CN106146466A - Vonoprazan fumarate intermediate, its preparation method and the method for preparation Vonoprazan fumarate - Google Patents

Vonoprazan fumarate intermediate, its preparation method and the method for preparation Vonoprazan fumarate Download PDF

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Publication number
CN106146466A
CN106146466A CN201610510427.5A CN201610510427A CN106146466A CN 106146466 A CN106146466 A CN 106146466A CN 201610510427 A CN201610510427 A CN 201610510427A CN 106146466 A CN106146466 A CN 106146466A
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Prior art keywords
vonoprazan fumarate
reducing agent
inert solvent
fumarate intermediate
sodium
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李剑峰
李海超
周文
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Zhuhai Siaion Pharmaceutical Ltd By Share Ltd (changsha) R & D Center
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Zhuhai Siaion Pharmaceutical Ltd By Share Ltd (changsha) R & D Center
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Priority to CN201810016539.4A priority Critical patent/CN108191829B/en
Priority to CN201610510427.5A priority patent/CN106146466A/en
Priority to CN201810016540.7A priority patent/CN108191830B/en
Publication of CN106146466A publication Critical patent/CN106146466A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/30—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
    • 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
    • C07D207/33—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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/30—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
    • C07D207/34—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Abstract

The present invention provides a kind of Vonoprazan fumarate intermediate, its preparation method and it is for the method preparing Vonoprazan fumarate intermediate, compared with prior art, Vonoprazan fumarate is prepared by Vonoprazan fumarate intermediate, having the advantages that this process route reactions steps is short, raw material easily obtains, and reaction condition is gentle, operation is simple, economic and environment-friendly, total recovery significantly improves, and is suitable for large-scale production.

Description

Vonoprazan fumarate intermediate, its preparation method and preparation Vonoprazan fumarate Method
Technical field
The invention belongs to Vonoprazan fumarate synthesis field, particularly to a kind of Vonoprazan fumarate intermediate, its Preparation method and the method for preparation Vonoprazan fumarate.
Background technology
Vonoprazan fumarate (TAK-438, Vonoprazan fumarate) is that one belongs to potassium ion (K+) competitive The new class gastric acid secretion inhibitor of acid blocker, it is possible in the final step of parietal cell gastric acid secretion, by suppression K pair The combination of H-K-ATP enzyme (proton pump), terminates the secretion of gastric acid in advance, has powerful, lasting gastric acid secretion inhibiting and makees With.It is used for clinically treating duodenal ulcer, gastric ulcer and reflux esophagitis, the gastric ulcer that low-dosage aspirin causes Or recurrent duodenal ulcer；Eradicate helicobacter pylori, the auxiliary following disease for the treatment of: gastric ulcer, duodenal ulcer, stomach MALT lymphoma, idiopathic thrombocytopenic purpura, early gastric cancer, HP infected gastritis.Its chemistry is entitled 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-methylamine fumarate (1:1), its structural formula is such as Under:
The synthetic route of the Vonoprazan fumarate of report has following several at present:
The synthetic route reaction equation of patent CN200680040789.7 report is as follows:
This route complex operation, needs low-temp reaction (-78 DEG C), and the 4th step palladium carbon reduction yield relatively low (18%), alcohol Being oxidized to aldehyde and also use the catalyst tetra-n-butyl peroxidating ruthenium of costliness, and reaction is not easy to control, multistep used post to purify, It is unfavorable for industrialized production.
The synthetic route reaction equation of patent CN201080018114.9 report is as follows:
This route is longer, complex operation, and uses two-step catalyzing hydrogenation reaction, and yield is low, is unfavorable for that industrialization is pacified Full production.
Summary of the invention
In order to overcome the deficiencies in the prior art, the present invention provides a kind of Vonoprazan fumarate intermediate, its preparation method With it for the method preparing Vonoprazan fumarate intermediate, this process route is simple, and reaction condition is gentle, is suitable for big Technical scale produces.
The concrete technical scheme of the present invention is as follows:
The present invention provides a kind of Vonoprazan fumarate intermediate, and its structure is as follows:
Wherein, R1For H or oxo；R2For H or pyridine-3-sulfonyl；
Work as R1For oxo, R2During for H, for Vonoprazan fumarate intermediate II；
Work as R1For H, R2During for H, for Vonoprazan fumarate intermediate III；
Work as R1For oxo, R2During for pyridine-3-sulfonyl, for Vonoprazan fumarate intermediate IV.
The Vonoprazan fumarate intermediate provided by the present invention prepares Vonoprazan fumarate mild condition, yield Height, is suitable for large-scale industrial production.
The present invention additionally provides the preparation method of Vonoprazan fumarate intermediate further, and concrete scheme is as follows.
