CN102108076A - Method for preparing amorphous dexlansoprazole - Google Patents
Method for preparing amorphous dexlansoprazole Download PDFInfo
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- CN102108076A CN102108076A CN2009102620686A CN200910262068A CN102108076A CN 102108076 A CN102108076 A CN 102108076A CN 2009102620686 A CN2009102620686 A CN 2009102620686A CN 200910262068 A CN200910262068 A CN 200910262068A CN 102108076 A CN102108076 A CN 102108076A
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Abstract
The invention relates to a method for preparing amorphous dexlansoprazole, which comprises the steps of dissolving dexlansoprazole or the crystal thereof in a single or mixed solvent, precipitating solids under alkaline conditions at a temperature of 5 DEG C below zero to 25 DEG C below zero, further filtering, washing and drying, and finally getting the amorphous dexlansoprazole.
Description
Technical field
The present invention relates to prepare the method for R-lansoprazole, especially a kind of method for preparing amorphous R-lansoprazole.
Background technology
R-lansoprazole is a kind of gastroesophageal reflux disease (GERD) new drug that is better than lansoprazole, and its structural formula is as shown below.
R-lansoprazole controlled release capsule (the dexlansoprazole of FDA approval Tap Pharmaceutical Products (US), Kapidex) listing, be used for the treatment of stomach burning sensation, erosive esophagitis (EE) and the EE that non-erosive gastroesophageal reflux (GERD) causes and keep treatment, be 1 medication on the one.This product is dual controlled release (DDR) proton pump inhibitor of 2 releases of first listing.The preparation specification is every 30 or 60mg.
Proton pump inhibitor is by suppressing the generation that H '/K '-ATP reduces hydrochloric acid in gastric juice.This product contains 2 types enteric coated particles, and the 2nd peak value of appearance in 4-5 hour appearred the 1st peak value in 1-2 hour, in the medicine oral back of peak value of visible 2 uniquenesses of curve for the moment.In addition, this product is not subjected to the influence of oral alimentation.
All can suffer the torment of pyrosis sense at GERD patient's daytime and night.Studies show that, can remove the pyrosis sense in 24 hours with this product of DDR technology preparation, for GERD patient provides infusive new treatment idea.Its untoward reaction is similar to lansoprazole.
R-lansoprazole is got permission to go on the market and is based on the global Efficacy Evaluation result at about 6000 routine erosives and non-erosive GERD patient that more than 20 country carries out.8 all randomized, double-blind comparative studies of 2 same design contrast the curative effect that this product and lansoprazole are used for the treatment of EE respectively.The result shows, during 8 weeks, this product (60mg) group curative ratio is than lansoprazole group height (in the 1st research both be respectively both are respectively 85% and 79% in 87% and 85%, the 2 research), and patient tolerability is good.This product 30mg keeps the data presentation that treatment EE schedules to last June, and its curative effect of curing EE and the sense of releasing pyrosis is than the placebo height.
CN1150186C discloses a kind of crystallization of R-lansoprazole and has prepared this crystalline method, this method relates to the method that obtains amorphous R-lansoprazole by optical resolution, but this method need split the finished product that just can obtain higher optical purity through inclusion repeatedly, complicated operation is unfavorable for amplifying and produces; And in the process for preparation of pharmaceutical composition, the crystal formation raw material is not so good as amorphous raw material aspect a lot, such as mobile aspect.
Summary of the invention
The object of the present invention is to provide a kind of method for preparing amorphous R-lansoprazole, this method comprises and is dissolved in single R-lansoprazole or its crystal or mixed solvent,-5 ℃～-25 ℃, under alkaline condition, separate out solid, more after filtration, washing and dry amorphous R-lansoprazole.
