CN108503621A - A kind of preparation method of Vonoprazan fumarate - Google Patents
A kind of preparation method of Vonoprazan fumarate Download PDFInfo
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Abstract
The present invention relates to a kind of preparation methods of Vonoprazan fumarate, belong to bulk pharmaceutical chemicals preparing technical field.Preparation method of the present invention includes the following steps：5 (2 fluorophenyl) 1H pyrroles, 3 formonitrile HCN is that starting material is reacted with 3 sulfonic acid chloride of pyridine, generates 5 (2 fluorophenyl) 1 (3 base sulfonyl of pyridine) 1H pyrroles, 3 nitrile；5 (2 fluorophenyl) 1 (3 base sulfonyl of pyridine) 1H pyrroles, 3 nitrile prepares 5 (2 fluorophenyl) 1 (3 base sulfonyl of pyridine) 1H pyrroles, 3 formaldehyde through reduction；Then Wo Nuolazan is prepared again；Again Vonoprazan fumarate is prepared through salt-forming steps.Technical solution of the present invention is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of Vonoprazan fumarate, belong to bulk pharmaceutical chemicals preparing technical field.
Background technology
Vonoprazan fumarate is to belong to the competitive sour retarding agent of potassium ion (K+) by one kind of Japanese military field pharmaceutical development
(P-CAB) new class inhibitor, can be in the final step of parietal cell gastric acid secretion, by inhibiting K+ to H+-K+-
The combination of ATP enzyme (proton pump) terminates the secretion of hydrochloric acid in gastric juice in advance, has powerful, lasting gastric acid secretion inhibiting effect.
Vonoprazan fumarate has completely new target spot, is entered in stomach with high concentration, and first administration just can generate maximum inhibition effect
It answers, and sustainable 24 hours.Vonoprazan fumarate is stablized in acid, rapid-action, long action time.
Vonoprazan fumarate, chemistry are entitled：1- [5- (2- fluorophenyls) -1- (pyridine -3- sulfonyls) -1H- pyrroles -3-
Base]-N- methyl methylamine list fumarates, under structure such as formula (1) shown in.
The synthetic route that Vonoprazan fumarate has disclosed report is mainly the following：
1. the synthetic route in Japan's force field disclosed in Chinese patent 201080018114 is as follows：
The synthetic route is primarily present two disadvantages：First, when cyano is converted to aldehyde radical, use Raney's nickel for catalyst
Hydrogenation reaction, used hydrogen are easy to set off an explosion, and there are huge security risks for industrialized production；Second is that aldehyde and first
Amine is generated with sodium borohydride reduction in Wo Nuolazan techniques after generating imines, is more than by once recrystallizing many impurity
0.1%.
2. synthetic route is as follows disclosed in Chinese patent CN105294653A：This route is long, troublesome in poeration, total recovery
Low, ortho-fluorostyrene amine reacts generation intermediate (III) with 2- bromine propionic aldehyde and needs column chromatography, is not suitable for industrialized production.
Invention content
Goal of the invention：In view of the deficiencies of the prior art, a kind of fertile promise of the fumaric acid of safe suitable industrialized production is provided
Preparation method is praised in drawing.
Technical solution：
The present invention provides a kind of preparation methods of Vonoprazan fumarate, include the following steps：
The technical scheme is that：A kind of preparation method of Vonoprazan fumarate, includes the following steps：
Step 1: using 5- (2- fluorophenyls) -1H- pyrroles -3- formonitrile HCNs shown in formula (7) as shown in starting material and formula (6)
Pyridine -3- sulfonic acid chlorides reaction, in the presence of basic catalyst, at 0-30 DEG C react production (5) compound represented 5-
(2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- nitriles.
This step reaction temperature is 0-30 DEG C, and preferable reaction temperature is 10-20 DEG C.
This step reaction time is 2~4h, preferred reaction time 3h.
Basic catalyst described in this step is triethylamine, 4-dimethylaminopyridine (DMAP), n,N-diisopropylethylamine
(DIPEA), triethylene diamine (DABCO), pyridine, tetramethylethylenediamine, preferably 4-dimethylaminopyridine (DMAP) and N, N- bis-
The mixture of wopropyl ethyl amine (DIPEA).
This step reaction solvent is acetonitrile, and tetrahydrofuran, dichloromethane, toluene, dioxane, preferably reaction dissolvent are second
Nitrile.