The preparation method of a kind of Vonoprazan fumarate intermediate II, this preparation method comprises the steps: that fumaric acid is irrigated Nola praises intermediate compound I in organic inert solvent, under the effect of catalyst, organic acid and deicer, is passed through hydrogen, reaction system Obtain Vonoprazan fumarate intermediate II；
Preferably, described organic inert solvent is oxolane；
Preferably, described catalyst is palladium carbon；
Preferably, described organic acid is formic acid or acetic acid；
Preferably, described deicer is molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate etc., it is preferable that described deicer is Anhydrous sodium sulfate.
Preferably, in above-mentioned reaction, the preferred palladium content of palladium carbon is the palladium carbon of 5%, every 1mol Vonoprazan fumarate intermediate The amount of the palladium carbon that I is used is about 0.001-10mol, it is preferable that 0.01-5mol；Often 1g Vonoprazan fumarate intermediate compound I institute The amount of the organic inert solvent used is about 1-1000mL, it is preferable that 3-30mL；Every 1mol Vonoprazan fumarate intermediate compound I The amount of the organic acid used is about 0.01-100mol, it is preferable that 0.1-50mol；Every 1mol Vonoprazan fumarate intermediate The amount of the deicer that I is used is about 0.01-100mol, it is preferable that 0.1-50mol；The Hydrogen Vapor Pressure of above-mentioned reaction is about 0-10atm, it is preferable that 1-3atm.The temperature of above-mentioned reaction is about-10-100 DEG C, it is preferable that 10-50 DEG C；The time of above-mentioned reaction It is about 0.5-24h, it is preferable that 1-10h.
The preparation method of a kind of Vonoprazan fumarate intermediate III, this preparation method comprises the steps: non-proton In organic inert solvent, Vonoprazan fumarate intermediate II carries out reduction reaction, preparation richness under the effect of reducing agent system Horse acid Wo Nuolazan intermediate III；
Preferably, described reducing agent system is selected from metallic boron hydrides reducing agent, AlH3、LiAlH4Diborane, diisobutyl Aluminum hydride, borine or organosilicon reducing agent；Preferably, described reducing agent system is metallic boron hydrides reducing agent, described metal Borohydride reduction agent is selected from metallic boron hydrides/iodine, metallic boron hydrides/boron trifluoride, metallic boron hydrides/trifluoro second Acid, metallic boron hydrides/trifluoromethanesulfanhydride anhydride, metallic boron hydrides/trim,ethylchlorosilane or metallic boron hydrides/trichlorine oxygen Phosphorus；Preferably, described reducing agent system is sodium borohydride/boron trifluoride or sodium borohydride/iodine；
Preferably, described non-proton organic inert solvent is selected from ethers, ethers and alcohols double solvents or dimethyl sulfoxide, Preferably, described non-proton organic inert solvent is oxolane.
Preferably, in above-mentioned reaction, the mol ratio of two kinds of materials in metallic boron hydrides reducing agent system can be to appoint Meaning ratio；The reducing agent system that every 1mol Vonoprazan fumarate intermediate II is used can provide the amount of hydrogen to be about 2.0- 20mol, it is preferable that 5.0-10mol, the molten non-proton organic inert solvent that every 1g Vonoprazan fumarate intermediate II is used Amount is about 1-100mL, it is preferable that 3-50mL；Above-mentioned reaction temperature is about-50-100 DEG C, it is preferable that-20-50 DEG C；During reaction Between be about 0.5-24h, it is preferable that 1-10h.
The preparation method of a kind of Vonoprazan fumarate intermediate IV, this preparation method comprises the steps: organic lazy Property solvent in, under the catalysis of alkali, is there is sulfonylation in Vonoprazan fumarate intermediate II and pyridine-3-sulfonic acid chloride, makes Obtain Vonoprazan fumarate intermediate IV；
Preferably, described organic inert solvent is oxolane or acetonitrile；
Preferably, described alkali is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, the tert-butyl alcohol Sodium, Sodium ethylate, potassium ethoxide, Feldalat NM, Feldalat KM, pyridine, lutidines, triethylamine, diisopropanol ethamine, 4-N, N-diformazan Aminopyridine；
Preferably, described alkali is sodium hydride or DMAP.
Preferably, in above-mentioned reaction, the pyridine-3-sulfonic acid chloride that every 1mol Vonoprazan fumarate intermediate II is used Amount is about 1-10mol, it is preferable that 1-5mol；The organic inert solvent that every 1g Vonoprazan fumarate intermediate II is used Amount is about 1-1000mL, it is preferable that 3-50mL；The amount of the alkali that every 1mol Vonoprazan fumarate intermediate II is used is about 0.01-10mol, it is preferable that 0.1-5mol；The temperature of above-mentioned reaction is about 0-100 DEG C, it is preferable that 10-50 DEG C；During above-mentioned reaction Between be about 0.5-24h, it is preferable that 1-8h.
