CN104926790B - A kind of high-purity Vonoprazan Fumarate compounds and its intermediate, impurity and their preparation method - Google Patents
A kind of high-purity Vonoprazan Fumarate compounds and its intermediate, impurity and their preparation method Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic 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
- C07D401/02—Heterocyclic 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
- C07D401/12—Heterocyclic 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
Vonoprazan Fumarate compounds the invention provides a kind of high-purity and preparation method thereof, its structure is shown in formula I, the purity of the Vonoprazan Fumarate compounds is more than 99.6%, and the content of impurity compound is less than 0.1% wherein shown in formula IV.Vonoprazan Fumarate intermediates present invention also offers high-purity and preparation method thereof, and Vonoprazan Fumarate impurity compound and preparation method thereof.The Vonoprazan Fumarate product purities are high, impurity content is few, and preparation method is simple to operation, low cost, and less energy consumption is significant to industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of high-purity Vonoprazan Fumarate and its preparation
Method, high-purity Vonoprazan Fumarate intermediates and preparation method thereof, and Vonoprazan Fumarate and its
The impurity contained in intermediate, and impurity preparation method.
Background technology
Vonoprazan Fumarate (TAK-438, also known as Vonoprazan fumarate, Formulas I), chemical name 5- (2- fluorobenzene
Base)-N- methyl isophthalic acids-(3- pyridyl sulfonyls) -1H- pyrroles's -3- methylamine fumarates are a kind of competitive acid of new potassium ion
Inhibitor (P-CAB), can be in the final step of parietal cell gastric acid secretion, by suppressing K+To H+-K+The combination of-ATP enzyme
Effect, terminates the secretion of hydrochloric acid in gastric juice in advance, is acted on powerful, lasting gastric acid secretion inhibiting.
The synthetic method of prior art (such as CN102421753A) report is with 5- (2- fluorophenyls) -1- [(pyridin-3-yl)
Sulfonyl] -1H- pyrroles -3- formaldehyde (Formula II), as key intermediate, TAK-438 obtains by reduction-amination, salt-forming reaction.
However, the present inventor's research finds, according to Vonoprazan Fumarate compounds prepared by art methods
Purity is extremely difficult to more than 99%, wherein containing extremely obstinate impurity, influenceing the quality of target product.By a small amount of prepare and
Structural identification, it was demonstrated that the structure of the impurity is as shown in formula IV.Formula IV impurity is similar with the structure of target product, the difficulty for isolating and purifying
Degree is very big, especially to take into account purity and yield simultaneously in purge process, just more difficult.Inventor has attempted various
The conventional purification process in field, including it is various under the conditions of chromatographic isolation, recrystallization etc., cannot all obtain formula IV impurity content low
In 0.1% Vonoprazan Fumarate compounds.
The present inventor further study show that, the generation of impurity and Formula II intermediate in Vonoprazan Fumarate
Synthesis is related.During formula II intermediates, the obstinate intermediate impurities of comparing are equally generated, prepared by a small amount of
And structural identification, it was demonstrated that as shown in formula III, HPLC contents maintain about more than 0.6% to the structure of the intermediate impurities, and should
Intermediate impurities also continuously participate in subsequent reactions, cause the generation of above-mentioned Vonoprazan Fumarate impurity.
Therefore, the present inventor wishes, in pharmaceutical intermediate preparatory phase, by specific means of purification, to prepare height in a hurry
The Formula II intermediate of purity, the influence with cancelling III impurity to subsequent reactions and end product quality, so as to obtain high-purity
Vonoprazan Fumarate compounds.Also not any to above-mentioned intermediate and final products in currently available technology
The relevant report that purity and contaminant problem are analyzed and solve.
The content of the invention
Present invention aim to address above-mentioned technical problem, research confirms in Vonoprazan Fumarate and Formula II
The impurity structure of mesosome, there is provided the Vonoprazan Fumarate and midbody compound of high-purity and their preparation side
Method, additionally provides above-mentioned critical impurities and its analysis, preparation method, is Vonoprazan Fumarate bulk drugs and preparation
Production and quality research are provided and ensured.
It is an aspect of the invention to provide a kind of Vonoprazan Fumarate compounds of high-purity, structure such as Formulas I
Shown, its HPLC purity is more than 99.6%, and the content of impurity compound is less than 0.1% wherein shown in formula IV.
The second aspect of the present invention is to provide a kind of side for preparing above-mentioned high-purity Vonoprazan Fumarate compounds
Method.
The third aspect of the present invention is to provide a kind of Vonoprazan Fumarate intermediates of high-purity, structure such as formula
Shown in II, its HPLC purity is more than 97.5%, and the content of impurity compound is less than 0.25% wherein shown in formula III.
The fourth aspect of the present invention is to provide a kind of side of the Vonoprazan Fumarate intermediates for preparing high-purity
Method.
The fifth aspect of the present invention is to provide a kind of impurity compound of Vonoprazan Fumarate, its structure such as formula
Shown in IV.
The sixth aspect of the present invention is to provide a kind of side of the impurity compound for preparing above-mentioned Vonoprazan Fumarate
Method.
Therefore, the present invention provides following technical scheme：
According to the first aspect of the invention, there is provided a kind of high-purity Vonoprazan Fumarate compounds, its structure is such as
Shown in Formulas I,
Characterized in that, the purity of the Vonoprazan Fumarate compounds is more than 99.6%, and wherein formula IV
The content of shown impurity compound is less than 0.1%；
The high-purity Vonoprazan Fumarate compounds, wherein the purity and content are determined with HPLC.
The HPLC assay methods are：
Chromatographic column：YMC Basic posts, 150mm × 4.6mm, 3 μm；
Mobile phase：A：30mmol/L sodium phosphate buffers salt (pH 6.0)-acetonitrile (95:5)；
B：30mmol/L sodium phosphate buffers salt (pH 6.0)-acetonitrile (40:60)；
Flow velocity：1.0ml/min；
Detection wavelength：230nm；
Column temperature：25℃；
Gradient：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 5 | 80 | 20 |
| 20 | 70 | 30 |
| 45 | 70 | 30 |
| 45.1 | 100 | 0 |
| 53 | 100 | 0 |
According to the second aspect of the invention, there is provided one kind prepares above-mentioned high-purity Vonoprazan Fumarate compounds
Method, including step：
1) 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde crude products are dissolved in good solvent
In, poor solvent is subsequently adding, crystallization obtains refined 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles
Cough up -3- formaldehyde；Wherein described good solvent is halogenated alkane, and the poor solvent is C4-C7 alkane or petroleum ether；
2) refined 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles -3- formaldehyde contracts with methylamine
Reaction is closed, group with imine moiety is obtained；Then under reducing agent effect there is reduction-aminating reaction in group with imine moiety, obtain
Vonoprazan free alkalis；
3) with fumaric acid there is salt-forming reaction in Vonoprazan free alkalis, obtain Vonoprazan Fumarate compounds；
Wherein step 1) in, one or two in the preferred dichloromethane of good solvent and chloroform；It is described not
In the preferred pentane of good solvent, hexamethylene, n-hexane, normal heptane, cycloheptane, methyl cyclopentane, hexahydrotoluene and petroleum ether
One or more；One or more more preferably in n-hexane, normal heptane and petroleum ether.
