CN104860926B - A kind of preparation method of Vonoprazan fumarate - Google Patents

A kind of preparation method of Vonoprazan fumarate Download PDF

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CN104860926B
CN104860926B CN201510318995.0A CN201510318995A CN104860926B CN 104860926 B CN104860926 B CN 104860926B CN 201510318995 A CN201510318995 A CN 201510318995A CN 104860926 B CN104860926 B CN 104860926B
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CN104860926A (en
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茆利平
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ZHEJIANG CHENG YI PHARMACEUTICAL CO Ltd
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to a kind of preparation of medical compounds, more particularly to a kind of preparation method of gastric antiacids thing Vonoprazan fumarate.The synthetic route of the compound is as follows:

Description

A kind of preparation method of Vonoprazan fumarate
Technical field:
The present invention relates to a kind of preparation of medical compounds, more particularly to a kind of gastric antiacids thing Vonoprazan fumarate Preparation method.
Background technology:
Vonoprazan fumarate, chemical constitution is as follows:
English name:Vonoprazan fumarate(TAK-438)
Chemical name:5- (2- fluorophenyls)-N- methyl isophthalic acids-(3- pyridyl sulfonyls) -1H- pyrroles's -3- methylamine fumarates The medicine belongs to new the one of the competitive acid retarding agent (Potassium-competitive acid blocker, P-CAB) of potassium ion Class inhibitor, with powerful, lasting gastric acid secretion inhibitory action, meanwhile, in the final step of parietal cell gastric acid secretion, By suppressing K to H, the combination of K-ATP enzyme (proton pump) also has termination in advance to gastric acid secretion.
The medicine is developed for Wu Tian companies of Japan, for erosive esophagitis, gastric ulcer, duodenal ulcer, helicobacter pylorus Mycorhiza except etc..
Chinese patent about the medicine is as follows:
Chinese patent 200680040789.7 discloses the preparation method of following Vonoprazan fumarate:
Reference example 63
5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde
At room temperature, the solution (96mL) to 5- (2- fluorophenyls) -1H- pyrroles -3- formaldehyde (475mg) in tetrahydrofuran Middle addition sodium hydride (60% in oil, 503mg), and the mixture is stirred 30 minutes.15- crown ethers -5 (2.77g) is added dropwise, and The mixture is stirred 30 minutes.Pyridine -3- sulfonyl chloride hydrochlorides (1.35g) is added, and further stirring 3 is small by the mixture When.Reactant mixture is diluted with saturated brine, and the mixture is extracted with ethyl acetate.Extract is washed with saturated salt Wash, dried with anhydrous magnesium sulfate, and be concentrated under reduced pressure.Residue is purified (eluent by silica gel column chromatography:Hexane-acetic acid Ethyl ester=7: 3 → 2: 3), and are crystallized with Di Iso Propyl Ether-ethyl acetate (4: 1), obtain title compound, it is colourless crystallization (yield 680mg, 82%).
Embodiment 8
1- [5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- bases]-N- methyl methylamine fumarates 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde (1.52g) is dissolved in methyl alcohol (30ml), in room Temperature is lower to add 40% methylamine methanol solution (3.57g), and the mixture is stirred 30 minutes.Sodium borohydride is added at room temperature (523mg), and the mixture is stirred 10 minutes.The hydrochloric acid (50mL) of 1mol/L is added, and the mixture is stirred 5 minutes. Reactant mixture saturated sodium bicarbonate aqueous solution is alkalized, and the mixture is extracted with ethyl acetate.Extract saturation Salt water washing, with anhydrous sodium sulfate drying, and is concentrated under reduced pressure.Residue is purified (eluent by alkaline silica gel column chromatography: Acetate-methanol=1: 0 → 7: 3), obtains the free salt of title compound, it is pale yellow oil (yield 1.30g). Gained free salt (750mg) is dissolved in ethyl acetate (30ml), fumaric acid (278mg) is added dropwise at room temperature in methyl alcohol (3mL) In solution.Stirring filters the crystallization obtained by collection in 30 minutes afterwards, and is washed with ethyl acetate, obtains title compound, and it is Colourless crystallization (yield 912mg, 74%).
