CN108191829B - Method for preparing Vonoprazan fumarate by using Vonoprazan fumarate intermediate IV - Google Patents
Method for preparing Vonoprazan fumarate by using Vonoprazan fumarate intermediate IV Download PDFInfo
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- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a method for preparing vonoprazan fumarate by using the intermediate IV of vonoprazan fumarate, which has the following beneficial effects that: the process route has the advantages of short reaction steps, easily obtained raw materials, mild reaction conditions, simple and easy operation, economy, environmental protection, obviously improved total yield and suitability for large-scale production.
Description
The application is a divisional application of Chinese patent application with the application number of 201610510427.5, the application date of 2016, 6 and 30, and the name of 'Vonoprazan fumarate intermediate, a preparation method thereof and a method for preparing Vonoprazan fumarate'.
Technical Field
The invention belongs to the field of vonoprazan fumarate synthesis, and particularly relates to a method for preparing vonoprazan fumarate by using a vonoprazan fumarate intermediate IV.
Background
Vonoprazan fumarate (TAK-438, Vonoprazan fumarate) is a potassium ion (K)+) A novel gastric acid secretion inhibitor of competitive acid blockers can stop gastric acid secretion in advance by inhibiting the binding of K to H-K-ATP enzyme (proton pump) in the last step of gastric acid secretion in gastric parietal cells, and has strong and lasting gastric acid secretion inhibition effect. Clinically used for treating duodenal ulcer, gastric ulcer and reflux esophagitis, gastric ulcer caused by low-dose aspirin or recurrent duodenal ulcer; eradicating helicobacter pylori, and assisting in treating the following diseases: gastric ulcer and duodenal ulcerUlcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, early stage gastric cancer, and gastritis infected by helicobacter pylori. The chemical name is 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine fumarate (1:1), and the structural formula is as follows:
the currently reported synthetic routes of vonoprazan fumarate include the following:
the reaction formula of the synthetic route reported in patent CN200680040789.7 is as follows:
the method has the disadvantages of complicated operation, low-temperature reaction (-78 ℃), low palladium-carbon reduction yield (18%) in the fourth step, expensive catalyst tetra-n-butyl ruthenium peroxide used for oxidizing alcohol into aldehyde, difficult reaction control, and multi-step column purification, and is not favorable for industrial production.
The reaction formula of the synthetic route reported in patent CN201080018114.9 is as follows:
the method has the advantages of longer route, complex operation, low yield and no contribution to industrial safety production, and two-step catalytic hydrogenation reaction is adopted.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a vonoprazan fumarate intermediate, a preparation method thereof and a method for preparing the vonoprazan fumarate intermediate.
The specific technical scheme of the invention is as follows:
the invention provides a Vonoprazan fumarate intermediate, which has the following structure:
wherein R is1Is H or oxo; r2Is H or pyridine-3-sulfonyl;
when R is1Is oxo, R2When the intermediate is H, the intermediate is Vonoprazan fumarate intermediate II;
when R is1Is H, R2When the intermediate is H, the intermediate is Vonoprazan fumarate intermediate III;
when R is1Is oxo, R2In the case of pyridine-3-sulfonyl, the intermediate IV of vonoprazan fumarate is obtained.
The Vonoprazan fumarate intermediate provided by the invention is used for preparing Vonoprazan fumarate, has mild conditions and high yield, and is suitable for large-scale industrial production.
The invention further provides a preparation method of the intermediate of the vonoprazan fumarate, and the specific scheme is as follows.
A preparation method of a Vonoprazan fumarate intermediate II comprises the following steps: introducing hydrogen into the intermediate I of the Vonoprazan fumarate in an organic inert solvent under the action of a catalyst, an organic acid and a water removing agent, and reacting to obtain an intermediate II of the Vonoprazan fumarate;
preferably, the organic inert solvent is tetrahydrofuran;
preferably, the catalyst is palladium on carbon;
preferably, the organic acid is formic acid or acetic acid;
preferably, the water removing agent is a molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and preferably, the water removing agent is anhydrous sodium sulfate.
