CN105646453A - Synthesis method of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methanamine fumarate TAK438 - Google Patents
Synthesis method of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methanamine fumarate TAK438 Download PDFInfo
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- CN105646453A CN105646453A CN201510991942.5A CN201510991942A CN105646453A CN 105646453 A CN105646453 A CN 105646453A CN 201510991942 A CN201510991942 A CN 201510991942A CN 105646453 A CN105646453 A CN 105646453A
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- 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
Abstract
The present invention relates to a synthesis method of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methanamine fumarate TAK438. The synthesis route of TAK 438 in the prior art reduces cyan into an aldehyde structure, which then performs a condensation reductive reaction with methylamine to generate a secondary amine structure; and the finally a salt-forming reaction with fumaric acid is conducted to obtain the product. The method of the invention converts an intermediate cyan to a primary amine structure, and then uses the alkylation of nitrogen atoms for the synthesis of a secondary amine structure, and finally conducts a salt-forming reaction for synthesis of the product. The method has diversity, on the one hand makes the synthesis operation more safe and reliable and on the other hand reduces production costs and ensures the diversity selection of synthesis.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is specifically related to the synthetic method of a kind of TAK438 compound.
Background technology
OnoprazanFumarate (TAK-438) is the one of Wu Tian company of Japan developmentNovelP-CAB (the competitive acid inhibitor of potassium ion), has carried out several III clinical trial phases in Japan. Reversible inhibition H+/K+ATPase, IC50For 19nM (pH6.5), control gastric acid secretion. Different from existing proton pump inhibitor (PPIs), Tak438, under acidity and neutral environment, can suppress H efficiently+,K+-ATPase��
The synthetic route of TAk438 is comparatively simple. Prior art mainly contains three kinds about the synthetic route of TAK438, asAccompanying drawing 1-3Shown in.
Synthetic route 1 take o-fluoro acetophenone as starting raw material, with bromine element, the �� hydrogen bromo-reaction of ketone occurs, and then generates [2-(2-fluorophenyl)-2-oxoethyl] propane dinitrile with propane dinitrile condensation. Afterwards with 4NHCl/EA occur ring closure reaction, Pd/C dechlorination reaction, sulfonylation, Raney's nickel reduction reaction, reduction amination with become fumarate synthetic product TAK438.
Synthetic route 2 uses ethyl cyanacetate to substitute propane dinitrile generation condensation reaction and generates [2-(2-fluorophenyl)-2-oxoethyl] ethyl cyanoacetate. Through ring-closure reaction, dechlorination reaction, diisobutyl aluminium hydride reduces, and crosses ruthenic acid four propylamine salt (TPAP)/N-methyl-N-morpholine oxide (NMO) oxidation, sulfonylation, reduction amination with become fumarate synthetic product.
Synthetic route 3 is different from route 1 and 2; reaction directly adopts pyrroles's-3-ethyl formate to be starting raw material; through NBS bromo-reaction; sulfonylation; then with 3-fluorobenzoic boric acid generation condensation reaction; diisobutyl aluminium hydride reduces, and crosses ruthenic acid four propylamine salt (TPAP)/N-methyl-N-morpholine oxide (NMO) oxidation, reduction amination with become fumarate synthetic product.
All comprising 3-pyrrole aldehyde substructure unit before synthetic route 1-3 reduction amination, route 1 uses Raney's nickel to reduce cyano group under an atmosphere of hydrogen and obtains aldehyde, and experimental implementation dangerous pole fire hazardous, is unsuitable for suitability for industrialized production. Route 2 and 3 synthesizes aldehyde, adopts the single step reaction of two-step reaction alternative route 1, it may also be useful to reagent expensive and experimental implementation is complicated. Given this, we design and are successfully authenticated a set of new operational path.
Summary of the invention
This patent is creatively designed and Implemented and is improved by original operational path.Cyano reduction is become aldehyde structure by existing operational path, then generates secondary amine structure with the reaction of first amine generation condensating reductive, and last and fumaric acid salt-forming reaction generates product. And intermediate cyano is changed into primary amine structure by this technique, then utilize the hydrocarbyl reaction of nitrogen-atoms, synthesis secondary amine structure, finally become salt synthetic product. Raney's nickel/hydrogen reducing cyano group is used to be aldehyde, complicated operation, danger coefficient height, equipment requirements is strict, production cost height. And utilize ester to be reduced into alcohol, and then alcohol is oxidized to the reaction of aldehyde, step is complicated, and reagent is expensive, does not have cost advantage. Cyano group is changed into primary amine by the present invention, then utilizes acid amides, imine reduction synthesis secondary amine, finally becomes salt. From reaction itself, cyano group is changed into primary amine method there is diversity, Pd/CH2 both can have been used to reduce, it is also possible to adopt various metal hydride reduction such as sodium borohydride, Sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride etc. Like this, make synthetic operation more safe and reliable on the one hand, reduce production cost on the other hand, and the diversity that can ensure building-up reactions is selected.