Further improve, Vonoprazan fumarate intermediate II prepare Vonoprazan fumarate intermediate IV time Waiting, can add crown ether in the reaction, this crown ether can select 15-crown-5-ether, 18-crown-6-ether etc.；Every 1mol fumaric acid The amount of the crown ether that Wo Nuolazan intermediate II is used is about 1-10mol, it is preferable that 1-5mol.
The preparation method of a kind of Vonoprazan fumarate intermediate V, this preparation method comprises the steps: organic lazy Property solvent in, under the catalysis of alkali, is there is sulfonylation in Vonoprazan fumarate intermediate III and pyridine-3-sulfonic acid chloride, makes Obtain Vonoprazan fumarate intermediate V；
Preferably, described organic inert solvent is oxolane or acetonitrile；
Preferably, described alkali is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, the tert-butyl alcohol Sodium, Sodium ethylate, potassium ethoxide, Feldalat NM, Feldalat KM, pyridine, lutidines, triethylamine, diisopropanol ethamine, 4-N, N-diformazan Aminopyridine；
Preferably, described alkali is sodium hydride or DMAP.
The Vonoprazan fumarate intermediate that another aspect of the present invention provides is mainly in preparation Vonoprazan fumarate Application.
Another aspect of the present invention additionally provides the side being prepared Vonoprazan fumarate by Vonoprazan fumarate intermediate Method, concrete scheme is as follows:
A kind of method applying Vonoprazan fumarate intermediate IV to prepare Vonoprazan fumarate, the method includes as follows Step: in non-proton organic inert solvent, Vonoprazan fumarate intermediate IV is carried out also under the effect of reducing agent system Former reaction, becomes salt to prepare Vonoprazan fumarate；
Further improving, described reducing agent system is selected from metallic boron hydrides reducing agent, diborane, borine or organosilicon Reducing agent；
Preferably, described reducing agent system is metallic boron hydrides reducing agent, and described metallic boron hydrides reducing agent is selected from Metallic boron hydrides/iodine, metallic boron hydrides/boron trifluoride, metallic boron hydrides/trifluoroacetic acid, metallic boron hydrides/trifluoro Methanesulfonic acid acid anhydride, metallic boron hydrides/trim,ethylchlorosilane or metallic boron hydrides/phosphorus oxychloride；
Preferably, described reducing agent system is sodium borohydride/boron trifluoride or sodium borohydride/iodine.
Further improving, non-proton organic inert solvent is sub-with alcohols double solvents or dimethyl selected from ethers, ethers Sulfone, it is preferable that described non-proton organic inert solvent is oxolane.
Preferably, in above-mentioned reaction, the reducing agent system that every 1mol Vonoprazan fumarate intermediate IV is used can carry The amount of hydrogen supply is about 2.0-20mol, it is preferable that 5.0-10mol；The non-matter that every 1g Vonoprazan fumarate intermediate IV is used The amount of sub-organic inert is about 1-100mL, it is preferable that about 3-50mL；Above-mentioned reaction temperature is about-50-100 DEG C, it is preferable that About-20-50 DEG C；Response time is about 0.5-24h, it is preferable that 1-10h.
Further improving, the Vonoprazan fumarate intermediate IV of preparation Vonoprazan fumarate is by the following method Prepare: in organic inert solvent, by Vonoprazan fumarate intermediate II and pyridine-3-sulfonic acid chloride in the catalysis of alkali Lower generation sulfonylation, prepares Vonoprazan fumarate intermediate IV；
Preferably, described organic inert solvent is oxolane or acetonitrile；
Preferably, described alkali is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, the tert-butyl alcohol Sodium, Sodium ethylate, potassium ethoxide, Feldalat NM, Feldalat KM, pyridine, lutidines, triethylamine, diisopropanol ethamine, 4-N, N-diformazan Aminopyridine；
Preferably, described alkali is sodium hydride or DMAP.
Further improving, the Vonoprazan fumarate intermediate II of preparation Vonoprazan fumarate intermediate IV is to pass through Following method prepares: Vonoprazan fumarate intermediate compound I is in organic inert solvent, at catalyst, organic acid with remove Under the effect of water preparation, being passed through hydrogen, reaction prepares Vonoprazan fumarate intermediate II；
Preferably, described organic inert solvent is oxolane；
Preferably, described catalyst is palladium carbon；
Preferably, described organic acid is formic acid or acetic acid；
Preferably, described deicer is molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate etc., it is preferable that described deicer is Anhydrous sodium sulfate.