Preferably, the palladium on carbon in the above reaction is preferably palladium on carbon with a palladium content of 5%, and the amount of the palladium on carbon used per 1mol of the vonoprazan fumarate intermediate I is about 0.001 to 10mol, preferably 0.01 to 5 mol; the amount of the organic inert solvent used per 1g of the intermediate I of vonoprazan fumarate is about 1 to 1000mL, preferably, 3 to 30 mL; the amount of the organic acid used per 1mol of the intermediate I of vonoprazan fumarate is about 0.01 to 100mol, preferably, 0.1 to 50 mol; the amount of the water scavenger used per 1mol of the vonoprazan fumarate intermediate I is about 0.01 to 100mol, preferably, 0.1 to 50 mol; the hydrogen pressure for the above reaction is about 0 to 10atm, preferably, 1 to 3 atm. The temperature of the above reaction is about-10 to 100 deg.C, preferably, 10 to 50 deg.C; the reaction time is about 0.5 to 24 hours, preferably 1 to 10 hours.
A preparation method of a vonoprazan fumarate intermediate III comprises the following steps: in an aprotic organic inert solvent, carrying out a reduction reaction on the Vonoprazan fumarate intermediate II under the action of a reducing agent system to prepare a Vonoprazan fumarate intermediate III;
preferably, the reducing agent system is selected from the group consisting of metal borohydride reducing agents, AlH3、LiAlH4Diborane, diisobutylaluminum hydride, borane, or an organosilicon reducing agent; preferably, the reducing agent system is a metal borohydride reducing agent selected from metal borohydride/iodine, metal borohydride/boron trifluoride, metal borohydride/trifluoroacetic acid, metal borohydride/trifluoromethanesulfonic anhydride, metal borohydride/trimethylchlorosilane, or metal borohydride/phosphorus oxychloride; preferably, the reducing agent system is sodium borohydride/boron trifluoride or sodium borohydride/iodine;
preferably, the aprotic organic inert solvent is selected from ethers, ether and alcohol complex solvents or dimethyl sulfoxide, and preferably, the aprotic organic inert solvent is tetrahydrofuran.
Preferably, in the above reaction, the molar ratio of the two substances in the metal borohydride reducing agent system can be any ratio; the reducing agent system used per 1mol of the intermediate II of Vonoprazan fumarate can provide about 2.0 to 20mol, preferably, 5.0 to 10mol of hydrogen, and the amount of the aprotic organic inert solvent used per 1g of the intermediate II of Vonoprazan fumarate is about 1 to 100mL, preferably, 3 to 50 mL; the reaction temperature is about-50 to 100 ℃, preferably-20 to 50 ℃; the reaction time is about 0.5 to 24 hours, preferably 1 to 10 hours.
A preparation method of a vonoprazan fumarate intermediate IV comprises the following steps: in an organic inert solvent, carrying out sulfonylation reaction on the Vonoprazan fumarate intermediate II and pyridine-3-sulfonyl chloride under the catalysis of alkali to obtain a Vonoprazan fumarate intermediate IV;
preferably, the organic inert solvent is tetrahydrofuran or acetonitrile;
preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, pyridine, lutidine, triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine;
preferably, the base is sodium hydride or 4-N, N-dimethylaminopyridine.
Preferably, the amount of pyridine-3-sulfonyl chloride used in the above reaction is about 1 to 10mol, preferably, 1 to 5mol, per 1mol of vonoprazan fumarate intermediate ii; the amount of the organic inert solvent used per 1g of the intermediate II of vonoprazan fumarate is about 1-1000mL, preferably, 3-50 mL; the amount of the base used per 1mol of the intermediate II of Vonoprazan fumarate is about 0.01 to 10mol, preferably, 0.1 to 5 mol; the temperature of the above reaction is about 0 to 100 deg.C, preferably, 10 to 50 deg.C; the reaction time is about 0.5 to 24 hours, preferably 1 to 8 hours.
In a further improvement, the intermediate II of the vonoprazan fumarate can be added with crown ether during the reaction for preparing the intermediate IV of the vonoprazan fumarate, and the crown ether can be selected from 15-crown-5-ether, 18-crown-6-ether and the like; the amount of the crown ether used per 1mol of the vonoprazan fumarate intermediate II is about 1 to 10mol, preferably, 1 to 5 mol.
