CN104926790A - High-purity Vonoprazan Fumarate compound, intermediate and impurity thereof and preparation methods of high-purity Vonoprazan Fumarate compound, intermediate and impurity - Google Patents
High-purity Vonoprazan Fumarate compound, intermediate and impurity thereof and preparation methods of high-purity Vonoprazan Fumarate compound, intermediate and impurity Download PDFInfo
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Abstract
The invention provides a high-purity Vonoprazan Fumarate compound and a preparation method thereof. The purity of the Vonoprazan Fumarate compound shown in structural formula I is higher than 99.6%, and the content of an impurity compound shown in formula IV is lower than 0.1%. The invention further provides an intermediate of the high-purity Vonoprazan Fumarate compound, a preparation method of the intermediate, the Vonoprazan Fumarate impurity compound and a preparation method thereof. Vonoprazan Fumarate products are high in purity and little in impurity content, and the preparation methods are simple and easy to operate, low in cost and little in energy consumption and are of great significance to industrial production.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of high purity Vonoprazan Fumarate and preparation method thereof, high purity Vonoprazan Fumarate intermediate and preparation method thereof, and the impurity contained in Vonoprazan Fumarate and intermediate thereof, and the preparation method of impurity.
Background technology
Vonoprazan Fumarate (TAK-438; have another name called fumaric acid Wo Nuolazan; formula I); chemical name 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-methylamine fumarate; it is the competitive acid inhibitor (P-CAB) of a kind of novel potassium ion; can in the final step of parietal cell gastric acid secretion, by suppressing K
+to H
+-K
+the keying action of-ATP enzyme, the secretion of premature termination hydrochloric acid in gastric juice, has powerful, lasting gastric acid secretion inhibiting effect.
The synthetic method that prior art (as CN102421753A) is reported all as key intermediate, obtains TAK-438 through reduction-amination, salt-forming reaction using 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (formula II).
But the present inventor studies discovery, be difficult to reach more than 99% according to Vonoprazan Fumarate compound purity prepared by art methods, wherein containing extremely obstinate impurity, affect the quality of target product.By preparing in a small amount and structural identification, confirm that the structure of this impurity is such as formula shown in IV.The similar of formula IV impurity and target product, the difficulty of separation and purification is very large, especially will take into account purity and yield in purge process simultaneously, just more difficult for.Contriver has attempted the conventional purification process in multiple this area, comprises the chromatographic separation under various condition, recrystallization etc., all cannot obtain formula IV foreign matter content lower than 0.1% Vonoprazan Fumarate compound.
The present inventor studies discovery further, and in Vonoprazan Fumarate, the generation of impurity is relevant to the synthesis of formula II intermediate.In the process of preparation formula II intermediate, create more obstinate intermediate impurities equally, by preparing in a small amount and structural identification, confirm that the structure of this intermediate impurities is as shown in formula III, HPLC content maintains about more than 0.6%, and this intermediate impurities also participates in subsequent reactions continuously, cause the generation of above-mentioned Vonoprazan Fumarate impurity.
Therefore, the present inventor wishes at pharmaceutical intermediate preparatory phase in a hurry, by specific means of purification, prepares highly purified formula II intermediate, to eliminate the impact of formula III impurity on subsequent reactions and end product quality, thus obtain highly purified Vonoprazan Fumarate compound.Also without any the relevant report of the purity of above-mentioned intermediate and the finished product and contaminant problem being carried out to analysis and solve in currently available technology.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, research confirms the impurity structure of Vonoprazan Fumarate and formula II intermediate, highly purified Vonoprazan Fumarate and midbody compound and their preparation method are provided, additionally provide above-mentioned critical impurities and analysis thereof, preparation method, for the production of Vonoprazan Fumarate bulk drug and preparation and quality approach provide guarantee.
One aspect of the present invention is to provide a kind of highly purified Vonoprazan Fumarate compound, and structure is such as formula shown in I, and its HPLC purity is greater than 99.6%, and shown in its Chinese style IV, the content of impurity compound is lower than 0.1%.
A second aspect of the present invention is to provide a kind of method preparing above-mentioned high purity Vonoprazan Fumarate compound.
A third aspect of the present invention is to provide a kind of highly purified Vonoprazan Fumarate intermediate, and structure is such as formula shown in II, and its HPLC purity is greater than 97.5%, and wherein the content of impurity compound shown in formula III lower than 0.25%.
A fourth aspect of the present invention is to provide a kind of method preparing highly purified Vonoprazan Fumarate intermediate.
A fifth aspect of the present invention is to provide the impurity compound of a kind of Vonoprazan Fumarate, and its structure is such as formula shown in IV.
A sixth aspect of the present invention is to provide a kind of method preparing the impurity compound of above-mentioned Vonoprazan Fumarate.
For this reason, the invention provides following technical scheme:
According to a first aspect of the invention, provide a kind of high purity Vonoprazan Fumarate compound, its structure such as formula shown in I,
It is characterized in that, the purity of described Vonoprazan Fumarate compound is greater than 99.6%, and the content of impurity compound shown in its Chinese style IV is lower than 0.1%;
Described high purity Vonoprazan Fumarate compound, wherein said purity and content HPLC measure.
