CN102399212B - Dexlansoprazole crystal form and preparation method thereof - Google Patents
Dexlansoprazole crystal form and preparation method thereof Download PDFInfo
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- CN102399212B CN102399212B CN201110243031.6A CN201110243031A CN102399212B CN 102399212 B CN102399212 B CN 102399212B CN 201110243031 A CN201110243031 A CN 201110243031A CN 102399212 B CN102399212 B CN 102399212B
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Abstract
The present invention relates to a dexlansoprazole crystal form and a preparation method thereof. The d values of characteristic peaks of the dexlansoprazole crystal form in an x-ray powder diffraction pattern are 12.234, 5.640, 5.401, 5.087, 4.990, 4.839, 4.605, 4.354, 3.959 and 3.648.
Description
Technical field
The present invention relates to new crystal of a kind of R-lansoprazole and preparation method thereof, the d value of its X-ray powder diffraction pattern characteristic peak is 12.234,5.640,5.401,5.087,4.990,4.839,4.605,4.354,3.959 and 3.648.
Background technology
CN1150186C discloses two kinds of crystal formations that are suitable for the R-lansoprazole of pharmacy.Wherein the X-ray powder diffraction analysis chart of A crystal formation locates to have characteristic peak in following spacing (d): 11.68,6.77,5.84,5.73,4.43,4.09,3.94,3.89, and 3.69,3.41 and 3.11 dusts; The X-ray powder diffraction analysis chart of B crystal formation locates to have characteristic peak in following spacing (d): 13.22,9.60,8.87,8.05,6.61,5.91,5.64,5.02, and 4.48,3.50 and 2.29 dusts.
Summary of the invention
The object of the present invention is to provide a kind of R-lansoprazole new crystal, the d value of its X-ray powder diffraction pattern characteristic peak is 12.234,5.640,5.401,5.087,4.990,4.839,4.605,4.354,3.959 and 3.648; Preferably, d value is 12.234,9.563,8.838,8.022,7.261,5.640,5.401,5.087,4.990,4.839,4.605,4.354,3.959 and 3.648; More preferably, its X-ray powder diffraction pattern as shown in Figure 1.
Another object of the present invention is to provide a kind of method of preparing described new crystal, the method is dissolved in crystallization in organic solvent by R-lansoprazole or its crystal formation and obtains described crystal formation, wherein said organic solvent particular methanol, more preferably contains the methyl alcohol of ammoniacal liquor, more preferably contains the ammoniacal liquor of 25% concentration.
Through X-ray diffraction analysis, the crystal formation of R-lansoprazole provided by the present invention is different from A crystal formation and B crystal formation, and its stable preparation process is controlled, favorable reproducibility; Conventional solvent as methyl alcohol, second alcohol and water in solvability suitable with B crystal formation with A crystal formation, draw moist quite with B crystal formation, stable crystal form is good, is suitable for pharmacy.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure that embodiment mono-makes Dexlansoprazole crystal form.
Embodiment
The preparation of embodiment mono-Dexlansoprazole crystal form
1, the chloro-3-picoline of 2-acetoxy-methyl-4-is synthetic
By chloro-raw material 4-2,3 dimethyl pyridine-N-oxide compound, 1083.7g, 6.88mol is dissolved in toluene (7000m1), is heated to 90 DEG C, slowly drips diacetyl oxide (2053.2g, 20.11mol), and temperature is controlled at 90-110 DEG C.Finish, be incubated 105-110 DEG C of reaction 1.5h, TLC detection reaction is complete.Slightly cold, 60 DEG C remove solvent under reduced pressure, obtain the chloro-3-picoline of 2-acetoxy-methyl-4-(yellow oil, 1627.2g).
2, the chloro-3-picoline of 2-methylol-4-is synthetic
Step 1 is made to the chloro-3-picoline of 2-acetoxy-methyl-4-and be dissolved in methyl alcohol (1450ml), be cooled to 0-5 DEG C, drip the solution of potassium hydroxide (1597.0g) and water (7000ml), control reacting liquid temperature below 10 DEG C, about 30min drips off, continue insulation reaction 20min, TLC detection reaction is complete.Pressure reducing and steaming methyl alcohol, with methylene dichloride (2300ml × 3) extraction, merges organic phase, uses 1000.0g anhydrous sodium sulfate drying.Filter, filtrate decompression concentrates to obtain the chloro-3-picoline of 2-methylol-4-(yellow oil, 913.1g).
