CN105440019A - Preparation method of drug for treating gastric acid related diseases - Google Patents
Preparation method of drug for treating gastric acid related diseases Download PDFInfo
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- CN105440019A CN105440019A CN201510955763.6A CN201510955763A CN105440019A CN 105440019 A CN105440019 A CN 105440019A CN 201510955763 A CN201510955763 A CN 201510955763A CN 105440019 A CN105440019 A CN 105440019A
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- SJBDFRUXIUOGMY-UHFFFAOYSA-N CCOC(C(CC(c(cccc1)c1F)=O)C#N)=O Chemical compound CCOC(C(CC(c(cccc1)c1F)=O)C#N)=O SJBDFRUXIUOGMY-UHFFFAOYSA-N 0.000 description 1
- QDNWNJSLWKHNTM-UHFFFAOYSA-N O=C(CBr)c(cccc1)c1F Chemical compound O=C(CBr)c(cccc1)c1F QDNWNJSLWKHNTM-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a preparation method of a drug TAK438 for treating gastric acid related diseases. According to the preparation method, 2-bromo-2'-fluoroacetophenone is taken as the primary raw material, and the target product TAK438 is obtained through the following reactions: condensation reaction, cyclization reaction, reduction reaction, sulfonylation reaction, and reductive amination reaction. The preparation method has the advantages of easily-available raw material, easy control, and high yield, and can be applied to industrial production.
Description
Technical field
The invention belongs to organic drug synthesis technical field, particularly relate to a kind of preparation method treating medicine 5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-methylamine of hydrochloric acid in gastric juice disease.
Background technology
Gastric acid related disease is a class disease the most common in digestive system, refer to that a class is due to gastroxia, or and that the cause general name of a class digestive tract diseases responsive especially to hydrochloric acid in gastric juice, common are gastroesophageal reflux disease, digestive system etc. that peptide ulceration, non-steroidal anti-inflammatory drugs cause.PPI is the class medicine that current Acidinhibitor is the strongest, as omeprazole, and lansoprazole, rabeprazole etc.Because PPI also exists nocturnal acid rebound phenomenon, result for the treatment of is undesirable, has expedited the emergence of the development direction that acid inhibitor is new thus: the competitive sour retarding agent (P-CAB) of potassium ion.Different from conventional P PI, P-CAB is worked by the K+ in competitive inhibition proton pump (H+, K+-ATPase), is a kind of reversible K+ antagonist.Because this medicine acid suppression effect and proton pump Activation have nothing to do, the generation of nocturnal acid knock-on obviously can be reduced clinically.One of TAK438 representative being this type of medicine.
TAK438; chemistry (5-(2-fluorophenyl)-N-methyl isophthalic acid-(3-pyridyl sulfonyl)-1H-pyrroles-3-methylamine fumarate) by name is developed by Takeda Pharmaceutical Company Limited; in clinical trial; the ability of this compound suppression proton pump is 400 times of lansoprazole; it is relative to Na+; the suppression selectivity of K+-ATPase is more than 1000 times; TAK438, in the diseases such as treatment erosive esophagitis, stomach ulcer, duodenal ulcer, helicobacter pylori eradication, shows good curative effect.Experiment in vitro research shows that it has quick-acting, powerful, lasting gastric acid secretion restraining effect, simultaneously tolerance and security good.
Patent US2011/306769 discloses the preparation method of TAK438, and the method total recovery is relatively low, and severe reaction conditions; The method that the present invention announces is simple to operate, total recovery is higher, is convenient to suitability for industrialized production.
Summary of the invention
The object of the invention is to, the preparation method of a kind of TAK438 is provided.Reaction scheme is:
For achieving the above object, the present invention adopts following technical scheme to prepare TAK438, in preparation process with the bromo-2'-fluoro acetophenone (I) of 2-for starting raw material, intermediate II is obtained by condensation reaction, intermediate II is carried out cyclization and is obtained intermediate III, carry out reduction reaction again and obtain key intermediate IV, intermediate IV and pyridine-3-SULPHURYL CHLORIDE are carried out sulfonamide reaction and are obtained intermediate V, and intermediate V and methylamine carry out reduction amination and namely obtain target product VI.
Concrete, described TAK438 preparation method, is characterized in that, comprise the following steps:
Start with raw material I, carry out condensation reaction with ethyl cyanoacetate and obtain intermediate II.
Preferably, described reaction base can be sodium carbonate, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, the mineral alkalis such as hydrated barta.Be more preferably salt of wormwood.
