CN106187852A - A kind of preparation method of Vonoprazan fumarate intermediate - Google Patents
A kind of preparation method of Vonoprazan fumarate intermediate Download PDFInfo
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- CN106187852A CN106187852A CN201610531849.0A CN201610531849A CN106187852A CN 106187852 A CN106187852 A CN 106187852A CN 201610531849 A CN201610531849 A CN 201610531849A CN 106187852 A CN106187852 A CN 106187852A
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- ZILJLCKRBMDVQV-UHFFFAOYSA-N CCOC(c1ccccc1F)=N Chemical compound CCOC(c1ccccc1F)=N ZILJLCKRBMDVQV-UHFFFAOYSA-N 0.000 description 1
- BFDBKMOZYNOTPK-UHFFFAOYSA-N CNCc(cc1-c2ccccc2F)c[n]1S(c1cnccc1)(=O)=O Chemical compound CNCc(cc1-c2ccccc2F)c[n]1S(c1cnccc1)(=O)=O BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 description 1
- MQULPEUCGKEHEG-UHFFFAOYSA-N O=Cc1c[nH]c(-c2ccccc2F)c1 Chemical compound O=Cc1c[nH]c(-c2ccccc2F)c1 MQULPEUCGKEHEG-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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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
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- Pyrrole Compounds (AREA)
Abstract
The present invention provides the preparation method of 5 (2 fluorophenyl) 1H pyrroles 3 formaldehyde of a kind of structural formula I, comprises the following steps: 1) alcoholysis reaction: with 2 fluorobenzonitriles as raw material, under conditions of strong acid exists, and C1～C4Saturated fatty alcohol reaction, obtain the compound of formula II, wherein, R is C1～C4Straight chained alkyl；2) cycloaddition reaction: the compound of formula II carries out cycloaddition reaction with furan under catalyst, obtains 5 (2 fluorophenyl) 1H pyrroles 3 formaldehyde of structural formula I.The present invention also provides for the preparation method of a kind of Vonoprazan fumarate, prepares 5 (2 fluorophenyl) 1H pyrroles 3 formaldehyde including by above-mentioned preparation method.The preparation method reactions steps of the present invention is few, and process route is succinct, and reaction condition is gentle, does not use the reagent of severe toxicity or costliness, equipment is not had particular/special requirement；Therefore, it is suitable for industrialized production.
Description
Technical field
The invention belongs to organic chemistry filed, be specifically related to the preparation method of a kind of Vonoprazan fumarate intermediate.
Background technology
Vonoprazan fumarate (Vonoprazan fumarate, TAK-438), is second reversible proton pump suppression
Agent, it is possible in the final step of parietal cell secretion gastric acid, by suppression potassium ion (K+) to H+-K+The combination of-ATP enzyme is made
With, terminate the secretion of gastric acid in advance.Vonoprazan fumarate is by Japan's military field pharmaceutical development, in December in 2014 26 days in Japan
Listing, trade name Takecad, for treating the root of erosive esophagitis, gastric ulcer, duodenal ulcer and helicobacter pylori
Remove.
Compared with traditional irreversible proton pump inhibitor (such as omeprazole, esomeprazole), Vonoprazan fumarate
There is obvious advantage: 1) onset is rapid, within first day, is administered the acid suppression effect that will reach maximum；2) long action time；3) mouth
Clothes are administered, and not by gastric acid destroying infection, do not need to make enteric form of medication；4) have some improvement work to investigation into nocturnal acid breakthrough
With.
Even if compared with first reversible proton pump inhibitor Revaprazan, Vonoprazan fumarate also has plurality of advantages,
As few in dosage (Vonoprazan fumarate daily dose 20mg, Revaprazan daily dose 100-200mg), untoward reaction is few；Drug effect
And difference that effective dose is between different patients is the most notable.
