CN111527067A - Process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic acid salt - Google Patents
Process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic acid salt Download PDFInfo
- Publication number
- CN111527067A CN111527067A CN201880082979.8A CN201880082979A CN111527067A CN 111527067 A CN111527067 A CN 111527067A CN 201880082979 A CN201880082979 A CN 201880082979A CN 111527067 A CN111527067 A CN 111527067A
- Authority
- CN
- China
- Prior art keywords
- pyrrole
- fluorophenyl
- compound
- protecting group
- represented
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to a method for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde by formylation and deprotection reactions, and a method for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine monofumarate by sulfonylation or the like.
Description
Technical Field
The present invention relates to a process for the manufacture of 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanamine monofumarate, which is an acid secretion inhibitor, and intermediates thereof.
Background
1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine monofumarate (hereinafter vonoprazan fumarate) represented by the following formula is a potassium ion competitive acid blocker, inhibits the binding of potassium ions to H +, K + -ATPase, and inhibits gastric acid secretion, and therefore, is used for the treatment and prevention of gastric/duodenal ulcer and the like, and for the intragastric pH adjustment at the time of the sterilization of helicobacter pylori. Vonoprazan fumarate is known to be stable to acids, reach an effective concentration quickly, show an action quickly after administration, and strongly inhibit gastric acid for a long period of time, as compared with conventional proton pump inhibitors.
Regarding the method for producing vonoprazan fumarate, for example, patent document 1 discloses a method for synthesizing a pyrrole-3-carbaldehyde derivative as a synthesis intermediate from a cyano compound represented by the following formula via an azole.
In this method, [ 2- (2-fluorophenyl) -2-oxoethyl ] malononitrile (a) is used as a starting material. It is described that this raw material can be produced by the method described in patent document 2, and the synthesis by the reaction of α -bromo o-fluoroacetophenone and malononitrile is disclosed. Further, it is described that α -bromo-o-fluoroacetophenone can be produced by a generally known method. Although not specifically described, for example, a method of reacting bromine in acetic acid (non-patent document 1) and a method of reacting bromine in the presence of aluminum chloride (non-patent document 2) are known. Since the synthesis of the raw material requires 2 steps, the production of the target compound requires a plurality of steps. In addition, in these reactions, propionitrile and bromine which are highly corrosive and irritant and are concerned about toxicity and influence on the environment are used, and therefore a production method which is further considered safe to the human body and the environment is desired. Further, 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde was synthesized from the starting material in a yield of 53% to 60%, and improvement of the yield was also desired.
Therefore, a production method which has less influence on the human body and the environment, has a shorter process, and has a good yield has been desired.
Documents of the prior art
Patent document
Patent document 1: japanese patent No. 5819494
Patent document 2: japanese patent No. 3140818
Non-patent document
Non-patent document 1: organic Synthesis, Coll, Vol.1, 127(1941)
Non-patent document 2: organic Synthesis, Coll, Vol.2, 480(1943)
Non-patent document 3: synthesis,49(16), 3692-3699; 2017
Non-patent document 4: journal of Organic Chemistry,75(9), 3109-; 2010
Disclosure of Invention
The purpose of the present invention is to provide a method for producing a pyrrole-3-carbaldehyde derivative, which is an intermediate for synthesizing vonoprazan fumarate, and a novel industrial production method for vonoprazan fumarate, which uses the derivative.
The present inventors have conducted intensive studies and, as a result, have found a method for producing a pyrrole-3-carbaldehyde derivative efficiently and easily by using a coupling reaction between readily available fluoroiodobenzene and pyrrole and a regioselective formylation reaction based on appropriate protection of the nitrogen atom on the pyrrole ring, and have completed the present invention.
That is to say that the first and second electrodes,
[1] the invention relates to a method for preparing 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde,
a protecting group is introduced into a nitrogen atom of a pyrrole ring in a pyrrole derivative represented by the following general formula (I) to obtain an N-protected pyrrole derivative represented by the following formula (II) (wherein P represents a protecting group), a pyrrole-3-carbaldehyde derivative represented by the following formula (III) is obtained by formylation, and a 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the following formula (IV) is obtained by deprotection reaction.
[2] The present invention also relates to the production method according to [1], wherein the protecting group represented by P is a silyl protecting group.
[3] The present invention also relates to the production method according to [1] or [2], wherein the protecting group represented by P is triisopropylsilyl.
[4] The present invention also relates to a process for producing the compound (I) according to the above [1] to [3], wherein the pyrrole derivative of the general formula (I) is obtained by reacting an o-fluorobenzene derivative represented by the following formula (V) (wherein L represents a leaving group) with pyrrole in the presence of a metal catalyst.
[5] The present invention also relates to the production method according to item 4 above, wherein the metal catalyst is a palladium catalyst.
[6] The present invention also relates to a process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine, which comprises reacting 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the general formula (IV) obtained by the above production process with pyridine-3-sulfonyl chloride or a salt thereof in the presence of an inorganic or organic base to obtain a pyrrole derivative represented by the following formula (VI), further condensing the pyrrole derivative with methylamine, and then subjecting the condensation reaction to a reduction reaction to obtain 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine represented by the following formula (VII).
