and fumaric acid are added, and the temperature is raised to form a salt, so that a high-purity fumaric acid Fu Nuola product can be obtained. Compared with other patents and documents, the method has the advantages that the method is simpler in operation, short in production period, less in multiple working procedures and steps, and more suitable for industrial mass production.

4. According to the purification preparation method of the vonolamine fumarate, the vonolamine base is used for forming phosphate in methanol and water in the first step, key impurities A and B and impurities without amino groups are removed, ethyl acetate is used as an extraction solvent in the second step, and residual polar impurities are removed by evaporating the ethyl acetate to dryness and then forming fumarate in the methanol. The purity of the produced product is more than 99.95 percent, and the method is a preparation method of high-purity fumaric acid Fu Nuola raw with simple operation and low cost.

In a word, the synthetic route of the method is simple to operate, reduces the use of solvents, has low raw material cost and production cost, generates little waste liquid amount, can recycle and reuse the solvents, is more environment-friendly in production, can achieve the purity of the obtained voronoi fumarate of more than 99.95 percent and the yield of more than 85.2 percent, and is more suitable for industrial large-scale production.

Detailed Description

The present invention will be further described with reference to specific examples, which are not intended to limit the scope of the invention.

In the embodiment of the invention, the liquid phase condition for checking the purity of fumaric acid Fu Nuola is as follows:

Chromatographic column: octadecylsilane chemically bonded silica as filler (CAPCELL PAK C MG II, 4.6 mm. Times.100 mm,3 μm or equivalent in potency);

mobile phase a: phosphate buffer (1.70 g of potassium dihydrogen phosphate and 4.47g of disodium hydrogen phosphate, 0.5ml of triethylamine, 1000ml of water are added to dissolve, and the pH value is adjusted to 6.8 by phosphoric acid) -methanol-acetonitrile (70:25:5);

Mobile phase B: phosphate buffer (1.70 g of potassium dihydrogen phosphate and 4.47g of disodium hydrogen phosphate, 0.5ml of triethylamine, 1000ml of water are added to dissolve, and the pH value is adjusted to 6.8 by phosphoric acid) -acetonitrile (30:70);

Detection wavelength: 230nm; flow rate: 1.0ml/min; column temperature: 30 ℃; sample injection volume: 20 μl.

Gradient elution was performed as follows:

Time (minutes)	Mobile phase a (%)	Mobile phase B (%)
			0	100	0
10	100	0
			30	50	50
40	0	100
			50	0	100
51	100	0
			60	100	0

The crude product of the vonolamine free base used in the embodiment of the invention is produced by Shandong Chenghui Shuangda pharmaceutical industry Co., ltd, and the purity is 98.3%, wherein the impurity A is 0.9%, and the impurity B is 0.6%.

Example 1:

Adding 150kg of methanol, 50kg of purified water and 50kg of Fu Nuola crude free alkali into a 500L reaction kettle, stirring and heating to 40-50 ℃ for dissolution, dropwise adding 13.47kg of phosphoric acid at the temperature of 40-50 ℃, stirring for 30min after the dropwise adding is finished, detecting the pH value of a system to be 3.67 by using a pH meter, slowly cooling to 0-10 ℃ for crystallization for 2h, and filtering to obtain a voronoi phosphate wet product. Adding 250kg of ethyl acetate and 50kg of purified water into a 500L reaction kettle, adding the wet product under stirring, regulating the pH of the system to 8-9 by using 10% potassium carbonate solution, standing for separating liquid, adding 0.5kg of activated carbon into an upper organic layer for decolorization and filtration, adding 250kg of methanol and 16.8kg of fumaric acid into the filtrate after evaporation, heating to 30-40 ℃ for reaction for 1h, cooling to 0-5 ℃ for crystallization and filtration, and drying to obtain 56.9kg of fumosla fumarate products, wherein the yield is 85.2%, the purity is 99.97%, the impurity A is 0.008% and the impurity B is 0.002%.

The methanol and water mother liquor is distilled to recover 176kg of aqueous methanol, the water content is 15.4%, and the aqueous methanol and water mother liquor can be used for the next batch after the water content is converted. The ethyl acetate mother liquor is distilled to recover 223kg of ethyl acetate, and can be directly used for the next batch. The methanol mother liquor is distilled to recover 235kg of methanol, which can be directly used for the next batch.

Example 2:

Adding 200kg of methanol, 50kg of purified water and 50kg of Fu Nuola crude free alkali into a 500L reaction kettle, stirring and heating to 40-50 ℃ for dissolution, dropwise adding 14.11kg of phosphoric acid at the temperature of 40-50 ℃, stirring for 30min after the dropwise adding is finished, detecting the pH value of a system to be 3.55 by using a pH meter, slowly cooling to 0-10 ℃ for crystallization for 2h, and filtering to obtain a voronoi phosphate wet product. Adding 300kg of ethyl acetate and 50kg of purified water into a 500L reaction kettle, adding the wet product under stirring, regulating the pH of the system to 8-9 by using 10% potassium carbonate solution, standing for separating liquid, adding 0.5kg of activated carbon into an upper organic layer for decolorization and filtration, adding 400kg of methanol and 16.8kg of fumaric acid into the filtrate after evaporation, heating to 30-40 ℃ for reaction for 1h, cooling to 0-5 ℃ for crystallization and filtration, and drying to obtain 57.8kg of a Furanolah fumarate product, wherein the yield is 86.5%, the purity is 99.96%, the impurity A is 0.005%, and the impurity B is 0.004%.

