CN102225909B - Preparation method of lansoprazole intermediate - Google Patents
Preparation method of lansoprazole intermediate Download PDFInfo
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- CN102225909B CN102225909B CN 201110114642 CN201110114642A CN102225909B CN 102225909 B CN102225909 B CN 102225909B CN 201110114642 CN201110114642 CN 201110114642 CN 201110114642 A CN201110114642 A CN 201110114642A CN 102225909 B CN102225909 B CN 102225909B
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- trifluoro ethoxy
- ethoxy pyridine
- methyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 title abstract description 10
- 229960003174 lansoprazole Drugs 0.000 title abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 39
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 abstract description 15
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000035484 reaction time Effects 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- AENYCMZUDXQARW-UHFFFAOYSA-N 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CCl AENYCMZUDXQARW-UHFFFAOYSA-N 0.000 abstract 2
- GMSURXZOJDDQEF-UHFFFAOYSA-N 2,3-dimethyl-1-oxido-4-(2,2,2-trifluoroethoxy)pyridin-1-ium Chemical compound CC1=C(C)[N+]([O-])=CC=C1OCC(F)(F)F GMSURXZOJDDQEF-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229950002342 bisfentidine Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- FXJAOWANXXJWGJ-UHFFFAOYSA-N n-[4-(2-methyl-1h-imidazol-5-yl)phenyl]-n'-propan-2-ylmethanimidamide Chemical compound C1=CC(NC=NC(C)C)=CC=C1C1=CN=C(C)N1 FXJAOWANXXJWGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4-trifluoroethoxy pyridine (IV). Specifically, under the protection of nitrogen, with dichloromethane as a reaction solvent and in the presence of triethylamine, 2,3-dimethyl-4- trifluoroethoxy pyridine-N-oxide (I) is further reacted with phosphorus oxychloride to produce 2-chloromethyl-3-methyl-4-trifluoroethoxy pyridine (IV). The method of the invention reduces the traditional three-step reaction to a one-step reaction, so that the reaction time is reduced, the raw materials are saved, and the discharge of "three wastes" is reduced, thus being suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of medicine intermediate, be specifically related to the preparation method of lansoprazole intermediate 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine.
Background technology
Lansoprazole is the s-generation H+/K+-ATP enzyme inhibitors of Japanese Wu Tian company exploitation listing.Compare with first-generation H+/K+-ATP enzyme inhibitors omeprazole, lansoprazole is owing to having introduced trifluoro ethoxy in pyridine 4-position, and thermodynamics and oxidative stability increase, and this has been apt to biological activity greatly, has better curative effect, less side effect.Lansoprazole has obvious injury in treating effect for Stomach duodenum ulcer and reflux esophagitis; The ulcer pathology that chronic ulcer, bisfentidine are difficult to cure has obvious healing promoter action.
2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV) is the important drugs synthetic intermediate of lansoprazole, and its structural formula is as follows:
2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV) is by obtaining 2-[[[3-methyl-4-(2 with 2-sulfydryl-1H-benzoglyoxaline condensation; 2; the 2-trifluoro ethoxy)-2-pyridyl]-methyl] sulfenyl]-the 1H-benzoglyoxaline; obtain 2-[[[3-methyl-4-(2 through oxidizing reaction again; 2; the 2-trifluoro ethoxy)-2-pyridyl]-methyl] sulfinyl]-1H-benzoglyoxaline, i.e. lansoprazole.
Traditional preparation technology of 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV) with 2,3-dimethyl-4-trifluoro ethoxy pyridine-
N-oxide compound (I) is starting raw material, prepares through three-step reaction, as the method that discloses in Chinese patent application CN101137371A: 2,3-dimethyl-4-trifluoro ethoxy pyridine-
N-oxide compound (I) at first generates 2-acetoxy-methyl-3-methyl-4-trifluoro ethoxy pyridine (II) with acetic anhydride generation rearrangement reaction, then add sodium hydroxide solution through hydrolysis reaction, obtain 2-methylol-3-methyl-4-trifluoro ethoxy pyridine (III), 2-methylol-3-methyl-4-trifluoro ethoxy pyridine (III) generates 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV) with thionyl chloride through chlorination reaction.The reaction scheme of this traditional technology is as follows:
This tradition preparation technology reactions steps is longer, trivial operations, and use a large amount of organic solvents and auxiliary material, easily cause the waste of resource and the energy, the pollution of environment.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of lansoprazole intermediate 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV), the method with 2,3-dimethyl-4-trifluoro ethoxy pyridine-
N-oxide compound (I) starting raw material only needs single step reaction.