A preparation method of vonoprazan fumarate intermediate V comprises the following steps: in an organic inert solvent, carrying out sulfonylation reaction on the Vonoprazan fumarate intermediate III and pyridine-3-sulfonyl chloride under the catalysis of alkali to prepare a Vonoprazan fumarate intermediate V;
preferably, the organic inert solvent is tetrahydrofuran or acetonitrile;
preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, pyridine, lutidine, triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine;
preferably, the base is sodium hydride or 4-N, N-dimethylaminopyridine.
The invention also provides the intermediate of the vonoprazan fumarate, which is mainly applied to the preparation of the vonoprazan fumarate.
The invention also provides a method for preparing the vonoprazan fumarate by using the intermediate of the vonoprazan fumarate, and the specific scheme is as follows:
a method for preparing vonoprazan fumarate by using a vonoprazan fumarate intermediate IV comprises the following steps: in an aprotic organic inert solvent, carrying out a reduction reaction on the intermediate IV of the Vonoprazan fumarate under the action of a reducing agent system, and salifying to obtain the Vonoprazan fumarate;
in a further refinement, the reducing agent system is selected from a metal borohydride reducing agent, diborane, borane, or an organosilicon reducing agent;
preferably, the reducing agent system is a metal borohydride reducing agent selected from metal borohydride/iodine, metal borohydride/boron trifluoride, metal borohydride/trifluoroacetic acid, metal borohydride/trifluoromethanesulfonic anhydride, metal borohydride/trimethylchlorosilane, or metal borohydride/phosphorus oxychloride;
preferably, the reducing agent system is sodium borohydride/boron trifluoride or sodium borohydride/iodine.
In a further improvement, the aprotic organic inert solvent is selected from ethers, ether and alcohol complex solvents or dimethyl sulfoxide, and preferably, the aprotic organic inert solvent is tetrahydrofuran.
Preferably, the reducing agent system used in the above reaction can provide hydrogen in an amount of about 2.0 to 20mol, preferably, 5.0 to 10mol, per 1mol of the vonoprazan fumarate intermediate iv; the amount of aprotic organic inert employed per 1g of vonoprazan fumarate intermediate iv is about 1 to 100mL, preferably, about 3 to 50 mL; the above reaction temperature is about-50 to 100 deg.C, preferably, about-20 to 50 deg.C; the reaction time is about 0.5 to 24 hours, preferably 1 to 10 hours.
In a further improvement, the intermediate IV of the vonoprazan fumarate for preparing the vonoprazan fumarate is prepared by the following method: in an organic inert solvent, carrying out sulfonylation reaction on the Vonoprazan fumarate intermediate II and pyridine-3-sulfonyl chloride under the catalysis of alkali to obtain a Vonoprazan fumarate intermediate IV;
preferably, the organic inert solvent is tetrahydrofuran or acetonitrile;
preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium chloride, potassium chloride, sodium chloride,
Potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, pyridine, lutidine, triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine;
preferably, the base is sodium hydride or 4-N, N-dimethylaminopyridine.
In a further improvement, the intermediate II of the vonoprazan fumarate for preparing the intermediate IV of the vonoprazan fumarate is prepared by the following method: introducing hydrogen into the intermediate I of the Vonoprazan fumarate in an organic inert solvent under the action of a catalyst, an organic acid and a water removing agent, and reacting to obtain an intermediate II of the Vonoprazan fumarate;
preferably, the organic inert solvent is tetrahydrofuran;
preferably, the catalyst is palladium on carbon;
preferably, the organic acid is formic acid or acetic acid;
preferably, the water removing agent is a molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and preferably, the water removing agent is anhydrous sodium sulfate.
A method for preparing vonoprazan fumarate by using a vonoprazan fumarate intermediate III, which comprises the following steps: in an organic inert solvent, carrying out sulfonylation reaction on the intermediate III of the Vonoprazan fumarate and pyridine-3-sulfonyl chloride under the catalysis of alkali to obtain the Vonoprazan fumarate;
preferably, the organic inert solvent is tetrahydrofuran or acetonitrile;
preferably, the base is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, pyridine, lutidine, triethylamine, diisopropylethylamine, 4-N, N-dimethylaminopyridine;
preferably, the base is diisopropylethylamine or 4-N, N-dimethylaminopyridine.