A kind of method applying Vonoprazan fumarate intermediate III to prepare Vonoprazan fumarate, the method includes as follows Step: in organic inert solvent, occurs Vonoprazan fumarate intermediate III and pyridine-3-sulfonic acid chloride under the catalysis of alkali Sulfonylation, becomes salt to prepare Vonoprazan fumarate；
Preferably, described organic inert solvent is oxolane or acetonitrile；
Preferably, described alkali is sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, the tert-butyl alcohol Sodium, Sodium ethylate, potassium ethoxide, Feldalat NM, Feldalat KM, pyridine, lutidines, triethylamine, diisopropanol ethamine, 4-N, N-diformazan Aminopyridine；
Preferably, described alkali is diisopropylethylamine or DMAP.
Preferably, in above-mentioned reaction, the pyridine-3-sulfonic acid chloride that every 1mol Vonoprazan fumarate intermediate III is used Amount is about 1-10mol, it is preferable that 1-5mol；The organic inert solvent that every 1g Vonoprazan fumarate intermediate III is used Amount is about 1-1000mL, it is preferable that 3-50mL；The amount of the alkali that every 1mol Vonoprazan fumarate intermediate III is used is about 0.01-10mol, it is preferable that 0.1-5mol；The temperature of above-mentioned reaction is about 0-100 DEG C, it is preferable that 10-50 DEG C；During above-mentioned reaction Between be about 0.5-24h, it is preferable that 1-8h.
Further improve, Vonoprazan fumarate intermediate III preparing Vonoprazan fumarate when, Ke Yi Adding crown ether in reaction, this crown ether can select 15-crown-5-ether, 18-crown-6-ether etc.；In every 1mol Vonoprazan fumarate The amount of the crown ether that mesosome II is used is about 1-10mol, it is preferable that 1-5mol.
The Vonoprazan fumarate intermediate utilizing the present invention to provide prepares the overall process route of Vonoprazan fumarate such as Under:
The present invention utilizes the method that Vonoprazan fumarate intermediate prepares Vonoprazan fumarate, with prior art phase Ratio, has the advantages that this process route reactions steps is short, and raw material easily obtains, and reaction condition is gentle, simple to operate easily OK, economic and environment-friendly, total recovery significantly improves, and is suitable for large-scale production.
Detailed description of the invention
Reference example 1N-methyl-2-cyano group-4-(2-fluorophenyl)-4-oxo butyramide (Vonoprazan fumarate intermediate compound I)
Its structure is as follows:
Vonoprazan fumarate intermediate compound I is prepared via a method which to obtain:
In dry 2000mL there-necked flask, add o-fluoro acetophenone 95g, ethyl acetate 500mL, stir lower 25 DEG C slowly Dropping bromine 120g and ethyl acetate 300mL mixed liquor, control to drip at 1h, and temperature is less than 35 DEG C；Drip, 25 DEG C of guarantors Temperature 1.5h, then drip 3% anhydrous sodium sulfite solution；After adding, 25 DEG C are incubated 1.5h again；PH=7 is adjusted then with sodium bicarbonate Layering, organic facies saturated brine washs 2 times, each 100mL；Obtain the bromo-1-of 2-(2-fluorophenyl) ethyl ketone ethyl acetate solution；
The bromo-1-of 2-(2-fluorophenyl) ethyl ketone ethyl acetate solution derived above is cooled down less than 5 DEG C, addition N-methyl- 2-cyanoacetamide 50g, stirring, below 10 DEG C, drip DIPEA 100g, drip 5-10 DEG C of reaction 2.5h, Add 1N hydrochloric acid and adjust PH=4-5, start decompression distillation, outer temperature 35 DEG C, steam to without fraction outflow, then add methanol 150mL and subtract Pressure is evaporated；Residue adds methanol 200mL and water 40mL, stirring intensification 55 DEG C, stirring 1h, is naturally cooling to about 25 DEG C, followed by Continue and be cooled to 0-5 DEG C of stirring 1h, filter, wash with methanol and water mixed liquid, forced air drying, obtain Vonoprazan fumarate intermediate I about 100g.
Embodiment 1N-methyl-5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide (Vonoprazan fumarate intermediate II)
Its structure is as follows:
The preparation method of this Vonoprazan fumarate intermediate II is as follows:
In dry 10L there-necked flask, it is sequentially added into 10g Vonoprazan fumarate intermediate compound I, 300mL oxolane, stirs Mix the palladium carbon of lower addition 1g content 5%, add 300mL glacial acetic acid and 2g anhydrous sodium sulfate；First replace continuously with nitrogen 3 times, Replacing continuously with hydrogen 3 times, start timing hydrogenation, reaction temperature is 20-35 DEG C；Detection after completion of the reaction, then is used Nitrogen replacing hydrogen 4 times, then filters, and filtrate is lowered the temperature less than 10 DEG C, drips 150mL water, filters, and collects filter cake, is dried, obtains rich Horse acid Wo Nuolazan intermediate II 7.2g, yield: 77.3%；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 does not detects.