Technical scheme disclosed above, wherein need that 15- crown ether -5 are added dropwise, while being purified using chromatographic column, 15- Crown ether -5 is expensive, complex operation, and chromatographic column equipment requirement high cost is high, is unfavorable for industrialization, gained fumaric acid Wo Nuola Praise and there are problems that needing to purify and go.
Chinese patent 201080018114.9 discloses the preparation method of following Vonoprazan fumarate:
Embodiment 4
5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde
By 5- (2- fluorophenyls) -1H- pyrroles -3- formaldehyde (5.00g, 26.43mmol), N, N- lutidines -4- amine (0.65g, 5.29mmol), diisopropylethylamine (4.78g, 37.00mmol) and acetonitrile (18.5ml) are added in four-neck flask, and Solution of pyridine -3- sulfonic acid chlorides (5.63g, 31.71mmol) in acetonitrile (5ml) is added afterwards.Further add acetonitrile (1.5ml), and internally 40-50 DEG C of temperature is stirred 1.5 hours by the mixture.Internal temperature is cooled to 30 DEG C, and by It is added dropwise to water (15ml).The mixture ph is adjusted to 4-5 with 0.5N hydrochloric acid.Add the kind of title compound brilliant (2.5mg), is then added dropwise over water (about 30ml).0.5 hour is stirred in 20-30 DEG C of internal temperature afterwards, by internal temperature Degree is cooled to 0-10 DEG C, then stirs the mixture 1 hour.Precipitated crystal is collected by filtration, with cold acetonitrile Washed with the mixed solution (1: 2,7.5ml) and water (7.5ml × 2) of water, and decompression, 50 DEG C of dryings until reach constant weight so as to Obtain title compound (7.57g, yield 86.7%).
Embodiment 5
1- [5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- bases]-N- methyl methylamine fumarates To addition DMA (108ml) and sodium borohydride (3.06g, 81.74mmol) in the flask purged through nitrogen, and The mixture is dissolved into (solution A).To addition 5- (2- fluorophenyls) -1- (pyridine -3- in another flask through nitrogen purging Base sulfonyl) -1H- pyrroles -3- formaldehyde (60.00g, 181.64mmol) and methyl alcohol (300ml), then it is added dropwise in room temperature 40% methylamine solution (18.34g, 236.13mmol) in methyl alcohol.By the mixture, internally 20-30 DEG C of temperature is further Stirring 30 minutes.Internal temperature is cooled to -10 DEG C, then internally temperature is added dropwise over the molten of previous preparation no more than 0 DEG C Liquid A.DMA (12ml) is added, then internally -10-0 DEG C of temperature is stirred 1 hour by the mixture. Internal temperature is added dropwise over 1N HCl (360ml) no more than 20 DEG C, and internally 10-20 DEG C of temperature stirs 30 by the mixture Minute.12.5% ammoniacal liquor (240ml), ethyl acetate (600ml) and water (180ml) are added, the mixture is then distributed.By water (240ml) and ethyl acetate (360ml) add to the water layer and extract the mixture again.Merge the organic layer to be used in combination 5% salt solution (360ml) is washed twice.The organic layer is concentrated to about 253g, and adds DMA (480ml).The mixture is heated to 50 DEG C of internal temperature, and adds fumaric acid (21.08g, 181.64mmol).By institute Internally temperature 50 C is stirred 30 minutes to state mixture, and then cooling is stirred at room temperature 1 hour.The crystal filtering that will be precipitated, First washed with the mixed solution (1: 2,90ml) of DMA with ethyl acetate, then with ethyl acetate (120ml) Washing, and in decompression, 50 DEG C of dryings so as to obtain crude product (62.73g).
Crude product (55.00g) derived above is suspended in mixed solution (7: 3,550ml) of the methyl alcohol with water, and 60-65 DEG C of dissolving of internal temperature.Activated carbon S HIRASAGI A (registration mark, 2.75g) are added, and the mixture is stirred 10 minutes, then filtering was washed with the mixed solution (7: 3,110ml) of methyl alcohol and water.The filtrate that will be merged is heated to inside About 55 DEG C of temperature, is cooled to room temperature, and internally 0-10 DEG C of temperature is further stirred 1 hour.The crystal filtering that will be precipitated, Washed with the mixed solution (1: 1,110ml) of methyl alcohol and water, and in decompression, 50 DEG C of dryings so as to obtain title compound (47.50g, yield 64.6%).