[7] The present invention also relates to a process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanamine monofumarate, which comprises using the compound of the general formula (VII) obtained by the above production process and fumaric acid.
The present invention can obtain 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde using easily available raw materials such as pyrrole and 2-fluoroiodobenzene at low cost in a short time and in a short process and in a good yield (70% or more), and is more economical and productive than conventional methods, and suitable for industrial production. Further, the use of the transition metal catalyst is suppressed to a very small amount and is used in an upstream process, whereby the possibility of residual metal impurities in the final product can be further reduced.
Detailed Description
The present invention will be described in further detail below.
In the general formula (V), examples of the leaving group represented by L include a halogen atom such as chlorine, bromine or iodine, a lower alkanesulfonyloxy group such as a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group, an arylsulfonyloxy group such as a benzenesulfonyloxy group or a p-toluenesulfonyloxy group, and the like.
In the above general formulae (II) and (III), examples of the pyrrole ring nitrogen-protecting group represented by P include a silyl-based protecting group, an alkyl-based protecting group, a heteroaryl-based protecting group, an acyl-based protecting group, a carbamate-based protecting group, and the like, and examples of the silyl-based protecting group include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, a t-butyldiphenylsilyl group, and the like, and preferably a t-butyldimethylsilyl group, a triisopropylsilyl group, and the like.
Examples of the alkyl-based protecting group include allyl, dimethoxymethyl, diethoxymethyl, tert-butyl, triphenylmethyl, benzyl, and 4-methoxybenzyl.
Examples of the heteroaryl-based protecting group include a 2-pyridyl group, a 4-pyridyl group, a 2-pyrazinyl group, a 2-pyrimidinyl group and a 2-triazinyl group.
Examples of the carbamate-based protecting group include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, p-methoxyphenyl-azobenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 3,4, 5-trimethoxybenzyloxycarbonyl, p-biphenylisopropoxycarbonyl, diisopropylmethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, and 9-fluorenylmethoxycarbonyl.
As other protecting groups, there may be used alkylsulfonyl such as methylsulfonyl, arylsulfonyl such as p-toluenesulfonyl, alkanoyl such as acetyl, and aroyl such as benzoyl.
Among these protecting groups, the protecting group is preferably a silyl-based protecting group, particularly preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a triisopropylsilyl group, and more preferably a triisopropylsilyl group, from the viewpoint of yield and the like.
In the present invention, as the metal catalyst used in the reaction for obtaining the compound (I) from the compound (V), a nickel catalyst, a palladium catalyst, or the like can be used.
Examples of the nickel catalyst used in the present invention include 0-valent nickel catalysts such as bis (1, 5-cyclooctadienyl) nickel and the like, and 2-valent nickel catalysts such as nickel chloride and bis (triphenylphosphine) nickel chloride and the like, and phosphine ligands such as triphenylphosphine, 2- (di-t-butylphosphino) biphenyl, Xantphos, bis [ 2- (diphenylphosphino) phenyl ] ether (hereinafter, DPEPhos), and (±) -2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl (hereinafter, (+ -) -BINAP), and the like, and N, N ' -tetramethylethylenediamine and the like may be added as necessary.
The palladium catalyst used in the present invention includes 0-valent palladium catalysts such as palladium carbon and tetrakis (triphenylphosphine) palladium, 2-valent palladium catalysts such as palladium chloride, palladium acetate and (dichlorobis (tri-o-tolylphosphine)) palladium, and phosphine ligands such as triphenylphosphine, 2- (di-t-butylphosphino) biphenyl, xanthphos, DPEPhos and (±) -BINAP may be added as necessary.
As the base used in the present invention, a tertiary amine such as triethylamine or diisopropylethylamine, a metal base such as lithium hydride, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide (hereinafter, LDA), lithium hexamethyldisilazide (hereinafter, LiHMDS), ethylmagnesium, sodium carbonate, or calcium carbonate, or the like can be added.
A method for producing a pyrrole-3-carbaldehyde derivative, which is a synthetic intermediate in producing vonoprazan fumarate according to the present invention, and a method for producing vonoprazan fumarate using the same are shown below.
(production of Compound (I))
Compound (I) can be produced by a cross-coupling reaction or the like described in non-patent document 3 and non-patent document 4. For example, the non-halogenated unsubstituted pyrrole can be used by radical coupling reaction under an inert gas atmosphere of nitrogen or argon to 1 to 3 equivalents of the above base, preferably a metal base, more preferably diethyl ether, cyclopropyl methyl ether, sodium hydride,Tetrahydrofuran, 4-methyltetrahydropyran, bis
1 to 3 equivalents of a solution of pyrrole/the above solvent is added dropwise to a solvent suspension of ethers such as alkane, monoglyme, diglyme, etc., or aromatic hydrocarbons such as benzene, toluene, xylene, etc., at-10 ℃ to room temperature, followed by stirring for 10 minutes to 1 hour, and then 1 to 3 equivalents of inorganic zinc such as zinc halide (zinc chloride, zinc bromide), etc., or organic zinc (preferably zinc halide, particularly preferably zinc chloride), such as zinc dipentanoyl, etc., are added thereto, followed by stirring for 10 minutes to 1 hour at room temperature. Then, compound (I) can be produced by adding 1 to 3 equivalents of compound (V), 0.0001 to 1.0 equivalent (preferably 0.001 to 0.003 equivalent) of the catalyst such as palladium and 0.0001 to 1.0 equivalent (preferably 0.001 to 0.003 equivalent) of the phosphine ligand, and reacting at room temperature to 150 ℃ (preferably 90 to 130 ℃) for 5 minutes to 24 hours.