Preferably, the amount of pyridine-3-sulfonyl chloride used in the above reaction is about 1 to 10mol, preferably, 1 to 5mol, per 1mol of vonoprazan fumarate intermediate iii; the amount of the organic inert solvent used per 1g of the intermediate of vonoprazan fumarate III is about 1-1000mL, preferably, 3-50 mL; the amount of the base used per 1mol of the intermediate of vonoprazan fumarate iii is about 0.01 to 10mol, preferably, 0.1 to 5 mol; the temperature of the above reaction is about 0 to 100 deg.C, preferably, 10 to 50 deg.C; the reaction time is about 0.5 to 24 hours, preferably 1 to 8 hours.
In a further improvement, the intermediate III of the vonoprazan fumarate can be added with crown ether during the reaction for preparing the vonoprazan fumarate, and the crown ether can be selected from 15-crown-5-ether, 18-crown-6-ether and the like; the amount of the crown ether used per 1mol of the vonoprazan fumarate intermediate II is about 1 to 10mol, preferably, 1 to 5 mol.
The total process route for preparing the vonoprazan fumarate by using the intermediate of the vonoprazan fumarate provided by the invention is as follows:
compared with the prior art, the method for preparing the vonoprazan fumarate by using the intermediate of the vonoprazan fumarate has the following beneficial effects: the process route has the advantages of short reaction steps, easily obtained raw materials, mild reaction conditions, simple and easy operation, economy, environmental protection, obviously improved total yield and suitability for large-scale production.
Detailed Description
Reference example 1N-methyl-2-cyano-4- (2-fluorophenyl) -4-oxobutanamide (Vonoprazan fumarate intermediate I)
The structure is as follows:
the intermediate I of the vonoprazan fumarate is prepared by the following method:
adding 95g of o-fluoro acetophenone and 500mL of ethyl acetate into a dry 2000mL three-necked bottle, slowly dropwise adding a mixed solution of 120g of bromine and 300mL of ethyl acetate at the temperature of 25 ℃ while stirring, and controlling the temperature not to exceed 35 ℃ after dropwise adding for 1 h; after the dropwise adding, keeping the temperature at 25 ℃ for 1.5h, and then dropwise adding a 3% anhydrous sodium sulfite solution; after the addition, the temperature is kept for 1.5h at 25 ℃; adjusting pH to 7 with sodium bicarbonate, then separating the layers, washing the organic phase with saturated saline for 2 times, each time 100 mL; obtaining a 2-bromo-1- (2-fluorophenyl) ethyl acetate solution of the ethyl acetate;
cooling the obtained ethyl 2-bromo-1- (2-fluorophenyl) ethanoate solution at the temperature of below 5 ℃, adding 50g of N-methyl-2-cyanoacetamide, stirring, dropwise adding 100g of N, N-diisopropylethylamine at the temperature of below 10 ℃, reacting for 2.5h at the temperature of 5-10 ℃, adding 1N hydrochloric acid to adjust the pH to be 4-5, starting reduced pressure distillation, carrying out external temperature of 35 ℃, distilling until no distillate flows out, and supplementing 150mL of methanol, and evaporating to dryness under reduced pressure; adding 200mL of methanol and 40mL of water into the residue, stirring and heating to 55 ℃, stirring for 1h, naturally cooling to about 25 ℃, then continuously cooling to 0-5 ℃, stirring for 1h, filtering, washing with a mixed solution of methanol and water, and drying by air blast to obtain about 100g of Vonoprazan fumarate intermediate I.
