CN104327048A - Lansoprazole thioether crystal form, and preparation method and application thereof - Google Patents
Lansoprazole thioether crystal form, and preparation method and application thereof Download PDFInfo
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- CN104327048A CN104327048A CN201410135180.4A CN201410135180A CN104327048A CN 104327048 A CN104327048 A CN 104327048A CN 201410135180 A CN201410135180 A CN 201410135180A CN 104327048 A CN104327048 A CN 104327048A
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- 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
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Abstract
The invention provides lansporazole thioether crystal form, and a preparation method and application thereof. The preparation method for the crystal form is extremely simple and mild in conditions, is in no need of heating reflux reaction, and is in no need of vacuum concentration or other solvent recrystallization. Besides, the method is high in yield, the yield can reach over 98% and purity is higher than or equal to 99.9%. Stability research shows that the crystal form product prepared by the method has good stability and related substances have no change. The crystal form can generate lansoprazole through oxidation or generate dexlansoprazole through asymmetric oxidation.
Description
Technical field
The present invention relates to field of medicine and chemical technology, be specifically related to the method that lansoprazole or R-lansoprazole are prepared in chemosynthesis.
Background technology
Lansoprazole (Lansoprazole), chemical name is: 2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methyl]-sulfinyl]-1H-benzoglyoxaline, molecular formula C
16h
14f
3n
3o
2s, molecular weight 369.36.Develop successfully by Japanese Wu Tian company, subsequently France, Japan, the U.S. goes on the market successively, is as after omeprazole, second listing proton pump inhibitor.The medicine of a kind of novel gastric acid secretion inhibiting of lansoprazole, it acts on the H+-K+-ATP enzyme of parietal cell, make its inactivation, suppress the gastric acid secretion that nervus centralis and peripheral nerve regulate, the clinical treatment being mainly used in stomach ulcer, duodenal ulcer, stoma ulcer, helicobacter pylori infection and the disease such as reflux esophagitis, gastrinoma, compared with the omeprazole gone on the market for many years, owing to introducing trifluoro ethoxy on pyridine ring, make it have better curative effect, less side effect and stronger stability.
R-lansoprazole (Dexlansoprazole) is is also researched and developed by Japanese Takeda Pharmaceutical Company Limited, obtain U.S. FDA approval listing on January 30th, 2009, be used for the treatment of the pyrosis relevant to Non-erosive gastroesophageal reflux disease (GERD) and erosive esophagitis in various degree.This medicine is the proton pump inhibitor class anti-ulcerative drug that first design provides point dual controlled release of 2 releases.
Lansoprazole thioether is the important intermediate preparing R-lansoprazole, its purity is directly connected to the product of final R-lansoprazole, therefore, the existing a lot of report of preparation method about lansoprazole thioether, such as CN102617555A, the improvement in synthesis (" fine-chemical intermediate " the 3rd phase Liu Yanfei in 2011 etc.) of lansoprazole, but these methods prepare lansoprazole thioether all to be needed to be heated to back flow reaction, reaction solution aftertreatment must through concentrating under reduced pressure, add toluene or ethyl acetate crystallization again, operate very loaded down with trivial details, reaction conditions is not gentle, and there are the problems such as foreign matter content is high.
If lansoprazole thioether is of low quality, then the process preparing lansoprazole and R-lansoprazole can be caused to produce other impurity, thus reduce quality and the yield of finished product.
Summary of the invention
The object of the present invention is to provide a kind of lansoprazole thioether crystal formation, it is characterized in that, its X-ray powder diffraction at angle of diffraction 2 θ is: 5.74,11.51,11.79,12.00,12.23,12.45,13.29,13.52,15.07,18.48,19.09,22.28,23.80,24.21,24.64,25.36,25.58,26.43,26.82,27.54,28.32, when 29.32, there is characteristic peak.
Lansoprazole thioether crystal formation of the present invention is favourable, because it draws azoles thioether purity higher, more stable than drag-line prepared in prior art, is therefore easier to processing and stores.
