CN1117747C - Preparation method of optical purity lansoprazole - Google Patents
Preparation method of optical purity lansoprazole Download PDFInfo
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- CN1117747C CN1117747C CN 00113036 CN00113036A CN1117747C CN 1117747 C CN1117747 C CN 1117747C CN 00113036 CN00113036 CN 00113036 CN 00113036 A CN00113036 A CN 00113036A CN 1117747 C CN1117747 C CN 1117747C
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Abstract
The present invention belongs to the field of preparing optical isomer compounds. An optical pure binaphthol compound is used as an inclusion host, racemic lansoprazole is used as a guest, and oily or syruplike optical pure lansoprazole is prepared by an inclusion and separation method. The oily or syruplike optical pure lansoprazole is dissolved in an alkaline solution or water/a small amount of organic solvent so as to prepare stable white powdery optical pure lansoprazole or slats thereof with a certain crystaline state or a noncrystalline state. The new method provided by the present invention not only can obtain the lansoprazole or the salts thereof with high optical purity and chemical purity, but also can obtain good yield, and the method has the advantages of good product stability, simple process and low cost.
Description
The invention belongs to the preparation field of optical isomer compound, particularly relate to the preparation method of optical purity lansoprazole.
Lansoprazole (Lansoprazole, commodity are called AG-1749) is the end of the eighties by the benzimidazoles derivative with sour secretion inhibition of Japanese Wu Tian company exploitation.At first synthetic in 1986 by Nohara Akira etc., and characteristics (EP1774726) such as antiulcer activity, control gastric acid secretion, protection stomach mucous membrane, toxicity are low are arranged by this compound of clinical trial certificate.Its chemistry is by name: 2-[3-methyl-4-(2,2, the 2-trifluoroethyl)-2-pyridyl]-methylsulfinyl-1H-benzoglyoxaline, structural formula following (I):
Lansoprazole is after omeprazole (Omeprazole), the proton pump inhibitor of second listing.Owing to introduced fluorine, make its character be different from omeprazole, thermodynamics and oxidative stability increase, and have improved biological activity (US 4689333) greatly.Lansoprazole has the obvious impairment therapeutic action for stomach, duodenal ulcer and reflux esophagitis; The ulcer pathology that chronic ulcer, bisfentidine are difficult to cure has tangible healing promoter action, and its effect is in some aspects than omeprazole better (Drugs FUT.1991).Lansoprazole is used for the treatment of duodenal ulcer clinically, and the back curative ratio can reach 95% around the medication; For the treatment of stomach ulcer, curative ratio can reach 99% after eight weeks of medication, alleviates the pain that ulcer causes after the medication rapidly, and curative effect obviously is better than Rantidine and bisfentidine.
Lansoprazole is ratified Initial Public Offering by exploitation unit Japan Wu Tian company and its co-market commercial law state Houde company in France in December, 1991, and 1992 in Japan's listing, existing by TAP ' drugmaker in U.S.'s listing (commodity are called Prevacid).Be used for the treatment of stomach ulcer, duodenal ulcer and reflux esophagitis, and be used for eliminating pylorus.Because its good tolerability and high curative ratio, its world's sales volume rises year after year, and only U.S. TAP company annual sales amount in 1998 just reaches 13.65 hundred million dollars, estimates to reach 28.49 hundred million dollars in 2002, with row world best-selling drugs the 9th is only second to omeprazole in medicine for digestive system.In China, this medicine by its shore pharmaceutical factory of Shantou Special Economic Zone, Guangdong fish in exploitation listing (tablet) in 1994, other has military field medicine company limited in Tianjin and Tianjin Lik-Sang pharmaceutical factory to produce capsule.
Lansoprazole has a chiral centre-sulphur atom, therefore has two optical isomers.And commercially available lansoprazole all is raceme without exception, clinical show headache is arranged, diarrhoea, untoward reaction such as feel sick, take the lansoprazole raceme for a long time and also may form hepatoma and carcinoid of stomach knurl.Study verifiedly in the raceme medicine, different enantiomers has different drug effects and toxicity, side effect; 1996, FDA planned after 2000, and the medicine with chiral centre must be with optically pure form listing.Recently, pharmacology studies show that its drug effect of lansoprazole of the lansoprazole of (R)-configuration and (S)-configuration all obviously is better than the lansoprazole raceme, and optically active lansoprazole toxic side effect is than racemization lansoprazole low (WO 99/38512 and WO 99/38513).Therefore, the preparation of optical activity lansoprazole and the applied research in medicine thereof are extremely important problems.
The structural formula of the enantiomer of lansoprazole is as follows:
S-(-)-isomer R-(+)-isomer
At present, racemic lansoprazole has more sophisticated synthetic method, and dropped into large-scale commercial production, and optically pure lansoprazole preparation is still relatively more difficult, bibliographical information has two kinds of methods that prepare optical purity lansoprazole from the raceme lansoprazole, a kind of method is a Split Method, comprises chemical resolution method and biological enzyme.Chemical resolution method is that the stereoselectivity nitrogen that is adopted among the patent DE 4035455 splits lansoprazole for derivatize, with the raceme lansoprazole through stereoselectivity nitrogen for derivatize, make a pair of diastereomer, after separating, hydrolysis obtains optically pure lansoprazole again, and this method has the following disadvantages: 1. the raceme lansoprazole will just can make optically pure lansoprazole through two-step reaction; 2. productive rate low (40%-50%), the sepn process complexity is difficult to realize industrialization.Enzyme process split be WO 96 17077 reports pass through microbe or the enzyme catalysis system is reduced into the thioether form with a certain enantiomorph in the racemic modification, another enantiomorph still exists with oxide form, then its separation can be obtained a kind of optical isomer of configuration, though this method selectivity is high, the cost costliness of enzyme requires harsh to reaction conditions, can only accomplish the milligram level at present, and when obtaining a kind of isomer, wasted another kind of isomer, industrial value is not high.
Recently, patent WO 96/02535 has reported a kind of improved Sharpless asymmetric oxidation method, the sulfoxide that is a certain configuration with prochiral thioether asymmetric oxidation prepares optically pure lansoprazole, e.e. value (enantiomer is excessive) can be brought up to more than 80%, but its yield is less than 30%, and this asymmetric oxidation method complicated operation, cost are higher, are difficult to scale operation.1997, patent WO 97/02261 has reported that again the lansoprazole that will have certain e.e. value is in acetonitrile during recrystallization, raceme is preferentially separated out, utilize this characteristics, crude product recrystallization in acetonitrile of the low e.e value that the asymmetric oxidation method makes, its e.e value can be brought up to greater than 90%, but total recovery generally has only about 25% in the example, and its raw material must have certain optical purity.WO 94/27988 and US 5,714,504 disclose lithium, sodium, potassium, the magnesium of the similar medicine-omeprazole of lansoprazole, the preparation method of calcium, but the preparation method of not mentioned optical purity lansoprazole salt.