The synthetic route of the present invention asAccompanying drawing 4Shown in.
AsAccompanying drawing 4Shown in, can with reference to relevant patent by compound 2-in-1 one-tenth compound 6. The present invention mainly improves by compound 6 synthetic product 1. Taking compound 6 as starting raw material, reduce through reductive agent and the cyano group in 6 is changed into primary amine and compound 7 (5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles's-3-first amine). Then a kind of of the compound such as compound 7 and formaldehyde, polycondensation formaldehyde, formic acid, methyl-formiate, ethyl formate generates imines or acid amides. Then add reductive agent reduction and generate corresponding secondary amine. Finally become salt with fumaric acid.
Cyano group is converted into primary amine and metal catalyst can be used such as palladium/charcoal, palladium hydroxide, platinum, platinum oxide. Hydrogen donor can be hydrogen, hydrochloric acid, ammonium formate etc. Reaction solvent comprises: active polar aprotic solvent is that alcohol class is such as methyl alcohol, ethanol, Virahol, butanols etc. Inert solvent comprises ether type solvent such as tetrahydrofuran (THF), ether, dioxane, 1,2-glycol dimethyl ether, Di Iso Propyl Ether, varsol is such as toluene or benzene, proton inertia polar organic solvent such as N, dinethylformamide, DMAC N,N' dimethyl acetamide, METHYLPYRROLIDONE, 1,3-dimethyl-2-imidazolidone or dimethyl sulfoxide (DMSO), halogenated hydrocarbon solvent is such as methylene dichloride, chloroform or 1,2-methylene dichloride, and esters solvent is such as ethyl acetate or methyl acetate.
Cyano group is converted into primary amine and metal hydride can also be used for reductive agent, and patent protection reductive agent is LiAlH4. Reaction carries out in aprotic solvent, the solvent that can use comprises, inert solvent comprises ether type solvent such as tetrahydrofuran (THF), ether, dioxane, 1,2-glycol dimethyl ether, Di Iso Propyl Ether, varsol is such as toluene or benzene, halogenated hydrocarbon solvent is such as methylene dichloride, chloroform or 1,2-methylene dichloride or mixed solvent.
Reacting next step for primary amine methylation reaction generation imines, reduction obtains secondary amine, last and fumaric acid salt-forming reaction. the reagent of generation imines or acid amides comprises reaction solvent and comprises formaldehyde, polycondensation formaldehyde, formic acid, methyl-formiate, ethyl formate etc. the reductive agent of reduction imines is sodium borohydride, Sodium triacetoxyborohydride, sodium cyanoborohydride, above-mentioned three kinds of reagent react solvents comprise inert solvent and comprise ether type solvent such as tetrahydrofuran (THF), ether, dioxane, 1, 2-glycol dimethyl ether, Di Iso Propyl Ether, varsol is such as toluene or benzene, proton inertia polar organic solvent is such as N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, METHYLPYRROLIDONE, 1, 3-dimethyl-2-imidazolidone or dimethyl sulfoxide (DMSO), halogenated hydrocarbon solvent is such as methylene dichloride, chloroform, or 1, 2-methylene dichloride, esters solvent is such as ethyl acetate or methyl acetate, water or its mixture.Lithium aluminium hydride reduction reaction reagent comprises ether type solvent such as tetrahydrofuran (THF), ether, dioxane, 1,2-glycol dimethyl ether, Di Iso Propyl Ether, varsol is such as toluene or benzene, and halogenated hydrocarbon solvent is such as methylene dichloride, chloroform or 1,2-methylene dichloride or mixed solvent.
Accompanying drawing explanation
Accompanying drawing 1Synthetic route 1
Accompanying drawing 2Synthetic route 2
Accompanying drawing 3Synthetic route 3
Accompanying drawing 4The synthetic route of synthetic route the present invention
Embodiment
The synthesis of embodiment 15-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles-3-first amine (7)
By 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles-3-nitrile (100g, 0.306mol), dehydrated alcohol 500ml, 10% palladium carbon 5g joins in single port flask. In a hydrogen atmosphere under (0.1MPa), by mixture room temperature vigorous stirring 4-6 hour. React completely, with nitrogen purge, filter, and wash with ethanol rinse (30ml �� 2). Filtrate being revolved and steam to 50ml, take off and revolve steaming, stir slow dripping and add 50ml water, produce a large amount of solid gradually, stirring at room temperature 30min, then ice bath stirs 1-2h. Take out filter filter, filter cake ethanol: water (1:1,15ml �� 2) washs. Collecting filter cake, 40-60 DEG C of drying under reduced pressure obtains white solid 71.3g, receipts rate 70.59%. C16H14FN3O2S, Mw:331.36mp150-152 DEG C of .1HNMR (DMSO-d6) 2.43 (s, 2H), 3.87 (s, 2H), 6.47 (s, 2H), 6.49 (d, J=1.8Hz, 1H), 7.07-7.13 (m, 1H), 7.49-7.56 (m, 1H), 7.59-7.64 (m, 1H), (7.74 d, J=1.8Hz, 1H), 7.86-7.90 (m, 1H), 8.56-8.57 (m, 1H), 8.87-8.89 (m, 1H).