Wherein,
Amorphous R-lansoprazole has as Fig. 1, Fig. 2, Fig. 3, Fig. 4 or X-ray powder diffraction pattern shown in Figure 5;
Single or mixed solvent comprises water-soluble solvent and water-insoluble solvent, the preferred ammoniacal liquor of water-soluble solvent, methyl alcohol, ethanol, propyl alcohol, butanols, acetone or its mixture, more preferably ammoniacal liquor, the preferred esters solvent of water-insoluble solvent, ether solvent, halogenated hydrocarbon solvent or its mixture;
Temperature is-5 ℃～-25 ℃, preferred-10 ℃～-20 ℃, more preferably-10 ℃;
It is 8～10 that alkaline condition is selected from pH, and preferred pH is 9;
Drying is selected from vacuum-drying, cross-flow drying, heat drying or air-dry, preferred vacuum-drying, more preferably room temperature vacuum-drying.
In the process for preparation of pharmaceutical composition, importantly drug substance is a kind of form that is convenient to operation and handles.Not only from the preparation method's that obtains viable commercial angle, and contain the angle of the pharmaceutical preparation of this active compound from preparation subsequently, this all is very important.
In addition, in the process of pharmaceutical compositions, importantly after patient's administration, provide a kind of reliable, reproducible and constant drug plasma concentration curve.
The chemical stability of activeconstituents, solid-state stability and " storage time " are important factors equally.This drug substance and the composition that comprises it should preferably can store the quite a while effectively, and the physics-chem characteristic of activeconstituents (for example its chemical constitution, density, draw moist and solubleness) does not show significant variation.
In addition, providing as far as possible, the medicine of chemical pure form is very important equally.
It will be understood by those skilled in the art that typically,, can provide following advantage so: be easy to handle, be easy to prepare suitable pharmaceutical preparation and have reliable dissolving characteristic if a kind of medicine can obtain with stable form at an easy rate.
Those skilled in the art should affirm, the best administration quantity of activeconstituents individual dose and look the character and the degree of treatment disease at interval, and form of administration, approach and position, the concrete patient of treatment and decide, and this preferred plan can be definite by common technology.Those skilled in the art also should be understood that the best course of treatment, and the dosage number of times that promptly gives activeconstituents in the given time every day can use the test of constant current modulation journey really commonly used to determine through those skilled in the art.
The amorphous R-lansoprazole of the inventive method preparation can oral or parenteral administration, can be made into to comprise that tablet, pill, pulvis and granule are used for various route of administration.In these solid preparations, activeconstituents mixes mutually with a kind of inert diluent at least.According to routine operation, oral preparations also can comprise inert diluent other materials in addition just, as lubricant, glidant and antioxidant.If make capsule, tablet and pill, comprise buffer reagent in the preparation.Tablet and pill also can be made into sustained release forms.
Although also can adopt the non-aqueous solution of emulsion, parenteral drug-delivery preparation of the present invention comprises aseptic aqueous solution.These formulations also can comprise adjuvant, as sanitas, wetting agent, permeate agent, buffer reagent, emulsifying agent and dispersion agent.Its sterilization can be adopted bacterium to hold back filter (bacteria retainingfilter) and filter, and adds disinfectant in composition, the method sterilization of irradiation composition or heating combination.
Compare with the method for the amorphous R-lansoprazole of the disclosed acquisition of CN1150186C, method of the present invention makes the finished product of higher optical purity, and simple to operate, helps amplifying producing.
Compare with the crystal R-lansoprazole, each physical properties and the crystal of the amorphous R-lansoprazole that present method invention makes are suitable, repeatable strong, has high optical purity, its stability of formulation, bioavailability, dissolution rate and to draw moist aspect suitable with the crystalline preparation, and have following advantage:
(1) has good mobility;
(2) omit the crystalline complex process, simplified technical process, be more suitable for suitability for industrialized production;
Description of drawings
Fig. 1, Fig. 2, Fig. 3, Fig. 4 and Fig. 5 are the X-ray powder diffraction pattern of amorphous R-lansoprazole.
Embodiment
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.
Embodiment one
The R-lansoprazole crude product (235.6g) that following step 6 is made at room temperature is dissolved in ammoniacal liquor (12.5%, 5040ml), remove by filter a little black insolubles, wash with methylene dichloride (1000ml * 3), water layer is under-10 ℃ of conditions, transfer about pH to 9 with glacial acetic acid (1290ml), separate out white solid.Stir 5min, filter, solid is with frozen water (1000ml) washing, room temperature vacuum-drying 24h, R-lansoprazole (the off-white color solid, 150.0g).Through accompanying drawing 1 conclusive evidence, this product is amorphous R-lansoprazole.