Described HPLC measuring method is:
Chromatographic column: YMC Basic post, 150mm × 4.6mm, 3 μm;
Moving phase: A:30mmol/L sodium phosphate buffer salt (pH 6.0)-acetonitrile (95:5);
B:30mmol/L sodium phosphate buffer salt (pH 6.0)-acetonitrile (40:60);
Flow velocity: 1.0ml/min;
Determined wavelength: 230nm;
Column temperature: 25 DEG C;
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 a second aspect of the invention, a kind of method preparing above-mentioned high purity Vonoprazan Fumarate compound is provided, comprises step:
1) 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product is dissolved in good solvent, then poor solvent is added, crystallization, obtains 5-(2-fluorophenyl)-1-[(pyridin-3-yl) the alkylsulfonyl]-1H-pyrroles-3-formaldehyde refined; Wherein said good solvent is halogenated alkane, and described poor solvent is C4-C7 alkane or sherwood oil;
2) refining 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde and methylamine generation condensation reaction, obtain group with imine moiety; Then group with imine moiety reduces-amination reaction under reductive agent effect, obtains Vonoprazan free alkali;
3) Vonoprazan free alkali and fumaric acid generation salt-forming reaction, obtain Vonoprazan Fumarate compound;
Wherein step 1) in, one or both in the preferred methylene dichloride of described good solvent and trichloromethane; One or more in the preferred Skellysolve A of described poor solvent, hexanaphthene, normal hexane, normal heptane, suberane, methylcyclopentane, methylcyclohexane and sherwood oil; More preferably one or more in normal hexane, normal heptane and sherwood oil.
Wherein step 1) in; described 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product is dissolved in good solvent can carry out under room temperature or heating condition; the scope of such as 20 DEG C ~ 60 DEG C; include but not limited to 25 DEG C, 30 DEG C, 40 DEG C, 50 DEG C etc., preferred 15-25 DEG C.
Wherein step 1) in; the crystallization of described 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde can carry out under room temperature or cold condition; such as-10 DEG C ~ 30 DEG C; include but not limited to-5 DEG C, 0 DEG C, 5 DEG C, 10 DEG C, 20 DEG C, 25 DEG C etc., preferred 15-25 DEG C.
Wherein step 1) in, the ratio of described 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product and good solvent is 1g:(1 ~ 6) mL, preferred 1g:(2 ~ 4) mL; The volume ratio of described good solvent and poor solvent is 1:(1 ~ 10), preferred 1:(2 ~ 6).
Wherein step 1) in; in described refining 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde; its HPLC purity is higher than 97.5%, and the content of the impurity compound shown in formula III is lower than 0.25%.
Wherein step 2) in, the reaction solvent of described condensation reaction is selected from the alcohol compounds such as methyl alcohol, ethanol, Virahol, is preferably methyl alcohol.The mol ratio of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde and methylamine is 1:(1 ~ 1.3), temperature of reaction is 0 DEG C ~ 30 DEG C, preferably 20 DEG C ~ 25 DEG C.
Wherein step 2) in, the reaction solvent of described reduction-amination reaction is DMF (DMF) or N,N-dimethylacetamide (DMAc).Reductive agent is the reductive agent that this area is commonly used, such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride etc.The mol ratio of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde and reductive agent is 1:(0.4 ~ 0.6), preferred 1:(0.4 ~ 0.5).Temperature of reaction is-10 DEG C ~ 10 DEG C, preferably 0 DEG C ~ 10 DEG C;
Wherein step 3) in, described salt-forming reaction carries out in mixed solvent, and described mixed solvent is selected from ethyl acetate/N,N-DIMETHYLACETAMIDE, volume ratio (1:1 ~ 3); Ethyl acetate/methanol, volume ratio 1:(1 ~ 3); Ethyl acetate/N,N-DIMETHYLACETAMIDE, volume ratio is preferably 1:(1 ~ 2).The mol ratio of Vonoprazan free alkali and fumaric acid is 1:(0.9 ~ 1.1).Temperature of reaction is 40 DEG C ~ 50 DEG C.
Wherein step 3) in, the Vonoprazan Fumarate crude compound of gained obtains highly purified Vonoprazan Fumarate by recrystallization, and recrystallization solvent is preferably methanol/water, volume ratio 1.5:1.
In addition, described step 2) and 3) also can method conventionally carry out.
According to a third aspect of the invention we, provide a kind of high purity Vonoprazan Fumarate midbody compound, 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde, structure such as formula shown in II,
It is characterized in that, the purity of described formula II compound is greater than 97.5%, and wherein the content of impurity compound shown in formula III is lower than 0.25%.
Described formula III impurity compound comprises the compound that Cl is positioned at 2,5 or 6.
Described high purity Vonoprazan Fumarate midbody compound, wherein said purity and content HPLC measure.
Described HPLC measuring method is:
Chromatographic column: octadecylsilane chemically bonded silica is weighting agent, 250mm × 4.6mm, 5 μm;
Moving phase: A: methyl alcohol-trifluoroacetic acid (100:0.01); B: water-trifluoroacetic acid (100:0.01);
Flow velocity: 1.0ml/min;
Determined wavelength: 235nm;
Column temperature: 30 DEG C;
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 a forth aspect of the invention; one is provided to prepare the method for above-mentioned high purity 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde; comprise: 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product is dissolved in good solvent; then poor solvent is added; crystallization, obtains 5-(2-fluorophenyl)-1-[(pyridin-3-yl) the alkylsulfonyl]-1H-pyrroles-3-formaldehyde refined.
Described good solvent is halogenated alkane, one or both in preferred methylene dichloride and trichloromethane.
Described poor solvent is selected from C4-C7 alkane or sherwood oil, one or more in preferred Skellysolve A, hexanaphthene, normal hexane, normal heptane, suberane, methylcyclopentane, methylcyclohexane, sherwood oil.
Described 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product is dissolved in good solvent can carry out under room temperature or heating condition; the scope of such as 20 DEG C ~ 60 DEG C; include but not limited to 25 DEG C, 30 DEG C, 40 DEG C, 50 DEG C etc., preferred 15-25 DEG C.
The crystallization of described 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde can carry out under room temperature or cold condition; such as-10 DEG C ~ 30 DEG C; include but not limited to-5 DEG C, 0 DEG C, 5 DEG C, 10 DEG C, 20 DEG C, 25 DEG C etc., preferred 15-25 DEG C.