The rate of charge of this step is：Formula (7) 5- (2- fluorophenyls) -1H- pyrroles's -3- formonitrile HCNs：Formula (6) pyridine -3- sulfonic acid chlorides：
DIPEA：The molar ratio range of DMAP is 1：1.1-1.3：1.2-1.6：0.13-0.17, preferably four molar ratio is 1：1.2：
1.4：0.15.Post-processing recrystallization solvent is tetrahydrofuran, acetonitrile, dioxane, the mixture of tetrahydrofuran and water, acetonitrile
With the mixture of water, the mixture of dioxane and water, preferably recrystallization solvent are the mixture of acetonitrile and water.
Step 2: with 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- nitriles shown in formula (5) four
Hydrogen furans, acetic acid, water are added Raney's nickel in pyridine, sodium hypophosphite are then added, is stirred to react, shown in formula (4)
5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.
In this step, rate of charge is：5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- nitriles：Acetic acid：
Pyridine：Raney's nickel：The mass ratio of sodium hypophosphite is 1：1-4：3-8：0.4-0.8 (water content：50%)：1.5-3 preferably five
The mass ratio of kind material is 1：2.6：5：0.5：2.Reaction temperature is 10-40 DEG C, and preferable reaction temperature is 15-25 DEG C.When reaction
Between be 3-5 hour, preferred reaction time be 4 hours.Post-process recrystallization solvent be selected from tetrahydrofuran, acetonitrile, dioxane,
The mixture of the mixture of the mixture of tetrahydrofuran and water, acetonitrile and water, dioxane and water, preferably recrystallization solvent are
The mixture of acetonitrile and water.
Step 3: with 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde shown in formula (4) with
Methylamine alcohol solution reacts in methyl alcohol first generates imines, and pyridine is added in backward reaction solution, and the N, N- bis- of catalyst is then added dropwise
Methylacetamide (DMA) solution is stirred to react the Wo Nuolazan to dissociate shown in production (3).Reaction dissolvent is methanol, second
Alcohol, acetonitrile, tetrahydrofuran, dioxane, n,N-Dimethylformamide, n,N-dimethylacetamide, N-Methyl pyrrolidone
(NMP), preferably reaction dissolvent is methanol, DMA.Reaction temperature is -20-10 DEG C, and preferable reaction temperature is -10-0 DEG C.When reaction
Between be 40 minutes to 90 minutes, preferable reaction temperature be 70 minutes.
Catalyst described in this step is selected from sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, three propionyloxy boron
Sodium hydride, preferably sodium borohydride.
In this step, rate of charge is：5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde and pyrrole
The molar ratio of pyridine is 1:0.5-2, preferred molar ratio 1:1.
In this step, rate of charge is：5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde and boron
The molar ratio of sodium hydride is 1:0.3-0.6, preferably the two molar ratio are 1:0.45.
Step 4: the Wo Nuolazan and the fumaric acid that dissociate shown in formula (3) be at reacting into salt, solvent is selected from methanol, ethyl alcohol,
N,N-dimethylacetamide, n,N-Dimethylformamide, N-Methyl pyrrolidone, dioxane, water, or these types of solvent
Two or more mixed solvents, preferably at salt solvent be DMA.Free Wo Nuolazan and fumaric acid at when salt at temperature when salt
It is 40-80 DEG C, is preferably 50 DEG C at salt temperature.Vonoprazan fumarate crude product recrystallization solvent be methanol, ethyl alcohol, DMA,
Two or more mixed solvents of DMF, NMP, dioxane, water, or these types of solvent, preferably recrystallization solvent are methanol
With the mixed solvent of water.The temperature of Vonoprazan fumarate crude product recrystallization is 60-80 DEG C, and preferably recrystallization temperature is 70 DEG C.
This step Vonoprazan fumarate crude product recrystallizes in the mixed solvent of methanol and water, and it is (single to can get high-purity
The miscellaneous Vonoprazan fumarate (formula 1) being less than 0.1%).
The route of optimum condition of the present invention is：
Beneficial effects of the present invention：
(1) it is Raney's nickel, sodium hypophosphite, with water, tetrahydrofuran, acetic acid, pyridine that cyano, which is converted into reaction condition when aldehyde radical,
For solvent, the use of hydrogen is avoided, this technique is environmentally protective, economical and practical, is suitble to industrialized production.