Embodiment two
As described in embodiment one, wherein temperature is-5 ℃, and pH is 8.
Through accompanying drawing 2 conclusive evidences, this product is amorphous R-lansoprazole.
Embodiment three
As described in embodiment one, wherein temperature is-25 ℃, and pH is 10.
Through accompanying drawing 3 conclusive evidences, this product is amorphous R-lansoprazole.
Embodiment four
As described in embodiment one, wherein temperature is-10 ℃, and pH is 8.
Through accompanying drawing 4 conclusive evidences, this product is amorphous R-lansoprazole.
Embodiment five
As described in embodiment one, wherein temperature is-20 ℃, and pH is 10.
Through accompanying drawing 5 conclusive evidences, this product is amorphous R-lansoprazole.
Wherein, the R-lansoprazole crude product is prepared by following method:
Synthesizing of step 1 2-acetoxy-methyl-4-chloro-3-picoline
(buying is from Shangyu, Zhejiang city three and medication chemistry company limited with 4-chloro-2,3 dimethyl pyridine-N-oxide compound; Specification: IG), 1083.7g, 6.88mol is dissolved in the toluene (7000ml), is heated to 90 ℃, and (2053.2g, 20.11mol), temperature is controlled at 90-110 ℃ slowly to drip diacetyl oxide.Finish, be incubated 105-110 ℃ of reaction 1.5h, the thin-layer chromatography detection reaction finishes.Cold slightly, 60 ℃ remove solvent under reduced pressure, 2-acetoxy-methyl-4-chloro-3-picoline (yellow oil, 1627.2g).
1HNMR(CDCl
3)δ：2.12(s，3H，CH
3CO)；2.48(s，3H，CH
3)；5.18(s，2H，CH
2)；7.20(d，1H，H-5)，8.22(d，1H，H-6)。
Synthesizing of step 2 2-methylol-4-chloro-3-picoline
Above-mentioned 2-acetoxy-methyl-4-chloro-3-picoline is dissolved in methyl alcohol (1450ml), be cooled to 0-5 ℃, drip the solution of potassium hydroxide (1597.0g) and water (7000ml), the control reacting liquid temperature is below 10 ℃, about 30min drips off, continue insulation reaction 20min, the thin-layer chromatography detection reaction finishes.Pressure reducing and steaming methyl alcohol with methylene dichloride (2300ml * 3) extraction, merges organic phase, uses the 973.4g anhydrous sodium sulfate drying.Filter, filtrate decompression concentrate 2-methylol-4-chloro-3-picoline synthetic (yellow oil, 913.1g).
1HNMR(DMSO-D
6，500M，ppm)δ：2.42(s，3H，CH
3)；4.93(s，2H，CH
2)；8.08(d，1H，H-5)，8.62(d，1H，H-6)。
Synthesizing of step 3 2-chloromethyl-4-chloro-3-picoline
Above-mentioned 2-methylol-4-chloro-3-picoline is dissolved in trichloromethane (4000ml), is cooled to 0 to-5 ℃, stir dripping thionyl chloride (590.3g down, 4.96mol), control reaction temperature is below 10 ℃, and about 40min drips off, continue insulation reaction 20min, the thin-layer chromatography detection reaction finishes.Concentrating under reduced pressure gets brown solid, slowly adds frozen water (3L), transfers pH to 8-9 with saturated sodium bicarbonate (3000ml) solution, extract with methylene dichloride (1700ml * 3), merge organic phase, with saturated nacl aqueous solution (3L) washing once, promptly get the solution of 2-chloromethyl-4-chloro-3-picoline.