The ratio of described 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product and good solvent is preferably 1g:(1 ~ 6) mL, more preferably 1g:(2 ~ 4) mL.
The volume ratio of described good solvent and poor solvent is preferably 1:(1 ~ 10), more preferably 1:(2 ~ 6).
According to a fifth aspect of the invention, provide the impurity compound of a kind of Vonoprazan Fumarate, its structure is such as formula shown in IV:
Described formula IV impurity compound relative retention time in the HPLC figure of Vonoprazan Fumarate is about 1.42.
Described formula IV impurity compound can use as impurity reference substance, such as in the Related substances separation of Vonoprazan Fumarate preparation as impurity reference substance.
According to a sixth aspect of the invention, a kind of method preparing the Vonoprazan Fumarate impurity compound shown in above-mentioned formula IV is provided, comprises step:
A) 5-(2-fluorophenyl)-1H-pyrroles-3-formaldehyde and 5-chloropyridine-3-SULPHURYL CHLORIDE are reacted, and obtain 5-(2-fluorophenyl)-1-[(5-chloropyridine-3-base) alkylsulfonyl]-1H-pyrroles-3-formaldehyde;
B) 5-(2-fluorophenyl)-1-[(5-chloropyridine-3-base) alkylsulfonyl]-1H-pyrroles-3-formaldehyde and methylamine generation condensation reaction; Products therefrom reduces-amination reaction under reductive agent effect, obtains 1-[5-(2-fluorophenyl)-1-(5-chloro-3-pyridyl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine;
C) 1-[5-(2-fluorophenyl)-1-(5-chloro-3-pyridyl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine and fumaric acid generation salt-forming reaction; obtain 1-[5-(2-fluorophenyl)-1-(5-chloro-3-pyridyl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine fumarate, i.e. formula IV impurity compound.
Wherein step reaction a) can be carried out in organic solvent, preferred non-protonic solvent, such as acetonitrile, tetrahydrofuran (THF), methylene dichloride, chloroform, pyridine etc.Reaction can be carried out in the basic conditions, such as diisopropylethylamine, diethylamide, triethylamine, DBU, piperidines, pyridine, DMAP etc., as acid-binding agent, described alkali can promote that reaction occurs to forward.Reaction can at room temperature be carried out.
Wherein step b) and c) can refer to step 2 in Vonoprazan Fumarate preparation method) and 3) carry out.Such as:
Wherein step b) in, the reaction solvent of described condensation reaction is selected from the alcohol compounds such as methyl alcohol, ethanol, Virahol, is preferably methyl alcohol.The mol ratio of 5-(2-fluorophenyl)-1-[(5-chloropyridine-3-base) alkylsulfonyl]-1H-pyrroles-3-formaldehyde and methylamine is 1:(1 ~ 1.3), temperature of reaction is 0 DEG C ~ 30 DEG C, preferably 20 DEG C ~ 25 DEG C.
Wherein step b) in, the reaction solvent of described reduction-amination reaction is DMF (DMF) or N,N-dimethylacetamide (DMAc).Reductive agent is the reductive agent that this area is commonly used, such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride etc.; The mol ratio of 5-(2-fluorophenyl)-1-[(5-chloropyridine-3-base) alkylsulfonyl]-1H-pyrroles-3-formaldehyde and reductive agent is 1:(0.4 ~ 0.6), preferred 1:(0.4 ~ 0.5).Temperature of reaction is-10 DEG C ~ 10 DEG C, preferably 0 DEG C ~ 10 DEG C;
Wherein step c) in, described salt-forming reaction carries out in mixed solvent, and described mixed solvent is selected from ethyl acetate/N,N-DIMETHYLACETAMIDE, volume ratio (1:1 ~ 3); Ethyl acetate/methanol, volume ratio 1:(1 ~ 3); Ethyl acetate/N,N-DIMETHYLACETAMIDE, volume ratio is preferably 1:(1 ~ 2).The mol ratio of 1-[5-(2-fluorophenyl)-1-(5-chloro-3-pyridyl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine and fumaric acid is 1:(0.9 ~ 1.1).Temperature of reaction is 40 DEG C ~ 50 DEG C.
Major technique advantage of the present invention is:
1, the invention solves Vonoprazan Fumarate compound and contain the problem that obstinate impurity and purity is difficult to mention, significantly improve the purity of formula I, also significantly reduce formula IV impurity wherein, obtain the VonoprazanFumarate compound that purity is very high.
2, the present invention is by repeated multiple times experiment, select specific preparation condition, obtain the formula II midbody compound that purity is very high, utilize highly purified formula II Intermediate Preparation Vonoprazan Fumarate compound, alleviate the operation pressure of Vonoprazan Fumaratec purification step dramatically, make can obtain high purity Vonoprazan Fumarate by known ordinary method, create unforeseeable technique effect.
3, the impurity that the present invention not only effectively reduces formula II intermediate is started with, effectively eliminate formula III impurity (comprising the impurity that Cl is positioned at 2,5 or 6) wherein, in the process of follow-up preparation Vonoprazan Fumarate, (only there is the impurity that a small amount of Cl is positioned at 5 in the chloro impurity also significantly reduced in VonoprazanFumarate, i.e. formula IV, its content is lower than 0.1%); Described method is simple and easy to operate, and yield is high, is very applicable to suitability for industrialized production.
4, critical impurities compound that the invention provides Vonoprazan Fumarate and preparation method thereof, can as impurity reference substance, for the quality approach of Vonoprazan Fumarate bulk drug and preparation thereof.
Embodiment
Following examples are used for understanding advantage of the present invention further, and do not limit the present invention in any way disclosed content.Unless stated otherwise, the reagent used in embodiment and instrument are common commercially available prod.