(production of Compound (II))
The compound (II) can be produced by introducing a protecting group into the compound (I), and the method for producing the protecting group varies depending on the protecting group selected, but a generally known method can be employed. For example, when a silyl protecting group is introduced, 1 to 1.5 equivalents of the above base, preferably a metal base, more preferably diethyl ether of sodium hydride, cyclopropylmethyl ether, tetrahydrofuran, 4-methyltetrahydropyran, or bis
Compound (I) is added dropwise to a solvent suspension of an ether such as an alkane, monoglyme, diglyme, or the like, an aprotic polar solvent such as N, N-dimethylformamide, or a mixed solvent thereof, preferably an ether, at-10 ℃ to room temperature, then a metal chelating agent such as a crown ether, tetraethylene diamine, or dimethylimidazolidinone, preferably dimethylimidazolidinone, is added dropwise, and then a protecting group-introducing reagent in an amount of 1 to 1.5 equivalents is added dropwise to the mixture to react the mixture for 5 minutes to 3 hours, whereby compound (II) can be produced.
When introducing a urethane-based protecting group, the urethane-based protecting group is usedThe reaction conditions vary depending on the kind, and for example, when a t-butoxycarbonyl (Boc group), a t-pentyloxycarbonyl (Aoc group), a benzyloxycarbonyl (Z group), a 9-fluorenylmethoxycarbonyl (Fmoc) group, a 2,2, 2-trichloroethoxycarbonyl group, a 2- (trimethylsilyl) ethoxycarbonyl group or the like is introduced into the compound (I), a di-n-ethyloxycarbonyl group or the like can be used
Alkane, di
In a solvent such as an alkane/water, methylene chloride or tetrahydrofuran, di-tert-butyl dicarbonate ((Boc) is reacted in the presence of an organic base such as triethylamine or pyridine, and an inorganic base such as sodium hydride, potassium hydroxide, sodium hydroxide, potassium hydrogen carbonate or sodium hydrogen carbonate2O), tert-butoxycarbonyl chloride, benzyloxycarbonyl chloride, tert-pentyloxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride, 2,2, 2-trichloroethyl chloroformate, 2- (trimethylsilyl) ethoxymethyl chloride, tert-butoxycarbonyl azide, benzyloxycarbonyl azide and the like, and 1 to 1.5 equivalents of a commonly known introducing reagent such as a Boc group and the like are reacted at 0 to 100 ℃ for 5 minutes to 10 hours.
(production of Compound (III))
The compound (III) can be produced by a generally known formylation reaction such as Vilsmeier reaction, Rieche reaction, Daff reaction, Reimer-Tiemann reaction, etc., for example, in the Vilsmeier reaction, Vilsmeier reagent ((chloromethylene) dimethylammonium chloride) is prepared from N, N-disubstituted formamide such as N, N-Dimethylformamide (DMF), N-Methylformanilide (MFA), N-formylmorpholine, N-diisopropylformamide, etc., and acid chlorides such as phosphorus oxychloride, oxalyl chloride, thionyl chloride, triphenylphosphine-bromide, hexachlorocyclotriphosphazene, etc., or a commercially available product is purchased, and the compound (II) is reacted with a solvent such as phosphorus oxychloride; or halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, etc.; aromatic hydrocarbons such as benzene, toluene, and nitrobenzene; tetrahydrofuran, methyltetrahydropyran, bis
The compound (III) can be produced by stirring ethers such as alkanes, aprotic polar solvents such as ethyl acetate, acetonitrile, N-dimethylformamide, or a mixed solvent thereof, preferably ether solvents, aromatic hydrocarbons, aprotic polar solvents, or a mixed solvent thereof, more preferably methyl tetrahydropyran at 0 to 100 ℃ (preferably 40 to 80 ℃) for 0.5 to 12 hours, and then reacting the mixture.
(production of Compound (IV))
The compound (IV) can be produced by deprotection reaction of the compound (III). The deprotection reaction differs depending on the protecting group, and a generally known method can be used, and for example, when the protecting group is a silyl protecting group, it can be produced by reacting a fluorine source such as tetrabutylammonium fluoride, HF pyridine complex, HF triethylamine complex or the like in a solution such as tetrahydrofuran at-10 ℃ to room temperature. The deprotection reaction of the silyl protecting group can be carried out in the same manner even under acidic conditions such as hydrochloric acid and trifluoroacetic acid or under basic conditions such as aqueous sodium hydroxide, whereby compound (IV) can be produced. The deprotecting reagent may be 3 to 10 equivalents (preferably 5 equivalents) of an aqueous sodium hydroxide solution with respect to the compound (III).
