CN104860926A - Preparation method of vonoprazan fumarate - Google Patents
Preparation method of vonoprazan fumarate Download PDFInfo
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- 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
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Abstract
The invention relates to preparation of a medical compound, and in particular relates to a preparation method of a stomach-acid resistant medicine vonoprazan fumarate. A synthetic route of the compound is as shown in the specification.
Description
Technical field:
The present invention relates to a kind of preparation of medical compounds, particularly the preparation method of a kind of gastric antiacids thing fumaric acid Wo Nuolazan.
Background technology:
Fumaric acid Wo Nuolazan, chemical structure is as follows:
English name: Vonoprazan fumarate (TAK-438)
Chemical name: 5-(2-fluorophenyl)-N-methyl isophthalic acid-this medicine of (3-pyridyl sulfonyl)-1H-pyrroles-3-methylamine fumarate belongs to competitive sour retarding agent (the Potassium-competitive acid blocker of potassium ion; P-CAB) new class inhibitor; there is powerful, lasting gastric acid secretion restraining effect; simultaneously; in the final step of parietal cell gastric acid secretion; by suppressing K to H; the keying action of K-ATP enzyme (proton pump), also has premature termination effect to gastric acid secretion.
This medicine is the exploitation of Japanese Wu Tian company, for erosive esophagitis, stomach ulcer, duodenal ulcer, helicobacter pylori eradication etc.
About the Chinese patent of this medicine is as follows:
Chinese patent 200680040789.7 discloses the preparation method of following fumaric acid Wo Nuolazan:
Reference example 63
5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-formaldehyde
Under room temperature, in 5-(2-fluorophenyl)-1H-pyrroles-3-formaldehyde (475mg) solution in tetrahydrofuran (THF) (96mL), adding sodium hydride, (60% in oil, 503mg), and this mixture is stirred 30 minutes.Drip 15-crown ether-5 (2.77g), and this mixture is stirred 30 minutes.Add pyridine-3-sulfonyl chloride hydrochloride (1.35g), and this mixture is stirred 3 hours further.Reaction mixture saturated brine is diluted, and this mixture is extracted with ethyl acetate.Extraction liquid saturated brine washs, with anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Residuum carries out purifying (elutriant: hexane-ethylacetate=7: 3 → 2: 3) by silica gel column chromatography, and with Di Iso Propyl Ether-ethyl acetate (4: 1) crystallization, obtain title compound, it is colourless crystallization (yield 680mg, 82%).
Embodiment 8
5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-formaldehyde (1.52g) is dissolved in methyl alcohol (30ml) by 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine fumarate; under room temperature, add the methylamine methanol solution (3.57g) of 40%, and this mixture is stirred 30 minutes.Under room temperature, add sodium borohydride (523mg), and this mixture is stirred 10 minutes.Add the hydrochloric acid (50mL) of 1mol/L, and this mixture is stirred 5 minutes.Reaction mixture saturated sodium bicarbonate aqueous solution is alkalized, and this mixture is extracted with ethyl acetate.Extraction liquid saturated brine washs, with anhydrous sodium sulfate drying, and concentrating under reduced pressure.Residuum carries out purifying by alkaline silica gel column chromatography, and (elutriant: acetate-methanol=1: 0 → 7: 3), obtains the free salt of title compound, and it is pale yellow oil (yield 1.30g).Gained free salt (750mg) is dissolved in ethyl acetate (30ml), under room temperature, drips the solution of fumaric acid (278mg) in methyl alcohol (3mL).After stirring 30 minutes, filter collects the crystallization obtained, and washs by ethyl acetate, and obtain title compound, it is colourless crystallization (yield 912mg, 74%).
Above-mentioned disclosed technical scheme, wherein needs to drip 15-crown ether-5, uses chromatographic column to carry out purifying simultaneously, 15-crown ether-5 is expensive, complicated operation, and chromatographic column equipment requirements high cost is high, be unfavorable for industrialization, gained fumaric acid Wo Nuolazan exists to be needed purifying and removes the problems such as impurity.