The HPLC detection method of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (formula II intermediate):
Chromatographic column: octadecylsilane chemically bonded silica is weighting agent, 250mm × 4.6mm, 5 μm;
Moving phase: A: methyl alcohol-trifluoroacetic acid (100:0.01); B: water-trifluoroacetic acid (100:0.01);
Flow velocity: 1.0ml/min;
Determined wavelength: 235nm;
Column temperature: 30 DEG C;
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 |
The HPLC detection method of 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-methylamine fumarate (Vonoprazan Fumarate):
Chromatographic column: YMC Basic post, 150mm × 4.6mm, 3 μm;
Moving phase: A:30mmol/L sodium phosphate buffer salt (pH 6.0)-acetonitrile (95:5);
B:30mmol/L sodium phosphate buffer salt (pH 6.0)-acetonitrile (40:60);
Flow velocity: 1.0ml/min;
Determined wavelength: 230nm;
Column temperature: 25 DEG C;
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 |
The preparation of [preparation example] 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product
With reference to CN102421753A specification sheets the 57th page of embodiment 4: synthesis 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product.Yield: 97%, crude product purity: 94.13%, formula III impurity: 0.58%.
[embodiment 1]
The preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in methylene dichloride (33mL), drip normal heptane (66mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains formula II intermediate 11.1g.Yield: 65%, purity: 97.64%, formula III impurity: 0.21%.
The preparation (with reference to CN102421753A specification sheets the 57th page of embodiment 5) of Vonoprazan Fumarate
At 20 ~ 25 DEG C; methyl alcohol (30.5mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (6.0g is added successively in 200ml round-bottomed flask; 18.3mol), the methanol solution (2.5g of methylamine; 30 ~ 33% methylamines; 23.8mol), stir 1.5 hours.Be cooled to 0 ~ 10 DEG C, drip NaBH
4the N,N-dimethylacetamide solution (9.1mL) of (346mg, 9.16mol), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (35mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (40mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (61mL) extraction, aqueous phase is extracted with ethyl acetate (35mL × 3).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 100mL round-bottomed flask, add N,N-dimethylacetamide (36mL), ethyl acetate (18mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, adds fumaric acid (2.13g, 18.3mmol).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake ethyl acetate/N,N-dimethylacetamide (1:1,28mL) mixed solvent is pulled an oar 30 minutes, filters.Filter cake uses ethyl acetate (28mL) to pull an oar again 30 minutes, filters, obtains crude product (6.3g).
At 55 ~ 60 DEG C, be dissolved in by crude product in the mixing solutions of methyl alcohol and water (1.5:1,92mL), add medicinal carbon (343mg), continue stirring 10 minutes, filter, the mixing solutions of filter cake methyl alcohol and water washs.Again clearly molten at all filtrate is incorporated in 55 ~ 60 DEG C, be cooled to 20 ~ 30 DEG C and stir 1 hour, and continue stirring and crystallizing 1.5 ~ 2 hours at 0 ~ 10 DEG C, filter, obtain Vonoprazan Fumarate (5.2g).HPLC detected result: purity: 99.79%, formula IV impurity: 0.05%.
[embodiment 2]
The preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in methylene dichloride (33mL), drip normal heptane (99mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 11.9g.Yield: 70%, purity: 97.57%, formula III impurity: 0.25%.
The preparation of Vonoprazan Fumarate
At 20 ~ 25 DEG C; methyl alcohol (30mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (6.0g is added successively in 200ml round-bottomed flask; 18.3mol), the methanol solution (2.1g of methylamine; 30 ~ 33% methylamines; 20.1mol), stir 1.5 hours.Be cooled to 0 ~ 10 DEG C, drip NaBH
4the DMF solution (9.1mL) of (346mg, 9.16mol), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (35mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (40mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (61mL) extraction, aqueous phase is extracted with ethyl acetate (35mL × 3 time).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 100mL round-bottomed flask, add N,N-dimethylacetamide (18mL), ethyl acetate (18mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, adds fumaric acid (2.13g, 18.3mmol).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake ethyl acetate/N,N-dimethylacetamide (1:1,28mL) mixed solvent is pulled an oar 30 minutes, filters.Filter cake uses ethyl acetate (28mL) to pull an oar again 30 minutes, filters, obtains crude product (5.9g).
At 55 ~ 60 DEG C, be dissolved in by crude product in the mixing solutions of methyl alcohol and water (1.5:1,85mL), add medicinal carbon (343mg), continue stirring 10 minutes, filter, the mixing solutions of filter cake methyl alcohol and water washs.Again clearly molten at all filtrate is incorporated in 55 ~ 60 DEG C, be cooled to 20 ~ 30 DEG C and stir 1 hour, and continue stirring and crystallizing 1.5 ~ 2 hours at 0 ~ 10 DEG C, filter, obtain Vonoprazan Fumarate (4.7g).HPLC detected result: purity: 99.67%, formula IV chloro impurity: 0.07%.
[embodiment 3]
The preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in methylene dichloride (33mL), drip normal heptane (132mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 12.2g.Yield 72%, purity: 98.01%, formula III chloro impurity: 0.22%.
The preparation of Vonoprazan Fumarate
At 20 ~ 25 DEG C; methyl alcohol (30mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (6.0g is added successively in 200ml round-bottomed flask; 18.3mol), the methanol solution (2.5g of methylamine; 30 ~ 33% methylamines; 23.8mol), stir 1.5 hours.Be cooled to 0 ~ 10 DEG C, drip NaBH
4the N,N-dimethylacetamide solution (9.1mL) of (311mg, 8.24mol), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (35mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (40mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (61mL) extraction, aqueous phase is extracted with ethyl acetate (35mL × 3).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 100mL round-bottomed flask, add N,N-dimethylacetamide (36mL), ethyl acetate (18mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, adds fumaric acid (2.34g, 20.1mmol).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake ethyl acetate/N,N-dimethylacetamide (1:1,28mL) mixed solvent is pulled an oar 30 minutes, filters.Filter cake uses ethyl acetate (28mL) to pull an oar again 30 minutes, filters, obtains crude product (6.1g).