EXAMPLE 1N-methyl-5- (2-fluorophenyl) -1H-pyrrole-3-carboxamide (Vonoprazan fumarate intermediate II)
The structure is as follows:
the preparation method of the Vonoprazan fumarate intermediate II comprises the following steps:
sequentially adding 10g of Vonoprazan fumarate intermediate I and 300mL of tetrahydrofuran into a dry 10L three-necked bottle, adding 1g of palladium-carbon with the content of 5% under stirring, and then adding 300mL of glacial acetic acid and 2g of anhydrous sodium sulfate; continuously replacing for 3 times by nitrogen, then continuously replacing for 3 times by hydrogen, starting timing and adding hydrogen, wherein the reaction temperature is 20-35 ℃; after the detection reaction is finished, replacing hydrogen with nitrogen for 4 times, then filtering, cooling the filtrate to below 10 ℃, dropwise adding 150mL of water, filtering, collecting a filter cake, and drying to obtain 7.2g of Vonoprazan fumarate intermediate II, wherein the yield is as follows: 77.3 percent;1H-NMR(400MHZ，DMSO-d6) δ (ppm): 2.81(s, 3H), 6.38-7.06(s, 2H), 7.10-7.63(m, 4H), 7.89(m, 1H), 1H were not detected.
EXAMPLE 2N-methyl-1- [5- (2-fluorophenyl) -1H-pyrrol-3-yl ] -N-methylamine (Vonoprazan fumarate intermediate III)
The structure is as follows:
the preparation method of the intermediate III of the vonoprazan fumarate comprises the following steps:
dissolving 43g of iodine in 70mL of tetrahydrofuran to prepare a solution; adding 110mL of tetrahydrofuran and 22.5g of Vonoprazan fumarate intermediate II into a reaction bottle, introducing nitrogen for replacement, stirring, and cooling; adding 14g of sodium borohydride in batches, controlling the temperature to be-5-15 ℃, dropwise adding a tetrahydrofuran solution of iodine, controlling the system temperature to be-5-15 ℃, after dropwise adding, heating to 15-25 ℃, and stirring for 1-1.5 h; heating to 55-65 ℃, carrying out heat preservation reaction for 3h, cooling to-5-5 ℃, dropwise adding 4N hydrochloric acid 50mL to quench reaction, and controlling the temperature to-5-20 ℃; heating the system to 35-45 ℃ and stirring for 0.5-1 h; concentrating tetrahydrofuran at 35-45 deg.C under reduced pressure to obtain concentrate; adding 100mL of purified water and 100mL of ethyl acetate into the concentrate, controlling the temperature to be 10-20 ℃, dropwise adding a 30% sodium hydroxide solution, adjusting the pH to be 11-12, separating an organic phase, extracting a water phase by using 50mL of ethyl acetate, combining ethyl acetate layers, drying the ethyl acetate layers by using anhydrous sodium sulfate, carrying out suction filtration, washing a filter cake by using ethyl acetate, and concentrating the filtrate at 45-50 ℃ under reduced pressure to obtain 17.5g of oily matter with the yield of 83.2%.
EXAMPLE 3N-methyl-5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxamide (Vonoprazan fumarate intermediate IV)
The structure is as follows:
the preparation method of the intermediate IV of the vonoprazan fumarate is as follows:
respectively adding 10g of Vonoprazan fumarate intermediate II and 350mL of tetrahydrofuran into a dry 1L three-necked bottle, stirring and cooling to below 10 ℃, adding 6.5g of sodium hydride under the protection of nitrogen, then adding 25g of 15-crown ether-5, stirring and cooling to below 10 ℃, dropwise adding 100mL of tetrahydrofuran solution containing 18g of 3-pyridine sulfonyl chloride, controlling the temperature to be 5-10 ℃ after dropwise adding, reacting for 2 hours, heating to 20-25 ℃, keeping the temperature for 30 minutes, dropwise adding water under the protection of nitrogen for quenching, pouring 300mL of water when no bubbles are generated, stirring for 10 minutes, adjusting the pH to 4 by using 1N hydrochloric acid, stirring to below 10 ℃ for solidification, carrying out suction filtration, leaching by using acetonitrile water mixed solution (1:1), pumping, drying at 50 ℃, and drying under reduced pressure to obtain 11g of light yellow to red solid powder, wherein the yield is 66.7%;
1H-NMR(400MHZ，DMSO-d6) δ (ppm): 2.92(s, 3H), 6.65-7.24(s, 2H), 7.03-7.15(m, 3H), 7.28-7.40(m, 1H), 7.54-7.61(m, 1H), 7.76-7.82(m, 1H), 8.36-8.43(m, 1H), 8.60-8.62(m, 1H), 1H were not detected.