Present invention also offers a kind of low cost, high yield, the method preparing lansoprazole thioether new crystal of low impurity content, employing molar ratio is 2-mercaptobenzimidazole and the 2-chloromethyl-3-methyl-4-(2 of 2.0-1.0: 1, 2, 2-trifluoro ethoxy) pyridine hydrochloride is starting raw material, using methyl alcohol as reaction solvent, the temperature condition of reaction is 0-50 DEG C, take mineral alkali as catalyzer, carry out condensation reaction, by product is not had to produce, after having reacted, add the water of the 1-10 times amount of reaction solvent, after stirring and crystallizing 0-12 hour, filter, the filter cake water washing of 0-10 times amount, drain, air blast or vacuum-drying obtain lansoprazole thioether crystal formation.Reaction is easy to control, and product purity can reach more than 99.9%, quality and stable crystal form.
The preferred 20-30 DEG C of temperature condition of reaction.
Described mineral alkali is sodium hydroxide or potassium hydroxide.
The monitoring method that described reaction completes is tlc or high performance liquid chromatography.
Present invention also offers the application of the lansoprazole thioether of described crystal formation, relate to the method that lansoprazole and R-lansoprazole are prepared in chemosynthesis.Described lansoprazole thioether crystal formation generates lansoprazole through oxidizing reaction or asymmetric oxidation reaction generates R-lansoprazole.
This crystal formation of the present invention and preparation method thereof is extremely simple, and mild condition, does not need heating reflux reaction, does not also need concentrating under reduced pressure and other solvent recrystallization.And the method yield is high, can more than 98% be reached, purity >=99.9%.By stability study, this crystal formation product stability that this method obtains is good, and related substance does not change.
Accompanying drawing explanation
Fig. 1 is the XRD figure spectrum of lansoprazole thioether crystal formation of the present invention.
Embodiment
Embodiment 1: prepared by lansoprazole thioether
Methyl alcohol 6.40g, 2-mercaptobenzimidazole 1.11g, 2-chloromethyl-3-methyl-4-(2 is added in reaction flask, 2,2-trifluoro ethoxy) pyridine hydrochloride 2.00g, stir, drip aqueous sodium hydroxide solution (0.64g sodium hydroxide is dissolved in 1.50g water) to finish, temperature of reaction 25 DEG C, tlc (TLC) monitoring reaction, after completion of the reaction, adds 64.00g water in reaction solution, stir 6 hours, filter, filter cake 64.00g water washing, drains, filter cake 45 DEG C of forced air dryings, obtain lansoprazole thioether crystal formation 2.65g.Molar yield 98.0%, purity more than 99.9%.Results of stability is good.
Prepared by embodiment 2 lansoprazole thioether
Methyl alcohol 6.40g, 2-mercaptobenzimidazole 2.18g, 2-chloromethyl-3-methyl-4-(2 is added in reaction flask, 2,2-trifluoro ethoxy) pyridine hydrochloride 2.00g, stir, drip aqueous sodium hydroxide solution (0.64g sodium hydroxide is dissolved in 1.50g water) to finish, temperature of reaction 25 DEG C, tlc (TLC) monitoring reaction, after completion of the reaction, adds 6.40g water in reaction solution, stir 12 hours, filter, filter cake 64.00g water washing, drains, filter cake 45 DEG C of forced air dryings, obtain lansoprazole thioether crystal formation 2.62g.Molar yield 97.6%, purity more than 99.9%.Results of stability is good.