The synthesis of embodiment 25-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles-3-first amine (7)
5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles-3-nitrile (100g, 0.306mol) is dissolved in 500mlTHF, is then slowly added drop-wise to lithium aluminum hydride in the solution of 500mlTHF. Stirring at room temperature 4-6h, some plate monitoring reacts completely. Slowly drip with frozen water 25ml under condition of ice bath, stir 1h, produce a large amount of solid, take out filter, filter cake THF drip washing. Filtrate 30-40 DEG C is revolved steaming, removes THF, then add EA (100ml*3) and extract three times. Merging organic layer, decompression is spin-dried for. Solid adds 50ml ethanol stirring at room temperature 1-2h, slowly drips and adds 50ml water, produces a large amount of solid gradually, stirring at room temperature 30min, and ice bath stirs 1-2h and takes out filter, filter cake ethanol: water (1:1,15ml �� 2) washs. Collecting filter cake, 40-60 DEG C of drying under reduced pressure obtains yellow solid 60.9g, receipts rate 60.3%.
The synthesis of embodiment 35-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first amine fumarate (TAK438)
Get 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles-3-first amine (50g, 0.151mol) to add methyl alcohol 200ml and dissolve, slowly add the 20g36% formalin of 200ml anhydrous alcohol solution. By mixture at stirring at room temperature 1-2h. Drip the solution adding sodium borohydride (2.856g, 0.075mol) in 50ml N,N-DIMETHYLACETAMIDE, drip to finish and mixture is stirred 1-2h at 0-10 DEG C. Reaction terminates, and drips and adds 20ml1N hydrochloric acid, stirring at room temperature 2h. Adding 200ml water afterwards, saturated sodium bicarbonate regulates PH7-9. Add ethyl acetate (200ml*3) extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying. Mixture heating up 50 DEG C, stirs 30min under adding fumaric acid (21.03g, 0.1812mol) uniform temp, near room temperature, ice bath 0-10 DEG C stirs 1h.Filtering, filter cake ethyl acetate is washed, and obtains product 55.74g, receipts rate 80%.
The synthesis of embodiment 45-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first amine fumarate (TAK438)
5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles-3-first amine (25g, 0.075mol) adds 100ml dissolve with methanol, adds 10g paraformaldehyde (massfraction is 91��93%). By reaction solution at stirring and refluxing 1-2h. It is down to room temperature, under condition of ice bath, slowly drips the solution adding and dripping and add sodium cyanoborohydride (3.142g, 0.050mol) in 20ml N,N-DIMETHYLACETAMIDE. Mixture is stirred 1-2h at 0-10 DEG C. Drip and add 15ml1N hydrochloric acid, stirring at room temperature 2h. Adding 100ml water afterwards, saturated sodium bicarbonate regulates PH7-9. Add ethyl acetate (100ml*3) extraction, saturated common salt water washing, anhydrous sodium sulfate drying. Mixture heating up 50 DEG C, stirs 30min under adding fumaric acid (10.52g, 0.091mol) uniform temp, near room temperature, ice bath 0-10 DEG C stirs 1h. Filtering, filter cake ethyl acetate is washed, and obtains product 25.64g, receipts rate 74%.
The synthesis of embodiment 55-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-first amine fumarate (TAK438)
5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles-3-first amine (25g, 0.075mol), formic acid (5.18g, 0.1125mol), 100ml methyl alcohol, joins in three-necked flask. By mixture at stirring at room temperature 1-2h. Drip the solution adding sodium cyanoborohydride (3.142g, 0.050mol) in 20ml N,N-DIMETHYLACETAMIDE. Mixture is stirred 1-2h at 0-10 DEG C. Drip and add 15ml1N hydrochloric acid, stirring at room temperature 2h. Adding 100ml water afterwards, 12.5% ammoniacal liquor regulates PH7-9. Add extraction into ethyl acetate (100ml*3), saturated common salt water washing, anhydrous sodium sulfate drying. Mixture heating up 50 DEG C, stirs 30min under adding fumaric acid uniform temp, near room temperature, ice bath 0-10 DEG C stirs 1h. Filtering, filter cake ethyl acetate is washed, and obtains product 23.14g, receipts rate 66.78%.