The inventive method is as follows: under nitrogen protection, with methylene dichloride (CH
3Cl
2) be reaction solvent, and at triethylamine (Et
3N) exist under, with 2,3-dimethyl-4-trifluoro ethoxy pyridine-
N-oxide compound (I) and phosphorus oxychloride (POCl
3) carry out single step reaction and obtain 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV).
The reaction process of the inventive method can illustrate by following reaction formula:
The reaction system of using the inventive method can realize the deoxidation of 1-position on pyridine ring and the chlorination reaction of 2-position methyl simultaneously through single step reaction, and traditional method needs could realize the deoxidation of 1-position and the chlorination reaction of 2-position methyl through rearrangement, hydrolysis, chlorination three-step reaction.The inventive method has obviously shortened reactions steps, has reduced the reaction times.
Because phosphorus oxychloride is easy to the water reaction, so in the methods of the invention, nitrogen can effectively completely cut off phosphorus oxychloride and contact with airborne steam, thereby reduces the consumption as the phosphorus oxychloride of raw material, improves reaction yield.
The described single step reaction of the inventive method under refluxad carries out.
In the methods of the invention, triethylamine not only as a kind of good Fu acid agent, can guarantee that also this single step reaction carries out smoothly simultaneously under the weak base condition.Triethylamine and 2,3-dimethyl-4-trifluoro ethoxy pyridine-
NThe molar equivalent ratio of-oxide compound (I) is 0.9～1.6: 1, preferred 1.1: 1.
In the methods of the invention, phosphorus oxychloride and 2,3-dimethyl-4-trifluoro ethoxy pyridine-
NThe molar equivalent ratio of-oxide compound (I) is 0.8～1.5: 1, preferred 1.1: 1.
The concrete steps of the inventive method: under nitrogen protection, with 2,3-dimethyl-4-trifluoro ethoxy pyridine-
N-oxide compound (I) is dissolved in methylene dichloride, under stirring at room, and drips the dichloromethane solution of phosphorus oxychloride in 30 minutes, drip finish after, be heated to reflux, slowly add triethylamine, back flow reaction 1 hour.After reaction finishes, reaction solution NaHCO
3The saturated aqueous solution washing is to neutral, and the water dichloromethane extraction merges organic phase, uses anhydrous Na
2SO
4Drying is filtered, the concentrated product 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV) that obtains of underpressure distillation.
The invention has the advantages that: the three-step reaction of traditional method is shortened to single step reaction, reduced the reaction times, reaction conditions is gentle, and easy to operate, yield is higher, and has saved raw material, has reduced the discharging of the three wastes, is suitable for suitability for industrialized production.
Embodiment
The invention will be further described below in conjunction with embodiment, but do not limit the present invention in any way.Starting raw material 2 in embodiment, 3-dimethyl-4-trifluoro ethoxy pyridine-
N-oxide compound (I) prepares according to the described method of Chinese patent application CN101137371A, and all the other reagent and raw material be commercially available getting all.
The preparation of embodiment 1:2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine
Under nitrogen protection, with 2,3-dimethyl-4-trifluoro ethoxy pyridine-
N-oxide compound (50mmol, 11.05g) be dissolved in methylene dichloride (50ml), under stirring at room, and dripped methylene dichloride (50ml) solution of phosphorus oxychloride (55mmol, 5.0ml) in 30 minutes, drip finish after, be heated to reflux, slowly add triethylamine (55mmol, 7.8ml), back flow reaction 1 hour.After reaction finishes, reaction solution NaHCO
3The saturated aqueous solution washing is to neutral, and water merges organic phase with methylene dichloride (50ml * 3) extraction, uses anhydrous Na
2SO
4Drying is filtered, and underpressure distillation is concentrated obtains oily product 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (10.78g), and yield is 90%.
The preparation of embodiment 2:2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine
Under nitrogen protection; 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (50mmol, 11.05g) is dissolved in methylene dichloride (50ml); under stirring at room; and dripped methylene dichloride (50ml) solution of phosphorus oxychloride (40mmol, 3.7ml) in 30 minutes, drip finish after; be heated to reflux; slowly add triethylamine (55mmol, 7.8ml), back flow reaction 1 hour.After reaction finishes, reaction solution is extremely neutral with the washing of NaHCO3 saturated aqueous solution, water extracts with methylene dichloride (50ml * 3), merge organic phase, dry with anhydrous Na 2SO4, filter, underpressure distillation is concentrated obtains oily product 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (8.39g), and yield is 70%.