Embodiment 2N-methyl isophthalic acid-[5-(2-fluorophenyl)-1H-pyrroles's-3-base]-N-methylamine is (in the middle of Vonoprazan fumarate Body III)
Its structure is as follows:
The preparation method of this Vonoprazan fumarate intermediate III is as follows:
43g iodine is dissolved in 70mL oxolane wiring solution-forming；By in 110mL oxolane, 22.5g Vonoprazan fumarate Mesosome II joins in reaction bulb, logical nitrogen displacement, stirring, cooling；Being dividedly in some parts 14g sodium borohydride, control temperature is-5-15 DEG C, the tetrahydrofuran solution of dropping iodine, control system temperature-5-15 DEG C, after dropping, be warming up to 15-25 DEG C, stir 1- 1.5h；It is warming up to 55-65 DEG C of insulation reaction, reacts 3h, be cooled to-5-5 DEG C, dropping 4N hydrochloric acid 50mL cancellation reaction, control temperature Spend-5-20 DEG C；System temperature is risen to 35-45 DEG C of stirring 0.5-1h；35-45 DEG C of concentrating under reduced pressure oxolane obtains concentrate；To Concentrate adds 100mL purified water, 100mL ethyl acetate, controls temperature 10-20 DEG C, drip 30% sodium hydroxide solution, adjust Joint pH is 11-12, separates organic facies, and aqueous phase 50mL ethyl acetate extracts, and combined ethyl acetate layer, ethyl acetate layer is with anhydrous Sodium sulfate is dried, sucking filtration, and filter cake ethyl acetate is washed, and filtrate obtains 17.5g grease, yield at 45-50 DEG C of concentrating under reduced pressure 83.2%.
Embodiment 3N-methyl-5-(2-fluorophenyl)-1-(pyridin-3-yl sulfonyl)-1H-pyrrole-3-carboxamide (rich horse Acid Wo Nuolazan intermediate IV)
Its structure is as follows:
The preparation method of this Vonoprazan fumarate intermediate IV is as follows:
In dry 1L there-necked flask, it is separately added into 10g Vonoprazan fumarate intermediate II, 350mL oxolane, stirs Mixing cooling less than 10 DEG C, nitrogen protection is lower adds 6.5g sodium hydride, then adds 25g15-crown ether-5, stirring cooling 10 DEG C with Under, the dropping tetrahydrofuran solution 100mL containing 3-pyridine sulfonyl chloride 18g, drip off rear temperature control 5-10 DEG C reaction 2h, be warming up to 20- 25 DEG C of insulation 30min, first drip shrend under nitrogen protection and go out, pour 300mL water when not having bubble formation into, stir 10min, use 1N hydrochloric acid adjusts PH=4, and 10 DEG C stirred below to solidifying, and sucking filtration, with acetonitrile water mixed liquid (1:1) drip washing, is drained, and 50 DEG C of decompressions are dry Dry, obtain pale yellow to red solid powder 11g, yield 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 does not detects.
Embodiment 4N-methyl isophthalic acid-(5-(2-fluorophenyl)-1-(pyridin-3-yl sulfonyl)-1H-pyrroles's-3-base)-N-first Amine (Vonoprazan fumarate intermediate V)
Its structure is as follows:
The preparation method of this Vonoprazan fumarate intermediate V is as follows:
In dry 1L there-necked flask, it is separately added into 10g Vonoprazan fumarate intermediate III, 350mL oxolane, stirs Mixing cooling less than 10 DEG C, nitrogen protection is lower adds 6.5g sodium hydride, then adds 25g15-crown ether-5, stirring cooling 10 DEG C with Under, the dropping tetrahydrofuran solution 100mL containing 3-pyridine sulfonyl chloride 18g, drip off rear temperature control 5-10 DEG C reaction 2h, be warming up to 20- 25 DEG C of insulation 30min, first drip shrend under nitrogen protection and go out, and when not having bubble formation to pour 300mL water into, stir 10min, use 1N Hydrochloric acid adjusts PH=4, and 10 DEG C stirred below to solidifying, and sucking filtration, with acetonitrile water mixed liquid (1:1) drip washing, is drained, and 50 DEG C of decompressions are dry Dry, obtain yellow solid powder 11.1g, yield 65.8%.