Embodiment 6
1- [5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- bases]-N- methyl methylamine fumarates
DMA (18ml) and sodium borohydride (0.52g, 13.6mmol) are added the burning purged through nitrogen In bottle, and the mixture is dissolved into (solution A).5- (2- fluorophenyls) -1- is added in another flask purged through nitrogen (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde (10.0g, 30.3mmol) and methyl alcohol (50ml), then dropwise add in room temperature Enter 40% methylamine solution (3.06g, 39.4mmol) in methyl alcohol, and internally 20-30 DEG C of temperature enters one by the mixture Step stirring 30 minutes.Internal temperature is reduced to 5 DEG C, and internally temperature is added dropwise over the molten of previous preparation no more than 0-10 DEG C Liquid A.DMA (2ml) is added, and internally 0-10 DEG C of temperature is stirred 1 hour by the mixture.Internally Temperature is added dropwise over 1N HCl (70ml) no more than 20 DEG C, and internally 15-25 DEG C of temperature is stirred 30 minutes by the mixture. 12.5% ammoniacal liquor (60ml) and ethyl acetate (100ml) are added so as to distribute the mixture.By 5% salt solution (50ml) and acetic acid Ethyl ester (50ml) is added in the water layer and extracts the mixture again.Merge the organic layer and with 5% salt solution (60ml) Wash twice.The organic layer is concentrated to about 25ml, ethyl acetate (70ml) is added, and the mixture is concentrated again To about 38.0ml.DMA (60ml) is added, the mixture 45 DEG C of internal temperature is heated to, and add Fumaric acid (3.51g, 30.3mmol).40-50 DEG C of temperature stirring 30 minutes internally afterwards, is added dropwise over ethyl acetate (30ml), and internally 40-50 DEG C of temperature is stirred 30 minutes by the mixture.By reactant mixture cooling, and in room Temperature stirring 1 hour.Precipitated crystal is collected by filtration, and it is molten with the mixing of DMA with ethyl acetate Liquid (1: 1,15ml) is washed, and is then washed with ethyl acetate (30ml) so as to obtain crude product (wet product).Will be derived above Crude product (wet product) is suspended in the mixed solution (1: 1,100ml) of methyl alcohol and water, and 60-70 DEG C of dissolving of temperature internally. Activated carbon SHIRASAGIA (registration mark, 0.30g) is added, and the mixture is stirred 10 minutes, then filtering uses methyl alcohol Mixed solution (1: 1,20ml) with water is washed.Internally about 55-65 DEG C of temperature dissolves the filtrate that will be merged again, cooling To room temperature, and internally 0-10 DEG C of temperature is further stirred 1 hour.Precipitated crystal is collected by filtration, with methyl alcohol and water Mixed solution (1: 1,20ml) washing, and in decompression, 50 DEG C of dryings are so as to obtain title compound (10.07g, yield 72.1%).
The shortcoming of the preparation method is:The Vonoprazan fumarate purity for obtaining is not high, and impurity therein includes N, N- Dimethylacetylamide, 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde and pyridine -3- sulphonyl The content of chlorine, particularly 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde and pyridine -3- sulfonic acid chlorides It is higher, and be difficult to remove, though can be more than 98.5% using above-mentioned prior art gained Vonoprazan fumarate content, wherein The content of above-mentioned two related impurities is more than 0.3%, have impact on the quality of product, and to reach higher standard requirement, the present invention enters The improvement gone in method.