In the case of the carbamate-based protecting group, the reaction conditions may vary depending on the type of the carbamate-based protecting group, and the reaction may be carried out by a generally known method, for example, by catalytic reduction under a hydrogen atmosphere in the presence of palladium black, palladium on carbon, or the like, or by appropriately selecting acetic acid/hydrogen bromide, trifluoroacetic acid, hydrochloric acid/an organic solvent, or the like according to the protecting group.
In addition, compound (IV) can be produced by one-pot operation without isolating compound (III) from compound (II). In this case, the deprotection can be carried out by adding a reagent for the deprotection to the reaction system after the reaction of the compounds (II) to (III) is completed.
The compound (IV) may be produced by one pot operation without separating the compound (II) and the compound (III) from the compound (I), and for example, after the reaction in the production of the compound (III) is completed, a reaction reagent in the production of the compound (IV) is added to the reaction system, and after the reaction is completed, a reagent for the deprotection reaction is further added to the reaction system, and the reaction is similarly performed, whereby the compound (IV) can be produced. The same amounts as described above can be used in relation to the amounts of the reagents in any production.
(production of Compound (VI))
Adding dropwise a solution of a compound (IV) such as tetrahydrofuran to a 1 to 1.5 equivalent of a sodium hydride/tetrahydrofuran suspension at-10 ℃ to room temperature, stirring the mixture for 0.5 to 1 hour, further stirring the mixture for 0.5 to 1 hour at-10 ℃ to room temperature in the presence of a metal chelating agent such as crown ether, tetramethylethylenediamine or dimethylimidazolidinone, subsequently adding pyridine-3-sulfonyl chloride, and stirring the mixture for 0.5 hour at 0 ℃. Further, pyridine-3-sulfonyl chloride is added thereto, and the mixture is stirred at-10 ℃ to room temperature for 0.5 to 1 hour, whereby the compound (VI) can be produced.
The compound (VI) can be produced by adding a base such as triethylamine or N, N-diisopropylamine, a catalytic amount of 4-dimethylaminopyridine or pyridine-3-sulfonyl chloride to a solution of the compound (IV) in dichloromethane or acetonitrile at 0 to room temperature, and stirring the mixture at room temperature to 100 ℃ for 0.5 to 12 hours.
(production of Compound (VII))
The compound (VII) can be obtained by adding a solution of methylamine in methanol or the like dropwise to a solution of the compound (VI) in methanol or the like at 0 ℃ to room temperature, stirring the mixture for 0.5 to 1 hour, and adding 1 to 3 equivalents of a reducing agent such as sodium borohydride or the like to the mixture at 0 ℃ to room temperature to react the mixture for 0.5 to 1 hour.
(Vonoprazan fumarate production)
Vonoprazan fumarate can be produced by adding a solution of fumaric acid in methanol or the like to a solution of compound (VII) in ethyl acetate, methanol or the like at 0 ℃ to room temperature, stirring for 0.5 to 1 hour, filtering the precipitated crystal, and, if necessary, recrystallizing with methanol/water.
Examples
The present invention will be described in more detail below with reference to examples, comparative examples and test examples, but the present invention is not limited to these examples.
Example 1
Production of 2- (2-fluorophenyl) -1H-pyrrole
After pyrrole (2.1mL, 30.0mmol) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2g, 30.0mmol) and tetrahydrofuran (10mL) under ice-cooling and stirred for 0.5 hour, zinc chloride (4.1g, 30.0mmol) was added and stirred at room temperature for 0.5 hour. Next, palladium acetate (11mg, 0.05mmol), 2- (di-t-butylphosphino) biphenyl (15mg, 0.05mmol) and 1-fluoro-2-iodobenzene (1.1mL, 10.0mmol) were added and degassed, followed by stirring at 60 ℃ for 6 hours. The reaction mixture was cooled at 0 ℃ and water was added dropwise thereto, and after insoluble matter was filtered, the mixture was separated with ethyl acetate. After adding ethyl acetate to the aqueous layer and re-extracting, the organic layers were combined and washed with saturated brine. The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography and dried under reduced pressure to obtain the title compound (1.18g, yield 74%).
Mass spectrum (ESI): m/z calcd for C10H7FN [ M-H ] -: 160.06, respectively; found: 160.18, respectively; 1H-NMR (400MHz, CDCl3) (ppm): 6.30-6.33 (m, 1H), 6.64-6.67 (m, 1H), 6.90-6.93 (m, 1H), 7.07-7.16 (m, 1H), 7.13-7.17 (m, 2H), 7.60-7.65 (m, 1H), 9.05(brs, 1H).
Example 2
Production of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole
After a solution of 2- (2-fluorophenyl) -1H-pyrrole (172mg, 1.07mmol) in tetrahydrofuran (2mL) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 64mg, 1.61mmol) and tetrahydrofuran (2mL) under ice-cooling and stirred for 0.5 hour, 15-crown-5-ether (0.32mL, 1.61mmol) was added and stirred at 0 ℃ for 0.5 hour. Triisopropylsilyl chloride (0.35mL, 1.61mmol) was then added dropwise and stirred at room temperature for 4 hours. Cooled to 0 ℃, water was added dropwise, and the mixture was separated with ethyl acetate. After re-extraction by adding ethyl acetate to the aqueous layer, the organic layers were combined and washed with saturated brine. After the solvent was distilled off under reduced pressure, the residue was purified by a silica gel column and dried under reduced pressure, whereby the title compound (272mg, yield 80%) was obtained.