Chinese patent 201080018114.9 discloses the preparation method of following fumaric acid Wo Nuolazan:
Embodiment 4
5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-formaldehyde
By 5-(2-fluorophenyl)-1H-pyrroles-3-formaldehyde (5.00g, 26.43mmol), N, N-lutidine-4-amine (0.65g, 5.29mmol), diisopropylethylamine (4.78g, 37.00mmol) and acetonitrile (18.5ml) add in four neck flasks, then add the solution of pyridine-3-SULPHURYL CHLORIDE (5.63g, 31.71mmol) in acetonitrile (5ml).Add acetonitrile (1.5ml) further, and described mixture is stirred 1.5 hours at internal temperature 40-50 DEG C.Internal temperature is cooled to 30 DEG C, and dropwise adds water (15ml).With 0.5N hydrochloric acid, described mixture ph is adjusted to 4-5.Add the kind crystalline substance (2.5mg) of title compound, then dropwise add water (about 30ml).After the internal temperature of 20-30 DEG C stirs 0.5 hour, internal temperature is cooled to 0-10 DEG C, then described mixture is stirred 1 hour.By the crystal that collecting by filtration precipitates, with the mixing solutions (1: 2 of cold acetonitrile and water, 7.5ml) and water (7.5ml × 2) washing, and in decompression, 50 DEG C of dryings being until reach constant weight thus obtain title compound (7.57g, yield 86.7%).
Embodiment 5
1-[5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine fumarate adds N in the flask through nitrogen purging; N-N,N-DIMETHYLACETAMIDE (108ml) and sodium borohydride (3.06g; 81.74mmol), and described mixture is dissolved (solution A).In the flask of nitrogen purging, 5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-formaldehyde (60.00g is added to another; 181.64mmol) and methyl alcohol (300ml); then the solution (18.34g, 236.13mmol) of 40% methylamine in methyl alcohol is dropwise added in room temperature.Described mixture is stirred 30 minutes further at internal temperature 20-30 DEG C.Internal temperature is cooled to-10 DEG C, is then no more than at internal temperature the solution A that 0 DEG C dropwise adds previously preparation.Add N,N-dimethylacetamide (12ml), then described mixture is stirred 1 hour internal temperature-10-0 DEG C.Be no more than 20 DEG C at internal temperature and dropwise add 1N HCl (360ml), and described mixture is stirred 30 minutes at internal temperature 10-20 DEG C.Add 12.5% ammoniacal liquor (240ml), ethyl acetate (600ml) and water (180ml), then distribute described mixture.Water (240ml) and ethyl acetate (360ml) added to described water layer and again extract described mixture.Merge described organic layer and wash twice with 5% salt solution (360ml).Described organic layer is concentrated to about 253g, and adds N,N-dimethylacetamide (480ml).Described mixture is heated to internal temperature 50 DEG C, and adds fumaric acid (21.08g, 181.64mmol).Described mixture is stirred 30 minutes internal temperature 50 DEG C, cooling, then stirring at room temperature 1 hour.Precipitated crystal is filtered, the mixing solutions (1: 2,90ml) of ethyl acetate and N,N-dimethylacetamide is first used to wash, then ethyl acetate (120ml) is used to wash, and in decompression, 50 DEG C of dryings thus obtain crude product (62.73g).
The crude product obtained above (55.00g) is suspended in the mixing solutions (7: 3,550ml) of methyl alcohol and water, and internal temperature 60-65 DEG C of dissolving.Add activated carbon S HIRASAGI A (registered trademark, 2.75g), and described mixture is stirred 10 minutes, filter, then use the mixing solutions (7: 3,110ml) of methyl alcohol and water to wash.Merged filtrate is heated to about 55 DEG C of internal temperature, cool to room temperature, and stirs 1 hour further at internal temperature 0-10 DEG C.Precipitated crystal is filtered, washs with the mixing solutions (1: 1,110ml) of methyl alcohol and water, and reducing pressure, 50 DEG C of dryings thus obtain title compound (47.50g, yield 64.6%).