Vonoprazan fumarate, chemical name: 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrroles-3-
Base]-N-methyl methylamine list fumarate, its structure is as follows:
5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde (compound of structural formula I) is in the key of Vonoprazan fumarate
Mesosome.In prior art, the preparation method of this intermediate of report mainly has a following two:
Synthetic route one: as described in patent WO2007026916: with 2-fluoro acetophenone as initiation material, obtain through bromination
To the bromo-2 '-fluoro acetophenone of 2-, then react with cyan-acetic ester and obtain 2-cyano group-4-(2-fluorophenyl)-4-ketobutyric acid second
Ester, then in the ethyl acetate solution of hydrogen chloride, cyclization obtains the chloro-5-of 2-(2-fluorophenyl)-1H-pyrroles's-3-carboxylic acid, ethyl ester,
Again at palladium carbon/H2The lower dechlorination of effect obtains 5-(2-fluorophenyl)-1H-pyrroles's-3-carboxylic acid, ethyl ester, 5-(2-fluorophenyl)-1H-pyrrole
Cough up-3-carboxylic acid, ethyl ester and carry out reduction reaction under diisobutyl aluminium hydride (DIBAL) acts on, finally enter under manganese dioxide effect
Row oxidation reaction obtains 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde of structural formula I.
Synthetic route two: as described in patent WO2010098351, equally with 2-fluoro acetophenone as initiation material, obtains through bromination
To the bromo-2 '-fluoro acetophenone of 2-, then react with Cyanoacetyl-Cyacetazid and obtain [2-(2-fluorophenyl)-2-oxoethyl] Cyanoacetyl-Cyacetazid, then at chlorine
Change cyclization in the ethyl acetate solution of hydrogen, at palladium carbon/H2The lower dechlorination of effect obtains 5-(2-fluorophenyl)-1H-pyrroles's-3-nitrile,
After at Raney's nickel/H2, reductive hydrolysis obtains 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde of structural formula I in acetic acid aqueous solution.
It is long all to there is route in above two synthetic route, and total recovery is low；And there is poor stability, valency in the reagent used
The shortcoming that lattice are expensive, such as: two lines all employ bromine hypertoxic, volatile, palladium charcoal, Raney's nickel and diisobutyl aluminium hydride
(DIBAL) also it is raw material inflammable, that price is high.It addition, both of which needs to hydrogenate special equipment.In a word, prior art
5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde preparation method because production security be difficult to ensure, high in cost of production defect, all
Be not suitable for industrialized great production.
Summary of the invention
For the problems referred to above, it is an object of the present invention to provide a kind of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde
New preparation method.The preparation method reactions steps of the present invention is few, total recovery is high, low cost, low in the pollution of the environment, safety
Good, easy and simple to handle, it is particularly suitable for industrialized great production.
In order to realize foregoing invention purpose, present invention employs following technical scheme:
A kind of preparation method of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde of structural formula I,
Comprise the following steps:
1) alcoholysis reaction: with 2-fluorobenzonitrile as raw material, under conditions of strong acid exists, and C1～C4Saturated fatty alcohol
Reaction, obtains the compound of formula II,
Wherein, R is C1～C4Straight chained alkyl；
2) cycloaddition reaction: the compound of formula II carries out cycloaddition reaction with furan under catalyst, obtains
5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde of structural formula I.
The preparation method of 5-of the present invention (2-fluorophenyl)-1H-pyrroles's-3-formaldehyde, its synthetic route is as follows:
Wherein, R is C1～C4Straight chained alkyl.
Preferably, described reactions steps 1) in, described strong acid is in hydrogen chloride gas, hydrogen chloride solution and oleum
One.
Preferably, described hydrogen chloride solution is that hydrogen chloride is dissolved in methanol, ethanol, ethyl acetate or oxolane equal solvent
In the solution that mass percent concentration is 10～40% that obtains.
Preferably, described reactions steps 1) in, described C1～C4Saturated fatty alcohol selected from methanol, ethanol, normal propyl alcohol and just
One in butanol.
Preferably, described reactions steps 1) in, reaction temperature is 0～50 DEG C, more preferably 20～30 DEG C.
Preferably, described reactions steps 1) in, 2-fluorobenzonitrile and described C1～C4The mol ratio of saturated fatty alcohol be 1:
1～1: 100, more preferably 1: 10～1: 50.
Preferably, described reactions steps 2) in, solvent for use is selected from methanol, ethanol, ethyl acetate, dichloromethane, tetrahydrochysene
One or more in furan and toluene.
Preferably, described reactions steps 2) in, used catalyst is selected from silver trifluoromethanesulfonate, PtCl2, AuCl and AuCl3In
One.
Preferably, described reactions steps 2) in, reaction temperature is 0～80 DEG C, more preferably 40～60 DEG C.
Preferably, described reactions steps 2) in, the compound of formula II and the mol ratio of furan are 1: 1～1: 30, more
It is preferably 1: 5～1: 20.