Mass spectrum (ESI): m/z calcd for C19H28FNNaSi [ M + Na ] +: 340.19, respectively; found: 340.16, respectively; 1H-NMR (400MHz, CDCl3) (ppm): 1.01(d, J ═ 6.9Hz, 18H), 1.13-1.21 (m, 3H), 6.25(dd, J ═ 3.2, 1.2Hz, 1H), 6.37(t, J ═ 3.2Hz, 1H), 6.93(dd, J ═ 2.8, 2.0Hz, 1H), 7.03-7.12 (m, 2H), 7.29-7.37 (m, 2H).
Example 3
Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
To a solution of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole (100mg, 0.32mmol) in dichloromethane (3.0mL) was added Vilsmeier reagent (123mg, 0.96mmol) under ice-cooling and stirred at 40 ℃ for 0.5 hour. After the solvent was distilled off under reduced pressure, an aqueous sodium hydroxide solution (1.0M, 3mL) was added thereto, and the mixture was stirred at room temperature for 6 hours, followed by addition of ethyl acetate for liquid separation. After re-extraction by adding ethyl acetate to the aqueous layer, the organic layers were combined and washed with saturated brine. Purification by silica gel column and drying under reduced pressure were carried out, whereby the title compound (48mg, yield 80%) was obtained.
Mass spectrum (ESI): m/z calcd for C11H8FNNaO [ M + Na ] +: 212.05, respectively; found: 212.03, respectively; 1H-NMR (400MHz, CDCl3) (ppm): 7.07(dd, J ═ 2.0, 1.2Hz, 1H), 7.12-7.26 (m, 3H), 7.53(dd, J ═ 2.8, 1.2Hz, 1H), 7.64(dt, J ═ 7.6, 1.6Hz, 1H), 9.45(brs, 1H), 9.86(s, 1H).
Example 4
Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
After pyrrole (2.1mL, 30.0mmol) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2g, 30.0mmol) and 4-methyltetrahydropyran (10mL) under ice-cooling and stirred for 0.5 hour, zinc chloride (4.1g, 30.0mmol) was added and stirred at room temperature for 0.5 hour. Palladium acetate (11mg, 0.05mmol), 2- (di-t-butylphosphino) biphenyl (15mg, 0.05mmol) and 1-fluoro-2-iodobenzene (1.1mL, 10.0mmol) were then added, and the mixture was stirred at 100 ℃ for 0.5 hour. The reaction mixture was cooled at 0 ℃ and 28% aqueous ammonia was added dropwise thereto, and after insoluble matter was filtered, the mixture was separated with ethyl acetate. After the solvent was distilled off under reduced pressure, 2- (2-fluorophenyl) -1H-pyrrole was obtained as a crude product.
To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 600mg, 15mmol) in tetrahydrofuran (10mL) and dimethylimidazolidinone (2mL) was added dropwise a solution of the resulting crude product of 2- (2-fluorophenyl) -1H-pyrrole in tetrahydrofuran (2mL) under ice-cooling, and stirred for 0.5 hour. Triisopropylsilyl chloride (3.2mL, 15mmol) was then added dropwise and stirred at room temperature for 2 hours. While cooling to 0 ℃, water was added dropwise and the solution was separated with ethyl acetate. After the solvent was distilled off under reduced pressure, liquid separation was again performed using heptane and water, and the solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was obtained as a crude product.
To a dichloromethane (50mL) solution of the resulting crude product of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was added Vilsmeier reagent (3.8g, 30mmol) under ice-cooling and stirred at 40 ℃ for 0.5 hour. After the solvent was distilled off under reduced pressure, an aqueous solution of sodium hydroxide (1.0M, 100mL) was added thereto, and the mixture was stirred at room temperature for 6 hours, followed by addition of ethyl acetate for liquid separation. The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. Recrystallization from heptane and ethyl acetate and drying under reduced pressure were carried out, whereby the title compound (1.34g, yield 70%) was obtained.
Example 5
Preparation of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde
After a solution of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (100mg, 0.53mmol) in tetrahydrofuran (2mL) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 32mg, 0.79mmol) and tetrahydrofuran (2mL) under ice-cooling and stirred for 0.5 hour, 15-crown-5-ether (0.16mL, 0.79mmol) was added and stirred for 0.5 hour at 0 ℃. Next, pyridine-3-sulfonyl chloride (95. mu.L, 0.79mmol) was added, and the mixture was stirred at 0 ℃ for 0.5 hour. Pyridine-3-sulfonyl chloride (95. mu.L, 0.79mmol) was further added and stirred at 0 ℃ for 0.5 hour. Water was added dropwise and the solution was separated with ethyl acetate. After re-extraction by adding ethyl acetate to the aqueous layer, the organic layers were combined and washed with saturated brine. After the solvent was distilled off under reduced pressure, the residue was purified by a silica gel column and dried under reduced pressure, whereby the title compound (167mg, yield 95%) was obtained.