Wherein step 1) in, 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde is thick
Product are dissolved in good solvent can be carried out under room temperature or heating condition, such as 20 DEG C~60 DEG C of scope, including but not limited to 25 DEG C,
30 DEG C, 40 DEG C, preferably 50 DEG C etc., 15-25 DEG C.
Wherein step 1) in, 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
Crystallization can be carried out under room temperature or cryogenic conditions, such as -10 DEG C~30 DEG C, including but not limited to -5 DEG C, 0 DEG C, 5 DEG C, 10 DEG C, 20
DEG C, 25 DEG C etc., preferably 15-25 DEG C.
Wherein step 1) in, 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde is thick
The ratio of product and good solvent is 1g:(1~6) mL, preferably 1g:(2~4) mL；The volume of the good solvent and poor solvent
Than being 1:(1~10), preferably 1:(2~6).
Wherein step 1) in, described refined 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles -3-
In formaldehyde, its HPLC purity is higher than 97.5%, and the content of the impurity compound shown in formula III is less than 0.25%.
Wherein step 2) in, the reaction dissolvent of the condensation reaction is selected from the alcohol compounds such as methyl alcohol, ethanol, isopropanol,
Preferably methyl alcohol.5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles -3- formaldehyde is with the mol ratio of methylamine
1:(1~1.3), reaction temperature is 0 DEG C~30 DEG C, preferably 20 DEG C~25 DEG C.
Wherein step 2) in, the reaction dissolvent of the reduction-aminating reaction is DMF (DMF) or N, N-
Dimethylacetylamide (DMAc).Reducing agent is reducing agent commonly used in the art, for example sodium borohydride, sodium cyanoborohydride, three second
Triacetoxyborohydride etc..5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles -3- formaldehyde and reducing agent
Mol ratio is 1：(0.4~0.6), preferably 1：(0.4~0.5).Reaction temperature is -10 DEG C~10 DEG C, preferably 0 DEG C~10 DEG C；
Wherein step 3) in, the salt-forming reaction is carried out in mixed solvent, the mixed solvent be selected from ethyl acetate/
Dimethylacetylamide, volume ratio (1：1~3)；Ethyl acetate/methanol, volume ratio 1：(1~3)；Ethyl acetate/dimethyl
Acetamide, volume ratio is preferably 1：(1~2).Vonoprazan free alkalis are 1 with the mol ratio of fumaric acid：(0.9~1.1).Instead
It is 40 DEG C~50 DEG C to answer temperature.
Wherein step 3) in, the Vonoprazan Fumarate crude compounds of gained can be high-purity by being recrystallized to give
The Vonoprazan Fumarate of degree, recrystallization solvent is preferably methanol/water, volume ratio 1.5：1.
Additionally, the step 2) and 3) can also be carried out according to the method for prior art.
According to the third aspect of the invention we, there is provided a kind of high-purity Vonoprazan Fumarate midbody compounds, 5-
(2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde, structure as shown in Formula II,
Characterized in that, the purity of the Formula II compound is more than 97.5%, impurity compound contains wherein shown in formula III
Amount is less than 0.25%.
The formula III impurity compound includes that Cl is located at the compound of 2,5 or 6.
The high-purity Vonoprazan Fumarate midbody compounds, wherein the purity and content are surveyed with HPLC
It is fixed.
The HPLC assay methods are：
Chromatographic column：Octadecylsilane chemically bonded silica is filler, 250mm × 4.6mm, 5 μm；
Mobile phase：A：Methyl alcohol-trifluoroacetic acid (100:0.01)；B：Water-trifluoroacetic acid (100:0.01)；
Flow velocity：1.0ml/min；
Detection wavelength：235nm；
Column temperature：30℃；
Gradient：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 60 | 40 |
| 15 | 60 | 40 |
| 25 | 80 | 20 |
| 35 | 80 | 20 |
| 35.1 | 60 | 40 |
| 45 | 60 | 40 |
According to the fourth aspect of the invention, there is provided one kind prepares above-mentioned high-purity 5- (2- fluorophenyls) -1- [(pyridine -3-
Base) sulfonyl] -1H- pyrroles's -3- formaldehyde method, including：By 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H-
Pyrroles's -3- formaldehyde crude products are dissolved in good solvent, are subsequently adding poor solvent, and crystallization obtains refined 5- (2- fluorophenyls) -1-
[(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde.
The good solvent is halogenated alkane, one or two preferably in dichloromethane and chloroform.
The poor solvent is selected from C4-C7 alkane or petroleum ether, preferably pentane, hexamethylene, n-hexane, normal heptane, ring
One or more in heptane, methyl cyclopentane, hexahydrotoluene, petroleum ether.
5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde crude products are dissolved in good solvent
Can be carried out under room temperature or heating condition, such as 20 DEG C~60 DEG C of scope, including but not limited to 25 DEG C, 30 DEG C, 40 DEG C, 50 DEG C
Deng preferably 15-25 DEG C.
The crystallization of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde can in room temperature or
Carried out under cryogenic conditions, such as -10 DEG C~30 DEG C, including but not limited to -5 DEG C, 0 DEG C, 5 DEG C, 10 DEG C, 20 DEG C, 25 DEG C etc., preferably
15-25℃。
5- (2- fluorophenyls) -1- [(pyridin-3-yl) the sulfonyl] -1H- pyrroles -3- formaldehyde crude products and good solvent
Ratio is preferably 1g:(1~6) mL, more preferably 1g:(2~4) mL.
The good solvent is preferably 1 with the volume ratio of poor solvent:(1~10), more preferably 1:(2~6).
According to the fifth aspect of the invention, there is provided a kind of impurity compound of Vonoprazan Fumarate, its structure is such as
Shown in formula IV：
Formula IV impurity compound relative retention time in the HPLC figures of Vonoprazan Fumarate is about
1.42.
The formula IV impurity compound can be used as impurity reference substance, such as in Vonoprazan Fumarate systems
As impurity reference substance in the Related substances separation of agent.