At 55 ~ 60 DEG C, be dissolved in by crude product in the mixing solutions of methyl alcohol and water (1.5:1,92mL), add medicinal carbon (343mg), continue stirring 10 minutes, filter, the mixing solutions of filter cake methyl alcohol and water washs.Again clearly molten at all filtrate is incorporated in 55 ~ 60 DEG C, be cooled to 20 ~ 30 DEG C and stir 1 hour, and continue stirring and crystallizing 1.5 ~ 2 hours at 0 ~ 10 DEG C, filter, obtain Vonoprazan Fumarate (5.0g).HPLC detected result: purity: 99.83%, formula IV chloro impurity: 0.04%.
[embodiment 4]
The preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
Under room temperature (20 ~ 25 DEG C), get crude product (17g) and be dissolved in methylene dichloride (33mL), drip normal heptane (165mL), stir 30 minutes, filter, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains 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; methyl alcohol (30.5mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (6.0g is added successively in 200ml round-bottomed flask; 18.3mol), the methanol solution (2.5g of methylamine; 30 ~ 33% methylamines; 23.8mol), stir 1.5 hours.Drip the N,N-dimethylacetamide solution (9.1mL) of NaBH4 (346mg, 9.16mol), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (35mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (40mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (61mL) extraction, aqueous phase is extracted with ethyl acetate (35mL × 3).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 100mL round-bottomed flask, add N,N-dimethylacetamide (36mL), ethyl acetate (18mL) and above-mentioned concentrated solution successively, mixed solution is heated to 40 ~ 45 DEG C, adds fumaric acid (2.13g, 18.3mmol).Stir 1 ~ 1.5 hour internal temperature 40 ~ 45 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake ethyl acetate/N,N-dimethylacetamide (1:1,28mL) mixed solvent is pulled an oar 30 minutes, filters.Filter cake uses ethyl acetate (28mL) to pull an oar again 30 minutes, filters, obtains crude product (6.5g).
At 55 ~ 60 DEG C, be dissolved in by crude product in the mixing solutions of methyl alcohol and water (1.5:1,96mL), add medicinal carbon (343mg), continue stirring 10 minutes, filter, the mixing solutions of filter cake methyl alcohol and water washs.Again clearly molten at all filtrate is incorporated in 55 ~ 60 DEG C, be cooled to 20 ~ 30 DEG C and stir 1 hour, and continue stirring and crystallizing 1.5 ~ 2 hours at 0 ~ 10 DEG C, filter, obtain Vonoprazan Fumarate (5.4g).HPLC detected result: purity: 99.75%, formula IV chloro impurity: 0.05%.
The preparation of [embodiment 5] 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in methylene dichloride (33mL), drip normal heptane (198mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 13.1g.Yield: 77%, purity: 97.84%, formula III chloro impurity: 0.21%.
The preparation of [embodiment 6] 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in trichloromethane (33mL), drip normal heptane (165mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 12.1g.Yield 71%, purity is 97.89%, and chloro thing foreign matter content is 0.20%.
The preparation of [embodiment 7] 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in methylene dichloride (33mL), drip normal hexane (165mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 12.4g.Yield 73%, purity is 97.86%, and chloro thing foreign matter content is 0.22%.
The preparation of [embodiment 8] 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in methylene dichloride (33mL), drip sherwood oil (165mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 12.5g.Yield: 73.5%, purity: 97.78%, formula III chloro impurity: 0.19%.
[reference examples 1]
The preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in ethyl acetate (33mL), drip methyl tertiary butyl ether (132mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 11g.Yield: 64.7%, purity: 97.22%, formula III chloro impurity: 0.59%.
The preparation of Vonoprazan Fumarate:
At 20 ~ 25 DEG C; methyl alcohol (21.8mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (4.3g is added successively in 100ml round-bottomed flask; 13.07mol), the methanol solution (1.76g of methylamine; 30 ~ 33% methylamines; 17.0mol), stir 1.5 hours.Be cooled to 0 ~ 10 DEG C, drip NaBH
4the N,N-dimethylacetamide solution (6.5mL) of (247mg, 6.54mol), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (25mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (28mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (44mL) extraction, aqueous phase is extracted with ethyl acetate (25mL × 3 time).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 100mL round-bottomed flask, add N,N-dimethylacetamide (26mL), ethyl acetate (13mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, adds fumaric acid (1.52g, 13.07mmol).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake ethyl acetate/N,N-dimethylacetamide (1:1,20mL) mixed solvent is pulled an oar 30 minutes, filters.Filter cake uses ethyl acetate (20mL) to pull an oar again 30 minutes, filters, obtains crude product (4.4g).
At 55 ~ 60 DEG C, be dissolved in by crude product in the mixing solutions of methyl alcohol and water (1.5:1,66mL), add medicinal carbon (245mg), continue stirring 10 minutes, filter, the mixing solutions of filter cake methyl alcohol and water washs.Again clearly molten at all filtrate is incorporated in 55 ~ 60 DEG C, be cooled to 20 ~ 30 DEG C and stir 1 hour, and continue stirring and crystallizing 1.5 ~ 2 hours at 0 ~ 10 DEG C, filter, obtain Vonoprazan Fumarate (3.4g).HPLC detected result: purity: 98.92%, formula VI chloro impurity: 0.231%.
[reference examples 2]
The preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
Under room temperature (20 ~ 25 DEG C), get crude product (17g) and be dissolved in ethyl acetate (33mL), drip isopropyl ether (132mL), stir 30 minutes, filter, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 11.4g.Yield: 67%, purity: 97.42%, formula III chloro impurity: 0.49%.