Preferably, the solvent being applicable to above-mentioned reaction is acetonitrile, acetone, ethanol, methyl alcohol, DMF, dioxane, ethyl acetate, the arbitrary combination of toluene etc. or above-mentioned solvent.Preferred solvent is acetone.
Preferably, the mol ratio of raw material I, ethyl cyanoacetate and alkali is 1:(5-9): (1-3), is more preferably 1:(6-8): (1.5-2.5).
Preferably, the reaction times is generally 12-24 hour, is more preferably 15-18 hour.
Intermediate II carries out cyclisation under hydrogenchloride condition, more namely obtains intermediate III by palladium hydrocarbonize.
Preferably, the solvent being applicable to above-mentioned reaction is acetonitrile, methylene dichloride, ethanol, methyl alcohol, tetrahydrofuran (THF), DMF, dioxane, ethyl acetate, the arbitrary combination of toluene etc. or above-mentioned solvent.A kind of preferred solvent is tetrahydrofuran (THF).
Preferably, the reaction times is 1-24 hour, is more preferably 3-12 hour.
Preferably, need lead to rare gas element for some time can carry out palladium hydrocarbonize after driving hydrogenchloride excessive in reaction solution away, and the time is preferably 10-30 minute.Hydrogenchloride and palladium carbon are that conventional commercialization can be purchased.
Intermediate III DIBAL-H carries out reducing and obtain key intermediate IV,
Preferably, the solvent being applicable to above-mentioned reaction is acetonitrile, ethanol, methyl alcohol, dioxane, the arbitrary combination of toluene etc. or above-mentioned solvent.A kind of preferred solvent is toluene.
The mol ratio of preferred intermediate III and DIBAL-H is 1:(1-6), be more preferably 1:(3-4).
Intermediate IV and pyridine-3-SULPHURYL CHLORIDE are reacted and obtain intermediate V.
Preferably, intermediate IV and pyridine-3-SULPHURYL CHLORIDE mol ratio are 1:(1-5), be more preferably 1:(1-2).
Preferably, being applicable to the solvent of above-mentioned reaction is acetonitrile, acetone, ethanol, methyl alcohol, waits or the arbitrary combination of above-mentioned solvent.Preferred solvent is acetonitrile.
Preferably, the described reaction times is 1-10 hour, is more preferably 1-5 hour.
Preferably, acylation catalyst can be pyridine, triethylamine, DMAP, HOBT, HOAT etc., be more preferably DMAP.
Intermediate V and methylamine sodium borohydride carry out reductive amination process and namely obtain target product VI.
Preferably, the mol ratio of intermediate V, methylamine, sodium borohydride is 1:(1-5): (0.3-1), is more preferably 1:(1-3): (0.3-0.6).
Preferably, the solvent being applicable to above-mentioned reaction is methyl alcohol, ethanol, propyl alcohol, butanols etc., is more preferably methyl alcohol.
Preferably, the reaction times is generally 1-5 hour, is more preferably 1-3 hour.
Preferably, after preparing fumarate, filtration washing mixed solvent is ethyl acetate and DMAC, and ratio is ethyl acetate: DMAC is 1:(2-5), be more preferably 1:(2-3).
Embodiment
In order to further illustrate the present invention, below in conjunction with embodiment, the preparation method to TAK-438 provided by the invention is described, and protection scope of the present invention is not limited by the following examples.
In the preparation method of the TAK-438 provided in the present invention, raw materials used or reagent all can be buied by market.
Embodiment 1
Get salt of wormwood (12.7g, 92.2mmol) add ethyl cyanacetate (34.5ml, 322.7mmol), be heated to 40-45 DEG C, stir 45 minutes, get the bromo-2'-fluoro acetophenone (10.0g, 46.1mmol) of 2-to be dissolved in acetone and slowly to add in said vesse, add in 30 minutes, add and be placed on room temperature reaction 16 hours, filter to get filtrate, concentrating under reduced pressure boils off acetone, then adds water, be extracted with ethyl acetate, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains II crude product.With normal hexane: ethyl acetate=8:1 crosses pillar and namely obtains II 9.2g altogether, yield 80%.
Embodiment 2
Get II altogether 9.2g to be dissolved in 60ml tetrahydrofuran (THF) and to be placed in ice bath, pass into hydrogenchloride 25g gas, react and pass into nitrogen 10 minutes after 3 hours, concentrating under reduced pressure, with normal hexane: ethyl acetate=8:1 crosses pillar and namely obtains purified, purified is dissolved in ethanol, adds the palladium carbon 0.5g of 10%, passes into hydrogen reaction 24 hours, filter, cross pillar after filtrate reduced in volume and obtain III, eluent normal hexane: ethyl acetate=8:1-1:1 crosses pillar and namely obtains 2.6g, yield 30%.