Preparation method about solid-state, neutral optical purity lansoprazole or its salt, do not see reported in literature, resulting optical purity S-(-) in the above patent-and R-(+)-lansoprazole be yellow or red oily or syrup, it is rotten that this deformed state causes optical purity lansoprazole very easily to decompose, and its production, store all very trouble, be not suitable as medicine.
The object of the present invention is to provide a kind of novel method that white powder has certain crystalline state or amorphous neutral optical purity lansoprazole or its salt for preparing, can obtain high optical purity and chemical purity, the yield that can obtain again, product stability is good, and its technology is simple, with low cost.
The objective of the invention is to realize by following technical solution:
With optically pure binaphthol compounds (Hla) is the inclusion main body, is object with racemic lansoprazole, adopts the inclusion method for splitting to prepare optically pure lansoprazole, makes oily or syrupy shape optical purity S-(-)-and R-(+)-lansoprazole; Oily that fractionation is obtained or melicera optical purity S-(-)-and R-(+)-lansoprazole again is prepared into more stable white powder and has certain crystalline state or amorphous optical purity lansoprazole or its salt: wherein in basic solution or water/a small amount of organic solvent:
(a) with racemic lansoprazole and 1: 2 in molar ratio～1: 6 ratio of optically pure binaphthol compounds, the best is 1: 2～1: 4, under 60～160 ℃, be dissolved in the organic solvent, perhaps under 10～80 ℃, in organic solvent, stirred 12～72 hours, organic solvent is an aromatic hydrocarbon, or the mixture of aromatic hydrocarbon/normal hexane, the volume ratio of mixture is aromatic hydrocarbon/normal hexane of 1: 1～10: 1; Quantity of solvent is every gram object 10～80ml; Placed 5～48 hours down in-10～30 ℃ then, filter, obtain the solid inclusion complex compound and the dominant filtrate of another configuration lansoprazole of optical purity main body and a certain configuration lansoprazole; Again solid inclusion complex compound is separated with conventional chromatography method respectively with filtrate, with the inclusion subject and object separately, can obtain two kinds of configurations dominant oilies or syrupy shape optical purity S-(-)-or R-(+)-lansoprazole respectively;
(b) with the oily that obtains among the above-mentioned preparation method or syrupy shape optical purity S-(-)-or R-(+)-lansoprazole under 50～120 ℃, be dissolved in the aqueous solution of mineral alkali, the concentration of solution is 1～10%, the best is 1.5～6%, the mol ratio of mineral alkali and optical purity lansoprazole is 1: 1～5: 1, and the best is 1.5: 1～3.5: 1; Stir after 5 minutes to 2 hours, the pH value is 10～13, obtain colourless or faint yellow optical purity lansoprazole solution, with the solution cooling, bathe stirring down 1-3 hour in cryosel, placed 5～20 hours in-20～10 ℃, filter, washing, vacuum drying at room temperature 10～20 hours can make the salt of oyster white or white non-crystalline state lansoprazole; Perhaps in colourless or faint yellow optical purity lansoprazole solution, add dissolving each other with water or the organic solvent of partial miscibility of 0.1～1 times of aqueous solution volume, add inorganic acid salt or methyl-formiate again, the mol ratio of itself and alkali is 0.5: 1～2: 1, the best is 1: 1～1.5: 1, control final pH value is 7～10, continue to stir after 0.5～6 hour, placed 5～20 hours in-20～10 ℃, filter, washing, vacuum drying at room temperature 10～20 hours makes that optical purity white is amorphous, the neutral lansoprazole; Again with resulting optical purity white amorphous S-(-)-R-(+)-lansoprazole be dissolved in dissolve each other with water or the organic solvent of partial miscibility in, quantity of solvent is 0.5～2.5ml/ gram optical purity lansoprazole, in every gram optical purity lansoprazole, add 5～25ml distilled water again, stirred 0.5～20 hour in-20～10 ℃, make the certain crystalline state of optical purity white, neutral S-(-)-or R-㈩-lansoprazole.
The solid inclusion complex compound that obtains among the above-mentioned preparation method also can be under 60～160 ℃, ratio in every gram inclusion complex compound 10～70ml solvent is dissolved in the aromatic hydrocarbon solvent, then, the alkane that adds 0～3 times of volume again, placed 5～48 hours down in-10～30 ℃, filter, obtain the higher inclusion complex compound of e.e. value, this process can repeat repeatedly, till to obtain the high main body/object of e.e. value be 2: 1 solid inclusion complex compound, again solid inclusion complex compound is separated with conventional chromatography method respectively with filtrate, with the inclusion subject and object separately, can obtain two kinds of configurations dominant oilies or syrupy shape optical purity S-(-)-or R-(+)-lansoprazole respectively.
If oily or syrupy shape optical purity S-(-)-or the color of R-(+)-lansoprazole is darker, obtain deep yellow solution after being dissolved in alkaline solution, then use activated carbon decolorizing, operation steps is as follows: add the water of every gram optical purity lansoprazole 2～15ml, add the gac of 0.3～1 times of optical purity lansoprazole weight again, under 80～120 ℃, stir decolouring 0.5～2 hour, the best is 1 hour, filters, obtain colourless extremely faint yellow optical purity lansoprazole solution, carry out subsequent step again.
Alkali used among the above-mentioned preparation method is meant NaOH, KOH, K
2CO
3, Na
2CO
3Deng, the best is NaOH.
Resulting optical purity S-(-) among the above-mentioned preparation method-or the salt of R-(+)-lansoprazole be meant sodium salt or sylvite.
Inorganic acid salt used among the above-mentioned preparation method is meant hydrosulfate, supercarbonate, dihydrogen phosphate etc., and the best is a kind of or how several in the supercarbonate.
Organic solvent that dissolve each other with water or partial miscibility is meant alkyl alcohol, alkyl ketone or the ethyl acetate below the C5, in pure preferably methyl alcohol, ethanol, Virahol, propyl carbinol or the sec-butyl alcohol one or more, ketone is one or more of acetone, butanone or cyclopentanone preferably, the best is the medium butanone of mutual solubility, and their effect is to help optically pure lansoprazole better to be scattered in the water.
The optical purity white, crystalline that above-mentioned preparation method is prepared or amorphous neutral S-(-)-or R-(+)-lansoprazole or its salt can be used for prevention and treat various and gastric acid secretion diseases associated, as stomach ulcer, duodenal ulcer, reflux esophagitis and Zuo-Ai (Zollinger-Ellison) syndromes (gastrinoma), and be used for eliminating pylorus, the gastrointestinal upset that treatment causes because of hydrochloric acid in gastric juice is as diseases such as non-ucler dyspepsias.