Illustrating just for helping the method understanding the present invention and core concept thereof of above embodiment. , it is also possible to the present invention carries out some improvement and modification, it is noted that for those skilled in the art, under the premise without departing from the principles of the invention these improve and modify and also fall into the present inventionClaimProtection domain in.
Claims (9)
1. the compound for the preparation of TAK438, it is characterised in that, described compound is: 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles's-3-first amine, and structural formula is as follows:
2. the preparation method of compound described in claim 1, it is obtained by the reduction of 5-(2-fluorophenyl)-1-(pyridine-3-alkylsulfonyl)-1H-pyrroles's-3-nitrile.
3. method according to claim 2, the catalyzer of described reduction is Pd/CH2Or LiAlH4��
4. method according to claim 3, Pd/CH2In reaction, solvent comprises: methyl alcohol, ethanol, Virahol, butanols, tetrahydrofuran (THF), ether, dioxane, 1,2-glycol dimethyl ether, Di Iso Propyl Ether, toluene, benzene, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, METHYLPYRROLIDONE, 1, one or more in 3-dimethyl-2-imidazolidone, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, 1,2-methylene dichloride, ethyl acetate or methyl acetate; The required solvent of lithium aluminium hydride reduction reaction comprises: one or more in tetrahydrofuran (THF), ether, dioxane, 1,2-glycol dimethyl ether, Di Iso Propyl Ether, toluene, benzene, methylene dichloride, chloroform or 1,2-methylene dichloride.
5. the preparation method of 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles's-3-first amine fumarate; its compound prepared by compound according to claim 1 or the claim 2-4 described method of arbitrary item is obtained by reacting imines or acid amides further; then add reductive agent reduction and generate corresponding secondary amine, finally become salt to obtain with fumaric acid.
6. method according to claim 5, its reaction is specific as follows:
7. method according to claim 5 or 6, imines or acid amides are obtained by reacting by one or more in described compound and formaldehyde, polycondensation formaldehyde, formic acid, methyl-formiate, ethyl formate.
8. method according to claim 5 or 6, the reductive agent required for imines, reduction of amide is sodium borohydride, Sodium triacetoxyborohydride, sodium cyanoborohydride or lithium aluminum hydride.
9. method according to claim 8, when sodium borohydride, Sodium triacetoxyborohydride or sodium cyanoborohydride reduction reaction, solvent for use is methyl alcohol, ethanol, Virahol, butanols, tetrahydrofuran (THF), ether, dioxane, 1,2-glycol dimethyl ether, Di Iso Propyl Ether, toluene, benzene, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, METHYLPYRROLIDONE, 1, one or more in 3-dimethyl-2-imidazolidone, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, 1,2-methylene dichloride, ethyl acetate or methyl acetate; When lithium aluminium hydride reduction reacts, solvent for use is one or more in tetrahydrofuran (THF), ether, dioxane, 1,2-glycol dimethyl ether, Di Iso Propyl Ether, toluene, benzene, methylene dichloride, chloroform or 1,2-methylene dichloride.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028436A (en) * | 2019-06-05 | 2019-07-19 | 杭州中美华东制药有限公司 | A kind of preparation method of Wo Nuolazan key intermediate |
| CN112194607A (en) * | 2020-08-27 | 2021-01-08 | 河北科博莱特医药科技有限公司 | Synthetic method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde |
| CN114487236A (en) * | 2022-01-26 | 2022-05-13 | 中山奕安泰医药科技有限公司 | Detection method of 2- [2- (2-fluorophenyl) -2-oxoethyl ] malononitrile |
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| CN104860923A (en) * | 2015-01-21 | 2015-08-26 | 山东康美乐医药科技有限公司 | Vonoprazan fumarate preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104860923A (en) * | 2015-01-21 | 2015-08-26 | 山东康美乐医药科技有限公司 | Vonoprazan fumarate preparation method |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028436A (en) * | 2019-06-05 | 2019-07-19 | 杭州中美华东制药有限公司 | A kind of preparation method of Wo Nuolazan key intermediate |
| CN110028436B (en) * | 2019-06-05 | 2020-10-16 | 杭州中美华东制药有限公司 | Preparation method of Vonoprazan key intermediate |
| CN112194607A (en) * | 2020-08-27 | 2021-01-08 | 河北科博莱特医药科技有限公司 | Synthetic method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde |
| CN114487236A (en) * | 2022-01-26 | 2022-05-13 | 中山奕安泰医药科技有限公司 | Detection method of 2- [2- (2-fluorophenyl) -2-oxoethyl ] malononitrile |
| CN114487236B (en) * | 2022-01-26 | 2023-11-07 | 中山奕安泰医药科技有限公司 | Detection method of 2- [2- (2-fluorophenyl) -2-oxo-ethyl ] malononitrile |
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Application publication date: 20160608 |