Embodiment 3
Diisobutyl aluminium hydride 2.4ml is dissolved in toluene, be placed in-78 DEG C, get III 2.3g to be dissolved in 100ml tetrahydrofuran (THF) and to be added dropwise in above-mentioned reactor, stir and slowly add 2ml water after 1 hour, move into stirring at room temperature 1 hour, add anhydrous magnesium sulfate drying, filter, filtrate is dissolved in 45ml acetonitrile after being concentrated into and doing, add 2.36gNMO, 0.46gTPAP, molecular sieve, room temperature reaction 1.5 hours, diatomite filtration obtains filtrate, concentrating under reduced pressure, eluent normal hexane: ethyl acetate=4:1-1:1 crosses pillar and namely obtains 1.1g, yield 60%.
Embodiment 4
Get IV and be total to 0.5g, DMAP 90mg, add acetonitrile 5ml, get N, N-diisopropylethylamine 1.5g adds above-mentioned reaction flask after dissolving with a small amount of acetonitrile, get pyridine-3-sulfonyl chloride hydrochloride 1.1g, reaction flask is added after dissolving with 5ml acetonitrile, room temperature is cooled to after being heated to 45 DEG C of stirring reaction 5h, add 5ml water, pH to 5 is adjusted with the hydrochloric acid soln of 0.5N, slow dropping 20ml water (now having a large amount of white solid to separate out), stirring at room temperature 0.5h, be cooled to less than 10 DEG C, stir 1h, filter, the filter cake mixture of a small amount of acetonitrile and water washs, 50 DEG C are drying to obtain V and are total to 0.69g, yield 78%.
Embodiment 5
Get V and be total to 0.69g 10ml dissolve with methanol, drip methylamine 0.33g (25%), less than-5 DEG C are cooled to after reacting 1h under normal temperature, add 35mg sodium borohydride, add 4ml N,N-DIMETHYLACETAMIDE, check after reaction 1h and react completely, the hydrochloric acid soln adding 1N adjusts pH to 3-4, continue to stir 0.5h, drip ammoniacal liquor and adjust pH to 8-9, stir 0.5h, add water, ethyl acetate, extraction, aqueous phase adds water again, ethyl acetate, extraction, merge organic phase, saturated common salt is washed, anhydrous sodium sulfate drying, filter, be evaporated to a small amount of, add N,N-DIMETHYLACETAMIDE 5ml, be heated to 50 DEG C, add fumaric acid, stir 0.5h, move into stirring at room temperature 1h, filter to obtain solid, solid with ethyl acetate and N,N-DIMETHYLACETAMIDE mixed solution (3:1) washing, use ethyl acetate drip washing again, 50 DEG C are drying to obtain product 0.73g, yield 77%.
Claims (6)
1. treat a preparation method for hydrochloric acid in gastric juice disease medicament, it is characterized in that specifically comprising the following steps:
Step 1. starts with raw material I, carries out condensation reaction obtain intermediate II with ethyl cyanoacetate,
Step 2. intermediate II carries out cyclisation under hydrogenchloride condition, then obtains intermediate III by palladium hydrocarbonize;
Step 3. intermediate III DIBAL-H carries out reducing and obtain key intermediate IV,
Step 4. intermediate IV and pyridine-3-SULPHURYL CHLORIDE are reacted and obtain intermediate V;
Step 5. intermediate V and methylamine sodium borohydride carry out reductive amination process and namely obtain target product VI;
2. in preparation method as described in claim I, it is characterized in that: reaction base described in step I can be the sodium carbonate in mineral alkali, salt of wormwood, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide or hydrated barta, be preferably salt of wormwood, the solvent being applicable to above-mentioned reaction is acetonitrile, acetone, ethanol, methyl alcohol, DMF, dioxane, ethyl acetate or toluene, or the arbitrary combination of above-mentioned solvent, preferred solvent is acetone, raw material I, the mol ratio of ethyl cyanoacetate and alkali is 1:(5-9): (1-3), be preferably 1:(6-8): (1.5-2.5), be preferably 15-18 hour.
3. as claimed in claim 1 in preparation method, it is characterized in that: the solvent that step 2 is applicable to above-mentioned reaction is acetonitrile, methylene dichloride, ethanol, methyl alcohol, tetrahydrofuran (THF), DMF, dioxane, ethyl acetate, or the arbitrary combination of toluene or above-mentioned solvent, preferred solvent is tetrahydrofuran (THF), and the preferred reaction times is 3-12 hour.