(2) to a small amount of pyridine is added in reaction solution when the imines that sodium borohydride reduction aldehyde radical and methylamine generate, by adding
Enter the partial reduction that pyridine inhibits pyridine ring on pyridine sulfonyl sulfonyl base, reduce the generation of impurity, by once recrystallizing
Obtain single miscellaneous Vonoprazan fumarate for being less than the high-purity that 0.1% meets pharmaceutical quality standard；Original grind technique primary crystallization it
Afterwards, many impurity are more than 0.1%.
Main innovation point of the present invention：One, it is Raney's nickel, sodium hypophosphite, Yi Shui, four that cyano, which is converted into reaction condition when aldehyde radical,
Hydrogen furans, acetic acid, pyridine are solvent, avoid the use of hydrogen, are suitble to industrialized production.Two, sodium borohydride reduction aldehyde radical with
To a small amount of pyridine is added in reaction solution when the imines that methylamine generates, pyridine ring on pyridine sulfonyl sulfonyl base is inhibited by the way that pyridine is added
Partial reduction, reduce the generation of this impurity of chemical constitution such as formula (2), can be obtained by list by once recrystallizing
The miscellaneous Vonoprazan fumarate for being less than the high-purity that 0.1% meets pharmaceutical quality standard.
Description of the drawings
The high-efficient liquid phase chromatogram of Fig. 1 embodiments 6
The high-efficient liquid phase chromatogram of Fig. 2 embodiments 8
The high-efficient liquid phase chromatogram of Fig. 3 embodiments 10
The high-efficient liquid phase chromatogram of Fig. 4 reference examples 1
Specific implementation mode
Embodiment 1：The preparation of formula (5) 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- nitriles
By 5- (2- fluorophenyls) -1H- pyrroles -3- nitriles (100g, 537.08mmole), 4- dimethylaminos pyrrole (9.84g,
80.56mmole), diisopropyl ethyl amine (97.18g, 751.81mmole), acetonitrile (600ml) are added to three-neck flask
In (3000ml), then stirring and dissolving at 10-20 DEG C is added dropwise pyridine -3- sulfonic acid chlorides (114.47g, 644.5mmole) and exists
Solution in acetonitrile (200ml) controls temperature in reaction solution and is no more than 30 DEG C, after being added dropwise, stirs 3 hours at such a temperature.
Then 1N hydrochloric acid tune PH value 4-5 are added, 1200ml water, mechanical agitation crystallization, filtering, solid drying is then added.By solid plus
Enter in 1000ml acetonitriles, heat 60-70 DEG C of dissolving, add activated carbon decolorizing, filter, mechanical agitation on filtrate is added dropwise
Crystallization is stirred at room temperature in the water of 1000ml, and filtering, 50 DEG C of solid dries to obtain light yellow product 5- (2- fluorophenyls) -1- (pyridine -3-
Base sulfonyl) -1H- pyrroles -3- nitriles 160.86g (yield 91.5%), HPLC purity is more than 99%.
Embodiment 2：The preparation of formula (5) 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- nitriles
By 5- (2- fluorophenyls) -1H- pyrroles -3- nitriles (100g, 537.08mmole), 4- dimethylaminos pyrrole (10.82g,
88.616mmole), diisopropyl ethyl amine (92.32g, 714.21mmole), acetonitrile (700ml) are added to three-neck flask
In (3000ml), then pyridine -3- sulfonic acid chlorides (120.19g, 676.73mmole) are added dropwise in stirring and dissolving at 10-20 DEG C
Solution in acetonitrile (300ml) controls temperature in reaction solution and is no more than 30 DEG C, after being added dropwise, stirs 3.5 at such a temperature
Hour.Then 1N hydrochloric acid tune pH value 4-5 are added, 1100ml water, mechanical agitation crystallization, filtering, solid drying is then added.It will
Solid is added in 1100ml acetonitriles, heats 60-70 DEG C of dissolving, adds activated carbon decolorizing, filters, and mechanical agitation on filtrate adds dropwise
Crystallization is stirred at room temperature in the water for entering 1100ml, and filtering, 50 DEG C of solid dries to obtain light yellow product 5- (2- fluorophenyls) -1- (pyridines -
3- bases sulfonyl) -1H- pyrroles -3- nitriles 158.4g (yield 90.1%), HPLC purity is more than 99%.