According to the sixth aspect of the invention, there is provided a kind of Vonoprazan Fumarate prepared shown in above-mentioned formula IV are miscellaneous
The method of matter compound, including step：
A) 5- (2- fluorophenyls) -1H- pyrroles -3- formaldehyde reacts with 5- chloropyridine -3- sulfonic acid chlorides, obtains 5- (2- fluorobenzene
Base) -1- [(5- chloropyridine -3- bases) sulfonyl] -1H- pyrroles's -3- formaldehyde；
B) 5- (2- fluorophenyls) -1- [(5- chloropyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde is condensed with methylamine
Reaction；There is reduction-aminating reaction in products therefrom, obtain 1- [5- (2- fluorophenyls) -1- (chloro- 3- pyrroles of 5- under reducing agent effect
Pyridine sulfonyl) -1H- pyrroles -3- bases]-N- methyl methylamines；
C) 1- [5- (2- fluorophenyls) -1- (5- chloro-3-pyridyls sulfonyl) -1H- pyrroles -3- bases]-N- methyl methylamines and richness
There is salt-forming reaction in horse acid, obtain 1- [5- (2- fluorophenyls) -1- (5- chloro-3-pyridyls sulfonyl) -1H- pyrroles -3- bases]-N- first
Base methylamine fumarate, i.e. formula IV impurity compound.
The wherein reaction of step a) can be carried out in organic solvent, preferably non-protonic solvent, for example acetonitrile, tetrahydrochysene furan
Mutter, dichloromethane, chloroform, pyridine etc..Reaction can be carried out in the basic conditions, such as diisopropylethylamine, diethylamide, three second
Amine, DBU, piperidines, pyridine, DMAP etc., the alkali can promote reaction to occur to forward direction as acid-binding agent.Reaction
Can carry out at room temperature.
Wherein step b) and c) can refer to step 2 in Vonoprazan Fumarate preparation methods) and 3) carry out.Example
Such as：
In wherein step b), the reaction dissolvent of the condensation reaction is selected from the alcohol compounds such as methyl alcohol, ethanol, isopropanol,
Preferably methyl alcohol.5- (2- fluorophenyls) -1- [(5- chloropyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde and methylamine mole
Than being 1:(1~1.3), reaction temperature is 0 DEG C~30 DEG C, preferably 20 DEG C~25 DEG C.
In wherein step b), the reaction dissolvent of the reduction-aminating reaction is DMF (DMF) or N, N-
Dimethylacetylamide (DMAc).Reducing agent is reducing agent commonly used in the art, for example sodium borohydride, sodium cyanoborohydride, three second
Triacetoxyborohydride etc.；5- (2- fluorophenyls) -1- [(5- chloropyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde and reduction
The mol ratio of agent is 1：(0.4~0.6), preferably 1：(0.4~0.5).Reaction temperature is -10 DEG C~10 DEG C, preferably 0 DEG C~10
℃；
In wherein step c), the salt-forming reaction is carried out in mixed solvent, the mixed solvent be selected from ethyl acetate/
Dimethylacetylamide, volume ratio (1：1~3)；Ethyl acetate/methanol, volume ratio 1：(1~3)；Ethyl acetate/dimethyl
Acetamide, volume ratio is preferably 1：(1~2).1- [5- (2- fluorophenyls) -1- (5- chloro-3-pyridyls sulfonyl) -1H- pyrroles -3-
Base] mol ratio of-N- methyl methylamine and fumaric acid is 1：(0.9~1.1).Reaction temperature is 40 DEG C~50 DEG C.
Major technique advantage of the invention is：
1st, the present invention solves that Vonoprazan Fumarate compounds contain obstinate impurity and purity is difficult to mention asks
Topic, significantly improves the purity of compound of formula I, has been significantly reduced formula IV impurity therein, obtains purity very high
Vonoprazan Fumarate compounds.
2nd, the present invention is by repeated multiple times experiment, the specific preparation condition of selection, in obtaining purity Formula II very high
Intermediate compounds therefor, Vonoprazan Fumarate compounds are prepared using the Formula II intermediate of high-purity, are dramatically mitigated
The operation pressure of Vonoprazan Fumaratec purification steps so that high-purity can be obtained by known conventional method
Vonoprazan Fumarate, generate unexpected technique effect.
3rd, the present invention not only start with by effective impurity for reducing Formula II intermediate, effectively eliminates formula III impurity therein (bag
Include the impurity that Cl is positioned at 2,5 or 6), during follow-up preparation Vonoprazan Fumarate, it is significantly reduced
Chloro impurity in Vonoprazan Fumarate (only exists the impurity that a small amount of Cl is positioned at 5, i.e. formula IV, its content is less than
0.1%)；Methods described is simple and easy to operate, high income, is especially suitable for industrialized production.
4th, the invention provides the critical impurities compound and preparation method thereof of Vonoprazan Fumarate, Ke Yizuo
It is impurity reference substance, for the quality research of Vonoprazan Fumarate bulk drugs and its preparation.
Specific embodiment
Following examples are used to further understand advantages of the present invention, and limit never in any form disclosed
Content.Unless stated otherwise, the reagent and instrument for being used in embodiment are ordinary commercial products.
The HPLC inspections of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles -3- formaldehyde (Formula II intermediate)
Survey method：
Chromatographic column：Octadecylsilane chemically bonded silica is filler, 250mm × 4.6mm, 5 μm；
Mobile phase：A：Methyl alcohol-trifluoroacetic acid (100:0.01)；B：Water-trifluoroacetic acid (100:0.01)；
Flow velocity：1.0ml/min；
Detection wavelength：235nm；
Column temperature：30℃；
Gradient：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 60 | 40 |
| 15 | 60 | 40 |
| 25 | 80 | 20 |
| 35 | 80 | 20 |
| 35.1 | 60 | 40 |
| 45 | 60 | 40 |
5- (2- fluorophenyls)-N- methyl isophthalic acids-(3- pyridyl sulfonyls) -1H- pyrroles's -3- methylamine fumarates
The HPLC detection methods of (Vonoprazan Fumarate)：
Chromatographic column：YMC Basic posts, 150mm × 4.6mm, 3 μm；
Mobile phase：A：30mmol/L sodium phosphate buffers salt (pH 6.0)-acetonitrile (95:5)；
B：30mmol/L sodium phosphate buffers salt (pH 6.0)-acetonitrile (40:60)；
Flow velocity：1.0ml/min；
Detection wavelength：230nm；
Column temperature：25℃；
Gradient：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 5 | 80 | 20 |
| 20 | 70 | 30 |
| 45 | 70 | 30 |
| 45.1 | 100 | 0 |
| 53 | 100 | 0 |
【Preparation example】The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde crude products
With reference to CN102421753A specifications embodiment 4 of page 57：Synthesis 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulphurs
Acyl group] -1H- pyrroles's -3- formaldehyde crude products.Yield：97%, crude product purity：94.13%, formula III impurity：0.58%.
【Embodiment 1】
The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in dichloromethane (33mL), normal heptane (66mL) is added dropwise, stir 30 minutes,
Filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain Formula II intermediate 11.1g.Yield：65%, purity：
97.64%, formula III impurity：0.21%.