The preparation of embodiment 3:2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine
Under nitrogen protection; 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (50mmol, 11.05g) is dissolved in methylene dichloride (50ml); under stirring at room; and dripped methylene dichloride (50ml) solution of phosphorus oxychloride (75mmol, 6.9ml) in 30 minutes, drip finish after; be heated to reflux; slowly add triethylamine (55mmol, 7.8ml), back flow reaction 1 hour.After reaction finishes, reaction solution is extremely neutral with the washing of NaHCO3 saturated aqueous solution, water extracts with methylene dichloride (50ml * 3), merge organic phase, dry with anhydrous Na 2SO4, filter, underpressure distillation is concentrated obtains oily product 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (9.94g), and yield is 83%.
The preparation of embodiment 4:2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine
Under nitrogen protection; 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (50mmol, 11.05g) is dissolved in methylene dichloride (50ml); under stirring at room; and dripped methylene dichloride (50ml) solution of phosphorus oxychloride (55mmol, 5.0ml) in 30 minutes, drip finish after; be heated to reflux; slowly add triethylamine (45mmol, 6.4ml), back flow reaction 1 hour.After reaction finishes, reaction solution is extremely neutral with the washing of NaHCO3 saturated aqueous solution, water extracts with methylene dichloride (50ml * 3), merge organic phase, dry with anhydrous Na 2SO4, filter, underpressure distillation is concentrated obtains oily product 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (10.18g), and yield is 85%.
The preparation of embodiment 5:2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine
Under nitrogen protection; 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (50mmol, 11.05g) is dissolved in methylene dichloride (50ml); under stirring at room; and dripped methylene dichloride (50ml) solution of phosphorus oxychloride (55mmol, 5.0ml) in 30 minutes, drip finish after; be heated to reflux; slowly add triethylamine (80mmol, 11.3ml), back flow reaction 1 hour.After reaction finishes, reaction solution is extremely neutral with the washing of NaHCO3 saturated aqueous solution, water extracts with methylene dichloride (50ml * 3), merge organic phase, dry with anhydrous Na 2SO4, filter, underpressure distillation is concentrated obtains oily product 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (9.35g), and yield is 78%.
Claims (6)
1.2-the preparation method of chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV); comprise: under nitrogen protection; take methylene dichloride as reaction solvent; and under triethylamine exists; 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (I) and phosphorus oxychloride are carried out single step reaction obtain 2-chloromethyl-3-methyl-4-trifluoro ethoxy pyridine (IV).
2. preparation method according to claim 1, is characterized in that described single step reaction under refluxad carries out.
3. preparation method according to claim 1, is characterized in that the molar equivalent ratio of described triethylamine and 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (I) is 0.9～1.6:1.
4. preparation method according to claim 3, is characterized in that the molar equivalent of described triethylamine and 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (I) is than being 1.1:1.
5. preparation method according to claim 1, is characterized in that the molar equivalent ratio of described phosphorus oxychloride and 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (I) is 0.8～1.5:1.
6. preparation method according to claim 5, is characterized in that the molar equivalent of described phosphorus oxychloride and 2,3-dimethyl-4-trifluoro ethoxy pyridine-N-oxide compound (I) is than being 1.1:1.
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| CN 201110114642 CN102225909B (en) | 2011-05-05 | 2011-05-05 | Preparation method of lansoprazole intermediate |
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|---|---|---|---|
| CN 201110114642 CN102225909B (en) | 2011-05-05 | 2011-05-05 | Preparation method of lansoprazole intermediate |
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| CN111320570B (en) * | 2020-03-24 | 2022-02-08 | 迪嘉药业集团有限公司 | Preparation method of lansoprazole key intermediate |
| CN114163419A (en) * | 2021-12-24 | 2022-03-11 | 辰欣药业股份有限公司 | Preparation method of lansoprazole |
| CN117534657B (en) * | 2023-11-20 | 2024-10-15 | 湖北省医药工业研究院有限公司 | Synthetic method and application of rabeprazole analogue |
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| ES2036502A6 (en) * | 1991-08-05 | 1993-05-16 | Genesis Para La Investigacion | Improvements in the subject matter of patent no. 9003113 for Process for obtaining 2-halomethyl-3,5-dimethyl-4- methoxypyridine hydrohalide |
| JP2010077030A (en) * | 2008-09-24 | 2010-04-08 | Ihara Nikkei Kagaku Kogyo Kk | Manufacturing method of 2-chloromethyl-6-methylpyridine |
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