The preparation of Vonoprazan Fumarate
At 20 ~ 25 DEG C; methyl alcohol (20mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (4.31g is added successively in 100ml round-bottomed flask; 13.07mol), the methanol solution (1.49g of methylamine; 30 ~ 33% methylamines; 14.4mol), stir 1.5 hours.Be cooled to 0 ~ 10 DEG C, drip NaBH
4the DMF solution (6.0mL) of (247mg, 6.54mol), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (25mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (28mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (44mL) extraction, aqueous phase is extracted with ethyl acetate (25mL × 3).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 100mL round-bottomed flask, add N,N-dimethylacetamide (26mL), ethyl acetate (13mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, adds fumaric acid (1.67g, 14.38mmol).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake ethyl acetate/N,N-dimethylacetamide (1:1,20mL) mixed solvent is pulled an oar 30 minutes, filters.Filter cake uses ethyl acetate (20mL) to pull an oar again 30 minutes, filters, obtains crude product (4.2g).
At 55 ~ 60 DEG C, be dissolved in by crude product in the mixing solutions of methyl alcohol and water (1.5:1,65mL), add medicinal carbon (245mg), continue stirring 10 minutes, filter, the mixing solutions of filter cake methyl alcohol and water washs.Again clearly molten at all filtrate is incorporated in 55 ~ 60 DEG C, be cooled to 20 ~ 30 DEG C and stir 1 hour, and continue stirring and crystallizing 1.5 ~ 2 hours at 0 ~ 10 DEG C, filter, obtain Vonoprazan Fumarate (3.3g).HPLC detected result: purity: 98.88%, formula VI chloro impurity: 0.22%.
[reference examples 3]
The preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 20 ~ 25 DEG C, get crude product (17g) and be dissolved in ethyl acetate (33mL), drip normal heptane (132mL), stirs 30 minutes, filtration, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 12g.Yield 70%, purity: 96.32%, formula III chloro impurity: 0.53%.
The preparation of Vonoprazan Fumarate
At 20 ~ 25 DEG C; methyl alcohol (21.8mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (4.3g is added successively in 100ml round-bottomed flask; 13.07mol), the methanol solution (1.76g of methylamine; 30 ~ 33% methylamines; 17.0mol), stir 1.5 hours.Be cooled to 0 ~ 10 DEG C, drip NaBH
4the N,N-dimethylacetamide solution (6.0mL) of (198mg, 5.23mol), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (25mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (28mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (44mL) extraction, aqueous phase is extracted with ethyl acetate (25mL × 3 time).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 100mL round-bottomed flask, add N,N-dimethylacetamide (26mL), ethyl acetate (13mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, adds fumaric acid (1.52g, 13.07mmol).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake ethyl acetate/N,N-dimethylacetamide (1:1,20mL) mixed solvent is pulled an oar 30 minutes, filters.Filter cake uses EA (20mL) to pull an oar again 30 minutes, filters, obtains crude product (4.3g).
At 55 ~ 60 DEG C, be dissolved in by crude product in the mixing solutions of methyl alcohol and water (1.5:1,66mL), add medicinal carbon (245mg), continue stirring 10 minutes, filter, the mixing solutions of filter cake methyl alcohol and water washs.Again clearly molten at all filtrate is incorporated in 55 ~ 60 DEG C, be cooled to 20 ~ 30 DEG C and stir 1 hour, and continue stirring and crystallizing 1.5 ~ 2 hours at 0 ~ 10 DEG C, filter, obtain Vonoprazan Fumarate (3.52g).HPLC detected result: purity: 99.1%, formula VI chloro impurity: 0.25%.
[reference examples 4]
The preparation of 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
Under room temperature (20 ~ 25 DEG C), get crude product (17g) and be dissolved in methylene dichloride (33mL), drip methyl tertiary butyl ether (165mL), stir 30 minutes, filter, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 13.6g.Yield 80%, purity: 96.64%, formula III chloro impurity: 0.55%.
The preparation of Vonoprazan Fumarate
At 0 ~ 10 DEG C; methyl alcohol (21.8mL), 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (4.3g is added successively in 100ml round-bottomed flask; 13.07mol), the methanol solution (1.73g of methylamine; 30 ~ 33% methylamines; 17.0mol), stir 1.5 hours.Drip NaBH
4the N,N-dimethylacetamide solution (7.0mL) of (250mg, 6.54mol), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (25mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (28mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (44mL) extraction, aqueous phase is extracted with ethyl acetate (25mL × 3).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 100mL round-bottomed flask, add N,N-dimethylacetamide (26mL), ethyl acetate (13mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, adds fumaric acid (1.37g, 11.76mmol).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake ethyl acetate/N,N-dimethylacetamide (1:1,20mL) mixed solvent is pulled an oar 30 minutes, filters.Filter cake uses ethyl acetate (20mL) to pull an oar again 30 minutes, filters, obtains crude product (4.6g).
At 55 ~ 60 DEG C, be dissolved in by crude product in the mixing solutions of methyl alcohol and water (1.5:1,70mL), add medicinal carbon (245mg), continue stirring 10 minutes, filter, the mixing solutions of filter cake methyl alcohol and water washs.Again clearly molten at all filtrate is incorporated in 55 ~ 60 DEG C, be cooled to 20 ~ 30 DEG C and stir 1 hour, and continue stirring and crystallizing 1.5 ~ 2 hours at 0 ~ 10 DEG C, filter, obtain Vonoprazan Fumarate (3.6g).HPLC detected result: purity: 98.8%, formula VI chloro impurity: 0.20%.