Embodiment 3：The preparation of formula (4) 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde
By 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- nitriles (150g, 458.2mmole), tetrahydrochysene
Furans (600ml), acetic acid (390g), water (600ml), pyridine (750g) are added in 5L three-neck flasks, stirring and dissolving, then
Raney's nickel (weight in wet base 75g) is added, 15-25 DEG C of reaction temperature stirs and sodium hypophosphite (300g) is added.It finishes, reaction 4 is small
When, it filters, layering, lower layer is water layer, is discarded, and supernatant liquid is organic layer, and about 600ml, concentrate are concentrated under reduced pressure at 80 DEG C
600ml water and 600ml ethyl acetate is added, separates organic layer, water layer uses 240ml ethyl acetate to extract again, merges organic layer,
It is concentrated under reduced pressure at 80 DEG C.When can not extremely concentrate out liquid, 240ml acetonitriles and 360ml water is added in residue, is added with stirring 1N
Hydrochloric acid (different with the remaining amount hydrochloric acid solution amount of pyridine distillation, but do not influence crystallization), adjust PH=4,10 DEG C of stirring and crystallizings 1
Hour.Filtering, 50 DEG C of drying of solid obtain crude product.Crude product is added in 1200ml acetonitriles, heats 60-70 DEG C of dissolving, adds activated carbon
Decoloration is filtered, and mechanical agitation on filtrate is added dropwise the water of 1200ml, crystallization is stirred at room temperature, and filters, and 50 DEG C of solid is dried
Light yellow product 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde 122g (yield 80.6%),
HPLC purity is more than 99%.
Embodiment 4：The preparation of formula (4) 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde
By 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- nitriles (150g, 458.2mmole), tetrahydrochysene
Furans (600ml), acetic acid (400g), water (600ml), pyridine (760g) are added in 5L three-neck flasks, stirring and dissolving, then
Raney's nickel (weight in wet base 80g) is added, 15-25 DEG C of reaction temperature stirs and sodium hypophosphite (310g) is added.It finishes, reaction 3.5
Hour, it filters, layering, lower layer is water layer, is discarded, and supernatant liquid is organic layer, and about 620ml is concentrated under reduced pressure at 80 DEG C, concentration
610ml water and 595ml ethyl acetate is added in liquid, separates organic layer, and water layer uses 261ml ethyl acetate to extract again, merges organic
Layer, it is concentrated under reduced pressure at 80 DEG C.When can not extremely concentrate out liquid, 235ml acetonitriles and 370ml water is added in residue, is added with stirring
The hydrochloric acid (different with the remaining amount hydrochloric acid solution amount of pyridine distillation, but do not influence crystallization) of 1N, adjusts PH=4,10 DEG C of stirring and crystallizings
1 hour.Filtering, 50 DEG C of drying of solid obtain crude product.Crude product is added in 1300ml acetonitriles, heats 60-70 DEG C of dissolving, adds activity
Carbon decoloring filters, and mechanical agitation on filtrate is added dropwise the water of 1300ml, crystallization is stirred at room temperature, and filters, 50 DEG C of drying of solid
Obtain light yellow product 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde 118.8g (yields
78.5%), HPLC purity is more than 99%.
Embodiment 5：The preparation of the free Wo Nuolazan of formula (3)
Modus ponens (4) 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde (114g,
It 345.45mmole) is dissolved in methanol (570ml), the methylethylolamine solution 43.32g of 20-30 DEG C of addition 30-33%, stirring 40
Minute, reaction solution is cooled to -10-0 DEG C, and pyridine 27.2 grams (345mmol) is added.Sodium borohydride (5.88g, 155.45mmole)
It is dissolved into 228 milliliters of DMA, is then added drop-wise among above-mentioned reaction solution, finishes at -10-0 DEG C, reaction continues in -10-0
It DEG C being stirred to react 1 hour, 800 milliliters of 1N hydrochloric acids of reaction solution, adjusts PH=4, control reacting liquid temperature is no more than 20 DEG C,
Then ammonium hydroxide is added and is adjusted to PH=9,500ml ethyl acetate and 500ml saturated nacl aqueous solutions are added into reaction solution, stirs
Standing is mixed, upper organic layer is separated, water layer is extracted again with 200ml ethyl acetate, merges organic layer, is concentrated under reduced pressure, and is concentrated under reduced pressure
116 grams of the Wo Nuolazan crude products that must dissociate.