Mass spectrum (ESI): m/z calcd for C16H11FN2NaO3S "M + Na" +: 353.04, respectively; found: 353.00; 1H-NMR (400MHz, CDCl3) (ppm): 6.68(d, J ═ 1.7Hz, 1H), 7.01-7.05 (m, 1H), 7.16-7.18 (m, 2H), 7.37-7.40 (m, 1H), 7.45-7.51 (m, 1H), 7.69-7.72 (m, 1H), 8.15(d, J ═ 1.8Hz, 1H), 8.58(d, J ═ 1.7Hz, 1H), 8.82(dd, J ═ 4.8, 1.5Hz, 1H), 9.90(s, 1H).
Example 6
Preparation of 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic fumarate
To a solution of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde (100mg, 0.30mmol) in methanol (3mL) was added dropwise a solution of methylamine in methanol (2.0M, 1.06mL, 2.12mmol) at room temperature, and the mixture was stirred for 0.5 hour. Cooled to 0 deg.C, sodium borohydride (34mg, 0.91mmol) was added and stirred for 0.5 h. 1N hydrochloric acid (3mL) was added dropwise at 0 ℃ and stirred at room temperature for 0.5 hour. Saturated sodium bicarbonate solution and ethyl acetate were added to separate the solution. After re-extraction by adding ethyl acetate to the aqueous layer, the organic layers were combined and washed with saturated brine. After the organic layer was concentrated, ethyl acetate (3mL) was added, and a solution of fumaric acid (39mg, 0.30mmol) in methanol (0.3mL) was added. After stirring at room temperature for 30 minutes, the precipitated crystals were filtered and washed with ethyl acetate and methanol to give a crude product. The obtained crude crystals were recrystallized from methanol and water, and the precipitated crystals were filtered and dried under reduced pressure to obtain the title compound (90mg, yield 64%).
Mass spectrum (ESI): m/z calcd for C17H17FN3NaO2S "M + H" +: 346.09, respectively; found: 346.11, respectively; 1H-NMR (400MHz, DMSO-d 6) (ppm): 2.39(s, 3H), 3.76(s, 2H), 6.44(d, J ═ 2.0Hz, 1H), 6.47(s, 2H), 7.10 to 7.13(m, 1H), 7.20 to 7.26(m, 2H), 7.50 to 7.56(m, 1H), 7.60 to 7.67(m, 2H), 7.85 to 7.89(m, 1H), 8.56(d, J ═ 2.8Hz, 1H), 8.87 to 8.89(m, 1H), 3H were not detected.
Example 7
Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
After pyrrole (15.7mL, 220.0mmol) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 8.8g, 220.0mmol) and 4-methyltetrahydropyran (100mL) under ice-cooling and stirred for 0.5 hour, zinc chloride (30.3g, 220.0mmol) was added and stirred at room temperature for 0.5 hour. Next, palladium acetate (56.1mg, 0.25mmol), 2- (di-t-butylphosphino) biphenyl (74.6mg, 0.25mmol) and 1-fluoro-2-iodobenzene (11.5mL, 100.0mmol) were added, and the mixture was stirred at about 100 ℃ for 1 hour. An aqueous solution of sodium hydroxide (5.0N, 220.0mmol) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour. Insoluble matter was filtered, washed with toluene (100mL), and the organic layer was separated and the aqueous layer was extracted with toluene (100 mL). The organic layers were combined and washed with distilled water (167mL) and saturated brine (167 mL). After the solvent was distilled off under reduced pressure, toluene (167mL) was added to the residue. The solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1H-pyrrole was obtained as a crude product (20.9 g).
To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 4.4g, 110.0mmol) in tetrahydrofuran (100mL) and dimethylimidazolidinone (32.6mL, 300.0mmol), a solution of the resulting crude product of 2- (2-fluorophenyl) -1H-pyrrole in tetrahydrofuran (10mL) was added dropwise under ice-cooling, washed with tetrahydrofuran (10mL) and stirred for 0.5 hour. Triisopropylsilyl chloride (23.5mL, 110.0mmol) was then added dropwise and stirred at room temperature for 1 hour. Distilled water (17mL) was added dropwise under an ice bath, and further distilled water (167mL) was added. Ethyl acetate (84mL) was used for 2 extractions, which were washed with distilled water (167mL) and saturated brine (167 mL). After the solvent was distilled off under reduced pressure, toluene (167mL) was added to the residue. After the solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was obtained as a crude product (45.2 g).
Oxalyl chloride (17.2mL, 200.0mmol) was added to dichloromethane (100mL), and DMF (15.5mL, 200.0mmol) was added dropwise under ice-cooling, followed by stirring for 0.5 hour. A solution of the resulting crude product of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole in 4-methyltetrahydropyran (100mL) was added in one portion and stirred at about 50 ℃ for 3 hours. Aqueous sodium hydroxide (5.0M, 100mL) was added under ice-cooling and stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was separated with ethyl acetate (200 mL). The organic layers were combined, washed with saturated brine (200mL), and the solvent was distilled off under reduced pressure. To the resulting solid residue was added ethyl acetate (47mL), which was dissolved at about 70 ℃ and heptane (300mL) was added. After cooling at room temperature, the mixture was stirred for 1 hour in an ice bath, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate/heptane (1:6, 70 mL). Dried under reduced pressure at 50 ℃ for 1.5 hours, whereby the title compound (13.6g, yield 72%) was obtained.