219Kg of methanol containing water and 13.2% of water are recovered from the mother solution of methanol and water by distillation, and the methanol and the water can be used for the next batch after being converted into water. The ethyl acetate mother liquor is distilled to recover 264kg of ethyl acetate, and can be directly used for the next batch. 359kg of methanol is recovered from the methanol mother liquor by distillation and can be directly used for the next batch.

Example 3:

Adding 300kg of methanol, 100kg of purified water and 100kg of Fu Nuola crude free alkali into a 1000L reaction kettle, stirring and heating to 40-50 ℃ for dissolution, dropwise adding 26.99kg of phosphoric acid at the temperature of 50-60 ℃, stirring for 30min after the dropwise adding is finished, detecting the pH value of a system to be 4.09 by using a pH meter, adding 0.56kg of phosphoric acid, stirring for 30min, detecting the pH value of the system to be 3.61 by using the pH meter again, slowly cooling to 0-10 ℃ for crystallization for 2h, and filtering to obtain a voronoi phosphate wet product. Adding 500kg of ethyl acetate and 100kg of purified water into a 1000L reaction kettle, adding the wet product under stirring, regulating the pH of the system to 8-9 by using 10% potassium carbonate solution, standing for separating liquid, adding 1kg of active carbon into an upper organic layer for decolorization and filtration, adding 500kg of methanol and 33.6kg of fumaric acid into the filtrate after evaporation, heating to 30-40 ℃ for reaction for 1h, cooling to 0-5 ℃ for crystallization and filtration, and drying to obtain 118.1kg of voronoi fumarate product with the yield of 88.39%, the purity of 99.97%, the impurity A of 0.004% and the impurity B not detected.

329Kg of methanol containing water and 329.7% of water are recovered from the mother solution of methanol and water by distillation, and the mother solution can be used for the next batch after the water is converted. The ethyl acetate mother liquor is distilled to recover 441kg of ethyl acetate, and the ethyl acetate mother liquor can be directly used for the next batch. 462kg of methanol is recovered from the methanol mother liquor by distillation and can be directly used for the next batch.

Example 4: (recycling solvent)

Adding 329kg (14.7% of water) of recovered methanol, 20kg of fresh methanol, 51kg of purified water and 100kg of Fu Nuola crude free alkali into a 1000L reaction kettle, stirring and heating to 40-50 ℃ for dissolution, dropwise adding 27.33kg of phosphoric acid at the temperature of 50-60 ℃, stirring for 30min after dropwise adding, detecting the pH value of a system to be 3.59 by using a pH meter, slowly cooling to 0-10 ℃ for crystallization for 2h, and filtering to obtain a voronoi phosphate wet product. Adding 441kg of recovered ethyl acetate and 100kg of purified water into a 1000L reaction kettle, adding the wet product under stirring, regulating the pH of the system to 8-9 by using 10% potassium carbonate solution, standing for separating liquid, adding 1kg of activated carbon into an upper organic layer for decolorization and filtration, adding 500kg of recovered methanol and 33.6kg of fumaric acid after evaporating filtrate to dryness, heating to 40-50 ℃ for reaction for 1h, cooling to 0-5 ℃ for crystallization and filtration, and drying to obtain 115.33kg of Furana fumarate product, wherein the yield is 86.32%, the purity is 99.95%, the impurity A is 0.003%, and the impurity B is 0.005%.

The above examples are provided to illustrate the disclosed embodiments of the invention and are not to be construed as limiting the invention. In addition, many modifications and variations of the methods and compositions of the invention set forth herein will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the invention. While the invention has been specifically described in connection with various specific preferred embodiments thereof, it should be understood that the invention should not be unduly limited to such specific embodiments. Indeed, it is intended that the invention be construed as limited to the various modifications which will be apparent to those skilled in the art, and that the invention also include other modifications which are intended to be within the scope of the invention.

Claims

S2: directly adding the wet product of the voronoi phosphate into ethyl acetate and water, regulating the pH to 8-9 by using potassium carbonate, separating liquid, adding active carbon into an ethyl acetate layer for decolorization and filtration, concentrating to dryness, adding methanol and fumaric acid, heating to 30-40 ℃ for reaction for 0.5-2h, cooling to 0-5 ℃, crystallizing and filtering to obtain the voronoi fumarate.

2. The purification preparation method of voronoi fumarate according to claim 1, wherein the mass ratio of the voronoi free base to phosphoric acid in step S1 is 0.2 to 1.0:1.

3. The purification preparation method of voronoi fumarate according to claim 2, wherein the mass ratio of the voronoi free base to phosphoric acid in step S1 is 0.25-0.35:1.

4. The process for the purification preparation of voronoi fumarate according to claim 1, wherein the pH in step S1 is in the range of 3.5-3.8.

5. The purification preparation method of voronoi fumarate according to claim 1, wherein the mass ratio of methanol to water in step S1 is 1.0-8.0:1.

6. The purification preparation method of voronoi fumarate according to claim 5, wherein the mass ratio of methanol to water in step S1 is 3.0 to 5.0:1.

7. The purification preparation method of voronoi fumarate according to claim 1, wherein the mass ratio of ethyl acetate to Fu Nuola th free base in step S2 is 5.0 to 8.0:1, wherein the mass ratio of the ethyl acetate to the water is 4-7:1.

8. The purification preparation method of vonolamine fumarate according to claim 1, wherein the mass ratio of methanol to vonolamine free base in step S2 is 3.0-20.0:1.

9. The purification preparation method of voronoi fumarate according to claim 8, wherein the mass ratio of methanol to voronoi free base in step S2 is 5.0 to 10.0:1.