The content of the invention:
To overcome the defect of prior art, the present invention to improve prior art, it is proposed that following technical scheme.This Invention provides a kind of preparation method of Vonoprazan fumarate, it is characterised in that synthetic route is as follows:
Preparation method of the invention, it is characterised in that step is as follows:
Step 1
5- (2- fluorophenyls) pyrroles's -3- formaldehyde, DMAP, triethylamine and acetonitrile are added into reactor, room temperature Stirring;Addition is dissolved in the pyridine -3- sulfonic acid chlorides of acetonitrile;It is heated to 45 DEG C of reactions;Room temperature is cooled to, water is added, will be anti-with hydrochloric acid Answer the ph values of liquid to adjust to 4-5, half an hour is stirred at room temperature;0-5 DEG C is cooled to stir 1 hour;Filtering, filter cake acetonitrile:Washing Wash, be washed with water and wash, be dried to obtain 5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) pyrroles's -3- formaldehyde;
Step 2
5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) pyrroles's -3- formaldehyde is dissolved in methyl alcohol;Stir at room temperature, will be dissolved in The methylamine solution of methyl alcohol adds reaction system, is stirred at room temperature 1 hour;Sodium cyanoborohydride is added, is stirred at room temperature 2 hours;Plus Enter hydrochloric acid stirring;PH to 9-10 is adjusted with alkali;Add ethyl acetate, stirring layering;Separate water phase, plus ethyl acetate stirring point Layer;Merge organic phase, plus saturated aqueous common salt stirring layering;Organic phase is spin-dried for, and adds ethyl acetate and is spin-dried for band water 2 times;It is remaining Thing adds absolute ethyl alcohol, is heated to 45 DEG C;Fumaric acid is added, 45 DEG C are stirred 1 hour;It is down to and 2 hours, crystallization is stirred at room temperature; Filtering, filter cake absolute ethyl alcohol drip washing, vacuum drying obtains Vonoprazan fumarate crude product;
Step 3:
Vonoprazan fumarate crude product is added into isopropanol and dichloromethane=2:The mixed solvent of 1 (v/v), adds activity Charcoal, is heated to reflux 1 hour, and activated carbon is filtered out while hot, is stirred 12 hours, separates out crystallization, is crystallized after suction filtration, uses isopropanol Wash twice, Vonoprazan fumarate sterling is obtained final product after drying.
Preferred preparation method of the invention, step is as follows:
Step 1,
5- (2- fluorophenyls) pyrroles's -3- formaldehyde 10g, DMAP 1.3g, triethylamine 7.5g and acetonitrile (40ml) Reaction bulb is added, is stirred at room temperature;Pyridine -3- sulfonic acid chlorides 11.3g and acetonitrile (10ml), instill reaction bulb;It is heated to 45 DEG C of reactions 1.5 hours;25 DEG C are cooled to, water (30ml) is added;System ph values are adjusted to 4-5 with concentrated hydrochloric acid, half an hour is stirred at 25 DEG C; 0-5 DEG C is cooled to stir 1 hour;Filtering, filter cake acetonitrile:Water (1:2) 30ml drip washing, then with water (20ml) drip washing 2 times, 50 DEG C Vacuum drying, obtains 5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) pyrroles's -3- formaldehyde 15g;
Step 2
5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) pyrroles's -3- formaldehyde 10g is dissolved in methyl alcohol (70ml);Nitrogen is protected Methylamine methanol solution (15g, 30% meter) at room temperature, is added dropwise to reaction system by stirring, and drop is complete to be stirred at room temperature 1 hour;At room temperature, Sodium cyanoborohydride (1.52g) is dividedly in some parts, is finished and is stirred at room temperature 2 hours;1N hydrochloric acid (100ml) is instilled into reaction system, It is stirred at room temperature 5 minutes;PH to 9-10 is adjusted with the NaOH aqueous solution;Add ethyl acetate (50ml), stirring layering;Water phase is separated, Plus ethyl acetate (50ml) stirring layering;Merge organic phase, plus saturated aqueous common salt (60ml), stirring layering;Organic phase is spin-dried for, then Ethyl acetate (20ml) is added to be spin-dried for band water 2 times;Residue adds absolute ethyl alcohol (120ml), is heated to 45 DEG C;By fumaric acid (5.28g) is added, and 45 DEG C are stirred 1 hour;It is down to and 2 hours, crystallization is stirred at room temperature;Filtering, filter cake absolute ethyl alcohol (30ml) drenches Wash, vacuum drying obtains Vonoprazan fumarate finished product 7.3g;
Step 3:
Vonoprazan fumarate crude product 5g is added isopropanol and dichloromethane=2 of 30ml:The mixed solvent of 1 (v/v), The activated carbon of 1g is added, is heated to reflux 1 hour, activated carbon is filtered out while hot, stirred 12 hours, separate out crystallization, obtained after suction filtration Crystallization, is washed twice with 20ml isopropanols, and Vonoprazan fumarate sterling 4.5g is obtained final product after drying.
