CN116023364A - Preparation method of voronoi fumarate - Google Patents

Preparation method of voronoi fumarate Download PDF

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CN116023364A
CN116023364A CN202310047009.7A CN202310047009A CN116023364A CN 116023364 A CN116023364 A CN 116023364A CN 202310047009 A CN202310047009 A CN 202310047009A CN 116023364 A CN116023364 A CN 116023364A
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fumarate
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郭恒杰
张树康
邵心茹
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Shandong Baoyuan Pharmaceutical Co ltd
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Abstract

The invention discloses a preparation method of voronoi fumarate, which takes pyridine-3-formaldehyde as an initial raw material, firstly performs bromination reaction, then performs sulfation with pyridine-3-sulfonyl chloride to generate 5-bromo-1- (pyridine-3-yl sulfonic group) -1H-pyrrole-3-formaldehyde, continuously performs Suzuki coupling reaction with 2-fluoroboric acid to generate 5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonic group) -1H-pyrrole-3-formaldehyde, and finally performs reductive aminomethylation and salification to obtain the voronoi fumarate. The preparation method avoids using materials such as bromine, hydrogen chloride and the like with strong corrosiveness, avoids using flammable catalysts such as palladium carbon, raney nickel and the like, has good safety and few operation steps, and is suitable for industrial production.

Description

Preparation method of voronoi fumarate
Technical Field
The invention relates to a preparation method of vorexant fumarate, and belongs to the technical field of pharmaceutical chemicals.
Background
Vonoprazan fumarate, chemical name: 1- (5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine monofumarate, trade name: takecab. Vonoprazan fumarate is a novel oral gastric acid resistant drug developed by the Wuta pharmaceutical company of Japan, and is first marketed in Japan in 12 months of 2014 for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, etc. The chemical structural formula is as follows:
Figure BDA0004055969620000011
at present, the synthesis method of Vonoprazan fumarate mainly comprises the following steps:
(1) Chinese patent CN102421753a discloses a preparation method of vorofan fumarate, which has the following specific synthetic route:
Figure BDA0004055969620000012
the method has complicated steps, uses materials such as hydrogen chloride with strong corrosiveness in the synthesis process, has high requirements on equipment, uses inflammable materials such as palladium carbon, raney nickel and the like in the reduction dechlorination and cyano reduction process, has great potential safety hazard, has high danger coefficient of industrial production operation and has high environmental protection pressure.
(2) Chinese patent CN101300229a discloses a preparation method of vorofan fumarate, which has the following specific synthetic route:
Figure BDA0004055969620000021
the synthesis route has complex operation, requires low-temperature reaction (-78 ℃), has lower palladium-carbon reduction yield (18 percent) in the fourth step, uses an expensive catalyst tetra-n-butyl ruthenium peroxide for oxidizing alcohol into aldehyde, is difficult to control, adopts multi-step column purification, is unfavorable for industrial production, uses sodium hydride as an acid binding agent in the reaction, easily generates material spraying in the feeding process, generates hydrogen in the reaction, has strong alkalinity, has large corrosion to equipment and multiple side reactions, also uses a phase transfer catalyst, has high price and high cost, and is not suitable for industrial scale-up production.
(3) Yu Qian in the research on synthesis and quality standards of voronoi fumarate (Shanghai pharmaceutical industry institute, 2017), a preparation method of voronoi fumarate is reported, and a specific synthetic route is as follows:
Figure BDA0004055969620000022
the synthesis route has complicated steps, uses materials such as bromine, hydrogen chloride and the like with strong corrosiveness in the synthesis process, has high requirements on equipment, uses palladium carbon in the reduction dechlorination process, has great potential safety hazard, requires low-temperature reaction (-78 ℃) in the sixth reaction, has high energy consumption, uses dangerous lithium aluminum hydride in the final amide reduction process, and is not suitable for industrial production.