Embodiment 6：The preparation of formula (1) fine work Vonoprazan fumarate
116 grams free of Wo Nuolazan crude products are dissolved in 580mlDMA, temperature 50 C are kept, then by fumaric acid
(40.8 grams, 351mmole) are added in reaction solution, are finished, and 50 DEG C are stirred 45 minutes, and it is small then to cool to 10 DEG C of stirrings 10
When, filtering, solid dries to obtain Vonoprazan fumarate crude product 126.4g (80.6%).By 126 grams of Vonoprazan fumarate crude products
It is added among 580 ml methanols and 580 milliliters of water, is dissolved at 70 DEG C, 5 grams of activated carbons are added, stir 10 minutes, filtering, filtrate
It is down to room temperature, is then stirred 8 hours at 0-10 DEG C, is filtered, drying obtains 114.6 grams of (yield 91%) fumaric acid Wo Nuola
It praises, high performance liquid chromatography detects purity, and chromatogram is shown in attached drawing 1, and list is miscellaneous to be less than 0.1%.
Embodiment 7：The preparation of the free Wo Nuolazan of formula (3)
Modus ponens (4) 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde (114g,
It 345.45mmole) is dissolved in methanol (600ml), the methylethylolamine solution 44.4g of 20-30 DEG C of addition 30-33% stirs 45 points
Clock, reaction solution are cooled to -10-0 DEG C, and pyridine 28.1 grams (355mmol) is added.Sodium borohydride (5.92g, 156.5mmole) is molten
It in solution to 240 milliliters of DMA, is then added drop-wise among above-mentioned reaction solution, finishes at -10-0 DEG C, reaction continues to stir at -10-0 DEG C
Reaction 50 minutes is mixed, 820 milliliters of 1N hydrochloric acids of reaction solution adjust PH=5, and control reacting liquid temperature is no more than 20 DEG C, then
Ammonium hydroxide is added and is adjusted to PH=9,510ml ethyl acetate and 510ml saturated nacl aqueous solutions are added into reaction solution, stirring is quiet
It sets, separates upper organic layer, water layer is extracted again with 220ml ethyl acetate, merges organic layer, is concentrated under reduced pressure, and trip is concentrated under reduced pressure to obtain
From 113 grams of Wo Nuolazan crude products.
Embodiment 8：The preparation of formula (1) fine work Vonoprazan fumarate
113 grams free of Wo Nuolazan crude products are dissolved in 600mlDMA, temperature 50 C are kept, then by fumaric acid
(41.8 grams, 359.6mmole) are added in reaction solution, are finished, and 50 DEG C are stirred 50 minutes, and it is small then to cool to 10 DEG C of stirrings 9
When, filtering, solid dries to obtain Vonoprazan fumarate crude product 121.6g (79.6%).By 121 grams of Vonoprazan fumarate crude products
It is added among 570 ml methanols and 570 milliliters of water, is dissolved at 70 DEG C, 4.9 grams of activated carbons are added, stir 10 minutes, filter, filter
Liquid is down to room temperature, is then stirred 9 hours at 0-10 DEG C, and filtering, drying obtains 109. grams of (yield 90.5%) fumaric acid and irrigates promise
La Zan, high performance liquid chromatography detect purity, and chromatogram is shown in attached drawing 2, and list is miscellaneous to be less than 0.1%.
Embodiment 9：The preparation of the free Wo Nuolazan of formula (3)
Modus ponens (4) 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde (120g, 363mmole)
It is dissolved in methanol (600ml), the methylethylolamine solution 45.8g of 20-30 DEG C of addition 30-33% stirs 45 minutes, reacts liquid cooling
But to -10-0 DEG C, pyridine 29.4 grams (372.9mmol) is added.Sodium borohydride (6.2g, 163.4mmole) is dissolved into 238 milliliters
It in DMA, is then added drop-wise among above-mentioned reaction solution, finishes at -10-0 DEG C, reaction continues at -10-0 DEG C to be stirred to react 1 small
When, 820 milliliters of 1N hydrochloric acids of reaction solution adjust PH=4, and control reacting liquid temperature is no more than 20 DEG C, ammonium hydroxide tune is then added
550ml ethyl acetate and 550ml saturated nacl aqueous solutions are added into reaction solution to PH=9 for section, and stirring is stood, and separates upper layer
Organic layer, water layer are extracted again with 210ml ethyl acetate, merge organic layer, are concentrated under reduced pressure, the Wo Nuola for being concentrated under reduced pressure free
Praise 118 grams of crude product.