The preparation of embodiment 5 Vonoprazan fumarate
500L reaction bulb is sequentially added into 30g Vonoprazan fumarate intermediate IV, 11.5g sodium borohydride and 120mL tetra- Hydrogen furan, agitation and dropping 57g boron trifluoride tetrahydrofuran complex solution under room temperature, drips complete temperature control 50 ± 5 DEG C reaction, after about 2h TLC monitors reaction process, until raw material speckle disappears, reaction is finished, and adds to reactant liquor, in 200L water, be then slowly added into 200mL concentrated hydrochloric acid, finishes, and temperature control 50 ± 5 DEG C reacts about 2h, until complex acidolysis is complete, temperature control less than 50 DEG C removes under reduced pressure Oxolane, proceeds in 2000mL reaction bulb by residue, is sequentially added into 250mL ethyl acetate, 250mL water, lowers the temperature and control Temperature drips about 40%NaOH solution below 10 DEG C, to pH=9～10, temperature control 5 ± 5 DEG C stirring reaction 30min, stands and divides Liquid, collects ethyl acetate layer, and water layer 200mL × 2 time ethyl acetate extracts, and combined ethyl acetate layer, with 50mL × 3 time 10% Sodium-chloride water solution washs, then washed once with 200mL water, ethyl acetate layer decompression distillation, stops when remaining about 50mL in residual liquid Only, it is warming up to 50 DEG C and molten rapidly joins the dimethyl formamide solution containing 9.5g fumaric acid clearly, stir lower 45-50 DEG C of insulation 10min, is naturally cooling to 15 DEG C, filters, and filter cake ethyl acetate is washed, and 50-60 DEG C of forced air drying obtains off-white color pressed powder About 30.8g, yield 80%, fusing point: 203-204 DEG C (decomposing time melted)；
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 is not Detection.
The preparation of embodiment 6 Vonoprazan fumarate
43g iodine is dissolved in 70mL oxolane wiring solution-forming；By in 110mL oxolane, 22.5g Vonoprazan fumarate Mesosome II joins in reaction bulb, logical nitrogen displacement, stirring, cooling；Being dividedly in some parts 14g sodium borohydride, control temperature is-5-15 DEG C, the tetrahydrofuran solution of dropping iodine, control system temperature-5-15 DEG C, after dropping, be warming up to 15-25 DEG C, stir 1- 1.5h；It is warming up to 55-65 DEG C of insulation reaction, reacts 3h, be cooled to-5-5 DEG C, dropping 4N hydrochloric acid 50mL cancellation reaction, control temperature Spend-5-20 DEG C；System temperature is risen to 35-45 DEG C of stirring 0.5-1h；35-45 DEG C of concentrating under reduced pressure oxolane obtains concentrate；To Concentrate adds 100mL purified water, 100mL ethyl acetate, controls temperature 10-20 DEG C, drip 30% sodium hydroxide solution, adjust Joint pH is 11-12, separates organic facies, and aqueous phase 50mL ethyl acetate extracts, and combined ethyl acetate layer, ethyl acetate layer is with anhydrous Sodium sulfate is dried, sucking filtration, and filter cake ethyl acetate is washed, when filtrate remains about 50mL in 45-50 DEG C is evaporated to residual liquid Stop, being warming up to 50 DEG C and molten rapidly join the dimethyl formamide solution containing 9.5g fumaric acid clearly, stir lower 45-50 DEG C of insulation 10min, is naturally cooling to 15 DEG C, filters, and filter cake ethyl acetate is washed, and 50-60 DEG C of forced air drying obtains off-white color pressed powder 28.1g, yield 73.0%.