Embodiment 6
1-[5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-base]-N-methyl methylamine fumarate
N,N-dimethylacetamide (18ml) and sodium borohydride (0.52g, 13.6mmol) are added in the flask of nitrogen purging, and described mixture is dissolved (solution A).In the flask of nitrogen purging, 5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-formaldehyde (10.0g is added at another; 30.3mmol) and methyl alcohol (50ml); then solution (the 3.06g of 40% methylamine in methyl alcohol is dropwise added in room temperature; 39.4mmol), and described mixture is stirred 30 minutes further at internal temperature 20-30 DEG C.Internal temperature is reduced to 5 DEG C, and is no more than at internal temperature the solution A that 0-10 DEG C dropwise adds previously preparation.Add N,N-dimethylacetamide (2ml), and described mixture is stirred 1 hour at internal temperature 0-10 DEG C.Be no more than 20 DEG C at internal temperature and dropwise add 1N HCl (70ml), and described mixture is stirred 30 minutes at internal temperature 15-25 DEG C.Add 12.5% ammoniacal liquor (60ml) and ethyl acetate (100ml) thus distribute described mixture.5% salt solution (50ml) and ethyl acetate (50ml) are added in described water layer and also again extract described mixture.Merge described organic layer and wash twice with 5% salt solution (60ml).Described organic layer is concentrated to about 25ml, adds ethyl acetate (70ml), and described mixture is concentrated to about 38.0ml again.Add N,N-dimethylacetamide (60ml), described mixture is heated to internal temperature 45 DEG C, and adds fumaric acid (3.51g, 30.3mmol).After internal temperature 40-50 DEG C is stirred 30 minutes, dropwise add ethyl acetate (30ml), and described mixture is stirred 30 minutes at internal temperature 40-50 DEG C.Described reaction mixture is cooled, and stirring at room temperature 1 hour.By the crystal that collecting by filtration precipitates, and wash with the mixing solutions (1: 1,15ml) of ethyl acetate and N,N-dimethylacetamide, then use ethyl acetate (30ml) to wash thus obtain crude product (wet product).The crude product obtained above (wet product) is suspended in the mixing solutions (1: 1,100ml) of methyl alcohol and water, and internal temperature 60-70 DEG C of dissolving.Add activated carbon SHIRASAGIA (registered trademark, 0.30g), and described mixture is stirred 10 minutes, filter, then use the mixing solutions (1: 1,20ml) of methyl alcohol and water to wash.Merged filtrate is dissolved again at internal temperature about 55-65 DEG C, cool to room temperature, and stir 1 hour further at internal temperature 0-10 DEG C.By the crystal that collecting by filtration precipitates, wash with the mixing solutions (1: 1,20ml) of methyl alcohol and water, and in decompression, 50 DEG C of dryings thus obtain title compound (10.07g, yield 72.1%).
The shortcoming of this preparation method is: the fumaric acid Wo Nuolazan purity obtained is not high, impurity wherein comprises N, N-N,N-DIMETHYLACETAMIDE, 5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-formaldehyde and pyridine-3-SULPHURYL CHLORIDE, particularly the content of 5-(2-fluorophenyl)-1-(pyridin-3-yl alkylsulfonyl)-1H-pyrroles-3-formaldehyde and pyridine-3-SULPHURYL CHLORIDE is higher, and be difficult to remove, though adopt above-mentioned prior art gained fumaric acid Wo Nuolazan content to be greater than 98.5%, but wherein the content of above-mentioned two related impuritieses is greater than 0.3%, have impact on the quality of product, for reaching higher standard requirement, invention has been the improvement in method.