Certain crystalline state optical purity S-(-)-or R-(+)-lansoprazole be determined with relative power (table 1 and table 2) by 2 θ angles, the d value of diffraction peak among powder X-ray-Ray diffractogram and the figure.
The neutral R-(+) of the certain crystalline state of table 1-relatively strong and weak 2 θ angle d values of Lansoprazole XRD data 2 θ angle d values are relatively 22.216 3.998 medium a little less than 21.595 4.112 medium 45.493 1.992 a little less than strong 36.910 2.432 weak 20.674 4.293 medium 37.480 2.397 in strong 28.820 3.095 weak 14.871 the last 5.948,29.767 2.999 medium 15.640 the last 5.660,31.040 2.878 weak 16.241 5.453 medium 31.635 2.825 weak 17.602 the last 5.033 35.320 2.538 weak 18.411 4.315 weak 35.870 2.501 weak 19.685 4.505 in strong and weak 6.641 13.305 medium 23.030 3.849 weak 8.176 10.809 weak 23.818 3.732 medium 9.156 9.648 medium 24.858 3.578 medium 9.917 the last 8.906,25.385 3.506 medium 10.950 the last 8.071 27.171 3.279 medium 12.296 7.188 medium 27.816 3.204 weak 13.349 6.628
The neutral S-(-) of the certain crystalline state of table 2-relatively strong and weak 2 θ angle d values of Lansoprazole XRD data 2 θ angle d values relatively strong and weak 6.074 13.098 weak 23.168 3.835 weak 9.200 9.604 medium 23.846 3.728 weak 9.978 the last 8.856,24.869 3.577 medium 10.988 8.040 medium 25.750 3.457 medium 12.355 7.158 weak 27.200 3.275 weak 13.420 6.590 medium 27.840 3.202 weak 14.900 5.940 medium 28.742 3.103 weak 15.668 the last 5.650,29.076 3.068 weak 16.302 5.432 weak 29.807 2.995 medium 17.625 the last 5.027 31.072 2.875 weak 18.444 4.806 weak 31.640 2.825 weak 19.709 4.500 medium 35.428 2.531 weak 20.994 4.227 medium 36.940 2.431 weak 21.620 4.107 medium 37.493 2.396 weak 22.246 3.991 are medium
Fig. 1 is the X-ray diffraction figure of the embodiment of the invention 36 resulting R-(+)-lansoprazoles.
Fig. 2 is the X-ray diffraction figure of the embodiment of the invention 37 resulting S-(-)-lansoprazoles.
From diffraction pattern, the resulting optically pure S-of the present invention (-)-or R-(+)-Lansoprazole have preferably crystallinity Energy.
Preparation method provided by the invention can obtain Lansoprazole or its salt of high-optical-purity and chemical purity, again can Obtain good yield, product stability is good, and its technology is simple, with low cost.
Be embodiments of the invention below.Among the embodiment, the solid yield is by main body: object is that 2: 1 inclusion complex compound is that benchmark calculates, mother liquor is 100% to calculate with half and unnecessary main body sum of raceme then, and the yield of the optical purity lansoprazole of two configurations be benchmark calculating with half of raceme then.
Given optical purity among the embodiment, promptly e.e. value (enantiomer is excessive) is by high-pressure liquid phase chromatogram therapy determining, and concrete parameter is as follows:
Chiral chromatographic column AGP (100 * 4.5m)
Moving phase acetonitrile: phosphate buffer solution (pH=7)
12∶88
Detect wavelength UV=300nm
Certain crystalline state optical purity S-(-)-or the powder monocrystalline of R-(+)-lansoprazole change the target X-ray diffractometer by Japan D/max-rA 12KW of science and measure, condition determination is as follows:
Monochromator: Cu target/graphite monochromator
Voltage: 40KV
Electric current: 40mA
Slit: Ds=Ss=1 °, Rs=0.3mm
Specific rotatory power given among the embodiment is measured by the PE-341 of PE company type polarimeter, and strength of solution is a 30mg/5ml methyl alcohol.
Embodiment one
With the racemic lansoprazole of 51mg (0.138mmol) and 78mg (0.276mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 60 ℃, be dissolved in 3.0ml benzene/normal hexane (volume ratio is 2: 1) mixed solvent, then, placed 12 hours down in 0 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 51mg of S-(-)-lansoprazole, yield is 78.4%, and the e.e. value of S-(-)-lansoprazole is 90.2%; Mother liquor concentrates the mixture that obtains 83mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 114.4%, and the e.e. value of R-(+)-lansoprazole is 65.1%.
Embodiment two
With the racemic lansoprazole of 51mg (0.138mmol) and 78mg (0.276mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 80 ℃, be dissolved in 2.0ml benzene/normal hexane (volume ratio is 2: 1) mixed solvent, then, placed 12 hours down in 5 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 65mg of S-(-)-lansoprazole, yield is 97.3%, and the e.e. value of S-(-)-lansoprazole is 82.0%; Mother liquor concentrates the mixture that obtains 71mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 73.1%, and the e.e. value of R-(+)-lansoprazole is 73.1%.
Embodiment three
With the racemic lansoprazole of 51mg (0.138mmol) and 78mg (0.276mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 80 ℃, be dissolved in 1.5ml benzene/normal hexane (volume ratio is 2: 1) mixed solvent, then, placed 10 hours down in 10 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 67mg of S-(-)-lansoprazole, yield is 102.9%, and the e.e. value of S-(-)-lansoprazole is 76.8%; Mother liquor concentrates the mixture that obtains 78mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 90.0%, and the e.e. value of R-(+)-lansoprazole is 78.8%.
Embodiment four
With the racemic lansoprazole of 51mg (0.138mmol) and 78mg (0.276mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 100 ℃, be dissolved in 4.0ml benzene/normal hexane (volume ratio is 1: 1) mixed solvent, then, placed 8 hours down in 10 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 46mg of S-(-)-lansoprazole, yield is 70.1%, and the e.e. value of S-(-)-lansoprazole is 70.5%; Mother liquor concentrates the mixture that obtains 80mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 125.8%, and the e.e. value of R-(+)-lansoprazole is 68.8%.
Embodiment five
With the racemic lansoprazole of 54mg (0.145mmol) and 83mg (0.290mmol) optically pure R-(+)-binaphthol Hla (mol ratio is 1: 2), under 120 ℃, be dissolved in 5.0ml benzene/normal hexane (volume ratio is 1: 1) mixed solvent, then, placed 6 hours down in 15 ℃, filter, drying obtains solid and is R-(+)-Hla of white and the inclusion complex compound 53mg of R-(+)-lansoprazole, yield is 78.0%, and the e.e. value of R-(+)-lansoprazole is 77.0%; Mother liquor concentrates the mixture that obtains 82mg R-(+)-binaphthol Hla and S-(-)-lansoprazole, and yield is 120.5%, and the e.e value of S-(-)-lansoprazole is 45.5%.