Disclosure of Invention
The invention overcomes the defects of the prior art, and provides a preparation method of voronoi fumarate, which takes pyridine-3-formaldehyde as an initial raw material, firstly performs bromination reaction, then performs sulfanilamide acylation with pyridine-3-sulfonyl chloride to generate 5-bromo-1- (pyridine-3-yl sulfonic acid) -1H-pyrrole-3-formaldehyde, and continuously performs Suzuki coupling reaction with 2-fluoroboric acid to generate 5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonic acid) -1H-pyrrole-3-formaldehyde, and finally performs reductive amine methylation and salification to obtain the voronoi fumarate. The preparation method avoids using materials such as bromine, hydrogen chloride and the like with strong corrosiveness, avoids using flammable catalysts such as palladium carbon, raney nickel and the like, has good safety and few operation steps, and is suitable for industrial production.
The technical scheme of the invention is as follows: a method for preparing voronoi fumarate, comprising the steps of:
1) Taking pyridine-3-formaldehyde as a starting material, and carrying out bromination reaction with a brominating agent to generate 5-bromo-1H-pyrrole-3-formaldehyde (compound II);
2) Under the catalysis of an alkaline catalyst, the compound II and pyridine-3-sulfonyl chloride sulfanilamide undergo an acylation reaction to generate 5-bromo-1- (pyridine-3-yl sulfonic group) -1H-pyrrole-3-formaldehyde (compound III);
3) Under the catalysis of a catalyst, the compound III and 2-fluorobenzeneboronic acid undergo a Suzuki coupling reaction to generate 5- (2-fluorophenyl) -1- (pyridine-3-yl sulfonic group) -1H-pyrrole-3-formaldehyde (compound IV);
4) In the presence of a reducing agent, the compound IV reacts with methylamine hydrochloride through reductive amine methylation, then forms salt with fumaric acid to generate Vonoprazan fumarate, and then forms salt with fumaric acid to generate Vonoprazan fumarate.
The specific synthetic route is as follows:
Figure BDA0004055969620000031
wherein, the liquid crystal display device comprises a liquid crystal display device,
preferably, the brominating agent in the step 1) is Br 2 、NBS、CuBr 2 Preferably NBS. The organic solvent used in the step 1) is ethyl acetate, methyl acetate, acetone, etc., preferably ethyl acetate. The reaction temperature of the step 1) is-15 to-5 ℃.
Preferably, the basic catalyst in the step 2) is one of t-BuOK, DIEPA (N, N-diisopropylethylamine)/DMAP (4-dimethylaminopyridine) and triethylamine, preferably DIEPA/DMAP. The organic solvent used in the step 2) is one or more of acetonitrile, dichloromethane, chloroform, toluene and methanol, preferably acetonitrile. The reaction temperature of the step 2) is 40-50 ℃.
Preferably, the catalyst in the step 3) is PdCl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 4 One of them, preferably Pd (PPh) 3 ) 4 . The organic solvent used in the step 3) is a mixed solvent of DMF and water, and the volume ratio is preferably 7:3. The reaction temperature of the step 3) is 100-110 ℃.
Preferably, the reducing agent in the step 4) is NaBH 4 、NaBH(OAc) 3 、NaBH 3 One of CN, preferably NaBH (OAc) 3 . The organic solvent used in the reductive amine methylation reaction in the step 4) is one or more of methanol, ethanol, tetrahydrofuran and dioxane, preferably methanol. The reductive amine methylation reaction temperature of the step 4) is-5 ℃.
Preferably, the molar feed ratio of pyridine-3-carbaldehyde to NBS in the step 1) is 1:1.0-1.5, preferably 1:1.2.
Preferably, in the step 2), the molar feed ratio of the 5-bromo-1H-pyrrole-3-formaldehyde, pyridine-3-sulfonyl chloride-sulfonamide and DIEPA to DMAP is 1:1.0-1.5:0.1-0.3, and preferably 1:1.2:0.2.
Preferably, the molar ratio of compound III to 2-fluorobenzeneboronic acid in step 3) is 1:1.2-1.8, preferably 1:1.6, and the molar ratio of compound III to Pd (PPh 3 ) 4 The mass feed ratio of (2) is 1:0.10-0.15, preferably 1:0.13.