Embodiment:
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
The preparation of fumaric acid Wo Nuolazan
Step 1,
5-(2-fluorophenyl) pyrroles-3-formaldehyde 10g, DMAP 1.3g, triethylamine 7.5g and acetonitrile (40ml) add reaction flask, stirring at room temperature; Pyridine-3-SULPHURYL CHLORIDE 11.3g and acetonitrile (10ml), instillation reaction flask; Be heated to 45 DEG C of reactions 1.5 hours; Be cooled to 25 DEG C, add water (30ml); With concentrated hydrochloric acid, system ph value is adjusted to 4-5, stirs half an hour at 25 DEG C; Be cooled to 0-5 DEG C to stir 1 hour; Filter, filter cake acetonitrile: water (1:2) 30ml drip washing, then use water (20ml) drip washing 2 times, 50 DEG C of vacuum-dryings, obtain 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde 15g;
Step 2
5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde 10g is dissolved in methyl alcohol (70ml); Methylamine methanol solution (15g, 30%) is added dropwise to reaction system under stirring room temperature by nitrogen protection, drips complete stirring at room temperature 1 hour; Under room temperature, sodium cyanoborohydride (1.52g) is added in batches, finish stirring at room temperature 2 hours; 1N hydrochloric acid (100ml) is instilled reaction system, stirring at room temperature 5 minutes; PH to 9-10 is regulated with the NaOH aqueous solution; Add ethyl acetate (50ml), stir layering; Separate aqueous phase, add ethyl acetate (50ml) and stir layering; Merge organic phase, add saturated aqueous common salt (60ml), stir layering; Organic phase is spin-dried for, then adds ethyl acetate (20ml) and be spin-dried for band water 2 times; Residuum adds dehydrated alcohol (120ml), is heated to 45 DEG C; Added by fumaric acid (5.28g), 45 DEG C are stirred 1 hour; Be down to stirring at room temperature 2 hours, crystallization; Filter, filter cake dehydrated alcohol (30ml) drip washing, vacuum-drying obtains fumaric acid Wo Nuola and agrees with product 7.3g.
Step 3:
Fumaric acid Wo Nuolazan crude product 5g is added the Virahol of 30ml and the mixed solvent of methylene dichloride=2:1 (v/v), add the gac of 1g, reflux 1 hour, filtered while hot falls gac, stir 12 hours, crystallization, obtains crystallization after suction filtration, by 20ml washed with isopropyl alcohol twice, after drying, namely obtain fumaric acid Wo Nuolazan sterling 4.5g.
Summary of the invention:
For overcoming the defect of prior art, the present invention improves prior art, proposes following technical scheme.The invention provides the preparation method of a kind of fumaric acid Wo Nuolazan, it is characterized in that, synthetic route is as follows:
Preparation method of the present invention, is characterized in that, step is as follows:
Step 1
By 5-(2-fluorophenyl) pyrroles-3-formaldehyde, DMAP, triethylamine and acetonitrile add reactor, stirring at room temperature; Add the pyridine-3-SULPHURYL CHLORIDE being dissolved in acetonitrile; Be heated to 45 DEG C of reactions; Be cooled to room temperature, add water, with hydrochloric acid, the ph value of reaction solution is adjusted to 4-5, stirring at room temperature half an hour; Be cooled to 0-5 DEG C to stir 1 hour; Filter, filter cake acetonitrile: water washing, then wash with water, drying obtains 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde;
Step 2
5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde is dissolved in methyl alcohol; Stirred at ambient temperature, adds reaction system by the methylamine solution being dissolved in methyl alcohol, stirring at room temperature 1 hour; Sodium cyanoborohydride is added, stirring at room temperature 2 hours; Add hydrochloric acid to stir; PH to 9-10 is regulated with alkali; Add ethyl acetate, stir layering; Separate aqueous phase, add ethyl acetate and stir layering; Merge organic phase, add saturated aqueous common salt and stir layering; Organic phase is spin-dried for, then adds ethyl acetate and be spin-dried for band water 2 times; Residuum adds dehydrated alcohol, is heated to 45 DEG C; Added by fumaric acid, 45 DEG C are stirred 1 hour; Be down to stirring at room temperature 2 hours, crystallization; Filter, filter cake dehydrated alcohol drip washing, vacuum-drying obtains fumaric acid Wo Nuolazan crude product;
Step 3:
Fumaric acid Wo Nuolazan crude product is added the mixed solvent of Virahol and methylene dichloride=2:1 (v/v), add gac, reflux 1 hour, filtered while hot falls gac, stir 12 hours, crystallization, obtains crystallization after suction filtration, by washed with isopropyl alcohol twice, after drying, namely obtain fumaric acid Wo Nuolazan sterling.