Embodiment 10：The preparation of formula (1) fine work Vonoprazan fumarate
118 grams free of Wo Nuolazan crude products are dissolved in 585mlDMA, 48 DEG C of temperature are kept, then by fumaric acid
(41.5 grams, 257mmole) are added in reaction solution, are finished, and 50 DEG C are stirred 50 minutes, and it is small then to cool to 10 DEG C of stirrings 11
When, filtering, solid dries to obtain Vonoprazan fumarate crude product 129.8g (81.4%).By 129 grams of Vonoprazan fumarate crude products
It is added among 600 ml methanols and 600 milliliters of water, is dissolved at 70 DEG C, 4.9 grams of activated carbons are added, stir 15 minutes, filter, filter
Liquid is down to room temperature, is then stirred 9 hours at 0-10 DEG C, and filtering, drying obtains 118 grams of (yield 91.5%) fumaric acid and irrigates promise
La Zan, high performance liquid chromatography detect purity, and chromatogram is shown in attached drawing 3, and list is miscellaneous to be less than 0.1%.
Reference examples 1：Prior art original grinds slave formula (4) 5- (2- fluorine of the patent CN201080018114 reports in Japanese military field
Phenyl)
The method that -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde prepares Wo Nuolazan
DMA (216 milliliters) and sodium borohydride are added into the flask purged through nitrogen) (6.12 grams, 163mmol), and will
The mixture dissolves (solution A).5- (2- fluorophenyls) -1- (pyridine -3- are added in the flask purged to another through nitrogen
Base sulfonyl) -1H- pyrroles -3- formaldehyde (120 grams, 363mmol) and methanol) (600 milliliters), then it is added dropwise at room temperature
The solution (36.68 grams, 473mmol) of 40% methylamine in methyl alcohol.By the mixture in internal temperature 20-30 degree into one
Step stirring 30 minutes.Internal temperature is cooled to -10 degree, is then no more than 0 degree in internal temperature and is added dropwise and previously prepared
Solution A.DMA (24 milliliters) is added, then stirs the mixture 1 hour in internal temperature -10-0 degree.In internal temperature
1N HCl (720 milliliters) are added dropwise under no more than 20 degree, and the mixture is stirred 30 points in internal temperature 10-20 degree
Clock.12.5% ammonium hydroxide (480 milliliters), ethyl acetate (1200 milliliters) and water (360 milliliters) is added, then distributes the mixing
Object.Water (480 milliliters) and ethyl acetate (720 milliliters) are added into the water layer and extract the mixture again.Described in merging
Organic layer is washed twice with 5% brine (720 milliliters).The organic layer is concentrated to about 506 grams, DMA (960 millis are added
It rises).50 degree will be warming up to inside the mixture, and fumaric acid (42.16 grams, 363mmol) is added.The mixture is existed
50 degree of internal temperature stirs 30 minutes, cooling, is then stirred at room temperature one hour, institute's precipitating crystalline is filtered, acetic acid is first used
Ethyl ester is washed with DMA mixed liquors, then (240 milliliters) washings of ethyl acetate, and is depressurized, and crude product is dried to obtain under 50 degree
(120 grams).
Crude product (120 grams) derived above is suspended in methanol and water (7:3) in mixed liquor (1200 milliliters), and
It is dissolved in internal temperature 60-65 degree, and activated carbon (5.3 grams) is added, and the mixture is stirred ten minutes.Filtering, methanol
Water washing, gained filtrate are heated to 55 degree.It is cooled to room temperature, and is futher stirred 1 hour under internal temperature 0-10 degree.It will
Gained precipitating crystalline filters, with first alcohol and water (7:3,220 milliliters) washing, and it is dried to obtain target compound depressurizing 50 degree
(102 grams, yield 85%).High performance liquid chromatography detects purity, and chromatogram is shown in attached drawing 4.
The high-efficient liquid phase chromatogram of 1 Vonoprazan fumarate of comparing embodiment 6,8,10 and reference examples, comparison result
It is recorded in table 1.