Example 4 preparation of Vonoprazan fumarate
Adding 30g of vonoprazan fumarate intermediate IV, 11.5g of sodium borohydride and 120mL of tetrahydrofuran into a 500L reaction bottle in sequence, stirring and dropwise adding 57g of boron trifluoride tetrahydrofuran complex solution at room temperature, controlling the temperature to 50 +/-5 ℃ for reaction after dropwise adding, monitoring the reaction process by TLC after about 2h until raw material spots disappear, adding the reaction solution into 200L of water after reaction, slowly adding 200mL of concentrated hydrochloric acid, controlling the temperature to 50 +/-5 ℃ for reaction for about 2h until the complex acid is completely hydrolyzed, controlling the temperature below 50 ℃ for vacuum distillation to remove tetrahydrofuran, transferring the residue into a 2000mL reaction bottle, sequentially adding 250mL of ethyl acetate and 250mL of water, cooling and controlling the temperature below 10 ℃ for dropwise adding about 40% of NaOH solution until the pH value is 9-10, controlling the temperature to 5 +/-5 ℃ for stirring reaction for 30min, standing for liquid separation, collecting an ethyl acetate layer, extracting a water layer by using 200mL of × 2 ethyl acetate, combining the ethyl acetate layer, washing by using × 3 mL of 10% sodium chloride solution with 200 +/-5%, washing the ethyl acetate layer by vacuum distillation for 30min, cooling and filtering, cooling the ethyl acetate layer, cooling and drying the residue to obtain a residual liquid, heating the residue, drying the residue by using 200.5 mL of acetic acid, cooling and filtering the residue, cooling the residue to obtain a residue, cooling the residue to obtain a residue, and filtering the residue, and dissolving the residue after cooling;
1H-NMR(400MHZ，DMSO-d6)δ(ppm)：2.45(s，3H)，3.89(s，2H)，6.48(s，2H) 6.50(d, 1H), 7.08-7.12(m, 1H), 7.20-7.25(m, 2H), 7.50-7.55(dd, 1H), 7.60-7.63(dd, 1H), 7.76(d, 1H), 7.87-7.90(dd, 1H), 8.56-8.60(d, 1H), 8.87-8.89(dd, 1H), 10.86-10.89(s, 2H), 1H were not detected.
Example 5 preparation of Vonoprazan fumarate
Adding 23.4g of Vonoprazan fumarate intermediate I and 468mL of tetrahydrofuran in sequence into a dry 10L three-necked bottle, adding 0.59g of palladium-carbon with the content of 5% under stirring, and then adding 13.2g of glacial acetic acid and 9.94g of anhydrous magnesium sulfate; continuously replacing for 3 times by nitrogen, then continuously replacing for 3 times by hydrogen, starting timing and adding hydrogen, wherein the reaction temperature is 25 ℃; after the detection reaction is finished, replacing hydrogen with nitrogen for 4 times, then filtering, cooling the filtrate to below 10 ℃, dropwise adding 150mL of water, filtering, collecting a filter cake, and drying to obtain 7.4g of Vonoprazan fumarate intermediate II, wherein the yield is as follows: 79.6 percent;
21.8g of Vonoprazan fumarate intermediate II and 436mL of acetonitrile are respectively added into a dry 1L three-necked flask, the temperature is reduced to below 10 ℃ by stirring, 18.9g of 4-N, N-dimethylaminopyridine is added under the protection of nitrogen, then adding 36g of 15-crown ether-5, stirring, cooling to below 10 ℃, dropwise adding 100mL of tetrahydrofuran solution containing 38.9g of 3-pyridine sulfonyl chloride, controlling the temperature to be 5-10 ℃ after dropwise adding, reacting for 2h, heating to 20-25 ℃, keeping the temperature for 30min, dropwise adding water under the protection of nitrogen to quench, when no bubbles are generated, pouring 300mL of water, stirring for 10min, adjusting the pH value to be 4 by using 1N hydrochloric acid, stirring until the mixture is solidified at the temperature below 10 ℃, carrying out suction filtration, carrying out drip washing by using acetonitrile water mixed liquor (1:1), carrying out suction drying, and carrying out reduced pressure drying at the temperature of 50 ℃ to obtain a Vonoprazan fumarate intermediate IV, wherein the yield is 69%;