Preferred preparation method of the present invention, step is as follows:
Step 1,
5-(2-fluorophenyl) pyrroles-3-formaldehyde 10g, DMAP 1.3g, triethylamine 7.5g and acetonitrile (40ml) add reaction flask, stirring at room temperature; Pyridine-3-SULPHURYL CHLORIDE 11.3g and acetonitrile (10ml), instillation reaction flask; Be heated to 45 DEG C of reactions 1.5 hours; Be cooled to 25 DEG C, add water (30ml); With concentrated hydrochloric acid, system ph value is adjusted to 4-5, stirs half an hour at 25 DEG C; Be cooled to 0-5 DEG C to stir 1 hour; Filter, filter cake acetonitrile: water (1:2) 30ml drip washing, then use water (20ml) drip washing 2 times, 50 DEG C of vacuum-dryings, obtain 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde 15g;
Step 2
5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde 10g is dissolved in methyl alcohol (70ml); Methylamine methanol solution (15g, 30%) is added dropwise to reaction system under stirring room temperature by nitrogen protection, drips complete stirring at room temperature 1 hour; Under room temperature, sodium cyanoborohydride (1.52g) is added in batches, finish stirring at room temperature 2 hours; 1N hydrochloric acid (100ml) is instilled reaction system, stirring at room temperature 5 minutes; PH to 9-10 is regulated with the NaOH aqueous solution; Add ethyl acetate (50ml), stir layering; Separate aqueous phase, add ethyl acetate (50ml) and stir layering; Merge organic phase, add saturated aqueous common salt (60ml), stir layering; Organic phase is spin-dried for, then adds ethyl acetate (20ml) and be spin-dried for band water 2 times; Residuum adds dehydrated alcohol (120ml), is heated to 45 DEG C; Added by fumaric acid (5.28g), 45 DEG C are stirred 1 hour; Be down to stirring at room temperature 2 hours, crystallization; Filter, filter cake dehydrated alcohol (30ml) drip washing, vacuum-drying obtains fumaric acid Wo Nuola and agrees with product 7.3g;
Step 3:
Fumaric acid Wo Nuolazan crude product 5g is added the Virahol of 30ml and the mixed solvent of methylene dichloride=2:1 (v/v), add the gac of 1g, reflux 1 hour, filtered while hot falls gac, stir 12 hours, crystallization, obtains crystallization after suction filtration, by 20ml washed with isopropyl alcohol twice, after drying, namely obtain fumaric acid Wo Nuolazan sterling 4.5g.
Through detecting, the fumaric acid Wo Nuolazan sterling content that the present invention obtains is more than 99.50%, and wherein the content of each related impurities is less than 0.1%.
The purification step focusing on fumaric acid Wo Nuolazan of the present invention, the fumaric acid Wo Nuolazan raw material of the purifying obtained, foreign matter content is few, good stability, side effect is little, and this depends primarily on the use of solvent in treating process, and the present invention adopts the mixed solvent of 5 times amount Virahols and methylene dichloride=2:1 (v/v) as recrystallization solvent recrystallization once, can obtain excellent technique effect be through screening obtain, screening process is as follows:
After the thick product of fumaric acid Wo Nuolazan synthesized adopts following different solvent treatment respectively, in each sample, the content of impurity is in table 1, and the step method of recrystallization is identical with step 3 of the present invention,
The content of impurity in each sample after table 1 fumaric acid Wo Nuolazan thick product different solvents recrystallization
| Solvent | Total impurities (%) |
| Methyl alcohol | 0.80 |
| Ethanol | 1.05 |
| Methylene dichloride | 0.72 |
| Virahol | 0.74 |
| Acetone | 0.92 |
| Ethyl acetate | 0.89 |
| Benzene | 0.86 |
| Acetonitrile | 0.88 |
| Virahol: methylene dichloride (1:1) | 0.71 |
| Virahol: methylene dichloride (1:2) | 0.73 |
| Virahol: methylene dichloride (1:4) | 0.70 |
| Virahol: methylene dichloride (2:1) | 0.63 |
| Virahol: methylene dichloride (4:1) | 0.78 |
Below by way of experimental data, further illustrate the present invention:
The fumaric acid Wo Nuolazan sterling that table 2 couple the present invention and prior art obtain carries out HPLC analysis, purity and foreign matter content % as follows:
| Prior art is using 50% methyl alcohol as recrystallization solvent | The present invention | |
| Fumaric acid Wo Nuolazan purity | 99.03 | 99.55 |
| Impurity 1 pyridine-3-SULPHURYL CHLORIDE | 0.35 | 0.09 |
| Impurity 2 | 0.23 | 0.08 |
| Impurity 3 | 0.30 | 0.07 |
Table 3 carries out accelerated stability (40 DEG C of placements) to the fumaric acid Wo Nuolazan sterling that fumaric acid Wo Nuolazan sterling of the present invention and prior art obtain and compares, and result is as follows:
From testing data, fumaric acid Wo Nuolazan sterling of the present invention is more stable, and degradation speed is slow.