Embodiment six
With the racemic lansoprazole of 54mg (0.145mmol) and 83mg (0.290mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 140 ℃, be dissolved in 2.0ml benzene/normal hexane (volume ratio is 4: 1) mixed solvent, then, placed 14 hours down in-5 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 58mg of S-(-)-lansoprazole, yield is 84.4%, and the e.e. value of S-(-)-lansoprazole is 85.8%; Mother liquor concentrates the mixture that obtains 85mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 112.8%, and the e.e. value of R-(+)-lansoprazole is 44.2%.
Embodiment seven
With the racemic lansoprazole of 54mg (0.145mmol) and 83mg (0.290mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 80 ℃, be dissolved in 1.5ml benzene/normal hexane (volume ratio is 4: 1) mixed solvent, then, placed 10 hours down in-5 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 49mg of S-(-)-lansoprazole, yield is 73.9%, and the e.e. value of S-(-)-lansoprazole is 86.0%; Mother liquor concentrates the mixture that obtains 90mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 125.4%, and the e.e. value of R-(+)-lansoprazole is 42.5%.
Embodiment eight
With the racemic lansoprazole of 54mg (0.145mmol) and 83mg (0.290mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 100 ℃, be dissolved in the 1.5ml benzene, then, placed 16 hours down in 0 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 43mg of S-(-)-lansoprazole, yield is 63.9%, and the e.e. value of S-(-)-lansoprazole is 92.5%; Mother liquor concentrates the mixture that obtains 96mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 130.0%, and the e.e. value of R-(+)-lansoprazole is 28.0%.
Embodiment nine
In (volume ratio is 2: 1) mixed solvent with the racemic lansoprazole of 54mg (0.145mmol) and 83mg (0.290mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2) suspension 3.0ml benzene/normal hexane, at N
2Protection was stirred 48 hours for 20 ℃ in room temperature down, placed 10 hours down for 0 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 62mg of S-(-)-lansoprazole, yield is 113.3%, and the e soap value of S-(-)-lansoprazole is 36.9%; Mother liquor concentrates the mixture that obtains 67mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 85.6%, and the e.e value of R-(+)-lansoprazole is 38.1%.
Embodiment ten
In (volume ratio is 2: 1) mixed solvent with the racemic lansoprazole of 54mg (0.145mmol) and 83mg (0.290mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2) suspension 3.0ml benzene/normal hexane, at Ar
2Protection in 70 ℃ of stirrings 48 hours, was placed 10 hours down for 0 ℃ down, filtered, and drying obtains solid and is white S-(-)-Hla and the inclusion complex compound 54mg of S-(-)-lansoprazole, and yield is 109.2%, and the e.e value of S-(-)-lansoprazole is 41.6%; Mother liquor concentrates the mixture that obtains 69mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 87.4%, and R-(+)-lansoprazole decomposes rotten.
Embodiment 11
With the racemic lansoprazole of 369.4mg (1.0mmol) and 572.6mg (2.0mmol) optically pure R-(+)-binaphthol Hla (mol ratio is 1: 2), under 80 ℃, be dissolved in the mixed solvent of 11.0ml benzene/normal hexane (volume ratio is 2: 1), then, placed 12 hours down in-5 ℃, filter, drying obtains solid and is R-(+)-Hla of white and the inclusion complex compound 435mg of R-(+)-lansoprazole, yield is 92.4%, and the e.e value of R-(+)-lansoprazole is 77.8%; Get the e.e value and be 77.8% inclusion complex compound 425mg, under 80 ℃, be dissolved in the 6.0ml benzene, then, add the 4.0ml normal hexane, place 18hr filtration, drying in-5 ℃, obtain solid and be R-(+)-Hla of white and the inclusion complex compound 397mg (the recrystallization yield is 93.4%) of R-(+)-lansoprazole, the e.e. value of R-(+)-lansoprazole is 92.2%; Get the e.e. value and be 92.2% inclusion complex compound 390mg, under 80 ℃, be dissolved in the 7.0ml benzene, then, add the 4.0ml normal hexane, place 18hr in-5 ℃, filter, dry, obtain solid and be R-(+)-Hla of white and the inclusion complex compound 314mg (the recrystallization yield is 80.5%) of R-(+)-lansoprazole, 300mg inclusion complex compound is again through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain R-(+)-binaphthol Hla160mg and e.e. value be R-(+)-lansoprazole 108mg of 98.9%, total recovery is 58.7%.Mother liquor concentrates the mixture that obtains 510mgR-(+)-binaphthol Hla and S-(-)-lansoprazole for the first time, equally through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain R-(+)-binaphthol Hla240mg and e.e. value be S-(-)-lansoprazole 242mg of 57.8%; Get the e.e. value and be S-(-)-lansoprazole 242mg of 57.8%, under room temperature, be dissolved in 1.5mlCH
2Cl
2In, then, add the 4.5ml ether, place 10hr in-5 ℃, filter, drying, obtain solid 90mg, e.e. value is 9.3%, obtains the e.e. value after mother liquor is concentrated and be S-(-)-lansoprazole 145mg of 98.5%, total recovery is 78.5%; The total yield of R-(+)-binaphthol Hla is 89.0%, and the e.e. value is 100%.
Embodiment 12
With the racemic lansoprazole of 369.4mg (1.0mmol) and 572.6mg (2.0mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 140 ℃, be dissolved in the mixed solvent of 12.0ml dimethylbenzene/normal hexane (volume ratio is 10: 1), then, placed 20 hours down in 30 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 528mg of S-(-)-lansoprazole, yield is 112.3%, and the e.e. value of S-(-)-lansoprazole is 71.3%; Get the e.e. value and be 71.3% inclusion complex compound 520mg, under 80 ℃, be dissolved in the 7.0ml benzene, then, add the 3.0ml normal hexane, place 18hr in-5 ℃, filtration, drying obtain solid and are S-(-)-Hla of white and the inclusion complex compound 376mg (the recrystallization yield is 72.3%) of S-(-)-lansoprazole, and the e.e. value of S-(-)-lansoprazole is 91.4%; Get the e.e value and be 91.4% inclusion complex compound 370mg, under 80 ℃, be dissolved in the 9.0ml benzene, then, add the 9.0ml normal hexane, place 18hr in-5 ℃, filter, dry, obtain solid and be S-(-)-Hla of white and the inclusion complex compound 280mg (the recrystallization yield is 75.9%) of S-(-)-lansoprazole, 250mg inclusion complex compound is again through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain S-(-)-binaphthol Hla 140mg and e.e. value be S-(-)-lansoprazole 90mg of 99.2%, total recovery is 56.7%.Mother liquor concentrates the mixture that obtains 430mg S-(-)-binaphthol Hla and R-(+)-lansoprazole for the first time, equally through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain S-(-)-binaphthol Hla 263mg and e.e. value be R-(+)-lansoprazole 153mg of 71.4%; Get the e.e. value and be R-(+)-lansoprazole 152mg of 71.4%, under room temperature, be dissolved in 1.2mlCH
2Cl
2In, then, add the 4.0ml ether, place 10hr in-5 ℃, filter, drying, obtain solid 45mg, e.e value is 0.3%, obtains the e.e. value after mother liquor is concentrated and be R-(+)-lansoprazole 102mg of 98.3%, total recovery is 55.3%; The total yield of S-(-)-binaphthol Hla is 70.2%, and the e.e. value is 100%.