Described in embodiment 1 or embodiment 2, the lansoprazole thioether crystal form samples of preparation is through copper target X powder diffraction, and experiment parameter is as shown in table 1:
Table 1 powder diffraction experiment parameter
| Anode | Wavelength 1 | Wavelength 2 | Voltage | Electric current | Angle intervals | The timed interval | Initial angle | End angle |
| Cu | 1.5408A° | 1.54331A° | 40KV | 40mA | 0.02° | 0.3s | 5° | 60° |
Obtain XRD figure spectrum as shown in Table 2 and Figure 1, its stability analysis is as shown in table 3:
Table 2 powder diffraction experiment data
| Angle (° 2Th.) | Peak height (cts) | Halfwidth (° 2Th.) | D-value (A) | Peak height (%) |
| 5.7456 | 2764.14 | 0.0974 | 15.38216 | 8.78 |
| 11.5137 | 4012.45 | 0.1299 | 7.68578 | 12.74 |
| 11.7870 | 6138.99 | 0.0974 | 7.50818 | 19.50 |
| 11.9964 | 10572.20 | 0.0649 | 7.37757 | 33.58 |
| 12.2264 | 14020.90 | 0.0649 | 7.23931 | 44.53 |
| 12.4543 | 8488.54 | 0.0649 | 7.10734 | 26.96 |
| 13.2876 | 16372.85 | 0.1299 | 6.66346 | 52.00 |
| 13.5205 | 6224.34 | 0.0974 | 6.54920 | 19.77 |
| 15.0699 | 4510.72 | 0.1299 | 5.87912 | 14.33 |
| 16.2768 | 1638.05 | 0.1299 | 5.44584 | 5.20 |
| 16.7645 | 2049.06 | 0.1624 | 5.28849 | 6.51 |
| 17.1817 | 1596.16 | 0.1299 | 5.16101 | 5.07 |
| 17.4690 | 860.54 | 0.0974 | 5.07677 | 2.73 |
| 17.9838 | 2254.03 | 0.1624 | 4.93259 | 7.16 |
| 18.4834 | 5411.49 | 0.1624 | 4.80036 | 17.19 |
| 19.0930 | 8566.03 | 0.3572 | 4.64846 | 27.21 |
| 20.4866 | 1342.63 | 0.0974 | 4.33529 | 4.26 |
| 20.7500 | 1465.18 | 0.1299 | 4.28085 | 4.65 |
| 21.6360 | 2224.26 | 0.1948 | 4.10751 | 7.06 |
| 22.2824 | 5112. 92 | 0.2598 | 3.98978 | 16.24 |
| 22.7174 | 2586.40 | 0.1299 | 3.91436 | 8.21 |
| 23.1865 | 2190.79 | 0. 1299 | 3.83622 | 6.96 |
| 23.7981 | 3522.85 | 0.1948 | 3.73901 | 11.19 |
| 24.2143 | 4726.48 | 0.0974 | 3.67568 | 15.01 |
| 24.6373 | 31486.71 | 0. 1624 | 3.61350 | 100.00 |
| 25.3627 | 8072.69 | 0.0974 | 3.51178 | 25.64 |
| 25.5816 | 14255.71 | 0.1624 | 3.48222 | 45.28 |
| 26.4261 | 3906.40 | 0. 1299 | 3.37283 | 12.41 |
| 26.8180 | 6507.03 | 0.1624 | 3.32443 | 20.67 |
| 27.5449 | 6706.94 | 0.1948 | 3.23833 | 21.30 |
| 28.3203 | 3362.61 | 0.1624 | 3.15141 | 10.68 |
| 29.1345 | 2807.17 | 0.1299 | 3.06516 | 8.92 |
| 29.3227 | 3476.37 | 0.1624 | 3.04591 | 11.04 |
Table 3 lansoprazole thioether stability of crystal form data
| Time | Proterties | Related substance (%) | Purity (%) | Moisture (%) |
| 0 month | White crystalline solid | 0.03 | 99.97 | 4.86 |
| January | White crystalline solid | 0.02 | 99.98 | 4.84 |
| February | White crystalline solid | 0.02 | 99.98 | 4.85 |
| March | White crystalline solid | 0.04 | 99.96 | 4.85 |
| June | White crystalline solid | 0.03 | 99.97 | 4.88 |
Prepared by embodiment 3 lansoprazole
Described in the 18.0g prepare embodiment 1 or embodiment 2, the lansoprazole thioether of crystal formation is put in 360mL trichloromethane, room temperature mechanical stirs lower slowly dropping 10.0g metachloroperbenzoic acid, TCL monitors reaction process, after completion of the reaction, the hypo solution 400mL adding 10% stirs half an hour, stratification, collected organic layer, steaming desolventizes, and adds water to be cooled to 5 ° of below C crystallizations and to obtain lansoprazole 16.0g, yield 85%.