Preferably, the compounds IV, methylamine hydrochloride and NaBH (OAc) of step 4) 3 The molar feed ratio of (2) is 1:2.0-3.0:1.2-1.8, preferably 1:2.5:1.5.
The preparation method of the invention specifically comprises the following steps:
1) Adding pyridine-3-formaldehyde and ethyl acetate solvent into a reaction vessel, cooling to-15 to-5 ℃, adding NBS, stirring and reacting, and performing aftertreatment after the reaction is finished to obtain a compound II;
2) Adding a compound II, DIEPA/DMAP and acetonitrile serving as a solvent into a reaction container, dropwise adding an acetonitrile solution of pyridine-3-sulfonyl chloride, keeping the temperature at 40-50 ℃ after the dropwise adding, and stirring for reaction; after the reaction is finished, obtaining a compound III through post-treatment;
3) Adding a mixed solvent of a compound III, 2-fluorobenzeneboronic acid, inorganic base, DMF and water into a reaction vessel, and adding Pd (PPh) under the nitrogen environment 3 ) 4 Heating to 100-110 ℃, stirring for reaction, and after the reaction is finished, carrying out post-treatment to obtain a compound IV;
4) Adding a compound IV, a methanol solvent, triethylamine and methylamine hydrochloride into a reaction vessel, cooling to-5 ℃ and stirring for reaction, and then adding NaBH (OAc) 3 Stirring for reaction; after the reaction is finished, salifying the obtained product with fumaric acid to obtain a coarse product of the vorofacian fumarate, and further refining the coarse product to obtain a refined product of the vorofacian fumarate.
Further, the refining is as follows: and adding the crude product into a mixed solvent of methanol and water, heating and refluxing, and then cooling and crystallizing to obtain a refined Vonoprazan fumarate product.
Further, the post-treatment of the step 1) is as follows: na was added dropwise to the reaction solution 2 SO 3 The aqueous solution of (2) is stirred and separated, and the organic phase is sequentially subjected to alkali washing, salt washing, drying and reduced pressure concentration to obtain the compound II.
Further, the post-treatment of the step 2) is as follows: adding acid into the reaction liquid to adjust the pH value to 3-4, and then cooling and crystallizing to obtain the compound III.
Further, the post-treatment of the step 3) is as follows: cooling the reaction liquid to room temperature, dropwise adding water, adding ethyl acetate, standing for separating liquid, performing alkali washing, salt washing, drying and concentrating under reduced pressure on an organic phase, and then recrystallizing by adopting a mixed solvent of ethyl acetate and n-heptane to obtain a compound IV.
Further, the step 4) is salified with fumaric acid after post-treatment, specifically: after the reaction is finished, dropwise adding water to quench the reaction, concentrating the reaction liquid, adding alkali to adjust the pH value to 9.5-10.5, extracting the reaction liquid with ethyl acetate, washing an organic phase to be neutral by water, then placing the organic phase in a mixed solvent of ethyl acetate and DMF, adding fumaric acid, heating to 45-50 ℃ to perform heat preservation reaction, and then cooling to room temperature to precipitate a solid to obtain a coarse vorofan fumarate product.
Preferably, the molar ratio of compound III to inorganic base in step 3) is 1:1.3.
Preferably, the molar ratio of compound IV and triethylamine in step 4) is 1:1.
The beneficial effects of the invention are as follows: the method avoids using materials such as bromine, hydrogen chloride and the like with strong corrosiveness, avoids using flammable catalysts such as palladium carbon, raney nickel and the like, has good safety and few operation steps, and is suitable for industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of vorexant prepared in example 1 of the present invention;
FIG. 2 is a mass spectrum of vorexant prepared in example 1 of the present invention;
FIG. 3 is an HPLC chart of vorexant fumarate prepared in example 1 of the present invention;
fig. 4 is an HPLC diagram of vorexant fumarate prepared in example 1 of the present invention.
Detailed Description
Example 1
1) Preparation of 5-bromo-1H-pyrrole-3-carbaldehyde (Compound II)
Figure BDA0004055969620000051
Adding 10g of pyridine-3-formaldehyde and 100mL of ethyl acetate into a 250mL reaction bottle, starting stirring, cooling to-10 ℃, adding 22.5g of NBS, stirring for reaction for 0.5-1 h, and dripping Na into the reaction solution after the reaction is finished 2 SO 3 A solution of 15.9g and 50mL of water was stirred for 1h and separated. The organic phase was washed successively with saturated NaHCO 3 Washing with saturated NaCl solution, anhydrous Na 2 SO 4 The organic phase was concentrated under reduced pressure and dried to give 16.5g of a pale yellow oil in 90.2% yield.
2) Preparation of 5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde (Compound III)
Figure BDA0004055969620000061
To a 250mL reaction flask, 10g of 5-bromo-1H-pyrrole-3-carbaldehyde prepared in step 1), 1.4g of 4-dimethylaminopyridine, 8.9g of N, N-diisopropylethylamine and 40mL of acetonitrile were added, stirring was started, an acetonitrile (10 mL) solution of pyridine-3-sulfonyl chloride (12.2 g) was slowly added dropwise, and the mixture was reacted at 40-50℃under stirring for 1 hour. After the reaction is finished, 1N hydrochloric acid is added dropwise to adjust the pH to 3-4, after the dripping is finished, stirring is carried out for 1h, cooling is carried out to 0-10 ℃, heat preservation crystallization is carried out for 2h, suction filtration is carried out, and drying is carried out, thus obtaining 15.7g of light yellow solid with the yield of 86.7%.
3) Preparation of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde (Compound IV)
Figure BDA0004055969620000062
Into a 250mL reaction flask were charged 12.0g of 5-bromo-1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde prepared in step 2), 8.5g of 2-fluorophenylboronic acid, and NaCO 3 5.3g, DMF 70mL and water 30mL, stirring was started and Pd (PPh 3 ) 4 1.6g, heating to 100-110 ℃, stirring and reacting for 20h, cooling to room temperature after the reaction is finished, dropwise adding 30mL of water, stirring for 0.5h, adding 50mL of ethyl acetate into the reaction solution, separating the solution, and sequentially using saturated NaHCO for the organic phase 3 Washing with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, concentrating the organic phase under reduced pressure, adding 10mL of ethyl acetate and 30mL of n-heptane into the concentrate, heating to 75-80 ℃, stirring for 1h, cooling to 0-10 ℃, stirring for crystallization for 2h, filtering, and drying to obtain light yellow solid with the yield of 10.3g and the yield of 81.9%.
4) Preparation of Vonoprazan fumarate
Figure BDA0004055969620000063
To a 250mL reaction flask was added 10g of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde prepared in step 3), 60mL of methanol, 3.1g of triethylamine and 5.1g of methylamine hydrochloride, cooled to 0℃and stirred for 0.5H, and NaBH (OAc) was added 3 9.6g, and the reaction was stirred for 1h. After the reaction, 25mL of water was added dropwise to quench the reaction, the mixture was concentrated until no liquid was dropped out, ammonia water was added to adjust the pH to 10, and the reaction solution was extracted with 50mL of ethyl acetate. Sampling and detecting, wherein the hydrogen spectrum of the product is shown in figure 1, the mass spectrum is shown in figure 2, (M+H) + ＝346。
The organic phase is washed to be neutral by water and then placed in 120mL of ethyl acetate and 50mL of DMF, 3.5g of fumaric acid is added, the temperature is raised to 45-50 ℃ and kept for 1h, the temperature is reduced to room temperature, stirring is continued for 1h, filtering and drying are carried out, and the coarse product of vorofaprazan fumarate is obtained.
Adding the whole Vonoprazan fumarate crude product, 70mL of methanol and 30mL of water into a 250mL reaction bottle, heating and refluxing for 10min, slowly cooling to room temperature, continuously stirring for 2h, filtering and drying to obtain off-white solid 10.1g, with a yield of 72.3%, an HPLC purity of 99.89%, and an HPLC diagram shown in figure 3.
Example 2
Preparation of Vonoprazan fumarate
Figure BDA0004055969620000071
To a 250mL reaction flask, 10g of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde, 60mL of methanol, 3.1g of triethylamine and 5.1g of methylamine hydrochloride were added, the mixture was cooled to 0℃and stirred for 0.5H, and NaBH was added 4 1.7g, and the reaction was stirred for 1h. After the reaction, 25mL of water was added dropwise to quench the reaction, the mixture was concentrated until no liquid was dropped out, ammonia water was added to adjust the pH to 10, and the reaction solution was extracted with 50mL of ethyl acetate.
The organic phase is washed to be neutral by water and then placed in 120mL of ethyl acetate and 50mL of DMF, 3.5g of fumaric acid is added, the temperature is raised to 45-50 ℃ and kept for 1h, the temperature is reduced to room temperature, stirring is continued for 1h, filtering and drying are carried out, and the coarse product of vorofaprazan fumarate is obtained. The crude product of the Vonoprazan fumarate, 70mL of methanol and 30mL of water are added into a 250mL reaction bottle, the mixture is heated and refluxed for 10min, slowly cooled to room temperature, continuously stirred for 2h, filtered and dried to obtain 9.1g of off-white solid, the yield is 65.3 percent, the HPLC purity is 97.21 percent, and an HPLC chart is shown in figure 4.

Claims (10)

1. A method for preparing voronoi fumarate, comprising the steps of:
1) Pyridine-3-formaldehyde is taken as an initial raw material and is subjected to bromination reaction with a brominating agent to generate a compound II;
2) Under the catalysis of an alkaline catalyst, the compound II and pyridine-3-sulfonyl chloride sulfanilamide undergo an acylation reaction to generate a compound III;
3) Under the catalysis of a catalyst, the compound III and 2-fluorobenzeneboronic acid undergo a Suzuki coupling reaction to generate a compound IV;
4) In the presence of a reducing agent, carrying out reductive amine methylation reaction on a compound IV and methylamine hydrochloride, and then forming a salt with fumaric acid to generate Vonoprazan fumarate;
Figure FDA0004055969610000011
2. the process for preparing voronoi fumarate according to claim 1, wherein said brominating agent in step 1) is Br 2 、NBS、CuBr 2 One of the following; the organic solvent used in the step 1) is ethyl acetate, methyl acetate or acetone; the reaction temperature in the step 1) is-15 to-5 ℃.
3. The method for preparing voronoi fumarates as claimed in claim 1, wherein the basic catalyst in the step 2) is one of t-BuOK, dieap/DMAP, and triethylamine; the organic solvent used in the step 2) is one or more of acetonitrile, dichloromethane, chloroform, toluene and methanol; the reaction temperature in the step 2) is 40-50 ℃.
4. The process for preparing voronoi fumarate according to claim 1, wherein said catalyst in step 3) is PdCl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 4 One of the following; the organic solvent used in the step 3) is a mixed solvent of DMF and water, and the reaction temperature in the step 3) is 100-110 ℃.
5. The process for preparing voronoi fumarate according to claim 1, wherein said reducing agent in step 4) is NaBH 4 、NaBH(OAc) 3 、NaBH 3 One of the CNs; the organic solvent used in the reductive amine methylation reaction is one or more of methanol, ethanol, tetrahydrofuran and dioxane; the reductive amine methylation reaction temperature is-5 ℃.
6. The method for preparing vorexant fumarate according to any of claims 1 to 5, wherein said method comprises the steps of:
1) Adding pyridine-3-formaldehyde and ethyl acetate solvent into a reaction vessel, cooling to-15 to-5 ℃, adding NBS, stirring and reacting, and performing aftertreatment after the reaction is finished to obtain a compound II;
2) Adding a compound II, DIEPA/DMAP and acetonitrile serving as a solvent into a reaction container, dropwise adding an acetonitrile solution of pyridine-3-sulfonyl chloride, keeping the temperature at 40-50 ℃ after the dropwise adding, and stirring for reaction; after the reaction is finished, obtaining a compound III through post-treatment;
3) Adding a mixed solvent of a compound III, 2-fluorobenzeneboronic acid, inorganic base, DMF and water into a reaction vessel, and adding Pd (PPh) under the nitrogen environment 3 ) 4 Heating to 100-110 ℃, stirring for reaction, and after the reaction is finished, carrying out post-treatment to obtain a compound IV;
4) Adding a compound IV, a methanol solvent, triethylamine and methylamine hydrochloride into a reaction vessel, cooling to-5 ℃ and stirring for reaction, and then adding NaBH (OAc) 3 Stirring for reaction; after the reaction is finished, salifying the obtained product with fumaric acid to obtain a coarse product of the vorofacian fumarate, and further refining the coarse product to obtain a refined product of the vorofacian fumarate.
7. The process for preparing vorexant fumarate according to claim 6, wherein,
the step 4) is salified with fumaric acid after post-treatment, and specifically comprises the following steps: after the reaction is finished, dropwise adding water to quench the reaction, concentrating the reaction liquid, adding alkali to adjust the pH value to 9.5-10.5, extracting the reaction liquid with ethyl acetate, washing an organic phase to be neutral by water, then placing the organic phase in a mixed solvent of ethyl acetate and DMF, adding fumaric acid, heating to 45-50 ℃ to perform heat preservation reaction, and then cooling to room temperature to precipitate a solid to obtain a coarse vorofan fumarate;
the refining of the step 4) is as follows: and adding the coarse Vonoprazan fumarate product into a mixed solvent of methanol and water, heating for reflux, and then cooling for crystallization to obtain the refined Vonoprazan fumarate product.
8. The method for preparing vorexant fumarate according to claim 6, wherein said post-treatment of step 1) is: na was added dropwise to the reaction solution 2 SO 3 The aqueous solution of (2) is stirred and separated, and the organic phase is sequentially subjected to alkali washing, salt washing, drying and reduced pressure concentration to obtain the compound II.
9. The method for preparing vorexant fumarate according to claim 6, wherein said post-treatment of step 2) is: adding acid into the reaction liquid to adjust the pH value to 3-4, and then cooling and crystallizing to obtain the compound III.
10. The method for preparing vorexant fumarate according to claim 6, wherein said post-treatment of step 3) is: cooling the reaction liquid to room temperature, dropwise adding water, adding ethyl acetate, standing for separating liquid, performing alkali washing, salt washing, drying and concentrating under reduced pressure on an organic phase, and then recrystallizing by adopting a mixed solvent of ethyl acetate and n-heptane to obtain a compound IV.
CN202310047009.7A 2023-01-31 2023-01-31 Preparation method of voronoi fumarate Pending CN116023364A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101300229A (en) * 2005-08-30 2008-11-05 武田药品工业株式会社 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors
CN106478597A (en) * 2015-09-02 2017-03-08 中美华世通生物医药科技（武汉）有限公司 Vonoprazan fumarate monocrystalline and its production and use
CN109006824A (en) * 2018-09-11 2018-12-18 江苏省血吸虫病防治研究所 2- aryl substituted pyrroles class compound is killing the application in double navel spiral shell drugs
CN112300123A (en) * 2019-08-02 2021-02-02 上海天慈国际药业有限公司 Preparation method of Vonoprazan intermediate
CN115232107A (en) * 2022-07-29 2022-10-25 南京唯创远医药科技有限公司 Preparation method of high-purity Voranolan fumarate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101300229A (en) * 2005-08-30 2008-11-05 武田药品工业株式会社 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors
CN106478597A (en) * 2015-09-02 2017-03-08 中美华世通生物医药科技（武汉）有限公司 Vonoprazan fumarate monocrystalline and its production and use
CN109006824A (en) * 2018-09-11 2018-12-18 江苏省血吸虫病防治研究所 2- aryl substituted pyrroles class compound is killing the application in double navel spiral shell drugs
CN112300123A (en) * 2019-08-02 2021-02-02 上海天慈国际药业有限公司 Preparation method of Vonoprazan intermediate
CN115232107A (en) * 2022-07-29 2022-10-25 南京唯创远医药科技有限公司 Preparation method of high-purity Voranolan fumarate

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