By detection, more than 99.50%, wherein each is related for the Vonoprazan fumarate sterling content that the present invention is obtained The content of impurity is less than 0.1%.
The purification step for focusing on Vonoprazan fumarate of the invention, the Vonoprazan fumarate of the purifying for obtaining is former Material, impurity content is few, good stability, Small side effects, and this depends primarily on the use of solvent in subtractive process, and the present invention uses 5 Isopropanol and dichloromethane=2 are measured again:The mixed solvent of 1 (v/v) is recrystallized once as recrystallization solvent, you can obtained excellent Have the technical effect that by screening obtain, screening process is as follows:
After the Vonoprazan fumarate crude product of synthesis is respectively adopted following different solvent treatment, impurity in each sample The step of content is shown in Table 1, recrystallization method and step 3 of the present invention are identical,
The Vonoprazan fumarate crude product of table 1 recrystallized with different solvents after in each sample impurity content
Solvent Total impurities (%)
Methyl alcohol 0.80
Ethanol 1.05
Dichloromethane 0.72
Isopropanol 0.74
Acetone 0.92
Ethyl acetate 0.89
Benzene 0.86
Acetonitrile 0.88
Isopropanol:Dichloromethane (1:1) 0.71
Isopropanol:Dichloromethane (1:2) 0.73
Isopropanol:Dichloromethane (1:4) 0.70
Isopropanol:Dichloromethane (2:1) 0.63
Isopropanol:Dichloromethane (4:1) 0.78
Below by way of experimental data, the present invention is further illustrated:
The Vonoprazan fumarate sterling that 2 couples of present invention of table and prior art are obtained carries out HPLC analyses, purity and impurity Content % is as follows:
Prior art is using 50% methyl alcohol as recrystallization solvent The present invention
Vonoprazan fumarate purity 99.03 99.55
Pyridine -3- the sulfonic acid chlorides of impurity 1 0.35 0.09
Impurity 2 0.23 0.08
Impurity 3 0.30 0.07
Table 3 enters to the Vonoprazan fumarate sterling that Vonoprazan fumarate sterling of the invention and prior art are obtained Row accelerated stability (40 DEG C of placements) compares, as a result as follows:
From in terms of test data, Vonoprazan fumarate sterling of the invention is more stablized, and degradation speed is slow.
Specific embodiment:
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1
The preparation of Vonoprazan fumarate
Step 1,
5- (2- fluorophenyls) pyrroles's -3- formaldehyde 10g, DMAP 1.3g, triethylamine 7.5g and acetonitrile (40ml) Reaction bulb is added, is stirred at room temperature;Pyridine -3- sulfonic acid chlorides 11.3g and acetonitrile (10ml), instill reaction bulb;It is heated to 45 DEG C of reactions 1.5 hours;25 DEG C are cooled to, water (30ml) is added;System ph values are adjusted to 4-5 with concentrated hydrochloric acid, half an hour is stirred at 25 DEG C; 0-5 DEG C is cooled to stir 1 hour;Filtering, filter cake acetonitrile:Water (1:2) 30ml drip washing, then with water (20ml) drip washing 2 times, 50 DEG C Vacuum drying, obtains 5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) pyrroles's -3- formaldehyde 15g;
Step 2
5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) pyrroles's -3- formaldehyde 10g is dissolved in methyl alcohol (70ml);Nitrogen is protected Methylamine methanol solution (15g, 30% meter) at room temperature, is added dropwise to reaction system by stirring, and drop is complete to be stirred at room temperature 1 hour;At room temperature, Sodium cyanoborohydride (1.52g) is dividedly in some parts, is finished and is stirred at room temperature 2 hours;1N hydrochloric acid (100ml) is instilled into reaction system, It is stirred at room temperature 5 minutes;PH to 9-10 is adjusted with the NaOH aqueous solution;Add ethyl acetate (50ml), stirring layering;Water phase is separated, Plus ethyl acetate (50ml) stirring layering;Merge organic phase, plus saturated aqueous common salt (60ml), stirring layering;Organic phase is spin-dried for, then Ethyl acetate (20ml) is added to be spin-dried for band water 2 times;Residue adds absolute ethyl alcohol (120ml), is heated to 45 DEG C;By fumaric acid (5.28g) is added, and 45 DEG C are stirred 1 hour;It is down to and 2 hours, crystallization is stirred at room temperature;Filtering, filter cake absolute ethyl alcohol (30ml) drenches Wash, vacuum drying obtains Vonoprazan fumarate finished product 7.3g.