1HNMR(CDCl
3)δ：2.49(s，3H，CH
3)；5.06(s，2H，CH
2)；7.82(d，1H，H-5)，8.53(d，1H，H-6)。
Synthesizing of step 4 2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfenyl) benzoglyoxaline
With sodium hydroxide (487.6g, 12.19mol) water-soluble (4800ml), be cooled to 10-15 ℃, add 2-mercaptobenzimidazole (raw material B) (487.6g, 3.25mol) and triethyl benzyl ammonia chloride (146.6g, 0.63mol), stirring 15min, drip the solution of above-mentioned 2-chloromethyl-4-chloro-3-picoline then, temperature control is below 15 ℃.Finish, in 25-30 ℃ of following stir about 2h, thin-layer chromatography detects intermediate 4 and reacts completely, and reaction solution is concentrated into about 6300ml, is cooled to 0 ℃ and stirs 1h, filter, solid washs with methylene dichloride (1150ml), water (1200ml * 3) washing, 40 ℃ of vacuum-drying 8h, 2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfenyl) benzoglyoxaline (the off-white color solid, 645.1g).
1HNMR(DMSO-D
6，500M，ppm)δ：8.29(d，1H)；7.46-7.44(m，3H)；7.11-7.14(m，2H)；4.80(s，2H)；2.45(s，3H)。
Synthesizing of step 5 2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfinyl) benzoglyoxaline
2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfenyl) benzoglyoxaline (645.1g), toluene (3600ml) and L-(+) diethyl tartrate (168ml) are mixed, be heated to 50-60 ℃ of reaction 0.5h, add tetraisopropoxy titanium (131ml), continue under this temperature, to react 1h.Reaction solution is cooled to 20 ℃, adds diisopropylethylamine (135ml), be cooled to-10 ℃, temperature control-10 ℃ adds 80% cumene hydroperoxide (1203ml) to 0 ℃, and controlled temperature is at-5 ℃ to 0 ℃ reaction 4h.The thin-layer chromatographic analysis primitive reaction finishes, the hypo solution (1600ml) of adding 30%, stir 10min, drip normal hexane (1550ml), t-butyl methyl ether (1550ml), normal hexane (13000ml) successively in 0 ℃ to 10 ℃, separate out white solid, filter, (4: 1,1250ml) washing was 1 time with t-butyl methyl ether-toluene.This solid is dissolved in the acetone (15L); filter; in filtrate, drip water (40L); separate out solid; filter, 50 ℃ of vacuum-drying 6h get 2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfinyl) benzoglyoxaline (322.2g; the HPLC normalization method detects: 99.6%, the S isomer does not detect).
1HNMR(DMSO-D
6，500M，ppm)δ：4.25(d，1H)；7.47(d，1H)；7.31-7.29(m，2H)；4.88(s，2H)；2.36(s，1H)。
Synthesizing of step 6 R-lansoprazole
In reaction flask, add 2-(((4-chloro-3-methyl-2-pyridyl) methyl) sulfinyl) benzoglyoxaline (322.2g), methyl-sulphoxide (2100ml), trifluoroethanol (727.8g), sodium hydroxide (235.6g) successively; be warmed up to 60-70 ℃; react about 4h, the thin-layer chromatographic analysis primitive reaction finishes.With the reaction solution cool to room temperature, dropping water (20L) is transferred about pH to 7 with the 330ml glacial acetic acid, separates out solid, stirs 5min, filters, and gets the off-white color solid.This solid is dissolved in ethyl acetate (5L), anhydrous magnesium sulfate (1000.0g) drying.Filter, filtrate decompression concentrate brown oil.With silica gel short column chromatography, eluent is ethyl acetate-normal hexane-methyl alcohol (10: 10: 1), collects qualified component with this oily matter, concentrate, with normal hexane (2L) band do R-lansoprazole (the spumescence solid, 235.6g).
MS-ESI：368.17(100)[M-H]+
1HNMR(CDCl
3，400M)δ：4.784-4.904(d-d，2H，CF
3 CH 2 O)，2.233(s，3H，-CH3)。
Claims (10)
1. a method for preparing amorphous R-lansoprazole is characterized in that, is dissolved in single R-lansoprazole or its crystal or mixed solvent, and temperature-5 ℃～-25 ℃ is separated out solid under alkaline condition, get amorphous R-lansoprazole with drying after filtration.