Further object is that the preparation method that a kind of Vonoprazan fumarate is provided, including by above-mentioned
Preparation method prepares 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde；Also include: 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde with
The reaction of 3-pyridine sulfonyl chloride obtains 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrroles's-3-formaldehyde, then with methylamine first
Alcoholic solution, under sodium borohydride effect, obtains 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrroles-3-]-N-first
Base methylamine, then become salt with fumaric acid, obtain Vonoprazan fumarate.
The method of above-mentioned preparation Vonoprazan fumarate route be synthesized, as follows:
Compared with prior art, the preparation method of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde that the present invention provides has
Following has the beneficial effect that
1, synthetic route is novel, succinctly, it is only necessary to just can obtain target product through alcoholysis, cycloaddition two-step reaction.
2, the yield of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde is high, and purity is good；Be conducive to improving finished product fumaric acid to irrigate
The purity that Nola praises, it is ensured that clinical drug safety.
3, avoid using the bromine of severe toxicity, improve the protection of the safety of production, beneficially personnel and environment.
4, with 2-fluorobenzonitrile cheap and easy to get as raw material, reaction gentleness, do not use the high and inflammable palladium carbon of price and
Raney's nickel, it is not necessary to special hydrogenation equipment, significantly reduces production cost, is more beneficial for safety in production.
In a word, the invention provides the system of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde of a kind of applicable industrialized production
Preparation Method.
Detailed description of the invention
Referring to specific embodiment, the present invention is described.Only it will be appreciated by those skilled in the art that these embodiments
For the present invention is described, it limits the scope of the present invention never in any form.
Experimental technique in following embodiment, if no special instructions, is conventional method.In following embodiment used former
Material, reagent material etc., if no special instructions, be commercially available purchase product.
Embodiment 1The preparation of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde
1) in 1000ml reaction bulb, 2-fluorobenzonitrile (50g, 0.41mol), ethanol 300ml, mass percent are added dense
Degree 30～the ethanol solution 200ml of 35% hydrogen chloride, after 20～30 DEG C of reactions 12 hours, decompression and solvent recovery, obtain structure
The compound (light yellow oil) of Formula II-A, it is not necessary to be further purified, be directly used in the next step.
2) by upper step react obtain the compound of formula II-A, furan (280g, 4.1mol), silver trifluoromethanesulfonate
(0.2g) put in 1000ml reaction bulb with 400ml ethanol, after 40～50 DEG C are reacted 12 hours, add the stirring of 500ml water, then
Making to be extracted with ethyl acetate three times (100ml*3), merge organic layer and be evaporated to do, crude product uses ethyl acetate/positive heptan
Alkane refines, and obtains 66.4g target product (light yellow solid).Yield 85%, HPLC purity: 99.2%.
1H-NMR (300MHz, DMSO-d6) (ppm): 6.91 (d, J=1.6Hz, 1H), 7.21-7.31 (m, 3H), 7.75-
7.80(m,2H),9.76(s,1H),12.17(brs,1H).
Embodiment 2The preparation of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde
1) in 1000ml reaction bulb, add 2-fluorobenzonitrile (50g, 0.41mol), normal propyl alcohol 500ml, be passed through hydrogen chloride
Gas, after 10～20 DEG C of reactions 8 hours, decompression and solvent recovery, obtain the compound (light yellow oil) of formula II-B,
Without being further purified, it is directly used in the next step.
2) by upper step react obtain the compound of formula II-B, furan (245g, 3.6mol), PtCl2(0.1g) and
400ml ethyl acetate puts in 1000ml reaction bulb, after 50～60 DEG C are reacted 12 hours, adds the stirring of 500ml water, then uses
Ethyl acetate three times (100ml*3) of extraction, merges organic layer and is evaporated to do, and crude product uses ethyl acetate/normal heptane essence
System, obtains 65.5g target product (light yellow solid).Yield 84%, HPLC purity: 99.0%.
1H-NMR (300MHz, DMSO-d6) (ppm): 6.90 (d, J=1.6Hz, 1H), 7.20-7.30 (m, 3H), 7.74-
7.79(m,2H),9.75(s,1H),12.16(brs,1H).