Example 8
Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (one-pot synthesis from 2- (2-fluorophenyl) -1H-pyrrole)
After dimethyl imidazolidinone (20.0mL, 186mmol) was added to a solution of 2- (2-fluorophenyl) -1H-pyrrole (10.0g, 62.0mmol) in 4-methyltetrahydropyran (62mL), sodium hydride (dispersed in 60% liquid paraffin, 2.7g, 68.2mmol) was slowly added under ice-cooling, and stirred for 10 minutes. Next, triisopropylsilyl chloride (14.6mL, 68.2mmol) was added dropwise and stirred under ice-cooling for 2 hours. To a solution of Vilsmeier reagent prepared from oxalyl chloride (10.6mL, 124mmol) and DMF (9.65mL, 124mmol) in dichloromethane (90mL) was added the reaction solution of 2- (2-fluorophenyl) -1H-pyrrole in one portion under ice-cooling, washed with 4-methyltetrahydropyran (20mL) and stirred at about 60 ℃ for 2 hours. Aqueous sodium hydroxide (2.0M, 310mL) was added under ice-cooling and stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was separated with ethyl acetate (120 mL). The organic layers were combined, washed with saturated brine (120mL), and the solvent was distilled off under reduced pressure. To the resulting solid residue was added ethyl acetate (29mL), which was dissolved at about 70 ℃ and heptane (180mL) was added. After cooling at room temperature, the mixture was stirred for 1 hour in an ice bath, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate/heptane (1:6, 42 mL). Dried at 50 ℃ for 1.5 hours under reduced pressure, whereby the title compound (8.30g, yield 71%) was obtained.
Claims (7)
1. A process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde, which comprises introducing a protecting group to the nitrogen atom of the pyrrole ring in a pyrrole derivative represented by the following formula (I) to obtain an N-protected pyrrole derivative represented by the following formula (II), formylating the N-protected pyrrole derivative to obtain a pyrrole-3-carbaldehyde derivative represented by the following formula (III), and deprotecting the N-protected pyrrole derivative to obtain 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the following formula (IV) wherein P represents a protecting group,
2. the production method according to claim 1, wherein the protecting group represented by P is a silyl protecting group.
3. The production process according to claim 1 or 2, wherein the protecting group represented by P is triisopropylsilyl.
4. A process for producing a compound (I) according to any one of claims 1 to 3, wherein the pyrrole derivative of the general formula (I) is obtained by reacting an o-fluorobenzene derivative represented by the following formula (V) with pyrrole in the presence of a metal catalyst,
in the formula (V), L represents a leaving group.
5. The production method according to claim 4, wherein the metal catalyst is a palladium catalyst.
6. A process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine, which comprises reacting 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the general formula (IV) obtained by the above production process with pyridine-3-sulfonyl chloride or a salt thereof in the presence of an inorganic or organic base to obtain a pyrrole derivative represented by the following formula (VI), further condensing the pyrrole derivative with methylamine, and then subjecting the condensation reaction to a reduction reaction to obtain 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine represented by the following formula (VII),
7. a process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanamine monofumarate, which comprises using a compound of the general formula (VII) obtained by the above production process and fumaric acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2017251749 | 2017-12-27 | ||
| JP2017-251749 | 2017-12-27 | ||
| PCT/JP2018/047697 WO2019131695A1 (en) | 2017-12-27 | 2018-12-26 | Production method for 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl]-n-methylmethanamine monofumarate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111527067A true CN111527067A (en) | 2020-08-11 |
Family
ID=67063705
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880082979.8A Pending CN111527067A (en) | 2017-12-27 | 2018-12-26 | Process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic acid salt |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP7227925B2 (en) |
| KR (2) | KR102443292B1 (en) |
| CN (1) | CN111527067A (en) |
| WO (1) | WO2019131695A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114573560A (en) * | 2022-03-17 | 2022-06-03 | 日照正济药业有限公司 | Preparation method of Voranolan fumarate |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113549054B (en) * | 2020-04-23 | 2024-03-15 | 鲁南制药集团股份有限公司 | Vonoprazan fumarate intermediate and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187852A (en) * | 2016-07-07 | 2016-12-07 | 江西同和药业股份有限公司 | A kind of preparation method of Vonoprazan fumarate intermediate |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5819494B2 (en) | 1978-11-06 | 1983-04-18 | トヨタ自動車株式会社 | Passive seat belt device |