Prepared by embodiment 4 R-lansoprazole
The lansoprazole thioether 2.4g of described crystal formation prepared by embodiment 1 or embodiment 2, toluene 12.0g joins in 50mL there-necked flask, be heated to 50-55 DEG C, add 0.64gL-diethyl tartrate and 0.02g water stirring reaction 1 hour, add titanium isopropylate 0.4g, continue reaction 1 hour, 0.3g N is added when being cooled to 10 DEG C, N-diisopropyl ethyl amine, relay protection temperature slowly drips 1.8 grams of hydrogen phosphide cumenes, after dropwising, continue reaction, high performance liquid chromatography (HPLC) monitoring is to thioether less than 3%, add 20% hypo solution of 12.0g, stir 30 minutes, stratification, get organic layer, 2.4g water is dripped successively under mechanical stirring, 4.8g normal heptane finishes rear stirring 3 hours, filter, filter cake 6 times amount toluene drip washing 3 times, drain, filter cake 45 DEG C of forced air dryings, obtain R-lansoprazole 2.3g, yield 90.8%.
Claims (8)
1. a lansoprazole thioether crystal formation, is characterized in that, its X-ray powder diffraction at angle of diffraction 2 θ is: 5.74,11.51,11.79,12.00,12.23,12.45,13.29,13.52,15.07,18.48,19.09,22.28,23.80,24.21,24.64,25.36,25.58,26.43,26.82,27.54,28.32, when 29.32, there is characteristic peak.
2. lansoprazole thioether crystal formation according to claim 1, is characterized in that, is stable and can not occurs easily to turn brilliant.
3. the preparation method of the lansoprazole thioether crystal formation described in claim 1 or 2, it is characterized in that, employing molar ratio is 2-mercaptobenzimidazole and the 2-chloromethyl-3-methyl-4-(2 of 2.0-1.0: 1, 2, 2-trifluoro ethoxy) pyridine hydrochloride is starting raw material, using methyl alcohol as reaction solvent, the temperature condition of reaction is 0-50 DEG C, take mineral alkali as catalyzer, carry out condensation reaction, after having reacted, add the water of the 1-10 times amount of reaction solvent, after stirring and crystallizing 0-12 hour, filter, the filter cake water washing of 0-10 times amount, drain, air blast or vacuum-drying obtain lansoprazole thioether crystal formation.
4. the preparation method of lansoprazole thioether crystal formation according to claim 3, is characterized in that, the preferred 20-30 DEG C of temperature condition of reaction.
5. the preparation method of lansoprazole thioether crystal formation according to claim 3, is characterized in that, described mineral alkali is sodium hydroxide or potassium hydroxide.
6. the preparation method of lansoprazole thioether crystal formation according to claim 3, is characterized in that, the monitoring method that described reaction completes is tlc or high performance liquid chromatography.
7. the lansoprazole thioether of crystal formation described in claim 1 or 2 is preparing the application in lansoprazole or R-lansoprazole.
8. application according to claim 7, is characterized in that, the lansoprazole thioether of described crystal formation generates lansoprazole through oxidizing reaction or asymmetric oxidation reaction generates R-lansoprazole.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188000A (en) * | 2016-07-11 | 2016-12-07 | 成都尚药科技有限公司 | A kind of synthetic method of Dexlansoprazole |
| CN113582973A (en) * | 2021-09-28 | 2021-11-02 | 丽珠医药集团股份有限公司 | Preparation method of thioether |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004056803A1 (en) * | 2002-12-23 | 2004-07-08 | Chemi Spa | Process for the preparation of sulphinyl derivatives by oxidation of the corresponding sulfides |
| WO2007138468A2 (en) * | 2006-06-01 | 2007-12-06 | Wockhardt Ltd | Processes for the preparation of lansoprazole |
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- 2014-04-04 CN CN201410135180.4A patent/CN104327048A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004056803A1 (en) * | 2002-12-23 | 2004-07-08 | Chemi Spa | Process for the preparation of sulphinyl derivatives by oxidation of the corresponding sulfides |
| WO2007138468A2 (en) * | 2006-06-01 | 2007-12-06 | Wockhardt Ltd | Processes for the preparation of lansoprazole |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188000A (en) * | 2016-07-11 | 2016-12-07 | 成都尚药科技有限公司 | A kind of synthetic method of Dexlansoprazole |
| CN113582973A (en) * | 2021-09-28 | 2021-11-02 | 丽珠医药集团股份有限公司 | Preparation method of thioether |
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