2. the method for the amorphous R-lansoprazole of preparation according to claim 1 is characterized in that, described amorphous R-lansoprazole has as Fig. 1, Fig. 2, Fig. 3, Fig. 4 or X-ray powder diffraction pattern shown in Figure 5.
3. the method for the amorphous R-lansoprazole of preparation according to claim 1 and 2 is characterized in that, described single or mixed solvent comprises water-soluble solvent and water-insoluble solvent.
4. the method for the amorphous R-lansoprazole of preparation according to claim 3 is characterized in that, described water-soluble solvent is selected from ammoniacal liquor, methyl alcohol, ethanol, propyl alcohol, butanols, acetone or its mixture; And described water-insoluble solvent is selected from esters solvent, ether solvent, halogenated hydrocarbon solvent or its mixture.
5. the method for the amorphous R-lansoprazole of preparation according to claim 4 is characterized in that, described water-soluble solvent is an ammoniacal liquor.
6. the method for the amorphous R-lansoprazole of preparation according to claim 1 and 2 is characterized in that, described temperature is-10 ℃～-20 ℃.
7. the method for the amorphous R-lansoprazole of preparation according to claim 1 and 2 is characterized in that, described alkaline condition is that pH is 8～10.
8. the method for the amorphous R-lansoprazole of preparation according to claim 7 is characterized in that, described alkaline condition is that pH is 9.
9. the method for the amorphous R-lansoprazole of preparation according to claim 1 and 2 is characterized in that, described drying is selected from vacuum-drying, cross-flow drying, heat drying or air-dry.
10. the method for the amorphous R-lansoprazole of preparation according to claim 9 is characterized in that, described drying is room temperature vacuum-drying.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484578A (en) * | 2018-04-09 | 2018-09-04 | 珠海润都制药股份有限公司 | A kind of method prepared by esomeprazole impurity |
| CN108794450A (en) * | 2018-07-24 | 2018-11-13 | 浙江三门恒康制药有限公司 | The method for preparing unformed Dexlansoprazole |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355798A (en) * | 1999-06-17 | 2002-06-26 | 武田药品工业株式会社 | Benzimidazole compound crystal |
| CN1681802A (en) * | 2002-03-27 | 2005-10-12 | 特瓦制药工业有限公司 | Lansoprazole polymorphs and processes for preparation thereof |
| US20060057195A1 (en) * | 2002-10-16 | 2006-03-16 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
| WO2009117489A1 (en) * | 2008-03-18 | 2009-09-24 | Dr. Reddy's Laboratories Ltd. | Dexlansoprazole process and polymorphs |
-
2009
- 2009-12-23 CN CN200910262068.6A patent/CN102108076B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355798A (en) * | 1999-06-17 | 2002-06-26 | 武田药品工业株式会社 | Benzimidazole compound crystal |
| CN1681802A (en) * | 2002-03-27 | 2005-10-12 | 特瓦制药工业有限公司 | Lansoprazole polymorphs and processes for preparation thereof |
| US20060057195A1 (en) * | 2002-10-16 | 2006-03-16 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
| WO2009117489A1 (en) * | 2008-03-18 | 2009-09-24 | Dr. Reddy's Laboratories Ltd. | Dexlansoprazole process and polymorphs |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484578A (en) * | 2018-04-09 | 2018-09-04 | 珠海润都制药股份有限公司 | A kind of method prepared by esomeprazole impurity |
| CN108484578B (en) * | 2018-04-09 | 2019-03-26 | 珠海润都制药股份有限公司 | A kind of method of esomeprazole impurity preparation |
| CN108794450A (en) * | 2018-07-24 | 2018-11-13 | 浙江三门恒康制药有限公司 | The method for preparing unformed Dexlansoprazole |
| CN108794450B (en) * | 2018-07-24 | 2022-08-19 | 浙江恒康药业股份有限公司 | Method for preparing amorphous dexlansoprazole |
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Effective date of registration: 20160322 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Patentee before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. |
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