The preparation (with reference to CN102421753A specifications embodiment 5 of page 57) of Vonoprazan Fumarate
At 20~25 DEG C, to sequentially adding methyl alcohol (30.5mL), 5- (2- fluorophenyls) -1- [(pyrroles in 200ml round-bottomed flasks
Pyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde (6.0g, 18.3mol), methanol solution (2.5g, 30~33% first of methylamine
Amine, 23.8mol), stir 1.5 hours.0~10 DEG C is cooled to, NaBH is added dropwise4The N of (346mg, 9.16mol), N- dimethyl second
Amide solution (9.1mL), during dropwise addition in system control temp at 0~10 DEG C, after dripping off, TLC tracking reaction.In interior Wen Buchao
20 DEG C of linear dropwise addition 1N hydrochloric acid (35mL) regulation systems pH=5~6 are crossed, is stirred 30 minutes.Adjusted with 12.5% ammoniacal liquor (40mL)
Section system pH=8~9, add ethyl acetate (61mL) extraction, and water is mutually extracted with ethyl acetate (35mL × 3).Merge organic phase,
5% saline solution (25mL) is washed, and organic phase is dried with anhydrous magnesium sulfate, filtering, and concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (36mL), ethyl acetate (18mL) and above-mentioned in 100mL round-bottomed flasks
Concentrate, 45~50 DEG C are heated to by mixed liquor, add fumaric acid (2.13g, 18.3mmol).Internally 45~50 DEG C of temperature is stirred
Mix 1~1.5 hour, be cooled to 20~25 DEG C, continue to stir 1~2 hour, filtering, filter cake ethyl acetate/N, N- dimethyl second
Acid amides (1:1,28mL) mixed solvent is beaten 30 minutes, filtering.Filter cake is beaten 30 minutes with ethyl acetate (28mL) again, filtering,
Obtain crude product (6.3g).
At 55~60 DEG C, crude product is dissolved in methyl alcohol and water (1.5:1,92mL) in mixed solution, medicinal carbon is added
(343mg), continues to stir 10 minutes, and filtering, filter cake is washed with methyl alcohol with the mixed solution of water.All filtrates are merged 55~
It is molten clear again at 60 DEG C, it is cooled to 20~30 DEG C and stirs 1 hour, and continue stirring and crystallizing 1.5~2 hours at 0~10 DEG C, mistake
Filter, obtains Vonoprazan Fumarate (5.2g).HPLC testing results：Purity：99.79%, formula IV impurity：0.05%.
【Embodiment 2】
The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in dichloromethane (33mL), normal heptane (99mL) is added dropwise, stir 30 minutes,
Filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 11.9g.Yield：70%, purity：97.57%, formula III
Impurity：0.25%.
The preparation of Vonoprazan Fumarate
At 20~25 DEG C, to sequentially added in 200ml round-bottomed flasks methyl alcohol (30mL), 5- (2- fluorophenyls) -1- [(pyridine -
3- yls) sulfonyl] -1H- pyrroles -3- formaldehyde (6.0g, 18.3mol), methylamine methanol solution (2.1g, 30~33% methylamines,
20.1mol), stir 1.5 hours.0~10 DEG C is cooled to, NaBH is added dropwise4The DMF of (346mg, 9.16mol)
Solution (9.1mL), during dropwise addition in system control temp at 0~10 DEG C, after dripping off, TLC tracking reaction.20 are no more than in interior temperature
It is DEG C linear that 1N hydrochloric acid (35mL) regulation systems pH=5~6 are added dropwise, stir 30 minutes.Body is adjusted with 12.5% ammoniacal liquor (40mL)
It is pH=8~9, adds ethyl acetate (61mL) extraction, water is mutually extracted with ethyl acetate (35mL × 3 time).Merge organic phase,
5% saline solution (25mL) is washed, and organic phase is dried with anhydrous magnesium sulfate, filtering, and concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (18mL), ethyl acetate (18mL) and above-mentioned in 100mL round-bottomed flasks
Concentrate, 45~50 DEG C are heated to by mixed liquor, add fumaric acid (2.13g, 18.3mmol).Internally 45~50 DEG C of temperature is stirred
Mix 1~1.5 hour, be cooled to 20~25 DEG C, continue to stir 1~2 hour, filtering, filter cake ethyl acetate/N, N- dimethyl second
Acid amides (1:1,28mL) mixed solvent is beaten 30 minutes, filtering.Filter cake is beaten 30 minutes with ethyl acetate (28mL) again, filtering,
Obtain crude product (5.9g).
At 55~60 DEG C, crude product is dissolved in methyl alcohol and water (1.5:1,85mL) in mixed solution, medicinal carbon is added
(343mg), continues to stir 10 minutes, and filtering, filter cake is washed with methyl alcohol with the mixed solution of water.All filtrates are merged 55~
It is molten clear again at 60 DEG C, it is cooled to 20~30 DEG C and stirs 1 hour, and continue stirring and crystallizing 1.5~2 hours at 0~10 DEG C, mistake
Filter, obtains Vonoprazan Fumarate (4.7g).HPLC testing results：Purity：99.67%, formula IV chloro impurity：
0.07%.
【Embodiment 3】
The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in dichloromethane (33mL), normal heptane (132mL) is added dropwise, stir 30 points
Clock, filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 12.2g.Yield 72%, purity：98.01%, formula
III chloro impurity：0.22%.
The preparation of Vonoprazan Fumarate
At 20~25 DEG C, to sequentially added in 200ml round-bottomed flasks methyl alcohol (30mL), 5- (2- fluorophenyls) -1- [(pyridine -
3- yls) sulfonyl] -1H- pyrroles -3- formaldehyde (6.0g, 18.3mol), methylamine methanol solution (2.5g, 30~33% methylamines,
23.8mol), stir 1.5 hours.0~10 DEG C is cooled to, NaBH is added dropwise4The DMA of (311mg, 8.24mol)
Solution (9.1mL), during dropwise addition in system control temp at 0~10 DEG C, after dripping off, TLC tracking reaction.20 are no more than in interior temperature
It is DEG C linear that 1N hydrochloric acid (35mL) regulation systems pH=5~6 are added dropwise, stir 30 minutes.Body is adjusted with 12.5% ammoniacal liquor (40mL)
It is pH=8~9, adds ethyl acetate (61mL) extraction, water is mutually extracted with ethyl acetate (35mL × 3).Merge organic phase, 5%
Saline solution (25mL) is washed, and organic phase is dried with anhydrous magnesium sulfate, filtering, and concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (36mL), ethyl acetate (18mL) and above-mentioned in 100mL round-bottomed flasks
Concentrate, 45~50 DEG C are heated to by mixed liquor, add fumaric acid (2.34g, 20.1mmol).Internally 45~50 DEG C of temperature is stirred
Mix 1~1.5 hour, be cooled to 20~25 DEG C, continue to stir 1~2 hour, filtering, filter cake ethyl acetate/N, N- dimethyl second
Acid amides (1:1,28mL) mixed solvent is beaten 30 minutes, filtering.Filter cake is beaten 30 minutes with ethyl acetate (28mL) again, filtering,
Obtain crude product (6.1g).