Claims (3)
1. a preparation method of fumaric acid Wo Nuolazan, is characterized in that, step is as follows:
2. preparation method according to claim 1, is characterized in that, step is as follows:
Step 1
By 5-(2-fluorophenyl) pyrroles-3-formaldehyde, DMAP, triethylamine and acetonitrile add reactor, stirring at room temperature; Add the pyridine-3-SULPHURYL CHLORIDE being dissolved in acetonitrile; Be heated to 45 DEG C of reactions; Be cooled to room temperature, add water, with hydrochloric acid, the ph value of reaction solution is adjusted to 4-5, stirring at room temperature half an hour; Be cooled to 0-5 DEG C to stir 1 hour; Filter, filter cake acetonitrile: water washing, then wash with water, drying obtains 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde;
Step 2
5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde is dissolved in methyl alcohol; Stirred at ambient temperature, adds reaction system by the methylamine solution being dissolved in methyl alcohol, stirring at room temperature 1 hour; Sodium cyanoborohydride is added, stirring at room temperature 2 hours; Add hydrochloric acid to stir; PH to 9-10 is regulated with alkali; Add ethyl acetate, stir layering; Separate aqueous phase, add ethyl acetate and stir layering; Merge organic phase, add saturated aqueous common salt and stir layering; Organic phase is spin-dried for, then adds ethyl acetate and be spin-dried for band water 2 times; Residuum adds dehydrated alcohol, is heated to 45 DEG C; Added by fumaric acid, 45 DEG C are stirred 1 hour; Be down to stirring at room temperature 2 hours, crystallization; Filter, filter cake dehydrated alcohol drip washing, vacuum-drying obtains fumaric acid Wo Nuolazan crude product;
Step 3:
Fumaric acid Wo Nuolazan crude product is added the mixed solvent of Virahol and methylene dichloride=2:1 (v/v), add gac, reflux 1 hour, filtered while hot falls gac, stir 12 hours, crystallization, obtains crystallization after suction filtration, by washed with isopropyl alcohol twice, after drying, namely obtain fumaric acid Wo Nuolazan sterling.