With the racemic lansoprazole of 54mg (0.145mmol) and 83mg (0.290mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2), under 90 ℃, be dissolved in 3.0ml toluene/normal hexane (volume ratio is 2: 1) mixed solvent, then, placed 12 hours down in-10 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 66mg of S-(-)-lansoprazole, yield is 97.7%, and the e.e. value of S-(-)-lansoprazole is 73.6%; Mother liquor concentrates the mixture that obtains 65mg S-(-)-binaphthol Hla and R-(+)-lansoprazole, and yield is 95.0%, and the e.e value of R-(+)-lansoprazole is 57.4%.
With the racemic lansoprazole of 1.107g (3.0mmol) and 1.716mg (6.0mmol) optically pure R-(+)-binaphthol Hla (mol ratio is 1: 2), under 60 ℃, be dissolved in the mixed solvent of 38.0ml benzene/normal hexane (volume ratio is 2: 1), then, placed 12 hours down in 10 ℃, filter, drying obtains solid and is R-(+)-Hla of white and the inclusion complex compound 1.602g of R-(+)-lansoprazole, yield is 105.5%, and the e.e. value of R-(+)-lansoprazole is 81.3%; Get the e.e. value and be 81.3% inclusion complex compound 1.600g, under 80 ℃, be dissolved in the 35.0ml benzene, then, add the 35.0ml normal hexane, place 18hr in-5 ℃, filtration, drying obtain solid and are R-(+)-Hla of white and the inclusion complex compound 1.403g (the recrystallization yield is 95.8%) of R-(+)-lansoprazole, and the e.e. value of R-(+)-lansoprazole is 87.1%; Get the e.e. value and be 87.1% inclusion complex compound 1.40g, under 80 ℃, be dissolved in the 24.0ml benzene, then, add the 10.0ml normal hexane, place 18hr in-5 ℃, filter, dry, obtain solid and be R-(+)-Hla of white and the inclusion complex compound 1.110g (the recrystallization yield is 79.2%) of R-(+)-lansoprazole, 1.1g the inclusion complex compound is again through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain R-(+)-binaphthol Hla 0.532g and e.e. value be R-(+)-lansoprazole 0.392g of 99.6%, total recovery is 71.9%.Mother liquor concentrates the mixture that obtains 1.20g R-(+)-binaphthol Hla and S-(-)-lansoprazole for the first time, equally through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain R-(+)-binaphthol Hla 0.793g and e.e. value be S-(-)-lansoprazole 0.508g of 77.9%; Get the e.e. value and be S-(-)-lansoprazole 0.500g of 77.9%, under room temperature, be dissolved in 12.0mlCH
2Cl
2In the mixed solvent of/ether (volume ratio is 1: 2), place 10hr in room temperature, filter, drying, obtain solid 102mg, e.e. value is 0.7%, obtains the e.e. value after mother liquor is concentrated and be S-(-)-lansoprazole 380mg of 98.4%, and total recovery is 68.6%; The total yield of R-(+)-binaphthol Hla is 77.0%, and the e.e. value is 100%.
Embodiment 15
With the racemic lansoprazole of 1.111g (3.0mmol) and 2.154g (7.5mmol) optically pure R-(+)-binaphthol Hla (mol ratio is 1: 2.5), under 60 ℃, be dissolved in 45.0ml benzene/normal hexane (volume ratio is 3: 1) mixed solvent, then, placed 12 hours down in-5 ℃, filter, drying obtains solid and is R-(+)-Hla of white and the inclusion complex compound 1.559g of R-(+)-lansoprazole, yield is 101.5%, and the e.e. value of R-(+)-lansoprazole is 75.5%; Get the e.e. value and be 81.3% inclusion complex compound 1.550g, under 80 ℃, be dissolved in the 45.0ml benzene, then, add the 22.0ml normal hexane, place 18hr in-5 ℃, filtration, drying obtain solid and are R-(+)-Hla of white and the inclusion complex compound 1.295g (the recrystallization yield is 83.5%) of R-(+)-lansoprazole, and the e.e. value of R-(+)-lansoprazole is 91.2%; Get the e.e. value and be 91.2% inclusion complex compound 1.290g, under 80 ℃, be dissolved in the 20.0ml benzene, then, add the 5.0ml normal hexane, place 18hr in-5 ℃, filter, drying, (the recrystallization yield is 80.6% for R-(+)-Hla of white and the inclusion complex compound 1.04g of R-(+)-lansoprazole to obtain solid, total recovery 73.5%), the e.e. value of R-(+)-lansoprazole is 99.3%.Mother liquor concentrates the mixture that obtains 1.545g R-(+)-binaphthol Hla and S-(-)-lansoprazole for the first time, through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain R-(+)-binaphthol Hla0.859g and e.e. value be S-(-)-lansoprazole 0.567g of 80.3%; Get the e.e. value and be S-(-)-lansoprazole 0.560g of 80.3%, under room temperature, be dissolved in 10.0mlCH
2Cl
2In the mixed solvent of/ether (volume ratio is 1: 2), place 10hr in room temperature, filter, drying, obtain solid 101mg, obtain the e.e. value after mother liquor concentrates and be S-(-)-lansoprazole 433mg of 99.3%, total recovery is 77.9%.
Embodiment 16
With the racemic lansoprazole of 1.111g (3.0mmol) and 2.154g (7.5mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 2.5), under 60 ℃, be dissolved in 28.0ml benzene/normal hexane (volume ratio is 6: 1) mixed solvent, then, placed 12 hours down in 5 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 1.342g of S-(-)-lansoprazole, yield is 94.9%, and the e.e. value of S-(-)-lansoprazole is 84.4%; Get the e.e value and be 84.4% inclusion complex compound 1.340g, under 80 ℃, be dissolved in the 24.0ml benzene, then, add the 8.0ml normal hexane, place 18hr in 5 ℃, filtration, drying obtain solid and are S-(-)-Hla of white and the inclusion complex compound 1.146g (the recrystallization yield is 85.5%) of S-(-)-lansoprazole, and the e.e. value of S-(-)-lansoprazole is 92.5%; Get the e.e. value and be 92.5% inclusion complex compound 1.144g, under 80 ℃, be dissolved in the 21.0ml benzene, then, add the 7.0ml normal hexane, place 18hr in 5 ℃, filter, drying, (the recrystallization yield is 83.0% for S-(-)-Hla of white and the inclusion complex compound 0.950g of S-(-)-lansoprazole to obtain solid, total recovery 67.3%), the e.e. value of S-(-)-lansoprazole is 99.1%.Mother liquor concentrates the mixture that obtains 1.845g S-(-)-binaphthol Hla and R-(+)-lansoprazole for the first time, through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain S-(-)-binaphthol Hla 1.059g and e.e. value be R-(+)-lansoprazole 0.607g of 67.3%; Get the e.e. value and be R-(+)-lansoprazole 0.600g of 67.3%, under room temperature, be dissolved in 1 5.0mlCH
2Cl
2In the mixed solvent of/ether (volume ratio is 1: 2), place 10hr in room temperature, filter, drying, obtain solid 196mg, obtain the e.e. value after mother liquor concentrates and be R-(+)-lansoprazole 401mg of 98.6%, total recovery is 72.2%.
With the racemic lansoprazole of 1.111g (3.0mmol) and 2.574g (9.0mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 3.0), under 60 ℃, be dissolved in 65.0ml benzene/normal hexane (volume ratio is 2: 1) mixed solvent, then, placed 8 hours down in-10 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 1.820g of S-(-)-lansoprazole, and the e.e. value of S-(-)-lansoprazole is 75.1%; Get the e.e. value and be 75.1% inclusion complex compound 1.810g, under 80 ℃, be dissolved in the 48.0ml benzene, then, add the 8.0ml normal hexane, place 18hr in-10 ℃, filtration, drying obtain the 1.206g (recrystallization yield be 66.3%) of solid for the inclusion complex compound of white S-(-)-Hla and S-(-)-lansoprazole, and the e.e. value of S-(-)-lansoprazole is 89.5%; Get the e.e. value and be 89.5% inclusion complex compound 1.200g, under 80 ℃, be dissolved in the 22.0ml benzene, then, add the 8.0ml normal hexane, place 18hr in-10 ℃, filter, drying, (the recrystallization yield is 66.70% for S-(-)-Hla of white and the inclusion complex compound 0.860g of S-(-)-lansoprazole to obtain solid, total recovery 60.9%), the e.e. value of S-(-)-lansoprazole is 99.0%.Mother liquor concentrates the mixture that obtains 1.805g S-(-)-binaphthol Hla and R-(+)-lansoprazole for the first time, through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain S-(-)-binaphthol Hla 1.159g and e.e. value be R-(+)-lansoprazole 0.596g of 69.8%; Get the e.e. value and be R-(+)-lansoprazole 0.594g of 69.8%, under room temperature, be dissolved in 8.0mlCH
2Cl
2In the mixed solvent of/ether (volume ratio is 1: 2), place 10hr in room temperature, filter, drying, obtain solid 178mg, obtain the e.e. value after mother liquor concentrates and be R-(+)-lansoprazole 391mg of 96.3%, total recovery is 70.4%.
With the racemic lansoprazole of 1.111g (3.0mmol) and 2.574g (9.0mmol) optically pure R-(+)-binaphthol Hla (mol ratio is 1: 3.0), under 60 ℃, be dissolved in 46.0ml benzene/normal hexane (volume ratio is 4: 1) mixed solvent, then, placed 10 hours down in 0 ℃, filter, drying obtains solid and is R-(+)-Hla of white and the inclusion complex compound 1.609g of R-(+)-lansoprazole, and the e.e. value of R-(+)-lansoprazole is 79.9%; Get the e.e. value and be 79.9% inclusion complex compound 1.60g, under 80 ℃, be dissolved in the 40.0ml benzene, then, add the 5.0ml normal hexane, place 18hr in 0 ℃, filtration, drying obtain solid and are R-(+)-Hla of white and the inclusion complex compound 1.234g (the recrystallization yield is 77.1%) of R-(+)-lansoprazole, and the e.e. value of R-(+)-lansoprazole is 90.2%; Get the e.e. value and be 90.2% inclusion complex compound 1.230g, under 80 ℃, be dissolved in the 32.0ml benzene, then, add the 4.0ml normal hexane, place 18hr in 0 ℃, filter, drying, (the recrystallization yield is 87.4% for R-(+)-Hla of white and the inclusion complex compound 1.075g of R-(+)-lansoprazole to obtain solid, total recovery 76.7%), the e.e. value of R-(+)-lansoprazole is 98.9%.Mother liquor concentrates the mixture that obtains 2.047g R-(+)-binaphthol Hla and S-(-)-lansoprazole for the first time, through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain R-(+)-binaphthol Hla 1.439g and e.e. value be S-(-)-lansoprazole 0.666g of 77.0%; Get the e.e. value and be S-(-)-lansoprazole 0.660g of 77.0%, under room temperature, be dissolved in 11.0mlCH
2Cl
2In the mixed solvent of/ether (volume ratio is 1: 2), place 10hr in room temperature, filter, drying, obtain solid 120mg, obtain the e.e. value after mother liquor concentrates and be S-(-)-lansoprazole 403mg of 97.0%, total recovery is 72.7%.
Embodiment 19
With the racemic lansoprazole of 1.111g (3.0mmol) and 5.148g (18.0mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 6.0), under 100 ℃, be dissolved in the 19.0ml benzene, then, placed 48 hours down in 10 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 1.488g of S-(-)-lansoprazole, and the e.e. value of S-(-)-lansoprazole is 82.6%; Get the e.e. value and be 82.6% inclusion complex compound 1.480g, under 80 ℃, be dissolved in the 20.0ml benzene, then, add the 2.0ml normal hexane, place 18hr in 5 ℃, filtration, drying obtain the 1.116g (recrystallization yield be 75.3%) of solid for the inclusion complex compound of white S-(-)-Hla and S-(-)-lansoprazole, and the e.e. value of S-(-)-lansoprazole is 89.5%; Get the e.e. value and be 89.5% inclusion complex compound 1.110g, under 80 ℃, be dissolved in the 15.0ml benzene, then, add the 3.0ml normal hexane, place 18hr in-5 ℃, filter, drying, (the recrystallization yield is 91.8% for S-(-)-Hla of white and the inclusion complex compound 1.01g of S-(-)-lansoprazole to obtain solid, total recovery 71.6%), the e.e. value of S-(-)-lansoprazole is 98.8%.Mother liquor concentrates the mixture that obtains 2.093g S-(-)-binaphthol Hla and R-(+)-lansoprazole for the first time, through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain S-(-)-binaphthol Hla 1.505g and e.e. value be R-(+)-lansoprazole 0.537g of 70.0%; Get the e.e. value and be R-(+)-lansoprazole 0.530g of 70.0%, under room temperature, be dissolved in 13.0mlCH
2Cl
2In the mixed solvent of/ether (volume ratio is 1: 2), place 10hr in room temperature, filter, drying, obtain solid 154mg, obtain the e.e value after mother liquor concentrates and be R-(+)-lansoprazole 378mg of 98.8%, total recovery is 68.1%.
With the racemic lansoprazole of 1.111g (3.0mmol) and 5.148g (18.0mmol) optically pure R-(+)-binaphthol Hla (mol ratio is 1: 6.0), under 90 ℃, be dissolved in the 29.0ml benzene, then, placed 12 hours down in 0 ℃, filter, drying obtains solid and is R-(+)-Hla of white and the inclusion complex compound 1.365g of R-(+)-lansoprazole, and the e.e. value of R-(+)-lansoprazole is 87.9%; Get the e.e. value and be 87.9% inclusion complex compound 1.360g, under 80 ℃, be dissolved in the 18.0ml benzene, then, add the 9.0ml normal hexane, place 48hr in 15 ℃, filtration, drying obtain solid and are R-(+)-Hla of white and the inclusion complex compound 1.162g (the recrystallization yield is 85.3%) of R-(+)-lansoprazole, and the e.e. value of R-(+)-lansoprazole is 93.0%; Get the e.e. value and be 93.0% inclusion complex compound 1.160g, under 80 ℃, be dissolved in the 18.0ml benzene, then, add the 6.0ml normal hexane, place 48hr in 15 ℃, filter, drying, (the recrystallization yield is 91.6% for R-(+)-Hla of white and the inclusion complex compound 1.062g of R-(+)-lansoprazole to obtain solid, total recovery 75.3%), the e.e. value of R-(+)-lansoprazole is %.Mother liquor concentrates the mixture that obtains 2.239g R-(+)-binaphthol Hla and S-(-)-lansoprazole for the first time, through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain R-(+)-binaphthol Hla 1.639g and e.e. value be S-(-)-lansoprazole 0.629g of 70.7%; Get the e.e value and be S-(-)-lansoprazole 0.620g of 70.7%, under room temperature, be dissolved in 11.0mlCH
2Cl
2In the mixed solvent of/ether (volume ratio is 1: 2), place 10hr in room temperature, filter, drying, obtain solid 200mg, obtain the e.e. value after mother liquor concentrates and be S-(-)-lansoprazole 418mg of 98.6%, total recovery is 75.5%.
With the racemic lansoprazole of 1.111g (3.0mmol) and 3.432g (12.0mmol) optically pure S-(-)-binaphthol Hla (mol ratio is 1: 4.0), under 60 ℃, be dissolved in the 40.0ml benzene, then, placed 12 hours down in 0 ℃, filter, drying obtains solid and is S-(-)-Hla of white and the inclusion complex compound 1.804g of S-(-)-lansoprazole, and the e.e. value of S-(-)-lansoprazole is 83.6%; Get the e.e. value and be 83.6% inclusion complex compound 1.80g, under 140 ℃, be dissolved in the 120.0ml dimethylbenzene, then, place 18hr in 30 ℃, filtration, drying, obtain the 1.482g (recrystallization yield be 82.3%) of solid for the inclusion complex compound of white S-(-)-Hla and S-(-)-lansoprazole, the e.e. value of S-(-)-lansoprazole is 89.1%; Get the e.e value and be 89.1% inclusion complex compound 1.482g, under 60 ℃, be dissolved in the 30.0ml benzene, add the 90.0ml normal hexane again, place 5hr for 20 ℃, filtration, drying, obtain solid and be S-(-)-Hla of white and the inclusion complex compound 0.926g (the recrystallization yield is 62.6%, total recovery 65.6%) of S-(-)-lansoprazole, the e.e. value of S-(-)-lansoprazole is 98.7%.Mother liquor concentrates the mixture that obtains 2.401g S-(-)-binaphthol Hla and R-(+)-lansoprazole for the first time, through column chromatography for separation, carry out gradient elution with ethyl acetate/petroleum ether (volume ratio is 1: 2) and methyl alcohol respectively, separate that to obtain S-(-)-binaphthol Hla 1.689g and e.e. value be R-(+)-lansoprazole 0.644g of 70.1%; Get the e.e. value and be R-(+)-lansoprazole 0.640g of 70.1%, under room temperature, be dissolved in 15.0mlCH
2Cl
2In the mixed solvent of/ether (volume ratio is 1: 2), place 10hr in room temperature, filter, drying, obtain solid 220mg, obtain the e.e. value after mother liquor concentrates and be R-(+)-lansoprazole 424mg of 97.3%, total recovery is 76.5%.
With 200mg (0.54mmol) scarlet syrupy shape R-(+)-lansoprazole, e.e. value is 83.7%, and chemical purity is 73.8% (area ratio), is dissolved under 70 ℃ in the NaOH solution (mol ratio of NaOH and lansoprazole is 3.5: 1) of 1.0ml6%, and stirring 0.5hr, solution is deep yellow; Then, add 2.0ml distilled water and 200mg gac, in 80 ℃ of stirred in water bath decolourings 1.0 hours, obtain yellow solution after the filtration, be concentrated into 2.0ml, aqueous-phase concentration is 100mg/1.0ml.Add 0.2ml ethanol, transfer pH=7.5 with methyl-formiate, stir 0.5hr under the room temperature, the solution becomes muddiness is placed 18hr in-10 ℃, filter, vacuum-drying 10hr obtains the Powdered R-of faint yellow non-crystalline state (+)-lansoprazole 91mg, and yield is 45.5%, chemical purity is 95.5% (area ratio), and the e.e. value is 87.5%.Get the 90mg chemical purity and be R-(+)-lansoprazole of 98.6%, be dissolved in the 0.6ml butanone, add 3.0ml distilled water again, cryosel is bathed and is stirred 1.0hr down, place 10hr for 0 ℃, filter, vacuum-drying obtains white powder R-(+)-lansoprazole 70mg, the recrystallization yield is 76.9%, total recovery is 35%, and chemical purity is 97.9% (area ratio), and the e.e. value is 87.9%.
With 350mg (0.95mmol) buff syrup shape R-(+)-lansoprazole, e.e. value is 99.6%, and chemical purity is 96.3% (area ratio), is dissolved under 90 ℃ in the NaOH solution (mol ratio of NaOH and lansoprazole is 3: 1) of 1.5ml 7%, and stirred 10 minutes, solution is light yellow; Then, add 2.5ml distilled water, be divided into three parts, aqueous-phase concentration is 87.5mg/1.0ml, carries out the experiment of embodiment 23～25.
Add 0.2ml ethanol, add Sodium phosphate dibasic and transfer pH=7.5, stir 0.5hr under the room temperature, the solution becomes muddiness is placed 18hr in-15 ℃, filter, vacuum-drying 10hr obtains the Powdered R-of faint yellow non-crystalline state (+)-lansoprazole 67mg, and yield is 57.0%, chemical purity is 98.8% (area ratio), and the e.e. value is 99.1%.