The preparation of [reference examples 5] 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
Under room temperature (20 ~ 25 DEG C), get crude product (17g) and be dissolved in methylene dichloride (33mL), drip isopropyl ether (165mL), stir 30 minutes, filter, filter cake forced air drying 3 hours at 20 ~ 25 DEG C, obtains product 11.7g.Yield: 68.8%, purity: 96.55%, formula III chloro impurity: 0.61%.
Refining of [reference examples 6] 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 30 ~ 40 DEG C, be dissolved in by crude product (19g) in methyl alcohol (57mL), drip pure water (114mL), drip and continue stirring 30 minutes, filter, filter cake vacuum-drying, obtains product 15.2g.Yield: 80%, purity: 96.04%, formula III chloro impurity: 0.66%.
The preparation of [reference examples 7] 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
At 30 ~ 40 DEG C, be dissolved in by crude product (19g) in acetonitrile (57mL), drip pure water (114mL), drip and continue stirring 30 minutes, filter, filter cake vacuum-drying, obtains product 15.8g.Yield: 83%, purity: 96.21%, formula III chloro impurity: 0.58%.
The preparation of [embodiment 9] formula IV impurity
The preparation of 5-(2-fluorophenyl)-1-[(5-chloropyridine-3-base) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
Acetonitrile (8mL) is added successively in 25mL round-bottomed flask, 5-(2-fluorophenyl)-1H-pyrroles-3-formaldehyde (0.848g), diisopropylethylamine (1.0mL), disposablely add 5-chloropyridine-3-SULPHURYL CHLORIDE (1.1g), stirring at room temperature 4h, TLC follow the tracks of reaction and terminate.Drip purified water (16mL), stir half an hour, filter, 50 DEG C of vacuum-dryings obtain solid 1.2g.
The preparation of 1-[5-(2-fluorophenyl)-1-(5-chloro-3-pyridyl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine fumarate (formula IV)
At 20 ~ 25 DEG C; methanol solution (the 369mg of methyl alcohol (8mL), 5-(2-fluorophenyl)-1-[(5-chloropyridine-3-base) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (1.0g), methylamine is added successively in 25ml round-bottomed flask; 30 ~ 33% methylamines), stir 1.5 hours.Be cooled to 0 ~ 10 DEG C, drip NaBH
4(52mg) N,N-dimethylacetamide solution (1.8mL), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (6mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (8mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (15mL) extraction, aqueous phase is extracted with ethyl acetate (10mL × 3 time).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 25mL round-bottomed flask, add N,N-dimethylacetamide (6mL), ethyl acetate (3mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, add fumaric acid (319mg).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake uses ethyl acetate (10mL) to pull an oar again 30 minutes, filters, obtains impurity IV (800mg).HPLC purity: 96.7%; MS (ESI, m/z) 380 (M+H
+, 100);
1h-NMR (DMSO-d
6, 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.
The preparation of [embodiment 10] formula IV impurity
The preparation of 5-(2-fluorophenyl)-1-[(5-chloropyridine-3-base) alkylsulfonyl]-1H-pyrroles-3-formaldehyde
Acetonitrile (9mL) is added successively in 25mL round-bottomed flask, 5-(2-fluorophenyl)-1H-pyrroles-3-formaldehyde (1g), diisopropylethylamine (1.18mL), disposablely add 5-chloropyridine-3-SULPHURYL CHLORIDE (1.3g), stirring at room temperature 4h, TLC follow the tracks of reaction and terminate.Drip purified water (18mL), stir half an hour, filter, 50 DEG C of vacuum-dryings obtain solid 1.4g.
The preparation of 1-[5-(2-fluorophenyl)-1-(5-chloro-3-pyridyl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine fumarate (formula IV)
At 20 ~ 25 DEG C; methanol solution (the 443mg of methyl alcohol (10mL), 5-(2-fluorophenyl)-1-[(5-chloropyridine-3-base) alkylsulfonyl]-1H-pyrroles-3-formaldehyde (1.2g), methylamine is added successively in 25ml round-bottomed flask; 30 ~ 33% methylamines), stir 1.5 hours.Be cooled to 0 ~ 10 DEG C, drip NaBH
4(62mg) N,N-dimethylacetamide solution (2.2mL), in dropping process, in system, control temp is at 0 ~ 10 DEG C, and after dripping off, TLC follows the tracks of reaction.Be no more than 20 DEG C in interior temperature and linearly drip 1N hydrochloric acid (7.2mL) regulation system pH=5 ~ 6, stir 30 minutes.Ammoniacal liquor (9.6mL) regulation system pH=8 ~ 9 with 12.5%, add ethyl acetate (15mL) extraction, aqueous phase is extracted with ethyl acetate (10mL × 3 time).Merge organic phase, 5% salt solution (25mL) washs, organic phase anhydrous magnesium sulfate drying, filters, concentrated, obtains concentrated solution.
In 25mL round-bottomed flask, add methyl alcohol (6mL), ethyl acetate (6mL) and above-mentioned concentrated solution successively, mixed solution is heated to 45 ~ 50 DEG C, add fumaric acid (383mg).Stir 1 ~ 1.5 hour internal temperature 45 ~ 50 DEG C, be cooled to 20 ~ 25 DEG C, continue stirring 1 ~ 2 hour, filter, filter cake uses ethyl acetate (10mL) to pull an oar again 30 minutes, filters, obtains impurity IV (960mg).Structural identification data are consistent with embodiment 9.
Above embodiment is only purpose of explanation, the basis that those of ordinary skill in the art can describe in the present invention carries out changing and modifying above-mentioned purpose, such as, selectively carry out after formula II compound dissolution filtering, the process such as charcoal absorption, filtered by other ordinary methods after crystallization, drying treatment, uses the good solvent close with the present invention and poor solvent etc.; Again such as; by high purity formula II compound of the present invention by prior art known or equivalent and the method for the unknown prepare Vonoprazan Fumarate etc.; as long as in the change made under spiritual prerequisite of the present invention, all belong to disclosed and the scope of protection.