At 55~60 DEG C, crude product is dissolved in methyl alcohol and water (1.5:1,92mL) in mixed solution, medical active is added
Charcoal (343mg), continues to stir 10 minutes, and filtering, filter cake is washed with methyl alcohol with the mixed solution of water.All filtrates are merged 55
It is molten clear again at~60 DEG C, it is cooled to 20~30 DEG C and stirs 1 hour, and continue stirring and crystallizing 1.5~2 hours at 0~10 DEG C, mistake
Filter, obtains Vonoprazan Fumarate (5.0g).HPLC testing results：Purity：99.83%, formula IV chloro impurity：
0.04%.
【Embodiment 4】
The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
Under room temperature (20~25 DEG C), take crude product (17g) and be dissolved in dichloromethane (33mL), normal heptane (165mL), stirring is added dropwise
30 minutes, filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 12.6g.Yield：74%, purity：
97.99%, formula III chlorinated compound impurity：0.22%.
The preparation of Vonoprazan Fumarate
At 0~10 DEG C, to sequentially adding methyl alcohol (30.5mL), 5- (2- fluorophenyls) -1- [(pyrroles in 200ml round-bottomed flasks
Pyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde (6.0g, 18.3mol), methanol solution (2.5g, 30~33% first of methylamine
Amine, 23.8mol), stir 1.5 hours.The DMA solution of NaBH4 (346mg, 9.16mol) is added dropwise
(9.1mL), during dropwise addition in system control temp at 0~10 DEG C, after dripping off, TLC tracking reaction.20 DEG C of lines are no more than in interior temperature
Property 1N hydrochloric acid (35mL) regulation systems pH=5~6 are added dropwise, stir 30 minutes.With 12.5% ammoniacal liquor (40mL) regulation system pH
=8~9, ethyl acetate (61mL) extraction is added, water is mutually extracted with ethyl acetate (35mL × 3).Merge organic phase, 5% salt
Water (25mL) is washed, and organic phase is dried with anhydrous magnesium sulfate, filtering, and concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (36mL), ethyl acetate (18mL) and above-mentioned in 100mL round-bottomed flasks
Concentrate, 40~45 DEG C are heated to by mixed liquor, add fumaric acid (2.13g, 18.3mmol).Internally 40~45 DEG C of temperature is stirred
Mix 1~1.5 hour, be cooled to 20~25 DEG C, continue to stir 1~2 hour, filtering, filter cake ethyl acetate/N, N- dimethyl second
Acid amides (1:1,28mL) mixed solvent is beaten 30 minutes, filtering.Filter cake is beaten 30 minutes with ethyl acetate (28mL) again, filtering,
Obtain crude product (6.5g).
At 55~60 DEG C, crude product is dissolved in methyl alcohol and water (1.5:1,96mL) in mixed solution, medicinal carbon is added
(343mg), continues to stir 10 minutes, and filtering, filter cake is washed with methyl alcohol with the mixed solution of water.All filtrates are merged 55~
It is molten clear again at 60 DEG C, it is cooled to 20~30 DEG C and stirs 1 hour, and continue stirring and crystallizing 1.5~2 hours at 0~10 DEG C, mistake
Filter, obtains Vonoprazan Fumarate (5.4g).HPLC testing results：Purity：99.75%, formula IV chloro impurity：
0.05%.
【Embodiment 5】The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in dichloromethane (33mL), normal heptane (198mL) is added dropwise, stir 30 points
Clock, filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 13.1g.Yield：77%, purity：97.84%, formula
III chloro impurity：0.21%.
【Embodiment 6】The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in chloroform (33mL), normal heptane (165mL) is added dropwise, stir 30 points
Clock, filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 12.1g.Yield 71%, purity is 97.89%, chlorine
It is 0.20% for thing impurity content.
【Embodiment 7】The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in dichloromethane (33mL), n-hexane (165mL) is added dropwise, stir 30 points
Clock, filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 12.4g.Yield 73%, purity is 97.86%, chlorine
It is 0.22% for thing impurity content.
【Embodiment 8】The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in dichloromethane (33mL), petroleum ether (165mL) is added dropwise, stir 30 points
Clock, filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 12.5g.Yield：73.5%, purity：97.78%,
Formula III chloro impurity：0.19%.
【Reference examples 1】
The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in ethyl acetate (33mL), methyl tertiary butyl ether(MTBE) (132mL), stirring is added dropwise
30 minutes, filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 11g.Yield：64.7%, purity：
97.22%, formula III chloro impurity：0.59%.
The preparation of Vonoprazan Fumarate：
At 20~25 DEG C, to sequentially adding methyl alcohol (21.8mL), 5- (2- fluorophenyls) -1- [(pyrroles in 100ml round-bottomed flasks
Pyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde (4.3g, 13.07mol), methanol solution (1.76g, 30~33% first of methylamine
Amine, 17.0mol), stir 1.5 hours.0~10 DEG C is cooled to, NaBH is added dropwise4The N of (247mg, 6.54mol), N- dimethyl second
Amide solution (6.5mL), during dropwise addition in system control temp at 0~10 DEG C, after dripping off, TLC tracking reaction.In interior Wen Buchao
20 DEG C of linear dropwise addition 1N hydrochloric acid (25mL) regulation systems pH=5~6 are crossed, is stirred 30 minutes.Adjusted with 12.5% ammoniacal liquor (28mL)
Section system pH=8~9, add ethyl acetate (44mL) extraction, and water is mutually extracted with ethyl acetate (25mL × 3 time).Merge organic
Phase, 5% saline solution (25mL) washing, organic phase is dried with anhydrous magnesium sulfate, filtering, and concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (26mL), ethyl acetate (13mL) and above-mentioned in 100mL round-bottomed flasks
Concentrate, 45~50 DEG C are heated to by mixed liquor, add fumaric acid (1.52g, 13.07mmol).Internally 45~50 DEG C of temperature
Stirring 1~1.5 hour, is cooled to 20~25 DEG C, continues to stir 1~2 hour, filtering, filter cake ethyl acetate/N, N- dimethyl
Acetamide (1:1,20mL) mixed solvent is beaten 30 minutes, filtering.Filter cake is beaten 30 minutes with ethyl acetate (20mL) again, mistake
Filter, obtains crude product (4.4g).