The preparation of embodiment 7 Vonoprazan fumarate
Dry 10L there-necked flask is sequentially added into 23.4g Vonoprazan fumarate intermediate compound I, 468mL oxolane, The lower palladium carbon adding 0.59g content 5% of stirring, adds 13.2g glacial acetic acid and 9.94g anhydrous magnesium sulfate；First continuous with nitrogen Replacing 3 times, replace continuously with hydrogen 3 times, start timing hydrogenation, reaction temperature is 25 DEG C；Detect after completion of the reaction, Using nitrogen replacing hydrogen 4 times again, then filter, filtrate is lowered the temperature less than 10 DEG C, drips 150mL water, filters, and collects filter cake, dry, Obtain Vonoprazan fumarate intermediate II 7.4g, yield: 79.6%；
21.8g Vonoprazan fumarate intermediate II, 436mL acetonitrile it is separately added into, stirring in dry 1L there-necked flask Lower the temperature less than 10 DEG C, add 18.9g4-N, N-dimethyl aminopyridine under nitrogen protection, then add 36g15-crown ether-5, Stirring cooling less than 10 DEG C, the dropping tetrahydrofuran solution 100mL containing 3-pyridine sulfonyl chloride 38.9g, drip off rear temperature control 5-10 DEG C Reaction 2h, is warming up to 20-25 DEG C of insulation 30min, first drips shrend and go out, pour into when not having bubble formation under nitrogen protection 300mL water, stirs 10min, adjusts PH=4 with 1N hydrochloric acid, and 10 DEG C stirred below to solidification, and sucking filtration, with acetonitrile water mixed liquid (1:1) Drip washing, drains, 50 DEG C of drying under reduced pressure, obtains Vonoprazan fumarate intermediate IV, pale yellow to red solid powder 11.4g, yield 69%；
500L reaction bulb is sequentially added into 35.9g Vonoprazan fumarate intermediate IV, 10.8g sodium borohydride and 718mL Oxolane, agitation and dropping 68g boron trifluoride tetrahydrofuran complex solution under room temperature, drips complete temperature control 50 ± 5 DEG C reaction, about 2h Rear TLC monitors reaction process, until raw material speckle disappears, reaction is finished, and adds to reactant liquor, in 200L water, be then slowly added into 200mL concentrated hydrochloric acid, finishes, and temperature control 50 ± 5 DEG C reacts about 2h, until complex acidolysis is complete, temperature control less than 50 DEG C removes under reduced pressure Oxolane, proceeds in 2000mL reaction bulb by residue, is sequentially added into 250mL ethyl acetate, 250mL water, lowers the temperature and control Temperature drips about 40%NaOH solution below 10 DEG C, to pH=9～10, temperature control 5 ± 5 DEG C stirring reaction 30min, stands and divides Liquid, collects ethyl acetate layer, and water layer 200mL × 2 time ethyl acetate extracts, and combined ethyl acetate layer, with 50mL × 3 time 10% Sodium-chloride water solution washs, then washed once with 200mL water, ethyl acetate layer decompression distillation, stops when remaining about 50mL in residual liquid Only, it is warming up to 50 DEG C and molten rapidly joins the dimethyl formamide solution containing 29g fumaric acid clearly, stir lower 45-50 DEG C of insulation 10min, is naturally cooling to 15 DEG C, filters, and filter cake ethyl acetate is washed, and 50-60 DEG C of forced air drying obtains off-white color pressed powder 31.7g, yield 82.3%, total recovery 45.2%, Vonoprazan fumarate purity 99.3%.
Each experimental procedure is to Vonoprazan fumarate intermediate and the investigation of Vonoprazan fumarate yield
Test example 1
Investigate different organic inert solvent, catalyst, organic acid and deicers etc. to Vonoprazan fumarate intermediate The impact of II yield, remaining preparation method, with embodiment 1, investigates result as shown in table 1.
Table 1 differential responses factor affects result to Vonoprazan fumarate intermediate II yield
From table 1 it follows that the present invention selects different organic inert solvent, different organic acid, the content of palladium carbon And deicer has appreciable impact to the yield of Vonoprazan fumarate intermediate II, it is tetrahydrochysene furan when affecting organic inert solvent Mutter, catalyst is the palladium carbon of content 5%, organic acid is glacial acetic acid and deicer select anhydrous sodium sulfate time, prepare fumaric acid The yield of Wo Nuolazan intermediate II can reach more than 77%.
Test example 2
Investigate the shadow to Vonoprazan fumarate intermediate IV yield such as different organic inert solvent, alkali and the reaction conditions etc. Ringing, remaining preparation method, with embodiment 3, investigates result as shown in table 2.
Table 2 differential responses factor affects result to Vonoprazan fumarate intermediate IV yield
From Table 2, it can be seen that the present invention selects different organic inert solvent, different alkali, pyridine-3-sulfonic acid chloride Consumption has appreciable impact to the yield of Vonoprazan fumarate intermediate IV.
Test example 3
Investigate different non-proton organic inert solvent, reducing agent system and reaction conditions etc. Vonoprazan fumarate is received The impact of rate, remaining preparation method, with embodiment 5, investigates result as shown in table 3.
Table 3 differential responses factor affects result to Vonoprazan fumarate yield
From table 3 it is observed that the present invention selects different non-proton organic inert solvent, different reducing agent systems pair The yield of Vonoprazan fumarate has appreciable impact.

Claims (10)

1. a Vonoprazan fumarate intermediate, its structure is as follows:
Wherein, R1For H or oxo；R2For H or pyridine-3-sulfonyl；
Work as R1For oxo, R2During for H, for Vonoprazan fumarate intermediate II；
Work as R1For H, R2During for H, for Vonoprazan fumarate intermediate III；
Work as R1For oxo, R2During for pyridine-3-sulfonyl, for Vonoprazan fumarate intermediate IV.