3, the chloro-3-picoline of 2-chloromethyl-4-is synthetic
Step 2 is made to the chloro-3-picoline of 2-methylol-4-and be dissolved in trichloromethane (4000ml), be cooled to 0～-5 DEG C, stir the lower sulfur oxychloride (590.3g that drips, 4.96mol), control temperature of reaction below 10 DEG C, about 40min drips off, and continues insulation reaction 20min, and TLC detection reaction is complete.Concentrating under reduced pressure obtains brown solid, slowly add frozen water (3L), with saturated sodium bicarbonate (3000ml) solution tune pH to 8-9, extract with methylene dichloride (1700ml × 3), merge organic phase, wash once with saturated nacl aqueous solution (3L), obtain the solution of the chloro-3-picoline of 2-chloromethyl-4-.
4,2-(((the chloro-3-methyl-2-of 4-pyridyl) methyl) sulfenyl)-1H-benzoglyoxaline is synthetic
By sodium hydroxide (487.6g, 12.19mol) water-soluble (4800ml), be cooled to 10～15 DEG C, add 2-mercaptobenzimidazole (487.6g, 3.25mol) and triethyl benzyl ammonia chloride (146.6g, 0.63mol), stir 15min, then the solution that drips the chloro-3-picoline of 2-chloromethyl-4-that step 3 makes, temperature control is below 15 DEG C.Finish, stir about 2h at 25～30 DEG C, TLC detects the chloro-3-picoline of 2-chloromethyl-4-and reacts completely, and reaction solution is concentrated into about 6000ml, is cooled to 0 DEG C and stirs 1h, filter, methylene dichloride for solid (1150ml) washing, water (1200ml × 3) washing, 40 DEG C of vacuum-drying 8h, obtain 2-(((the chloro-3-methyl-2-of 4-pyridyl) methyl) sulfenyl)-1H-benzoglyoxaline (off-white color solid, 645.1g).
5, R-2-(((the chloro-3-methyl-2-of 4-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline is synthetic
2-(((the chloro-3-methyl-2-of 4-pyridyl) methyl) sulfenyl)-1H-benzoglyoxaline (645.1g), toluene (3600ml) and L-(+) diethyl tartrate (168ml) that step 4 is made mix, be heated to 50-60 DEG C of reaction 0.5h, add tetraisopropoxy titanium (131ml), continue to react 1h at this temperature.Reaction solution is cooled to 20 DEG C, adds diisopropylethylamine (135ml), be cooled to-10 DEG C, temperature control-10 DEG C add 80% cumene hydroperoxide (1203ml) to 0 DEG C, control temperature at-5 DEG C to 0 DEG C reaction 4h.It is complete that TLC analyzes primitive reaction, add 30% hypo solution (1600ml), stir 10min, drip successively normal hexane (1550ml), t-butyl methyl ether (1550ml), normal hexane (13000ml) in 0 DEG C to 10 DEG C, separate out white solid, filter, with t-butyl methyl ether-toluene (4: 1,1250ml) washing 1 time.This solid is dissolved in acetone (15L); filter; in filtrate, drip water (40L); separate out solid; filter, 50 DEG C of vacuum-drying 6h, obtain R-2-(((the chloro-3-methyl-2-of 4-pyridyl) methyl) sulfinyl)-1H-benzoglyoxaline (322.2g; HPLC normalization method detects: 99.6%, S isomer does not detect).
6, R-lansoprazole crude product is synthetic
To R-2-(((the chloro-3-methyl-2-of 4-pyridyl) methyl) the sulfinyl)-1H-benzoglyoxaline (322.2g), methyl-sulphoxide (2100ml), trifluoroethanol (727.8g), the sodium hydroxide (235.6g) that add successively step 5 to make in reaction flask; be warmed up to 60～70 DEG C; react about 4h, it is complete that TLC analyzes primitive reaction.By reaction solution cool to room temperature, drip water (20L), adjust pH to 7 left and right with glacial acetic acid, separate out solid, stir 5min, filter, obtain off-white color solid.This solid is dissolved in to ethyl acetate (5L), and anhydrous magnesium sulfate (1000.0g) is dry.Filter, filtrate decompression concentrates to obtain brown oil.By silica gel short column column chromatography for this oily matter, eluent is ethyl acetate-normal hexane-methyl alcohol (10: 10: 1), collects qualified component, concentrated, obtains spumescence solid (235.6g).This solid is at room temperature dissolved in ammoniacal liquor (12.5%, 5040ml), filters, filtrate is adjusted pH to 9 left and right with methylene dichloride (1000ml × 3) washing, water layer with glacial acetic acid, separates out white solid.Stir 5min, filter, frozen water for solid (1000ml) washing, dry 24h, obtains R-lansoprazole crude product (off-white color solid, 150.0g).