At 55~60 DEG C, crude product is dissolved in methyl alcohol and water (1.5:1,66mL) in mixed solution, medical active is added
Charcoal (245mg), continues to stir 10 minutes, and filtering, filter cake is washed with methyl alcohol with the mixed solution of water.All filtrates are merged 55
It is molten clear again at~60 DEG C, it is cooled to 20~30 DEG C and stirs 1 hour, and continue stirring and crystallizing 1.5~2 hours at 0~10 DEG C, mistake
Filter, obtains Vonoprazan Fumarate (3.4g).HPLC testing results：Purity：98.92%, Formula IV chloro impurity：
0.231%.
【Reference examples 2】
The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
Under room temperature (20~25 DEG C), take crude product (17g) and be dissolved in ethyl acetate (33mL), isopropyl ether (132mL) is added dropwise, stir
Mix 30 minutes, filter, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 11.4g.Yield：67%, purity：
97.42%, formula III chloro impurity：0.49%.
The preparation of Vonoprazan Fumarate
At 20~25 DEG C, to sequentially added in 100ml round-bottomed flasks methyl alcohol (20mL), 5- (2- fluorophenyls) -1- [(pyridine -
3- yls) sulfonyl] -1H- pyrroles -3- formaldehyde (4.31g, 13.07mol), methanol solution (1.49g, 30~33% first of methylamine
Amine, 14.4mol), stir 1.5 hours.0~10 DEG C is cooled to, NaBH is added dropwise4The DMF solution of (247mg, 6.54mol)
(6.0mL), during dropwise addition in system control temp at 0~10 DEG C, after dripping off, TLC tracking reaction.20 DEG C of lines are no more than in interior temperature
Property 1N hydrochloric acid (25mL) regulation systems pH=5~6 are added dropwise, stir 30 minutes.With 12.5% ammoniacal liquor (28mL) regulation system pH
=8~9, ethyl acetate (44mL) extraction is added, water is mutually extracted with ethyl acetate (25mL × 3).Merge organic phase, 5% salt
Water (25mL) is washed, and organic phase is dried with anhydrous magnesium sulfate, filtering, and concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (26mL), ethyl acetate (13mL) and above-mentioned in 100mL round-bottomed flasks
Concentrate, 45~50 DEG C are heated to by mixed liquor, add fumaric acid (1.67g, 14.38mmol).Internally 45~50 DEG C of temperature
Stirring 1~1.5 hour, is cooled to 20~25 DEG C, continues to stir 1~2 hour, filtering, filter cake ethyl acetate/N, N- dimethyl
Acetamide (1:1,20mL) mixed solvent is beaten 30 minutes, filtering.Filter cake is beaten 30 minutes with ethyl acetate (20mL) again, mistake
Filter, obtains crude product (4.2g).
At 55~60 DEG C, crude product is dissolved in methyl alcohol and water (1.5:1,65mL) in mixed solution, medical active is added
Charcoal (245mg), continues to stir 10 minutes, and filtering, filter cake is washed with methyl alcohol with the mixed solution of water.All filtrates are merged 55
It is molten clear again at~60 DEG C, it is cooled to 20~30 DEG C and stirs 1 hour, and continue stirring and crystallizing 1.5~2 hours at 0~10 DEG C, mistake
Filter, obtains Vonoprazan Fumarate (3.3g).HPLC testing results：Purity：98.88%, Formula IV chloro impurity：
0.22%.
【Reference examples 3】
The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 20~25 DEG C, take crude product (17g) and be dissolved in ethyl acetate (33mL), normal heptane (132mL) is added dropwise, stir 30 points
Clock, filtering, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 12g.Yield 70%, purity：96.32%, formula III
Chloro impurity：0.53%.
The preparation of Vonoprazan Fumarate
At 20~25 DEG C, to sequentially adding methyl alcohol (21.8mL), 5- (2- fluorophenyls) -1- [(pyrroles in 100ml round-bottomed flasks
Pyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde (4.3g, 13.07mol), methanol solution (1.76g, 30~33% first of methylamine
Amine, 17.0mol), stir 1.5 hours.0~10 DEG C is cooled to, NaBH is added dropwise4The N of (198mg, 5.23mol), N- dimethyl second
Amide solution (6.0mL), during dropwise addition in system control temp at 0~10 DEG C, after dripping off, TLC tracking reaction.In interior Wen Buchao
20 DEG C of linear dropwise addition 1N hydrochloric acid (25mL) regulation systems pH=5~6 are crossed, is stirred 30 minutes.Adjusted with 12.5% ammoniacal liquor (28mL)
Section system pH=8~9, add ethyl acetate (44mL) extraction, and water is mutually extracted with ethyl acetate (25mL × 3 time).Merge organic
Phase, 5% saline solution (25mL) washing, organic phase is dried with anhydrous magnesium sulfate, filtering, and concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (26mL), ethyl acetate (13mL) and above-mentioned in 100mL round-bottomed flasks
Concentrate, 45~50 DEG C are heated to by mixed liquor, add fumaric acid (1.52g, 13.07mmol).Internally 45~50 DEG C of temperature
Stirring 1~1.5 hour, is cooled to 20~25 DEG C, continues to stir 1~2 hour, filtering, filter cake ethyl acetate/N, N- dimethyl
Acetamide (1:1,20mL) mixed solvent is beaten 30 minutes, filtering.Filter cake is beaten 30 minutes with EA (20mL) again, and filtering is obtained
Crude product (4.3g).
At 55~60 DEG C, crude product is dissolved in methyl alcohol and water (1.5:1,66mL) in mixed solution, medical active is added
Charcoal (245mg), continues to stir 10 minutes, and filtering, filter cake is washed with methyl alcohol with the mixed solution of water.All filtrates are merged 55
It is molten clear again at~60 DEG C, it is cooled to 20~30 DEG C and stirs 1 hour, and continue stirring and crystallizing 1.5~2 hours at 0~10 DEG C, mistake
Filter, obtains Vonoprazan Fumarate (3.52g).HPLC testing results：Purity：99.1%, Formula IV chloro impurity：
0.25%.
【Reference examples 4】
The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
Under room temperature (20~25 DEG C), take crude product (17g) and be dissolved in dichloromethane (33mL), methyl tertiary butyl ether(MTBE) is added dropwise
(165mL), stirs 30 minutes, filtering, and filter cake forced air drying 3 hours at 20~25 DEG C obtain product 13.6g.Yield 80%,
Purity：96.64%, formula III chloro impurity：0.55%.