Embodiment 3The preparation of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde
1) in 1000ml reaction bulb, 2-fluorobenzonitrile (50g, 0.41mol), methanol 300ml, 30～35% chlorination are added
Hydrogen methanol solution 200ml, after 30～40 DEG C of reactions 12 hours, decompression and solvent recovery, the compound obtaining formula II-C is (shallow
Yellow oil), it is not necessary to it is further purified, is directly used in the next step.
2) by upper step react obtain the compound of formula II-C, furan (421g, 6.2mol), silver trifluoromethanesulfonate
(0.2g) put in 1000ml reaction bulb with 400ml methanol, after 30～40 DEG C are reacted 12 hours, add the stirring of 500ml water, then
Making to be extracted with ethyl acetate three times (100ml*3), organic layer concentrating under reduced pressure is done, and crude product uses ethyl acetate/normal heptane to refine,
To 67g target product (light yellow solid).Yield 86%, HPLC detects purity: 99.1%.
1H-NMR (300MHz, DMSO-d6) (ppm): 6.92 (d, J=1.6Hz, 1H), 7.22-7.31 (m, 3H), 7.76-
7.80(m,2H),9.77(s,1H),12.18(brs,1H).
Embodiment 4The preparation of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde
1) in 1000ml reaction bulb, 2-fluorobenzonitrile (50g, 0.41mol), n-butyl alcohol 450ml, 30～35% chlorine are added
Change hydroacetic acid ethyl ester solution 200ml, after 40～50 DEG C of reactions 12 hours, decompression and solvent recovery, obtain the change of formula II-D
Compound (light yellow oil), it is not necessary to be further purified, be directly used in the next step.
2) by upper step react obtain the compound of formula II-D, furan (558g, 8.2mol), AuCl3(0.1g) and
300ml oxolane puts in 1000ml reaction bulb, after 50～55 DEG C are reacted 12 hours, adds the stirring of 500ml water, then uses
Ethyl acetate three times (100ml*3) of extraction, organic layer concentrating under reduced pressure is dry, and crude product uses ethyl acetate/normal heptane to refine, and obtains
64.7g target product.Yield 83%, purity: 99.4%.
1H-NMR (300MHz, DMSO-d6) (ppm): 6.90 (d, J=1.6Hz, 1H), 7.23-7.33 (m, 3H), 7.75-
7.78(m,2H),9.78(s,1H),12.19(brs,1H).
Embodiment 5The preparation of Vonoprazan fumarate
Under nitrogen protection, put in 1000ml reaction bulb 400ml oxolane and 60% sodium hydrogen (11.6g,
0.29mol), in 10～20 DEG C of 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde adding by several times embodiments 1 preparation (50g,
0.26mol), finish, in 10～20 DEG C of droppings 3-pyridine sulfonyl chloride (51.7g, 0.29mol), drip complete, anti-in 40～45 DEG C
After answering 5 hours, add 200ml water, ethyl acetate extraction (200ml*3), after organic layer concentrating under reduced pressure is dry, use methanol/H2O essence
System, obtains 74.2g yellow solid 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrroles's-3-formaldehyde, yield 85%.
Under nitrogen protection, put in 1000ml reaction bulb walk the 5-2-fluorophenyl-1-pyridine-3-sulfonyl of preparation-
1H-pyrroles's-3-formaldehyde (50g, 0.15mol) and 400ml methanol, in 20～30 DEG C drip 30% methylamine methanol solutions (23.5g,
0.23mol), drip and finish after 20～30 DEG C of reactions 30 minutes, be cooled to 0～5 DEG C of dropping sodium borohydride (2.9g, 0.076mol)
DMF solution 30ml, drips and finishes after 0～5 DEG C of reaction 1 hour, in 0～15 DEG C of dropping 5N hydrochloric acid (50ml), after stirring 30 minutes, subtract
Pushing back receiving portions solvent, add ethyl acetate 400ml, after using ammonia to adjust PH to 8～9, separate organic layer, water layer re-uses second
Acetoacetic ester (100ml) extracts once, merges twice ethyl acetate layer, and ethyl acetate layer uses water (100ml) washing, ethyl acetate
Layer concentrating under reduced pressure is done, and adds 50ml DMF, be warming up to 45～50 DEG C of stirrings molten clear after, add fumaric acid (17.6g, 0.15mol),
Cold go to 0-10 DEG C stirring 2 hours after, filter, ethyl acetate wash, decompression drying obtains 60g target product (white solid).
Yield 85%, HPLC purity 99.8%.