4. as claimed in claim 1 in preparation method, it is characterized in that: the solvent that step 3 is applicable to above-mentioned reaction is acetonitrile, ethanol, methyl alcohol, the arbitrary combination of dioxane or toluene or above-mentioned solvent, preferred solvent is toluene, and the mol ratio of intermediate III and DIBAL-H is 1:(1-6), be preferably 1:(3-4).
5. as claimed in claim 1 in preparation method; it is characterized in that: step 4 intermediate IV and pyridine-3-SULPHURYL CHLORIDE mol ratio are 1:(1-5); be preferably 1:(1-2), the solvent being applicable to above-mentioned reaction is acetonitrile, acetone; ethanol; methyl alcohol, wait or the arbitrary combination of above-mentioned solvent, preferred solvent is acetonitrile; acylation catalyst is pyridine, triethylamine, DMAP, HOBT or HOAT, is preferably DMAP.
6. as claimed in claim 1 in preparation method, it is characterized in that: the mol ratio of step 5 intermediate V, methylamine, sodium borohydride is 1:(1-5): (0.3-1), be preferably 1:(1-3): (0.3-0.6), the solvent being applicable to above-mentioned reaction is methyl alcohol, ethanol, propyl alcohol or butanols, be preferably methyl alcohol, reaction times is generally 1-5 hour, be preferably 1-3 hour, after preparing fumarate, filtration washing mixed solvent is ethyl acetate and DMAC, ratio is ethyl acetate: DMAC is 1:(2-5), be preferably 1:(2-3).
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778207A (en) * | 2016-08-25 | 2018-03-09 | 广东东阳光药业有限公司 | Vonoprazan fumarate intermediate and its production and use |
| WO2019131695A1 (en) * | 2017-12-27 | 2019-07-04 | 日本ケミファ株式会社 | Production method for 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl]-n-methylmethanamine monofumarate |
| CN110272409A (en) * | 2019-03-11 | 2019-09-24 | 南京百迪尔生物医药有限公司 | The new method of one-step synthesis method Wo Nuolazan |
| CN110734424A (en) * | 2018-07-19 | 2020-01-31 | 成都弘达药业有限公司 | preparation method of vonoprazan fumarate |
Citations (3)
| 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 |
| CN102421753A (en) * | 2009-02-25 | 2012-04-18 | 武田药品工业株式会社 | Process for producing pyrrole compound |
| CN104327051A (en) * | 2014-10-13 | 2015-02-04 | 成都盛迪医药有限公司 | Crystal form of fumarate of pyrrole derivative |
-
2015
- 2015-12-17 CN CN201510955763.6A patent/CN105440019A/en active Pending
Patent Citations (3)
| 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 |
| CN102421753A (en) * | 2009-02-25 | 2012-04-18 | 武田药品工业株式会社 | Process for producing pyrrole compound |
| CN104327051A (en) * | 2014-10-13 | 2015-02-04 | 成都盛迪医药有限公司 | Crystal form of fumarate of pyrrole derivative |
Non-Patent Citations (1)
| Title |
|---|
| YASUYOSHI ARIKAWA等: "Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (PCAB)", 《J. MED. CHEM.》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778207A (en) * | 2016-08-25 | 2018-03-09 | 广东东阳光药业有限公司 | Vonoprazan fumarate intermediate and its production and use |
| WO2019131695A1 (en) * | 2017-12-27 | 2019-07-04 | 日本ケミファ株式会社 | Production method for 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl]-n-methylmethanamine monofumarate |
| JPWO2019131695A1 (en) * | 2017-12-27 | 2021-01-14 | 日本ケミファ株式会社 | Method for producing 1- [5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrol-3-yl] -N-methylmethaneamine monofumarate |
| JP7227925B2 (en) | 2017-12-27 | 2023-02-22 | 日本ケミファ株式会社 | Method for producing 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate |
| CN110734424A (en) * | 2018-07-19 | 2020-01-31 | 成都弘达药业有限公司 | preparation method of vonoprazan fumarate |
| CN110734424B (en) * | 2018-07-19 | 2022-12-13 | 四川弘远药业有限公司 | Preparation method of vonoprazan fumarate |
| CN110272409A (en) * | 2019-03-11 | 2019-09-24 | 南京百迪尔生物医药有限公司 | The new method of one-step synthesis method Wo Nuolazan |
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Application publication date: 20160330 |