The preparation of Vonoprazan Fumarate
At 0~10 DEG C, to sequentially adding methyl alcohol (21.8mL), 5- (2- fluorophenyls) -1- [(pyrroles in 100ml round-bottomed flasks
Pyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde (4.3g, 13.07mol), methanol solution (1.73g, 30~33% first of methylamine
Amine, 17.0mol), stir 1.5 hours.NaBH is added dropwise4The DMA solution of (250mg, 6.54mol)
(7.0mL), during dropwise addition in system control temp at 0~10 DEG C, after dripping off, TLC tracking reaction.20 DEG C of lines are no more than in interior temperature
Property 1N hydrochloric acid (25mL) regulation systems pH=5~6 are added dropwise, stir 30 minutes.With 12.5% ammoniacal liquor (28mL) regulation system pH
=8~9, ethyl acetate (44mL) extraction is added, water is mutually extracted with ethyl acetate (25mL × 3).Merge organic phase, 5% salt
Water (25mL) is washed, and organic phase is dried with anhydrous magnesium sulfate, filtering, and concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (26mL), ethyl acetate (13mL) and above-mentioned in 100mL round-bottomed flasks
Concentrate, 45~50 DEG C are heated to by mixed liquor, add fumaric acid (1.37g, 11.76mmol).Internally 45~50 DEG C of temperature
Stirring 1~1.5 hour, is cooled to 20~25 DEG C, continues to stir 1~2 hour, filtering, filter cake ethyl acetate/N, N- dimethyl
Acetamide (1:1,20mL) mixed solvent is beaten 30 minutes, filtering.Filter cake is beaten 30 minutes with ethyl acetate (20mL) again, mistake
Filter, obtains crude product (4.6g).
At 55~60 DEG C, crude product is dissolved in methyl alcohol and water (1.5:1,70mL) in mixed solution, medicinal carbon is added
(245mg), continues to stir 10 minutes, and filtering, filter cake is washed with methyl alcohol with the mixed solution of water.All filtrates are merged 55~
It is molten clear again at 60 DEG C, it is cooled to 20~30 DEG C and stirs 1 hour, and continue stirring and crystallizing 1.5~2 hours at 0~10 DEG C, mistake
Filter, obtains Vonoprazan Fumarate (3.6g).HPLC testing results：Purity：98.8%, Formula IV chloro impurity：
0.20%.
【Reference examples 5】The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
Under room temperature (20~25 DEG C), take crude product (17g) and be dissolved in dichloromethane (33mL), isopropyl ether (165mL) is added dropwise, stir
Mix 30 minutes, filter, filter cake forced air drying 3 hours at 20~25 DEG C obtain product 11.7g.Yield：68.8%, purity：
96.55%, formula III chloro impurity：0.61%.
【Reference examples 6】5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde it is refined
At 30~40 DEG C, crude product (19g) is dissolved in methyl alcohol (57mL), pure water (114mL) is added dropwise, dripped continuation and stir
30 minutes, filtering, filter cake vacuum drying obtained product 15.2g.Yield：80%, purity：96.04%, formula III chloro impurity：
0.66%.
【Reference examples 7】The preparation of 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde
At 30~40 DEG C, crude product (19g) is dissolved in acetonitrile (57mL), pure water (114mL) is added dropwise, dripped continuation and stir
30 minutes, filtering, filter cake vacuum drying obtained product 15.8g.Yield：83%, purity：96.21%, formula III chloro impurity：
0.58%.
【Embodiment 9】The preparation of formula IV impurity
The preparation of 5- (2- fluorophenyls) -1- [(5- chloropyridine -3- bases) sulfonyl] -1H- pyrroles's -3- formaldehyde
To sequentially adding acetonitrile (8mL), 5- (2- fluorophenyls) -1H- pyrroles's -3- formaldehyde in 25mL round-bottomed flasks
(0.848g), diisopropylethylamine (1.0mL) is disposable to add 5- chloropyridine -3- sulfonic acid chlorides (1.1g), and 4h, TLC is stirred at room temperature
Tracking reaction terminates.Purified water (16mL) is added dropwise, stirs half an hour, filtering, 50 DEG C of vacuum drying obtain solid 1.2g.
1- [5- (2- fluorophenyls) -1- (5- chloro-3-pyridyls sulfonyl) -1H- pyrroles -3- bases]-N- methyl methylamine fumaric acid
The preparation of salt (formula IV)
At 20~25 DEG C, to sequentially adding methyl alcohol (8mL), 5- (2- fluorophenyls) -1- [(5- chlorine pyrroles in 25ml round-bottomed flasks
Pyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde (1.0g), the methanol solution (369mg, 30~33% methylamines) of methylamine, stirring
1.5 hours.0~10 DEG C is cooled to, NaBH is added dropwise4The DMA solution (1.8mL) of (52mg), during dropwise addition
Control temp at 0~10 DEG C, after dripping off, react by TLC tracking in system.In interior temperature no more than 20 DEG C of linear dropwise additions 1N hydrochloric acid (6mL)
Regulation system pH=5~6, stir 30 minutes.With 12.5% ammoniacal liquor (8mL) regulation system pH=8~9, ethyl acetate is added
(15mL) is extracted, and water is mutually extracted with ethyl acetate (10mL × 3 time).Merge organic phase, 5% saline solution (25mL) washing is organic
Dried with anhydrous magnesium sulfate, filtering, concentration obtains concentrate.
To sequentially adding DMAC N,N' dimethyl acetamide (6mL), ethyl acetate (3mL) and above-mentioned concentration in 25mL round-bottomed flasks
Liquid, 45~50 DEG C are heated to by mixed liquor, add fumaric acid (319mg).Internally 45~50 DEG C of temperature is stirred 1~1.5 hour,
20~25 DEG C are cooled to, continue to stir 1~2 hour, filtering, filter cake is beaten 30 minutes with ethyl acetate (10mL) again, filtering is obtained
To impurity IV (800mg).HPLC purity:96.7%；MS(ESI,m/z)380(M+H+,100)；1H-NMR(DMSO-d6,
400MHz):2.454 (s, 3H), 3.840 (s, 2H), 6.477 (s, 2H), 6.533 (d, J=2.0Hz, 2H), 7.153-7.112
(m, 1H), 7.277-7.224 (m, 2H), 7.579-7.523 (m, 1H), 7.798 (d, J=2.0Hz, 1H), 7.948 (d, J=
2.5Hz, 1H), 8.518 (d, J=2.5Hz, 1H), 8.993 (d, J=2.5Hz, 1H), 10.292 (brs, 2H) ppm.
【Embodiment 10】The preparation of formula IV impurity
The preparation of 5- (2- fluorophenyls) -1- [(5- chloropyridine -3- bases) sulfonyl] -1H- pyrroles's -3- formaldehyde
To sequentially adding acetonitrile (9mL), 5- (2- fluorophenyls) -1H- pyrroles -3- formaldehyde (1g), two in 25mL round-bottomed flasks
Wopropyl ethyl amine (1.18mL), it is disposable to add 5- chloropyridine -3- sulfonic acid chlorides (1.3g), 4h, TLC tracking reaction knots is stirred at room temperature
Beam.Purified water (18mL) is added dropwise, stirs half an hour, filtering, 50 DEG C of vacuum drying obtain solid 1.4g.