7, the preparation of Dexlansoprazole crystal form
By R-lansoprazole crude product (150.0g), be dissolved in 95% methyl alcohol (600ml), add 25% ammoniacal liquor (37.5ml), in stirring at room temperature 30min, filter, filtrate is concentrated, cooling, separate out a large amount of off-white color solids, filter, be dried to obtain Dexlansoprazole crystal form 105.0g.
1HNMR(CDCl
3，400M)δ：4.784-4.904(d-d，2H，CF
3 CH 2 O)，2.233(s，3H，-CH3)。
Confirm through accompanying drawing 1, this product is R-lansoprazole new crystal.
The each crystal formation solvability of test example one and draw moist simultaneous test
Conclusion (of pressure testing): crystal formation provided by the present invention solvability and A crystal formation, B crystal formation in the conventional solvents such as methyl alcohol, ethanol, water is suitable; Draw moist aspect, suitable with B crystal formation, all have draw moist.
Test example two embodiment mono-make the stability test accelerated test (25 DEG C of RH60%) of crystal formation
Test of long duration (2-8 DEG C)
Test of long duration (20 DEG C)
From stability test result, the stable crystal form that the present invention obtains is effective, is applicable to pharmaceutical applications.
Claims (5)
1. a Dexlansoprazole crystal form, its X-ray powder diffraction pattern as shown in Figure 1.
2. prepare a method for Dexlansoprazole crystal form as claimed in claim 1, wherein R-lansoprazole or its crystal formation are dissolved in to crystallization in organic solvent and obtain described crystal formation.
3. the method for preparing Dexlansoprazole crystal form according to claim 2, wherein said organic solvent is methyl alcohol.
4. the method for preparing Dexlansoprazole crystal form according to claim 3, wherein adds ammoniacal liquor in methyl alcohol.
5. the method for preparing Dexlansoprazole crystal form according to claim 4, wherein said ammonia concn is 25%.
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102234265B (en) * | 2011-08-08 | 2013-11-20 | 天津市汉康医药生物技术有限公司 | Lansoprazole compound |
| CN103664889B (en) * | 2013-12-19 | 2014-11-19 | 悦康药业集团有限公司 | Lansoprazole compound |
| CN103772359B (en) * | 2014-01-27 | 2015-09-30 | 马魁 | A kind of compound of Lansoprazole |
| CN104086532A (en) * | 2014-07-21 | 2014-10-08 | 上海右手医药科技开发有限公司 | Dexlansoprazole polycrystalline type generated by alkylamine inducing as well as preparation method and pharmaceutical composition thereof |
| CN105017218A (en) * | 2015-07-01 | 2015-11-04 | 合肥安德生制药有限公司 | R-lansoprazole crystal form and preparation method therefor |
| CN104958276A (en) * | 2015-07-30 | 2015-10-07 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical lansoprazole composition capsule for treating gastric ulcer |
| CN104997738A (en) * | 2015-08-10 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine lansoprazole compound dry suspension treating gastropathy |
| CN106749182A (en) * | 2016-11-08 | 2017-05-31 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal-form compound and preparation method thereof |
| CN108084158A (en) * | 2016-11-23 | 2018-05-29 | 江苏豪森药业集团有限公司 | The preparation method of R-lansoprazole |
| CN108164507A (en) * | 2016-12-07 | 2018-06-15 | 天津药物研究院有限公司 | A kind of R-lansoprazole monocrystalline and its preparation method and application |
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| EP2265605A4 (en) * | 2008-03-18 | 2011-08-03 | Reddys Lab Ltd Dr | Dexlansoprazole process and polymorphs |
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