3. preparation method according to claim 2, is characterized in that, step is as follows:
Step 1,
5-(2-fluorophenyl) pyrroles-3-formaldehyde 10g, DMAP 1.3g, triethylamine 7.5g and acetonitrile (40ml) add reaction flask, stirring at room temperature; Pyridine-3-SULPHURYL CHLORIDE 11.3g and acetonitrile (10ml), instillation reaction flask; Be heated to 45 DEG C of reactions 1.5 hours; Be cooled to 25 DEG C, add water (30ml); With concentrated hydrochloric acid, system ph value is adjusted to 4-5, stirs half an hour at 25 DEG C; Be cooled to 0-5 DEG C to stir 1 hour; Filter, filter cake acetonitrile: water (1:2) 30ml drip washing, then use water (20ml) drip washing 2 times, 50 DEG C of vacuum-dryings, obtain 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde 15g;
Step 2
5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl) pyrroles-3-formaldehyde 10g is dissolved in methyl alcohol (70ml); Methylamine methanol solution (15g, 30%) is added dropwise to reaction system under stirring room temperature by nitrogen protection, drips complete stirring at room temperature 1 hour; Under room temperature, sodium cyanoborohydride (1.52g) is added in batches, finish stirring at room temperature 2 hours; 1N hydrochloric acid (100ml) is instilled reaction system, stirring at room temperature 5 minutes; PH to 9-10 is regulated with the NaOH aqueous solution; Add ethyl acetate (50ml), stir layering; Separate aqueous phase, add ethyl acetate (50ml) and stir layering; Merge organic phase, add saturated aqueous common salt (60ml), stir layering; Organic phase is spin-dried for, then adds ethyl acetate (20ml) and be spin-dried for band water 2 times; Residuum adds dehydrated alcohol (120ml), is heated to 45 DEG C; Added by fumaric acid (5.28g), 45 DEG C are stirred 1 hour; Be down to stirring at room temperature 2 hours, crystallization; Filter, filter cake dehydrated alcohol (30ml) drip washing, vacuum-drying obtains fumaric acid Wo Nuola and agrees with product 7.3g;
Step 3:
Fumaric acid Wo Nuolazan crude product 5g is added the Virahol of 30ml and the mixed solvent of methylene dichloride=2:1 (v/v), add the gac of 1g, reflux 1 hour, filtered while hot falls gac, stir 12 hours, crystallization, obtains crystallization after suction filtration, by 20ml washed with isopropyl alcohol twice, after drying, namely obtain fumaric acid Wo Nuolazan sterling 4.5g.
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| CN105130955A (en) * | 2015-09-16 | 2015-12-09 | 海口南陆医药科技有限公司 | Preparation method of Vonoprazan fumarate |
| 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 |
| CN106366071A (en) * | 2016-08-22 | 2017-02-01 | 山东金城医药股份有限公司 | Vonoprazan fumarate preparation method |
| CN106478597A (en) * | 2015-09-02 | 2017-03-08 | 中美华世通生物医药科技（武汉）有限公司 | Vonoprazan fumarate monocrystalline and its production and use |
| 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 |
| 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 |
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| CN106478597A (en) * | 2015-09-02 | 2017-03-08 | 中美华世通生物医药科技（武汉）有限公司 | Vonoprazan fumarate monocrystalline and its production and use |
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| CN105503828A (en) * | 2015-12-24 | 2016-04-20 | 北京康立生医药技术开发有限公司 | Preparation method of fumarate of pyrrole derivatives |
| CN106366071B (en) * | 2016-08-22 | 2019-05-07 | 山东金城医药集团股份有限公司 | The preparation method of Vonoprazan fumarate |
| CN106366071A (en) * | 2016-08-22 | 2017-02-01 | 山东金城医药股份有限公司 | Vonoprazan fumarate preparation method |
| 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 |
| 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 |
| 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 |
| CN110272409A (en) * | 2019-03-11 | 2019-09-24 | 南京百迪尔生物医药有限公司 | The new method of one-step synthesis method Wo Nuolazan |
| CN115124506A (en) * | 2021-03-25 | 2022-09-30 | 广州白云山天心制药股份有限公司 | Preparation method of medicine for digestive system |
| CN115124506B (en) * | 2021-03-25 | 2024-04-09 | 广州白云山天心制药股份有限公司 | Preparation method of digestive system medicine |
| CN114573560A (en) * | 2022-03-17 | 2022-06-03 | 日照正济药业有限公司 | Preparation method of Voranolan fumarate |
| CN114573560B (en) * | 2022-03-17 | 2024-02-06 | 日照正济药业有限公司 | Preparation method of voronoi fumarate |
| CN115232107A (en) * | 2022-07-29 | 2022-10-25 | 南京唯创远医药科技有限公司 | Preparation method of high-purity Voranolan fumarate |
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