Table 1
| Embodiment 6 | Embodiment 8 | Embodiment 10 | Reference examples 1 | |
| Primary crystallization, purity | Impurity peaks are few | Impurity peaks are few | Impurity peaks are few | Impurity peaks are more |
| Primary crystallization, it is single miscellaneous whether more than 0.1% | It is no | It is no | It is no | It is |
Table 1 is statistics indicate that technical solution of the present invention of the embodiment of the present invention is obtained by the postprocessing working procedures of primary crystallization
The Vonoprazan fumarate of high-purity.
Claims (10)
1. a kind of preparation method of Vonoprazan fumarate, which is characterized in that include the following steps：
Step 1: using 5- (2- fluorophenyls) -1H- pyrroles -3- formonitrile HCNs shown in formula (7) as pyrrole shown in starting material and formula (6)
Pyridine -3- sulfonic acid chlorides react, and in the presence of basic catalyst, production (5) compound represented 5- (2- fluorine is reacted at 0-30 DEG C
Phenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- nitriles；
Step 2: with 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- nitriles shown in formula (5) in tetrahydrochysene furan
It mutters, acetic acid, water is added Raney's nickel in pyridine, sodium hypophosphite is then added, is stirred to react, 5- (2- shown in formula (4)
Fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde；
Step 3: with 5- (2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde and methylamine shown in formula (4)
Alcoholic solution reacts in methyl alcohol first generates imines, and pyridine is added in backward reaction solution, and the N of catalyst, N- dimethyl is then added dropwise
Acetamide solution, be stirred to react shown in production (3) dissociate Wo Nuolazan, reaction dissolvent be selected from methanol, ethyl alcohol, acetonitrile,
Tetrahydrofuran, dioxane, n,N-Dimethylformamide, n,N-dimethylacetamide, N-Methyl pyrrolidone, reaction temperature
It is -20-10 DEG C；
Step 4: the Wo Nuolazan to dissociate shown in formula (3) is selected from methanol, ethyl alcohol, N, N- with fumaric acid at salt, solvent is reacted into
Two kinds of dimethylacetylamide, n,N-Dimethylformamide, N-Methyl pyrrolidone, dioxane, water, or these types of solvent
Or a variety of mixed solvents, free Wo Nuolazan and fumaric acid at temperature when salt are 40-80 DEG C at when salt；Vonoprazan fumarate
Crude product recrystallization solvent be methanol, ethyl alcohol, n,N-dimethylacetamide, n,N-Dimethylformamide, N-Methyl pyrrolidone, two
Two or more mixed solvents of six ring of oxygen, water, or these types of solvent, the temperature of Vonoprazan fumarate crude product recrystallization are
60-80℃。
2. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that the reaction temperature of step 1 is
0-30℃。
3. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that the reaction temperature of step 1 is
10-20℃。
4. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that base catalysis described in step 1
Agent is selected from triethylamine, 4-dimethylaminopyridine, n,N-diisopropylethylamine, triethylene diamine, pyridine, tetramethylethylenediamine.
5. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that base catalysis described in step 1
Agent is selected from 4-dimethylaminopyridine and N, the mixture of N- diisopropylethylamine.
6. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that the rate of charge of step 1 is：Formula
(7) 5- (2- fluorophenyls) -1H- pyrroles's -3- formonitrile HCNs：Formula (6) pyridine -3- sulfonic acid chlorides：N, N- diisopropylethylamine：4- dimethylaminos
The molar ratio range of pyridine is 1：1.1-1.3：1.2-1.6：0.13-0.17.
7. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that the rate of charge of step 2 is：5-
(2- fluorophenyls) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- nitriles：Acetic acid：Pyridine：Raney's nickel：The quality of sodium hypophosphite
Than being 1：1-4：3-8：0.4-0.8 (water content：50%)：1.5-3.
8. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that catalyst described in step 3 selects
From sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, three propionyloxy sodium borohydrides.
9. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that step 3 reaction temperature be-
10-0℃。
10. according to the preparation method of Vonoprazan fumarate described in claim 1, which is characterized in that step 4 fumaric acid Wo Nuola
The temperature for praising crude product recrystallization is 70 DEG C.
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| CN110452222A (en) * | 2019-08-29 | 2019-11-15 | 杭州中美华东制药有限公司 | A kind of preparation method of Vonoprazan fumarate |
| CN111018835A (en) * | 2019-12-16 | 2020-04-17 | 株洲千金药业股份有限公司 | Purification method of Vonoprazan |
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