Claims (10)
1. a high purity Vonoprazan Fumarate compound, its structure such as formula shown in I,
It is characterized in that, the purity of described Vonoprazan Fumarate compound is greater than 99.6%, and the content of impurity compound shown in its Chinese style IV is lower than 0.1%,
2. high purity Vonoprazan Fumarate compound as claimed in claim 1, wherein said purity and content HPLC measure, and described HPLC measuring method is:
Chromatographic column: YMC Basic post, 150mm × 4.6mm, 3 μm;
Moving phase: A:30mmol/L sodium phosphate buffer salt (pH 6.0)-acetonitrile (95:5);
B:30mmol/L sodium phosphate buffer salt (pH 6.0)-acetonitrile (40:60);
Flow velocity: 1.0ml/min;
Determined wavelength: 230nm;
Column temperature: 25 DEG C;
Gradient:
。
3. prepare a method for the high purity Vonoprazan Fumarate compound described in any one of claim 1 or 2, comprise step:
1) 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product is dissolved in good solvent, then poor solvent is added, crystallization, obtains 5-(2-fluorophenyl)-1-[(pyridin-3-yl) the alkylsulfonyl]-1H-pyrroles-3-formaldehyde refined; Wherein said good solvent is halogenated alkane, and described poor solvent is C4-C7 alkane or sherwood oil;
2) refining 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde and methylamine generation condensation reaction, obtain group with imine moiety; Then group with imine moiety reduces-amination reaction under reductive agent effect, obtains Vonoprazan free alkali;
3) Vonoprazan free alkali and fumaric acid generation salt-forming reaction, obtain Vonoprazan Fumarate compound.
4. as claimed in claim 3 method, wherein step 1) in, one or both in the preferred methylene dichloride of described good solvent and trichloromethane; One or more in the preferred Skellysolve A of described poor solvent, hexanaphthene, normal hexane, normal heptane, suberane, methylcyclopentane, methylcyclohexane and sherwood oil; More preferably one or more in normal hexane, normal heptane and sherwood oil.
5. method as claimed in claim 3, wherein step 1) in, the ratio of described 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product and good solvent is 1g:(1 ~ 6) mL, preferred 1g:(2 ~ 4) mL; The volume ratio of described good solvent and poor solvent is 1:(1 ~ 10), preferred 1:(2 ~ 6).
6. method as claimed in claim 3, wherein step 1) in, in described refining 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde, its HPLC purity is higher than 97.5%, and the content of the impurity compound shown in formula III is lower than 0.25%;
7. high purity 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde, structure such as formula shown in II,
It is characterized in that, the purity of described formula II compound is greater than 97.5%, and wherein the content of impurity compound shown in formula III is lower than 0.25%.
8. prepare the method for high purity 5-according to claim 7 (2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde for one kind, comprise: 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product is dissolved in good solvent, then poor solvent is added, crystallization, obtains 5-(2-fluorophenyl)-1-[(pyridin-3-yl) the alkylsulfonyl]-1H-pyrroles-3-formaldehyde refined; Described good solvent is halogenated alkane, one or both in preferred methylene dichloride and trichloromethane; Described poor solvent is selected from C4-C7 alkane or sherwood oil, one or more in preferred Skellysolve A, hexanaphthene, normal hexane, normal heptane, suberane, methylcyclopentane, methylcyclohexane, sherwood oil.
9. method as claimed in claim 8, the ratio of wherein said 5-(2-fluorophenyl)-1-[(pyridin-3-yl) alkylsulfonyl]-1H-pyrroles-3-formaldehyde crude product and good solvent is 1g:(1 ~ 6) mL, preferred 1g:(2 ~ 4) mL; The volume ratio of described good solvent and poor solvent is 1:(1 ~ 10), preferred 1:(2 ~ 6).
10. an impurity compound of Vonoprazan Fumarate, its structure is such as formula shown in IV:
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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 |
| 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 |
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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 |
| 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 |
| CN107778286B (en) * | 2016-08-25 | 2024-05-10 | 四川弘远药业有限公司 | Synthesis process of voronoi 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 |
| CN109843869A (en) * | 2016-09-29 | 2019-06-04 | 江苏吉贝尔药业股份有限公司 | 1- [(pyridin-3-yl-sulfonyl) -1H- pyrroles -3- base] methylamine derivative and its pharmaceutical composition and purposes |
| CN109843869B (en) * | 2016-09-29 | 2021-07-16 | 江苏吉贝尔药业股份有限公司 | 1- [ (pyridin-3-yl-sulfonyl) -1H-pyrrol-3-yl ] methylamine derivatives, pharmaceutical compositions and uses 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 |
| CN108205021A (en) * | 2016-12-19 | 2018-06-26 | 成都弘达药业有限公司 | A kind of detection method of Vonoprazan fumarate in relation to substance |
| 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 |
| CN107941946A (en) * | 2017-11-24 | 2018-04-20 | 中山奕安泰医药科技有限公司 | A kind of detection method of Vonoprazan fumarate |
| CN110590746A (en) * | 2019-09-23 | 2019-12-20 | 北京澳合药物研究院有限公司 | Preparation method of low-impurity vonoprazan fumarate |
| CN110590746B (en) * | 2019-09-23 | 2023-08-29 | 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 |
| CN115850238A (en) * | 2022-11-29 | 2023-03-28 | 山东新华制药股份有限公司 | Post-treatment method of fluoro pranoprazan intermediate |
| CN115850238B (en) * | 2022-11-29 | 2024-06-11 | 山东新华制药股份有限公司 | Post-treatment method of fluarprazan intermediate |
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