adding 35.9g of vonoprazan fumarate intermediate IV, 10.8g of sodium borohydride and 718mL of tetrahydrofuran into a 500L reaction flask in sequence, stirring and dropwise adding 68g of boron trifluoride tetrahydrofuran complex solution at room temperature, controlling the temperature to be 50 +/-5 ℃ for reaction after dropwise adding, monitoring the reaction process by TLC after about 2 hours until the raw material spots disappear, after the reaction is finished, adding the reaction liquid into 200L of water, then slowly adding 200mL of concentrated hydrochloric acid, controlling the temperature to be 50 +/-5 ℃ for reaction for about 2 hours until the complex acid is completely hydrolyzed, controlling the temperature to be below 50 ℃ for vacuum evaporation to remove the tetrahydrofuran, transferring the residue into a 2000mL reaction flask, sequentially adding 250mL of ethyl acetate and 250mL of water, cooling and controlling the temperature to be below 10 ℃ and dropwise adding about 40% of NaOH solution until the pH value is 9-10, controlling the temperature to be 5 +/-5 ℃ for reaction for 30 minutes, standing, separating, collecting an ethyl acetate layer, extracting a water layer by using 200mL of × 2 ethyl acetate, combining the ethyl acetate layer, washing by using 50mL of × 3% sodium chloride solution with 200 +/-5 ℃, washing by distillation for 30 minutes, cooling, filtering a residual liquid containing 50.45% of acetic acid, keeping the temperature, drying the residual liquid containing 50.7-15% of ethyl acetate, and filtering to obtain a residual liquid containing 50.15% of a white residue, and obtaining a finished product with 10.15% yield of a finished product, and a finished product with a finished product.
Experimental example 1 for examining yield of intermediate and yield of vonoprazan fumarate in each experimental procedure
The influence of different organic inert solvents, catalysts, organic acids, water removal agents and the like on the yield of the vonoprazan fumarate intermediate II is examined, the rest preparation methods are the same as example 1, and the examination results are shown in table 1.
TABLE 1 results of the influence of different reaction factors on the yield of Vonoprazan fumarate intermediate II
As can be seen from table 1, the selection of different organic inert solvents, different organic acids, different contents of palladium and carbon, and a water removal agent has a significant effect on the yield of the voronoazan fumarate intermediate ii, and when the influence on the yield of the voronoazan fumarate intermediate ii is that tetrahydrofuran is used as the organic inert solvent, palladium and carbon with a content of 5% is used as the catalyst, glacial acetic acid is used as the organic acid, and anhydrous sodium sulfate is used as the water removal agent, the yield of the voronoazan fumarate intermediate ii can reach above 77%.
Test example 2
The influence of different organic inert solvents, bases, reaction conditions and the like on the yield of the intermediate IV of vonoprazan fumarate is examined, the rest preparation methods are the same as example 3, and the examination results are shown in table 2.
TABLE 2 influence of different reaction factors on yield of Vonoprazan fumarate intermediate IV
As can be seen from Table 2, the selection of different organic inert solvents, different bases and the amount of pyridine-3-sulfonyl chloride has a significant effect on the yield of Vonoprazan fumarate intermediate IV.
Test example 3
The influence of different aprotic organic inert solvents, reducing agent systems, reaction conditions and the like on the yield of vonoprazan fumarate is examined, the rest of the preparation methods are the same as example 4, and the examination results are shown in table 3.
TABLE 3 influence of different reaction factors on the yield of Vonoprazan fumarate
As can be seen from table 3, the present invention selects different aprotic organic inert solvents, different reducing agent systems, and has a significant effect on the yield of vonoprazan fumarate.
Claims (1)
1. A method for preparing vonoprazan fumarate by using a vonoprazan fumarate intermediate IV, which is characterized by comprising the following steps: in an aprotic organic inert solvent, carrying out a reduction reaction on the intermediate IV of the Vonoprazan fumarate under the action of a reducing agent system, and salifying to obtain the Vonoprazan fumarate;
the reducing agent system is sodium borohydride/boron trifluoride or sodium borohydride/iodine; the aprotic organic inert solvent is tetrahydrofuran.
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