| IL87222A (en) * | 1987-07-29 | 1993-04-04 | American Cyanamid Co | Arylpyrroles, methods for thepreparation thereof andinsecticidal, acaricidal andnematicidal compositionscontaining them |
| US5101042A (en) | 1990-12-11 | 1992-03-31 | American Cyanamid Company | Process for the preparation of insecticidal, nematicidal and acaricidal 2-halo-3-substituted-5-arylpyrrole compounds |
| PL1919865T3 (en) | 2005-08-30 | 2011-09-30 | Takeda Pharmaceuticals Co | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
| EP3241826B1 (en) | 2009-02-25 | 2019-10-30 | Takeda Pharmaceutical Company Limited | Process for producing pyrrole compound |
| CN105440019A (en) | 2015-12-17 | 2016-03-30 | 昆明贵研药业有限公司 | Preparation method of drug for treating gastric acid related diseases |
| CN106146466A (en) | 2016-06-30 | 2016-11-23 | 珠海赛隆药业股份有限公司（长沙）医药研发中心 | Vonoprazan fumarate intermediate, its preparation method and the method for preparation Vonoprazan fumarate |
| CN106366071B (en) | 2016-08-22 | 2019-05-07 | 山东金城医药集团股份有限公司 | The preparation method of Vonoprazan fumarate |
-
2018
- 2018-12-26 WO PCT/JP2018/047697 patent/WO2019131695A1/en active Application Filing
- 2018-12-26 KR KR1020207019383A patent/KR102443292B1/en active IP Right Grant
- 2018-12-26 JP JP2019562062A patent/JP7227925B2/en active Active
- 2018-12-26 CN CN201880082979.8A patent/CN111527067A/en active Pending
- 2018-12-26 KR KR1020227030825A patent/KR102500124B1/en active IP Right Grant
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187852A (en) * | 2016-07-07 | 2016-12-07 | 江西同和药业股份有限公司 | A kind of preparation method of Vonoprazan fumarate intermediate |
Non-Patent Citations (2)
| Title |
|---|
| FARNAZ JAFARPOU ET AL.: ""Triethanolamine-Mediated Palladium-Catalyzed Regioselective C-2 Direct Arylation of Free NH-Pyrroles"", 《J. ORG. CHEM.》 * |
| YASUYOSHI ARIKAWA ET AL.: ""Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (PCAB)"", 《J. MED. CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114573560A (en) * | 2022-03-17 | 2022-06-03 | 日照正济药业有限公司 | Preparation method of Voranolan fumarate |
| CN114573560B (en) * | 2022-03-17 | 2024-02-06 | 日照正济药业有限公司 | Preparation method of voronoi fumarate |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2019131695A1 (en) | 2019-07-04 |
| JPWO2019131695A1 (en) | 2021-01-14 |
| JP7227925B2 (en) | 2023-02-22 |
| KR20200096598A (en) | 2020-08-12 |
| KR20220127369A (en) | 2022-09-19 |
| KR102443292B1 (en) | 2022-09-14 |
| KR102500124B1 (en) | 2023-02-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101294432B1 (en) | 3-alkyl-5-(4-alkyl-5-oxo-tetrahydrofuran-2-yl)pyrrolidin-2-one derivatives as intermediates in the synthesis of renin inhibitors | |
| KR20150008875A (en) | Lysin-glutamic acid dipeptide derivatives | |
| CN113039178A (en) | Synthesis of pyrido [2,3-d ] pyrimidin-7 (8H) -ones | |
| CN111527067A (en) | Process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic acid salt | |
| JP2009531418A (en) | Coupling method for the preparation of quinolone intermediates | |
| WO2016002918A1 (en) | Method for producing indole compound | |
| WO2019049824A1 (en) | Protected l-carnosine derivative, l-carnosine, and method for producing crystalline l-carnosine zinc complex | |
| CN113861167A (en) | Preparation method of Voranolan fumarate | |
| WO2007049293A1 (en) | An improved process for preparation of irbesartan | |
| WO2007071750A1 (en) | Intermediates and processes for the preparation of valsartan | |
| CN114641468A (en) | Process for the synthesis of the sodium salt of 4- [ [ (1R) -2- [5- (2-fluoro-3-methoxyphenyl) -3- [ [ 2-fluoro-6- (trifluoromethyl) -phenyl ] methyl ] -3, 6-dihydro-4-methyl-2, 6-dioxo-1 (2H) -pyrimidinyl ] -1-phenylethyl ] amino ] -butyric acid (ELAGOLIX sodium salt) and intermediates of said process | |
| US20230025246A1 (en) | Process for preparing chroman compounds | |
| JP4181233B2 (en) | Method for producing pyrrolidine-2,4-dione derivative | |
| JP4258658B2 (en) | Method for producing acetylene compound | |
| JP2004238322A (en) | Method for producing (r)-3-aminopentanenitrile methanesulfonic acid salt | |
| KR20200068678A (en) | Process for manufacturing spiro derivatives | |
| JP6277470B2 (en) | Method for producing trans-1,2-diaminocyclohexane | |
| EP0854135A2 (en) | Process for preparing 2-cyanobiphenyl compound | |
| CN110683943B (en) | Fluoro 1, 3-eneyne compound and preparation method thereof | |
| CN108148044B (en) | Amide compound and method for preparing Vonoprazan fumarate from same | |
| JP2022035954A (en) | N-boc-lactam derivative and method for producing the same, and method for producing cyclic amine derivative | |
| WO2024064745A1 (en) | Synthesis of reldesemtiv | |
| WO2023100110A1 (en) | Process for preparing brivaracetam | |
| CN111187197A (en) | Synthesis method of Tezacaftor intermediate | |
| WO2005063678A1 (en) | Process for producing phenylacetic acid derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |