CN114149412A - Intermediate compound for preparing Vonoprazan - Google Patents
Intermediate compound for preparing Vonoprazan Download PDFInfo
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- CN114149412A CN114149412A CN202010935231.7A CN202010935231A CN114149412A CN 114149412 A CN114149412 A CN 114149412A CN 202010935231 A CN202010935231 A CN 202010935231A CN 114149412 A CN114149412 A CN 114149412A
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- vonoprazan
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- 229950003825 vonoprazan Drugs 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 title claims abstract description 31
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 title claims abstract description 12
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 230000002829 reductive effect Effects 0.000 claims abstract description 19
- 238000003756 stirring Methods 0.000 claims description 86
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- 239000000243 solution Substances 0.000 claims description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 239000007787 solid Substances 0.000 claims description 35
- 238000010438 heat treatment Methods 0.000 claims description 29
- 238000000967 suction filtration Methods 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000001816 cooling Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 20
- 238000004321 preservation Methods 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 19
- 238000001291 vacuum drying Methods 0.000 claims description 19
- 239000012065 filter cake Substances 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- -1 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide Chemical compound 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 239000001530 fumaric acid Substances 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012022 methylating agents Substances 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 27
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 4
- 231100000025 genetic toxicology Toxicity 0.000 abstract description 4
- 230000001738 genotoxic effect Effects 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract description 3
- 125000003368 amide group Chemical group 0.000 abstract description 2
- 150000008282 halocarbons Chemical class 0.000 abstract description 2
- 231100000956 nontoxicity Toxicity 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000015556 catabolic process Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 238000007069 methylation reaction Methods 0.000 abstract 1
- 238000006462 rearrangement reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 14
- 239000012071 phase Substances 0.000 description 10
- 239000008213 purified water Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- BZWNGOCDFFQIEN-UHFFFAOYSA-N [5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]methanamine Chemical compound FC1=C(C=CC=C1)C1=CC(=CN1S(=O)(=O)C=1C=NC=CC=1)CN BZWNGOCDFFQIEN-UHFFFAOYSA-N 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 7
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- QHKNXUIHYFZESD-UHFFFAOYSA-N 3-[4-(bromomethyl)-2-(2-fluorophenyl)pyrrol-1-yl]sulfonylpyridine Chemical compound FC1=C(C=CC=C1)C1=CC(=CN1S(=O)(=O)C=1C=NC=CC=1)CBr QHKNXUIHYFZESD-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000019057 Cytochrome P-450 CYP2C19 Human genes 0.000 description 1
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940121353 acid pump inhibitor Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an intermediate compound I for preparing Vonoprazan; the invention also provides a method for preparing the Vonoprazan by using the intermediate compound I through degradation rearrangement reaction and methylation reaction. The method avoids hydrogenation reaction operation with higher risk in the process of converting cyano into amido; according to the technical scheme for preparing the Vonoprazan, when the N-methyl group is introduced for reaction, the use of reactants with genotoxicity warning structures such as halogenated hydrocarbon and aldehyde is avoided, the generation of the impurity A, B, C, E, F is avoided, the impurity content is further reduced, the purity of the final product is higher, and the total yield is improved. The technical scheme of the invention has the advantages of easily obtained starting materials, greenness and no toxicity, and provides a safe, efficient, green and environment-friendly process route for the industrial production and preparation of Vonoprazan fumarate.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a Vonoprazan fumarate intermediate compound and a preparation method and application thereof.
Background
Vonoprazan fumarate, having a chemical formula of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine fumarate, is a potassium ion (K) developed by Wutian pharmaceutical of Japan+) Competitive acid pump inhibitors (P-CAB) with strong and durable inhibition of gastric acid secretion, less association of vonoprazan fumarate metabolism with the liver pharmacologic enzyme CYP2C19, and inhibition of proton pump by vonoprazan fumarate without acid activation, which is absorbed in high concentration in the stomach of the target organ, can produce nearly maximal efficacy the first day of administration, and which can last for 24 hours, the structure of vonoprazan fumarate is as follows:
the synthetic route reported in patent CN102421753 adopts cyano group to reduce into aldehyde, but the reaction operation is more complicated, and reaction steps such as reduction ammoniation and the like are not avoided, and aldehyde group with genotoxicity warning structure may be introduced in the reaction step, which affects the product quality of the final product;
patent CN104860923 reports that a method of reducing cyano group into amino group is adopted, and then the reaction with paraformaldehyde and sodium borohydride is carried out, so that the reaction route is short, but the step of reduction is not avoided, dangerous operations such as hydrogenation are needed in the operation process, polyformaldehyde with high toxicity is used, a complicated post-treatment process is needed to avoid residue of paraformaldehyde, and other over-reduction impurities are inevitably introduced in the process of reducing imine by using a reducing agent;
patent CN107778286A mentions that the synthesis process of the prior art requires a final reduction to obtain N-methyl-1- (3-pyridylsulfonyl) -5- (2-fluorophenyl) -1H-pyrrole-3-methylamine, and thus produces a series of key impurities as follows:
the reason is that the activity of the step of introducing methyl in reductive amination is high, polysubstituted impurities are easy to generate, meanwhile, reduction of other functional groups can be caused in the process of reducing imine, and methylamine is extremely easy to volatilize, so that the generation of impurities is easy to cause.
In summary, although the existing literature has disclosed various preparation methods of vonoprazan, the existing literature still has the problems of long reaction route, complicated reaction operation process and unsuitability for industrial production, and substances with genotoxicity, such as haloalkane, paraformaldehyde and the like, are introduced in the reaction process, so that the difficulty of post-treatment is increased, certain potential safety hazards are brought to the quality of products, and researches show that the routes disclosed by the existing literature often generate impurities a, B, C, D, E, F and the like, and are not easy to remove. Therefore, it is still important to develop a relatively green, economical and environmentally friendly synthetic route, and there is a need to provide a new synthetic method which is suitable for industrial production and can effectively avoid the residue of toxic impurities.
Disclosure of Invention
Aiming at the problems that the operation process is complicated, dangerous operations such as hydrogenation reduction are needed and excessive residues are introduced by impurities in the existing preparation process of the Vonoprazan, the invention aims to provide a novel intermediate compound for preparing the Vonoprazan fumarate and a method for preparing the Vonoprazan fumarate by using the intermediate compound. The method can avoid using dangerous reaction steps such as hydrogenation reduction and the like, changes the synthesis idea of introducing the N-methyl, and reduces or even avoids the generation of toxic impurities such as impurity A, B, C, D, E, F and the like to the maximum extent; in addition, the method is relatively simple to operate, efficient in reaction, green and safe, and suitable for industrial production of vonoprazan fumarate.
The specific technical content of the invention is as follows:
firstly, the invention provides an intermediate compound for preparing vonoprazan, which has a structure shown in a formula I:
secondly, the invention provides a preparation method of vonoprazan fumarate, which comprises the following specific preparation steps:
preferably, the method for preparing vonoprazan fumarate by using the intermediate compound I specifically comprises the following steps:
the method comprises the following steps: dissolving NaOH in water, stirring, cooling, adding Br2Stirring at a constant temperature, then dropwise adding an organic solution of a compound 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide shown in the formula I, stirring at room temperature after dropwise adding, then heating, stirring at a constant temperature, adjusting the pH to 1-2 after reaction, adjusting the pH with an alkali liquor, performing suction filtration, and recrystallizing after filtrate is subjected to reduced pressure concentration to obtain a solid compound shown in the formula II;
step two: dissolving a compound shown in a formula II in an organic solvent, adding alkali and a methylating agent, heating, and carrying out heat preservation reflux reaction; after the reflux is finished, cooling to room temperature, and carrying out post-treatment to obtain a solid product, namely a compound shown in a formula III;
step three: adding the compound shown in the formula III into a methanol aqueous solution, heating to dissolve, adding fumaric acid, keeping the temperature, stirring, cooling, continuously stirring, performing suction filtration, and performing vacuum drying on a filter cake to obtain vonoprazan fumarate.
Preferably, the solvent used in the organic solution in the step one is one or more of methanol, ethanol, acetonitrile and propionitrile; acetonitrile is preferred.
Preferably, the mass-to-volume ratio of the compound of formula I to the organic solvent in the organic solution in the first step is 1: 1-5, the mass is g, and the volume is mL; preferably 1: 3.
preferably, the compound of formula I is reacted with NaOH and Br in step one2The molar ratio of (A) to (B) is 1: 1.5-4: 1-2.
Preferably, the temperature for stirring and cooling in the first step is-10 to 5 ℃; preferably 0 deg.c.
Preferably, the temperature of the heat preservation stirring in the first step is 60-100 ℃; preferably 80 deg.c.
Preferably, the pH value in the step one is 10-12; preferably 11.
Preferably, the methylating agent in the second step is dimethyl carbonate, dimethyl sulfate or methyl iodide; more preferably dimethyl carbonate.
Preferably, the molar ratio of the compound of formula II to the methylating agent in step two is 1:1 to 4.
Preferably, the alkali in the second step is one or more of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide; preferably potassium carbonate or sodium carbonate.
Preferably, the molar ratio of the compound of formula II to the base in step two is 1:1 to 4.
Preferably, the organic solvent in the second step is one or more of N, N-dimethylformamide, dimethyl sulfoxide and dioxane.
Preferably, the mass-to-volume ratio of the compound of formula II to the organic solvent in step two is 1: 5-20; preferably 1: 6-10; wherein the mass is in g and the volume is in mL.
Preferably, the time of the heat preservation reflux in the step two is 12-36 h; preferably 20-25 h.
Preferably, the post-treatment process after the reaction in the step two specifically includes:
adding one to two times volume amount (calculated by reaction liquid) of purified water and one to two times volume amount (calculated by reaction liquid) of ethyl acetate into the solution, adjusting the pH to 8-9 by 1mol/L of hydrochloric acid, stirring for 5-10min after adjustment, standing for liquid separation, washing a lower layer solution twice by one to two times volume amount (calculated by reaction liquid) of ethyl acetate, then combining ethyl acetate phases, washing 3-5 times by one time volume amount (calculated by reaction liquid) of saturated salt water, adding anhydrous sodium sulfate into an organic phase for drying, filtering, concentrating under reduced pressure at 40-50 ℃, adding 2-6 times volume mass ratio (calculated by a compound of a formula II) of ethyl acetate and 2-6 times volume mass ratio (calculated by the compound of the formula II) of petroleum ether after concentration, stirring for 10-30 min, continuously dropwise adding 4-12 times volume mass ratio (calculated by the compound of the formula II) of petroleum ether, and stirring for 1-2 h after the dropwise addition is finished, performing suction filtration, and performing vacuum drying on a filter cake to obtain a white-like solid.
Preferably, the solvent for salt-forming refining in the third step is 40-80% methanol water solution; preferably 70% aqueous methanol.
Preferably, the molar ratio of the compound in the formula III to the fumaric acid in the step III is 1: 1-1.5; preferably 1:1 to 1.2.
Preferably, the time of the heat preservation stirring in the third step is 0.5-1 h.
Preferably, the temperature reduction in the third step is 0-10 ℃.
Preferably, the time for continuing stirring in the third step is 0.5-2 h.
Compared with the prior art, the invention has the following technical effects:
firstly, the invention provides an intermediate compound I for preparing the Vonoprazan; secondly, the preparation method provided by the invention avoids hydrogenation reaction operation with higher risk in the process of converting cyano into amido; according to the technical scheme for preparing the Vonoprazan, when the N-methyl group is introduced for reaction, the use of reactants with genotoxicity warning structures such as halogenated hydrocarbon and aldehyde is avoided, the generation of the impurity A, B, C, E, F is avoided, the impurity content is further reduced, the purity of the final product is higher, and the total yield is improved. The technical scheme of the invention has the advantages of easily obtained starting materials, greenness and no toxicity, and provides a safe, efficient, green and environment-friendly process route for the industrial production and preparation of Vonoprazan fumarate.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
EXAMPLE 1 preparation of Compounds of formula I
Weighing 39.5g of 5- (2-fluorophenyl) -3-bromomethyl 1- (3-pyridylsulfonyl) -1H-pyrrole, adding the weighed 5- (2-fluorophenyl) -3-bromomethyl 1- (3-pyridylsulfonyl) -1H-pyrrole into 120ml of methanol, adding 5.88g of NaCN, heating to 50 ℃, preserving heat for reaction for 2.0H, adding a proper amount of sodium thiosulfate after the reaction is finished, stirring for 0.5H, cooling to 0-10 ℃, starting dropwise adding 360ml of water, generating a solid in the dropwise adding process, performing suction filtration and vacuum drying after the dropwise adding is finished, and obtaining 30.08g of the solid 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetonitrile with the yield of 88.16%.
Dissolving 30.08g of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetonitrile in 100mL of tetrahydrofuran solution, adding 6g of 20% NaOH aqueous solution, heating to 55 ℃, dropwise adding 12.0g of 30% hydrogen peroxide solution, preserving heat for reacting for 1H after dropwise adding, cooling to 5 ℃ after reacting, dropwise adding 300mL of purified water, generating solid in the dropwise adding process, preserving heat and stirring for 1H after dropwise adding, performing suction filtration, and performing vacuum drying on a filter cake at 50-60 ℃ to obtain 27.31g of solid 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide, wherein the yield is 86.24%.
And (3) structure confirmation: ESI-MS (M/z) 359.33[ M + H]+；1H NMR(400MHz,DMSO-d6)δ：8.70～8.76(m,1H)，8.60～8.61(d,J＝2.0Hz,1H)，7.69～7.72(m,1H)，7.44～7.46(m,2H)，7.35～7.39(m,1H)，7.14～7.20(m,2H)，7.01～7.04(t,J＝4.5Hz,1H)，6.68(d,J＝1.8Hz,1H)；4.55(s,2H)13C NMR(100MHz,DMSO-d6)δ：161.6，160.2，159.8，153.4，148.1，135.5，135.0，133.5，131.3，129.0，128.0，123.5～123.6，119.8，118.8～118.9，117.0，115.3～115.5。
And (3) purity detection: [ HPLC area normalization method: chromatography column Waters Symmetry-C18 column (4.6 mm. times.250 mm, 5 μm); mobile phase A: 0.1% phosphoric acid water; b: acetonitrile; gradient elution 0-40min a (70%): b (30%); 40-50min A (30%): b (70%), detection wavelength 235 nm; the column temperature is 35 ℃; flow rate 1.0ml/min ].
Example 2 preparation of Vonoprazan fumarate (formula IV)
7.57g NaOH is dissolved in 15ml water, then stirred and cooled to 0 ℃, and 19.01g Br is added2Stirring for 1.0H under heat preservation, keeping the temperature at 0 ℃, dropwise adding an acetonitrile solution of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide (34.0 g of an intermediate I and 100ml of the acetonitrile solution), stirring for 0.5H at room temperature after dropwise adding, then heating to 80 ℃, stirring for 1.0H under heat preservation, adjusting the pH to 1-2 with hydrochloric acid after the reaction is finished, stirring for 0.5H, adjusting the pH to 11 with alkali liquor, performing suction filtration, concentrating the filtrate under reduced pressure, and recrystallizing to obtain 28.51g of a solid with the yield of 90.04%.
Dissolving 28.51g of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine in 200ml of dimethyl sulfoxide solution, adding 20.26g of potassium carbonate and 15.37g of dimethyl carbonate, heating to 120 ℃, keeping the temperature and refluxing for 20H, cooling to room temperature after the refluxing is finished, adding 400ml of purified water and 400ml of ethyl acetate into the solution, adjusting the pH to 8-9 by using 1mol/L hydrochloric acid, stirring for 5-10min after the adjustment is finished, standing for liquid separation, washing a lower layer solution twice by using 200ml of ethyl acetate, combining ethyl acetate phases, washing 3 times by using 200ml of saturated saline, adding anhydrous sodium sulfate into an organic phase, drying, filtering, concentrating at 40-50 ℃ under reduced pressure, adding 60ml of ethyl acetate and 60ml of petroleum ether after the concentration is finished, stirring for 10min, and continuously dropwise adding 120ml of petroleum ether, stirring for 1h after dropwise adding, carrying out suction filtration, and carrying out vacuum drying on a filter cake at the temperature of 20-30 ℃ to obtain an off-white solid with the yield of 27.11g of 91.26%. HPLC purity 99.69%, no impurity A, B, C, E, F, no impurity D.
Adding the obtained solid into 70% methanol water solution, heating to 60-65 ℃ for complete dissolution, then adding 9.98g of fumaric acid, keeping the temperature and stirring for 0.5h, then cooling to 0-10 ℃, keeping the temperature and stirring for 1.0h, performing suction filtration, and performing vacuum drying on a filter cake to obtain 32.72g of Vonoprazan fumarate solid, wherein the yield is 90.45%, the HPLC purity is 99.96%, the impurity A, B, C, E, F is not detected, and the impurity D is 0.01%.
And (3) purity detection: [ HPLC area normalization method: chromatographic column Ultimate XB-C18 column (4.6 mm. times.250 mm, 5 μm); mobile phase 0.04mol/L sodium dihydrogen phosphate buffer (pH 6.0 adjusted by phosphoric acid) acetonitrile 3: 7; the detection wavelength is 254 nm; the column temperature is 30 ℃; flow rate 1.0ml/min ].
Example 3 preparation of Vonoprazan fumarate (formula IV)
5.68g NaOH is dissolved in 15ml water, then stirred and cooled to 0 ℃, and 15.84g Br is added2Stirring for 1.0H under heat preservation, keeping the temperature at 0 ℃, dropwise adding an acetonitrile solution (34.0 g of an intermediate I and 70ml of the acetonitrile solution) of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide, stirring for 0.5H at room temperature after dropwise adding, then heating to 80 ℃, stirring for 1.0H under heat preservation, adjusting the pH to 1-2 with hydrochloric acid after the reaction is finished, stirring for 0.5H, adjusting the pH to 11 with alkali liquor, performing suction filtration, concentrating the filtrate under reduced pressure, and recrystallizing to obtain 27.28g of a solid with the yield of 86.16%.
Dissolving 27.28g of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine in 300ml of dimethyl sulfoxide solution, adding 11.91g of potassium carbonate and 7.69g of dimethyl carbonate, heating to 120 ℃, keeping the temperature and refluxing for 20H, cooling to room temperature after the refluxing is finished, adding 400ml of purified water and 400ml of ethyl acetate into the solution, adjusting the pH to 8-9 by using 1mol/L hydrochloric acid, stirring for 5-10min after the adjustment is finished, standing for liquid separation, washing a lower layer solution twice by using 200ml of ethyl acetate, combining ethyl acetate phases, washing 3 times by using 200ml of saturated saline, adding anhydrous sodium sulfate into an organic phase, drying, filtering, concentrating at 40-50 ℃ under reduced pressure, adding 60ml of ethyl acetate and 60ml of petroleum ether after the concentration is finished, stirring for 10min, and continuously dropwise adding 120ml of petroleum ether, stirring for 1h after dropwise adding, carrying out suction filtration, and carrying out vacuum drying on a filter cake at the temperature of 20-30 ℃ to obtain an off-white solid with the yield of 88.69%. HPLC purity 99.69%, no impurity A, B, C, E, F, no impurity D.
Adding the obtained solid into 80% methanol water solution, heating to 60-65 ℃ for complete dissolution, then adding 10.64g of fumaric acid, keeping the temperature and stirring for 1h, then cooling to 0-10 ℃, keeping the temperature and stirring for 2h, performing suction filtration, and performing vacuum drying on a filter cake to obtain 31.88g of vonoprazan fumarate solid, wherein the yield is 90.21%, the HPLC purity is 99.95%, the impurity A, B, C, E, F is not detected, and the impurity D is 0.01%.
Example 4 preparation of Vonoprazan fumarate (formula IV)
15.14g NaOH was dissolved in 15ml water, then stirred and cooled to 0 deg.C, 33.26g Br was added2Stirring for 1.0H under heat preservation, keeping the temperature at 0 ℃, dropwise adding an acetonitrile solution (34.0 g of an intermediate I and 160ml of the acetonitrile solution) of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide, stirring for 0.5H at room temperature after dropwise adding, then heating to 80 ℃, stirring for 1.0H under heat preservation, adjusting the pH to 1-2 with hydrochloric acid after the reaction is finished, stirring for 0.5H, adjusting the pH to 11 with alkali liquor, performing suction filtration, concentrating the filtrate under reduced pressure, and recrystallizing to obtain 24.43g of a solid with the yield of 86.23%.
Dissolving 24.43g of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine in 150ml of dimethyl sulfoxide solution, adding 47.67g of potassium carbonate and 30.74g of dimethyl carbonate, heating to 120 ℃, keeping the temperature and refluxing for 20H, cooling to room temperature after the refluxing is finished, adding 400ml of purified water and 400ml of ethyl acetate into the solution, adjusting the pH to 8-9 by using 1mol/L hydrochloric acid, stirring for 5-10min after the adjustment is finished, standing for liquid separation, washing the lower layer solution twice by using 200ml of ethyl acetate, then combining ethyl acetate phases, washing 3 times by using 200ml of saturated saline solution, adding anhydrous sodium sulfate into an organic phase for drying, filtering, concentrating at 40-50 ℃ under reduced pressure, adding 60ml of ethyl acetate and 60ml of petroleum ether after the concentration is finished, stirring for 10min, and continuously dropwise adding 120ml of petroleum ether, stirring for 1h after dropwise adding, carrying out suction filtration, and carrying out vacuum drying on a filter cake at the temperature of 20-30 ℃ to obtain an off-white solid with the yield of 87.56%. HPLC purity 99.69%, no impurity A, B, C, E, F, no impurity D.
Adding the obtained solid into 40% methanol aqueous solution, heating to 60-65 ℃ for complete dissolution, then adding 12.03g of fumaric acid, keeping the temperature and stirring for 0.5h, then cooling to 0-10 ℃, keeping the temperature and stirring for 1.0h, performing suction filtration, and performing vacuum drying on a filter cake to obtain 31.25g of vonoprazan fumarate solid, wherein the yield is 90.06%, the HPLC purity is 99.95%, the impurity A, B, C, E, F is not detected, and the impurity D is 0.01%.
Example 5 preparation of Vonoprazan fumarate (formula IV)
7.57g NaOH is dissolved in 15ml water, then stirred and cooled to 0 ℃, 16.63g Br is added2Stirring for 1.0H under heat preservation, keeping the temperature at 0 ℃, dropwise adding an acetonitrile solution of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide (34.0 g of an intermediate I and 100ml of a methanol solution), stirring for 0.5H at room temperature after dropwise adding, then heating to 80 ℃, stirring for 1.0H under heat preservation, adjusting the pH to 1-2 with hydrochloric acid after the reaction is finished, stirring for 0.5H, adjusting the pH to 11 with an alkali liquor, performing suction filtration, concentrating the filtrate under reduced pressure, and recrystallizing to obtain 28.40g of a solid with the yield of 89.69%.
Dissolving 28.40g of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine in 200ml of N, N-dimethylformamide solution, adding 15.58g of sodium carbonate and 21.44g of dimethyl sulfate, heating to 100 ℃, keeping the temperature and refluxing for 20H, cooling to room temperature after the reflux is finished, adding 400ml of purified water and 400ml of ethyl acetate into the solution, adjusting the pH to 8-9 by using 1mol/L of hydrochloric acid, stirring for 5-10min after the adjustment is finished, separating liquid and standing, washing the lower layer solution twice by using 200ml of ethyl acetate, then combining ethyl acetate phases, washing 3 times by using 200ml of saturated saline water, adding anhydrous sodium sulfate into an organic phase, drying, filtering, concentrating at 40-50 ℃ under reduced pressure, adding 60ml of ethyl acetate and 60ml of petroleum ether after the concentration is finished, stirring for 10min, continuously dropwise adding 120ml of petroleum ether, stirring for 1h after dropwise adding, performing suction filtration, and performing vacuum drying on a filter cake at the temperature of 20-30 ℃ to obtain a white-like solid with the yield of 85.62 g. HPLC purity 99.69%, no impurity A, B, C, E, F, no impurity D.
Adding the obtained solid into 70% methanol water solution, heating to 60-65 ℃ for complete dissolution, then adding 9.75g of fumaric acid, keeping the temperature and stirring for 0.5h, then cooling to 0-10 ℃, keeping the temperature and stirring for 1.0h, performing suction filtration, and performing vacuum drying on a filter cake to obtain 31.79g of Vonoprazan fumarate solid, wherein the yield is 90.43%, the HPLC purity is 99.96%, the impurity A, B, C, E, F is not detected, and the impurity D is 0.01%.
Example 6 preparation of Vonoprazan fumarate (formula IV)
7.57g NaOH is dissolved in 15ml water, then stirred and cooled to 0 ℃, 16.63g Br is added2Stirring for 1.0H under heat preservation, keeping the temperature at 0 ℃, dropwise adding an acetonitrile solution of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide (34.0 g of an intermediate I and 100ml of a methanol solution), stirring for 0.5H at room temperature after dropwise adding, then heating to 80 ℃, stirring for 1.0H under heat preservation, adjusting the pH to 1-2 with hydrochloric acid after the reaction is finished, stirring for 0.5H, adjusting the pH to 11 with an alkali liquor, performing suction filtration, concentrating the filtrate under reduced pressure, and recrystallizing to obtain 28.36g of a solid with the yield of 89.56%.
Dissolving 28.36g of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine in 200ml of dimethyl sulfoxide solution, adding 8.25g of potassium hydroxide and 15.37g of dimethyl carbonate, heating to 120 ℃, keeping the temperature and refluxing for 20H, cooling to room temperature after the refluxing is finished, adding 400ml of purified water and 400ml of ethyl acetate into the solution, adjusting the pH to 8-9 by using 1mol/L hydrochloric acid, stirring for 5-10min after the adjustment is finished, standing for liquid separation, washing a lower layer solution twice by using 200ml of ethyl acetate, combining ethyl acetate phases, washing 3 times by using 200ml of saturated saline water, adding anhydrous sodium sulfate into an organic phase, drying, filtering, concentrating at 40-50 ℃ under reduced pressure, adding 60ml of ethyl acetate and 60ml of petroleum ether after the concentration is finished, stirring for 10min, and continuously dropwise adding 120ml of petroleum ether, stirring for 1h after dropwise adding, carrying out suction filtration, and carrying out vacuum drying on a filter cake at the temperature of 20-30 ℃ to obtain a white-like solid with the yield of 25.63g of 86.26%. HPLC purity 98.76%, no impurity A, B, C, E, F, no impurity D.
Adding the obtained solid into 70% methanol water solution, heating to 60-65 ℃ for complete dissolution, then adding 9.75g of fumaric acid, keeping the temperature and stirring for 0.5h, then cooling to 0-10 ℃, keeping the temperature and stirring for 1.0h, performing suction filtration, and performing vacuum drying on a filter cake to obtain 30.89g of Vonoprazan fumarate solid, wherein the yield is 90.32%, the HPLC purity is 99.93%, the impurity A, B, C, E, F is not detected, and the impurity D is 0.02%.
Example 7 preparation of Vonoprazan fumarate (formula IV)
19.92g NaOH are dissolved in 15ml water, then stirred and cooled to 0 ℃, and 39.60g Br are added2Stirring for 1.0H under heat preservation, keeping the temperature at 10 ℃, dropwise adding an acetonitrile solution of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide (34.0 g of an intermediate I and 200ml of the acetonitrile solution), stirring for 0.5H at room temperature after dropwise adding, then heating to 80 ℃, stirring for 1.0H under heat preservation, adjusting the pH to 1-2 with hydrochloric acid after the reaction is finished, stirring for 0.5H, adjusting the pH to 11 with alkali liquor, performing suction filtration, concentrating the filtrate under reduced pressure, and recrystallizing to obtain 25.73g of a solid with the yield of 81.26%.
Dissolving 25.73g of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine in 200ml of dimethyl sulfoxide solution, adding 51.76g of potassium carbonate and 34.86g of dimethyl carbonate, heating to 120 ℃, keeping the temperature and refluxing for 10H, cooling to room temperature after the refluxing is finished, adding 400ml of purified water and 400ml of ethyl acetate into the solution, adjusting the pH to 8-9 by using 1mol/L hydrochloric acid, stirring for 5-10min after the adjustment is finished, standing for liquid separation, washing a lower layer solution twice by using 200ml of ethyl acetate, combining ethyl acetate phases, washing 3 times by using 200ml of saturated saline, adding anhydrous sodium sulfate into an organic phase, drying, filtering, concentrating at 40-50 ℃ under reduced pressure, adding 60ml of ethyl acetate and 60ml of petroleum ether after the concentration is finished, stirring for 10min, and continuously dropwise adding 120ml of petroleum ether, stirring for 1h after dropwise adding, carrying out suction filtration, and carrying out vacuum drying on a filter cake at the temperature of 20-30 ℃ to obtain 21.55g of off-white solid with the yield of 82.38%. HPLC purity 98.76%, no impurity A, B, C, E, F, no impurity D.
Adding the obtained solid into 70% methanol water solution, heating to 60-65 ℃ for complete dissolution, then adding 7.93g of fumaric acid, keeping the temperature and stirring for 0.5h, then cooling to 0-10 ℃, keeping the temperature and stirring for 1.0h, performing suction filtration, and performing vacuum drying on a filter cake to obtain 25.98g of Vonoprazan fumarate solid, wherein the yield is 89.98%, the HPLC purity is 98.89%, the impurity A, B, C, E, F is not detected, and the impurity D is 0.06%.
Example 8 preparation of Vonoprazan fumarate (formula IV)
7.57g NaOH is dissolved in 15ml water, then stirred and cooled to 0 ℃, and 19.01g Br is added2Stirring for 1.0H under heat preservation, keeping the temperature at 0 ℃, dropwise adding an acetonitrile solution of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide (34.0 g of an intermediate I and 100ml of the acetonitrile solution), stirring for 0.5H at room temperature after dropwise adding, then heating to 80 ℃, stirring for 1.0H under heat preservation, adjusting the pH to 1-2 with hydrochloric acid after the reaction is finished, stirring for 0.5H, adjusting the pH to 11 with alkali liquor, performing suction filtration, concentrating the filtrate under reduced pressure, and recrystallizing to obtain 28.47g of a solid with the yield of 89.96%.
Dissolving 28.47g of 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine in 200ml of dimethyl sulfoxide solution, adding 20.26g of potassium carbonate and 15.37g of dimethyl carbonate, heating to 120 ℃, keeping the temperature and refluxing for 20H, cooling to room temperature after the reflux is finished, adding 400ml of purified water and 400ml of ethyl acetate into the solution, adjusting the pH to 8-9 by using 1mol/L hydrochloric acid, stirring for 5-10min after the adjustment is finished, standing for liquid separation, washing a lower layer solution twice by using 200ml of ethyl acetate, combining ethyl acetate phases, washing 3 times by using 200ml of saturated saline, adding anhydrous sodium sulfate into an organic phase, drying, filtering, concentrating at 40-50 ℃ under reduced pressure, adding 40ml of ethyl acetate and 40ml of petroleum ether after the concentration is finished, stirring for 10min, and continuously dropwise adding 80ml of petroleum ether, stirring for 1h after dropwise adding, carrying out suction filtration, and carrying out vacuum drying on a filter cake at the temperature of 20-30 ℃ to obtain an off-white solid with the yield of 82.18% of 24.41 g. HPLC purity 99.62%, no impurity A, B, C, E, F, no impurity D.
Adding the obtained solid into 70% methanol water solution, heating to 60-65 ℃ for complete dissolution, then adding 8.98g of fumaric acid, keeping the temperature and stirring for 0.5h, then cooling to 0-10 ℃, keeping the temperature and stirring for 1.0h, performing suction filtration, and performing vacuum drying on a filter cake to obtain 29.12g of Vonoprazan fumarate solid, wherein the yield is 89.43%, the HPLC purity is 99.94%, the impurity A, B, C, E, F is not detected, and the impurity D is 0.02%.
Claims (10)
1. An intermediate compound for preparing Vonoprazan is characterized in that the specific structure is shown as formula I:
2. the preparation method of vonoprazan fumarate is characterized by comprising the following specific preparation steps:
the method comprises the following steps: dissolving NaOH in water, stirring, cooling, adding Br2Stirring at a constant temperature, then dropwise adding an organic solution of a compound 5- (2-fluorophenyl) -1- (3-pyridylsulfonyl) -1H-pyrrole-3-acetamide shown in the formula I, stirring at room temperature after dropwise adding, then heating, stirring at a constant temperature, adjusting the pH to 1-2 after reaction, adjusting the pH with an alkali liquor, performing suction filtration, and recrystallizing after filtrate is subjected to reduced pressure concentration to obtain a solid compound shown in the formula II;
step two: dissolving a compound shown in a formula II in an organic solvent, adding alkali and a methylating agent, heating, and carrying out heat preservation reflux reaction; after the reflux is finished, cooling to room temperature, and carrying out post-treatment to obtain a solid product, namely a compound shown in a formula III;
step three: adding the compound shown in the formula III into a methanol aqueous solution, heating to dissolve, adding fumaric acid, keeping the temperature, stirring, cooling, continuously stirring, performing suction filtration, and performing vacuum drying on a filter cake to obtain vonoprazan fumarate.
3. The preparation method according to claim 2, wherein the organic solvent in the first step is one or more of methanol, ethanol, acetonitrile and propionitrile; wherein the mass-volume ratio of the compound of the formula I to the organic solvent is 1: 1-5, the mass is g, and the volume is mL.
4. The process of claim 2, wherein in step one the compound of formula I is reacted with NaOH and Br2The molar ratio of (A) to (B) is 1: 1.5-4: 1-2.
5. The preparation method according to claim 2, wherein the temperature for stirring and cooling in the first step is-10 to 5 ℃; the temperature of the heat preservation stirring is 60-100 ℃.
6. The method of claim 2, wherein the methylating agent in step two is dimethyl carbonate, dimethyl sulfate or methyl iodide.
7. The method of claim 2, wherein the molar ratio of the compound of formula II to the methylating agent in step two is 1:1 to 4.
8. The preparation method of claim 2, wherein the base in the second step is one or more of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.
9. The process of claim 2, wherein the molar ratio of the compound of formula II to the base in step two is 1:1 to 4.
10. The preparation method according to claim 2, wherein the organic solvent in the second step is one or more of N, N-dimethylformamide, dimethyl sulfoxide and dioxane; in the second step, the mass volume ratio of the compound of the formula II to the organic solvent is 1: 5-20, wherein the mass is in g, and the volume is in mL.
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