1- [5- (2- fluorophenyls) -1- (5- chloro-3-pyridyls sulfonyl) -1H- pyrroles -3- bases]-N- methyl methylamine fumaric acid
The preparation of salt (formula IV)
At 20~25 DEG C, to sequentially adding methyl alcohol (10mL), 5- (2- fluorophenyls) -1- [(5- chlorine pyrroles in 25ml round-bottomed flasks
Pyridine -3- bases) sulfonyl] -1H- pyrroles -3- formaldehyde (1.2g), the methanol solution (443mg, 30~33% methylamines) of methylamine, stirring
1.5 hours.0~10 DEG C is cooled to, NaBH is added dropwise4The DMA solution (2.2mL) of (62mg), during dropwise addition
Control temp at 0~10 DEG C, after dripping off, react by TLC tracking in system.In interior temperature no more than 20 DEG C of linear dropwise addition 1N hydrochloric acid
(7.2mL) regulation system pH=5~6, stir 30 minutes.With 12.5% ammoniacal liquor (9.6mL) regulation system pH=8~9, add
Ethyl acetate (15mL) is extracted, and water is mutually extracted with ethyl acetate (10mL × 3 time).Merge organic phase, 5% saline solution (25mL) is washed
Wash, organic phase is dried with anhydrous magnesium sulfate, filtering, concentration obtains concentrate.
To methyl alcohol (6mL), ethyl acetate (6mL) and above-mentioned concentrate is sequentially added in 25mL round-bottomed flasks, by mixed liquor
45~50 DEG C are heated to, fumaric acid (383mg) is added.Internally 45~50 DEG C of temperature is stirred 1~1.5 hour, it is cooled to 20~
25 DEG C, continue to stir 1~2 hour, filtering, filter cake is beaten 30 minutes with ethyl acetate (10mL) again, filtering obtains impurity IV
(960mg).Structural identification data is consistent with embodiment 9.
Above example is only purpose of explanation, and those of ordinary skill in the art can be on the basis of present invention description
On be changed and modified above-mentioned purpose, such as selectively filtered after Formula II compound dissolving, charcoal absorption etc.
Reason, is filtered, dried process after crystallization by other conventional methods, using with close good solvent of the invention and bad molten
Agent etc.；Again for example, by high-purity Formula II compound of the invention by method known in the art or equivalent and unknown
Vonoprazan Fumarate etc. are prepared, as long as the change made under the premise of without prejudice to spirit of the invention, belongs to this hair
Bright disclosed and protection scope.
Claims (11)
1. a kind of method of the high-purity Vonoprazan Fumarate compounds prepared shown in formula (I),
Including step：
1) 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde crude products are dissolved in good solvent,
Poor solvent is subsequently adding, crystallization obtains refined 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles -3-
Formaldehyde；Wherein described good solvent be selected from dichloromethane and chloroform in one or two, the poor solvent be C4-C7
Alkane or petroleum ether；The good solvent is 1 with the volume ratio of poor solvent:(1~10)；
2) with methylamine there is condensation instead in refined 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles -3- formaldehyde
Should, obtain group with imine moiety；Then under reducing agent effect there is reduction-aminating reaction in group with imine moiety, obtain
Vonoprazan free alkalis；
3) with fumaric acid there is salt-forming reaction in Vonoprazan free alkalis, obtain Vonoprazan Fumarate compounds.
2. the method for claim 1, wherein step 1) in, the poor solvent be selected from pentane, hexamethylene, just oneself
One or more in alkane, normal heptane, cycloheptane, methyl cyclopentane, hexahydrotoluene and petroleum ether.
3. method as claimed in claim 2, wherein step 1) in, the poor solvent is selected from n-hexane, normal heptane and oil
One or more in ether.
4. the method for claim 1, wherein step 1) in, described 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulphonyl
Base] ratio of -1H- pyrroles -3- formaldehyde crude product and good solvent is 1g:(1~6) mL.
5. method as claimed in claim 4, wherein the 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles
The ratio for coughing up -3- formaldehyde crude product and good solvent is 1g:(2~4) mL；The good solvent is 1 with the volume ratio of poor solvent:
(2~6).
6. the method for claim 1, wherein step 1) in, refined 5- (2- the fluorophenyls) -1- [(pyridine -3-
Base) sulfonyl] in -1H- pyrroles's -3- formaldehyde, its HPLC purity is higher than 97.5%, the content of the impurity compound shown in formula III
Less than 0.25%；
7. a kind of high-purity 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles -3- prepared shown in formula (II)
The method of formaldehyde,
Including：5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles's -3- formaldehyde crude products are dissolved in good solvent
In, poor solvent is subsequently adding, crystallization obtains refined 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles
Cough up -3- formaldehyde；The good solvent be selected from dichloromethane and chloroform in one or two；The poor solvent is selected from
C4-C7 alkane or petroleum ether；The good solvent is 1 with the volume ratio of poor solvent:(1~10).
8. method as claimed in claim 7, wherein the poor solvent be selected from pentane, hexamethylene, n-hexane, normal heptane,
One or more in cycloheptane, methyl cyclopentane, hexahydrotoluene, petroleum ether.
9. method as claimed in claim 7, wherein the 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles
The ratio for coughing up -3- formaldehyde crude product and good solvent is 1g:(1~6) mL.
10. method as claimed in claim 9, wherein the 5- (2- fluorophenyls) -1- [(pyridin-3-yl) sulfonyl] -1H- pyrroles
The ratio for coughing up -3- formaldehyde crude product and good solvent is 1g:(2~4) mL；The good solvent is 1 with the volume ratio of poor solvent:
(2~6).
A kind of 11. impurity compounds of Vonoprazan Fumarate, its structure is as shown in formula IV：
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| CN107778286A (en) * | 2016-08-25 | 2018-03-09 | 成都弘达药业有限公司 | A kind of synthesis technique of Vonoprazan fumarate |
| CN106380464A (en) * | 2016-08-31 | 2017-02-08 | 山东新华制药股份有限公司 | Preparation method of vonoprazan key intermediate |
| 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 |
| WO2018059455A1 (en) * | 2016-09-29 | 2018-04-05 | 江苏吉贝尔药业股份有限公司 | 1-[(pyridin-3-yl-sulfonyl)-1h-pyrrol-3-yl] methanamine derivative and pharmaceutical composition and use thereof |
| CN108205021B (en) * | 2016-12-19 | 2021-04-02 | 成都弘达药业有限公司 | Detection method of Vonoprazan fumarate related substances |
| CN107941946B (en) * | 2017-11-24 | 2021-03-16 | 中山奕安泰医药科技有限公司 | Detection method of Vonoprazan fumarate |
| CN116987063A (en) * | 2019-09-23 | 2023-11-03 | 吉林汇康制药有限公司 | Preparation method of low-impurity Vonoprazan fumarate |
| CN114380796A (en) * | 2020-10-22 | 2022-04-22 | 杭州中美华东制药有限公司 | Preparation method of vonoprazan fumarate |
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