1H-NMR (400MHz, DMSO-d6) (ppm): 2.44 (s, 3H), 3.89 (s, 2H), 6.49-6.50 (m, 3H),
7.07-7.12(m,1H),7.20-7.25(m,2H),7.50-7.55(m,1H),7.60-7.63(m,1H),7.74-7.75(m,
1H),7.87-7.89(m,1H),8.55-8.56(m,1H),8.87-8.89(m,1H)；3 H are that active hydrogen does not detects.
Specific description of embodiments of the present invention above is not limiting as the present invention, and those skilled in the art can be according to this
Various change or deformation are made in invention, without departing from the spirit of the present invention, all should belong to the model of claims of the present invention
Enclose.
Claims (10)
1. a preparation method for 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde of structural formula I,
Comprise the following steps:
1) alcoholysis reaction: with 2-fluorobenzonitrile as raw material, under conditions of strong acid exists, and C1～C4Saturated fatty alcohol reaction,
Obtain the compound of formula II,
Wherein, R is C1～C4Straight chained alkyl；
2) cycloaddition reaction: the compound of formula II carries out cycloaddition reaction with furan under catalyst, obtains structure
5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde of Formulas I.
Preparation method the most according to claim 1, it is characterised in that described reactions steps 1) in, described strong acid is selected from chlorine
Change the one in hydrogen, hydrogen chloride solution and oleum；
Preferably, described hydrogen chloride solution is that hydrogen chloride is dissolved in methanol, ethanol, ethyl acetate or oxolane the matter obtained
Amount percent concentration is the solution of 10～40%.
Preparation method the most according to claim 1 and 2, its feature is being, described reactions steps 1) in, described C1～C4
Saturated fatty alcohol one in methanol, ethanol, normal propyl alcohol and n-butyl alcohol.
Preparation method the most according to any one of claim 1 to 3, it is characterised in that described reactions steps 1) in, reaction
Temperature is 0～50 DEG C, more preferably 20～30 DEG C.
5. according to preparation method according to any one of Claims 1-4, it is characterised in that described reactions steps 1) in, 2-fluorobenzene
Formonitrile HCN and described C1～C4The mol ratio of saturated fatty alcohol be 1:1～1:100, more preferably 1:10～1:50.
Preparation method the most according to any one of claim 1 to 5, it is characterised in that described reactions steps 2) in, used
One or more in solvent selected from methanol, ethanol, ethyl acetate, dichloromethane, oxolane and toluene.
Preparation method the most according to any one of claim 1 to 6, it is characterised in that described reactions steps 2) in, used
Catalyst is selected from silver trifluoromethanesulfonate, PtCl2, AuCl and AuCl3In one.
Preparation method the most according to any one of claim 1 to 7, it is characterised in that described reactions steps 2) in, reaction
Temperature is 0～80 DEG C, more preferably 40～60 DEG C.
Preparation method the most according to any one of claim 1 to 8, it is characterised in that described reactions steps 2) in, structure
The compound of Formula II and the mol ratio of furan are 1:1～1:30, more preferably 1:5～1:20.
10. a preparation method for Vonoprazan fumarate, including by the preparation side according to any one of claim 1 to 9
Method prepares 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde；Also include: 5-(2-fluorophenyl)-1H-pyrroles's-3-formaldehyde and 3-pyridine
Sulfonic acid chloride reaction obtains 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrroles's-3-formaldehyde, then with methylamine methanol solution
Under sodium borohydride effect, obtain 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrroles-3-]-N-methyl first
Amine, then become salt with fumaric acid, obtain Vonoprazan fumarate.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107935902A (en) * | 2017-11-20 | 2018-04-20 | 杭州中美华东制药有限公司 | The synthetic method of Wo Nuolazan key intermediates |
| WO2019131695A1 (en) * | 2017-12-27 | 2019-07-04 | 日本ケミファ株式会社 | Production method for 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl]-n-methylmethanamine monofumarate |
| 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 |
| CN112961092A (en) * | 2021-03-17 | 2021-06-15 | 枣庄市润安制药新材料有限公司 | Preparation method of vonoprazan fumarate intermediate |
| CN113845459A (en) * | 2021-10-14 | 2021-12-28 | 山东诚创蓝海医药科技有限公司 | Preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde |
| CN113861166A (en) * | 2021-10-18 | 2021-12-31 | 浙江手心制药有限公司 | Preparation method of high-purity Voranolan fumarate |
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