Step 3:
Vonoprazan fumarate crude product 5g is added isopropanol and dichloromethane=2 of 30ml:The mixed solvent of 1 (v/v), The activated carbon of 1g is added, is heated to reflux 1 hour, activated carbon is filtered out while hot, stirred 12 hours, separate out crystallization, obtained after suction filtration Crystallization, is washed twice with 20ml isopropanols, and Vonoprazan fumarate sterling 4.5g is obtained final product after drying.

Claims (1)

1. a kind of preparation method of Vonoprazan fumarate, it is characterised in that methods described step is as follows:
Step 1,
5- (2- fluorophenyls) pyrroles's -3- formaldehyde 10g, DMAP 1.3g, triethylamine 7.5g and 40ml acetonitrile add anti- Bottle is answered, is stirred at room temperature;Pyridine -3- sulfonic acid chloride 11.3g and 10ml acetonitriles, instill reaction bulb;45 DEG C are heated to react 1.5 hours; 25 DEG C are cooled to, 30ml water is added;System pH is adjusted to 4-5 with concentrated hydrochloric acid, half an hour is stirred at 25 DEG C;It is cooled to 0-5 DEG C stirring 1 hour;Filtering, filter cake 30ml acetonitriles:Water=1:2 drip washing, then with 20ml water wash 2 times, 50 DEG C of vacuum drying are obtained To 5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) pyrroles's -3- formaldehyde 15g;
Step 2,
5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) pyrroles's -3- formaldehyde 10g is dissolved in 70ml methyl alcohol;Nitrogen protects teeter chamber Under temperature, 30% methylamine methanol solution 15g is added dropwise to reaction system, drop is complete to be stirred at room temperature 1 hour;At room temperature, by 1.52g cyano group Sodium borohydride is dividedly in some parts, and finishes and is stirred at room temperature 2 hours;100ml 1N hydrochloric acid is instilled into reaction system, is stirred at room temperature 5 minutes; PH to 9-10 is adjusted with the NaOH aqueous solution;Add 50ml ethyl acetate, stirring layering;Water phase is separated, plus 50ml ethyl acetate is stirred Mix layering;Merge organic phase, plus 60ml saturated aqueous common salts, stirring layering;Organic phase is spin-dried for, and adds 20ml ethyl acetate and is spin-dried for Band water 2 times;Residue adds 120ml absolute ethyl alcohols, is heated to 45 DEG C;5.28g fumaric acid is added, 45 DEG C are stirred 1 hour;Drop To 2 hours, crystallization are stirred at room temperature;Filtering, filter cake 30ml absolute ethyl alcohol drip washing, vacuum drying obtain Vonoprazan fumarate into Product 7.3g;
Step 3,
Vonoprazan fumarate crude product 5g is added isopropanol and dichloromethane=2 of 30ml:The mixed solvent of 1 (v/v), adds The activated carbon of 1g, is heated to reflux 1 hour, and activated carbon is filtered out while hot, is stirred 12 hours, separates out crystallization, is crystallized after suction filtration, Washed twice with 20ml isopropanols, Vonoprazan fumarate sterling 4.5g is obtained final product after drying.
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CN106478597A (en) * 2015-09-02 2017-03-08 中美华世通生物医药科技(武汉)有限公司 Vonoprazan fumarate monocrystalline and its production and use
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CN105503828A (en) * 2015-12-24 2016-04-20 北京康立生医药技术开发有限公司 Preparation method of fumarate of pyrrole derivatives
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CN106478601A (en) * 2016-09-27 2017-03-08 海口南陆医药科技股份有限公司 A kind of Vonoprazan fumarate novel crystal forms and preparation method thereof
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