2. the preparation method of a Vonoprazan fumarate intermediate II, it is characterised in that described preparation method includes walking as follows Rapid: Vonoprazan fumarate intermediate compound I, in organic inert solvent, under the effect of catalyst, organic acid and deicer, is passed through Hydrogen, reaction prepares Vonoprazan fumarate intermediate II；
Preferably, described organic inert solvent is oxolane；
Preferably, described catalyst is palladium carbon；
Preferably, described organic acid is formic acid or acetic acid；
Preferably, described deicer is molecular sieve, anhydrous magnesium sulfate or anhydrous sodium sulfate, it is preferable that described deicer is anhydrous Sodium sulfate.
3. the preparation method of a Vonoprazan fumarate intermediate III, it is characterised in that described preparation method includes walking as follows Rapid: in non-proton organic inert solvent, Vonoprazan fumarate intermediate II is reduced under the effect of reducing agent system Reaction, prepares Vonoprazan fumarate intermediate III；
The most described reducing agent system is selected from metallic boron hydrides reducing agent, diborane, borine or organosilicon reducing agent；Preferably Ground, described reducing agent system is metallic boron hydrides reducing agent, described metallic boron hydrides reducing agent selected from metallic boron hydrides/ Iodine, metallic boron hydrides/boron trifluoride, metallic boron hydrides/trifluoroacetic acid, metallic boron hydrides/trifluoromethanesulfanhydride anhydride, metal Boron hydride/trim,ethylchlorosilane or metallic boron hydrides/phosphorus oxychloride；Preferably, described reducing agent system is sodium borohydride；
Preferably, described non-proton organic inert solvent is selected from ethers, ethers and alcohols double solvents or dimethyl sulfoxide, preferably Ground, described non-proton organic inert solvent is oxolane.
4. the preparation method of a Vonoprazan fumarate intermediate IV, it is characterised in that described preparation method includes walking as follows Rapid: in organic inert solvent, under the catalysis of alkali, be there is sulphur in Vonoprazan fumarate intermediate II and pyridine-3-sulfonic acid chloride Acylation reaction, prepares Vonoprazan fumarate intermediate IV；
Preferably, described organic inert solvent is oxolane or acetonitrile；
Preferably, described alkali be sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, Sodium ethylate, potassium ethoxide, Feldalat NM, Feldalat KM, pyridine, lutidines, triethylamine, diisopropanol ethamine, 4-N, N-diformazan ammonia Yl pyridines；
Preferably, described alkali is sodium hydride or DMAP.
5. Vonoprazan fumarate intermediate application in preparation Vonoprazan fumarate.
6. apply the method that Vonoprazan fumarate intermediate IV prepares Vonoprazan fumarate for one kind, it is characterised in that described Method comprises the steps: that, in non-proton organic inert solvent, Vonoprazan fumarate intermediate IV is in reducing agent system Carry out reduction reaction under effect, become salt to prepare Vonoprazan fumarate；
7. method as claimed in claim 6, it is characterised in that described reducing agent system selected from metallic boron hydrides reducing agent, Diborane, borine or organosilicon reducing agent；
Preferably, described reducing agent system is metallic boron hydrides reducing agent, and described metallic boron hydrides reducing agent is selected from metal Boron hydride/iodine, metallic boron hydrides/boron trifluoride, metallic boron hydrides/trifluoroacetic acid, metallic boron hydrides/fluoroform sulphur Anhydride, metallic boron hydrides/trim,ethylchlorosilane or metallic boron hydrides/phosphorus oxychloride；
Preferably, described reducing agent system is sodium borohydride/boron trifluoride or sodium borohydride/iodine.
8. method as claimed in claim 6, it is characterised in that described non-proton organic inert solvent selected from ethers, ethers with Alcohols double solvents or dimethyl sulfoxide, it is preferable that described non-proton organic inert solvent is oxolane.
9. apply the method that Vonoprazan fumarate intermediate III prepares Vonoprazan fumarate for one kind, it is characterised in that described Method comprises the steps: in organic inert solvent, by Vonoprazan fumarate intermediate III with pyridine-3-sulfonic acid chloride at alkali Catalysis under there is sulfonylation, become salt to prepare Vonoprazan fumarate；
10. method as claimed in claim 9, it is characterised in that described organic inert solvent is oxolane or acetonitrile；
Preferably, described alkali be sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, Sodium ethylate, potassium ethoxide, Feldalat NM, Feldalat KM, pyridine, lutidines, triethylamine, diisopropanol ethamine, 4-N, N-diformazan ammonia Yl pyridines；
Preferably, described alkali is diisopropylethylamine or DMAP.
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