Embodiment 24
Add 0.2ml methyl alcohol, add Sodium phosphate dibasic and transfer pH=8.0, stir 0.5hr under the room temperature, the solution becomes muddiness continues to stir 2.0hr, becomes faint yellow mashed prod, place 18hr in-5 ℃, filter, use distilled water wash, vacuum-drying 10hr, obtain the Powdered R-of faint yellow non-crystalline state (+)-lansoprazole 73mg, yield is 62.4%, and chemical purity is 98.9% (area ratio), and the e.e. value is 98.9%.
Add the 0.2ml butanone, add Sodium phosphate dibasic and transfer pH=8.5, stir 0.5hr under the room temperature, the solution becomes muddiness continues to stir 2.0hr, becomes white paste, in 0 ℃ of placement 18hr, filter, use distilled water wash, vacuum-drying 10hr, obtain the Powdered R-of white non-crystalline state (+)-lansoprazole 78mg, yield is 66.7%, and chemical purity is 100% (area ratio), e.e. value is 99.1%, [α]
D 20 ℃=+144.5 °.
Embodiment 26
With 250mg (0.68mmol) scarlet syrupy shape R-(+)-lansoprazole, e.e. value is 98.4%, and chemical purity is 95.8% (area ratio), is dissolved under 100 ℃ in the NaOH solution (mol ratio of NaOH and lansoprazole is 4: 1) of 2.1ml5%, and stirring 0.5hr, solution is deep yellow; Then, add 2.0ml distilled water and 200mg gac, in 80 ℃ of stirred in water bath decolourings 1.0 hours, obtain yellow solution after the filtration, be concentrated into 2.0ml, aqueous-phase concentration is 125mg/1.0ml.Add 0.2ml acetone, transfer pH=9.0 with methyl-formiate, stir 0.5hr under the room temperature, the solution becomes muddiness is placed 18hr in 0 ℃, filter, vacuum-drying 10hr obtains the Powdered R-of faint yellow non-crystalline state (+)-lansoprazole 191mg, and yield is 76.4%, chemical purity is 98.6% (area ratio), and the e.e. value is 95.9.Get the 170mg chemical purity and be R-(+)-lansoprazole of 98.6%, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 4: 1) of 1.0ml7%, and stir 0.5hr, solution is faint yellow; Then, add 1.0ml distilled water, aqueous-phase concentration is 90mg/1.0ml, add 0.2ml acetone again, transfer pH=7.5, stir 0.5hr under the room temperature with methyl-formiate, the solution becomes muddiness is placed 18hr, filtration in 0 ℃, vacuum-drying 10hr, obtain the Powdered R-of white non-crystalline state (+)-lansoprazole 145mg, the recrystallization yield is 75.9%, and total recovery is 57.9%, chemical purity is 99.6% (area ratio), and the e.e. value is 96.7%.
Embodiment 27
With 234mg (0.63mmol) buff syrup shape R-(+)-lansoprazole, e.e. value is 95.7%, and chemical purity is 99.3% (area ratio), is dissolved under 110 ℃ in the NaOH solution (mol ratio of NaOH and lansoprazole is 3: 1) of 2.6ml4%, and stirring 10min, solution is light yellow; Add the 0.3ml butanone, transfer pH=9.5, stir 0.5hr under the room temperature with Sodium phosphate dibasic, the solution becomes muddiness continues to stir 2.0hr, becomes white paste, in-10 ℃ of placement 18hr, filter, use distilled water wash, vacuum-drying 10hr, obtain the Powdered R-of white non-crystalline state (+)-lansoprazole 78mg, yield is 66.7%, and chemical purity is 99.0% (area ratio), e.e. value is 98.9%, [α]
D 20 ℃=+143.3 °.
With 413mg (1.12mmol) scarlet syrupy shape S-(-)-lansoprazole, e.e. value is 99.7%, chemical purity is 94.3% (area ratio), under 120 ℃, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 3.5: 1) of 2.6ml 5%, and stirring 10min, solution is deep yellow; Then, add 2.5ml distilled water and 369mg gac, in 90 ℃ of stirred in water bath decolourings 2.0 hours, obtain yellow solution after the filtration, be concentrated into 3.0ml, be divided into four parts, aqueous-phase concentration is 137.7mg/1.0ml, carries out the experiment of embodiment 28～hentriaconta-three.
Embodiment 28
Add 0.2ml distilled water, cryosel is bathed and is stirred, and adds Sodium phosphate dibasic and transfers pH=7.5, continues to stir 0.5hr, the solution becomes muddiness, place 18hr, filtration, vacuum-drying 10hr in 0 ℃, obtain the Powdered S-of faint yellow non-crystalline state (-)-lansoprazole 72mg, yield is 69.9%, and chemical purity is 98.1% (area ratio), and the e.e. value is 99.0%.
Add the 0.2ml Virahol, cryosel is bathed and is stirred, and adds sodium pyrosulfate and transfers pH=8.0, continues to stir 0.5hr, the solution becomes muddiness, place 15hr, filtration, vacuum-drying 10hr in 5 ℃, obtain the Powdered S-of oyster white non-crystalline state (-)-lansoprazole 42mg, yield is 40.8%, and chemical purity is 99.1% (area ratio), and the e.e. value is 98.7%.
Embodiment 30
Add 0.2ml ethanol, cryosel is bathed and is stirred, and adds sal enixum and transfers pH=8.5, continues to stir 0.5hr, the solution becomes muddiness, place 10hr, filtration, vacuum-drying 10hr in 10 ℃, obtain the Powdered S-of faint yellow non-crystalline state (-)-lansoprazole 50.8mg, yield is 49.3%, and chemical purity is 98.8% (area ratio), and the e.e. value is 98.6%.
The embodiment hentriaconta-
Add the 0.2ml butanone, cryosel is bathed and is stirred, and adds Sodium phosphate dibasic and transfers pH=9.0, continue to stir 0.5hr, the solution becomes muddiness is placed 8hr, filtration in 0 ℃, vacuum-drying 10hr, obtain the Powdered S-of white non-crystalline state (-)-lansoprazole 73.0mg, yield is 70.9%, and chemical purity is 99.8% (area ratio), e.e. value is 99.3%, [α]
D 20 ℃=-143.9 °.
With 1.116g (3.02mmol) scarlet syrupy shape R-(+)-lansoprazole, e.e. value is 98.1%, chemical purity is 99.5% (area ratio), under 120 ℃, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 3.5: 1) of 4.3ml 9%, and stirring 0.5hr, solution is deep yellow; Then, add 10.0ml distilled water and 1.0g gac, in 100 ℃ of stirred in water bath decolourings 1.0 hours, obtain yellow solution 20ml after the filtration, aqueous-phase concentration is 55.8mg/1.0ml.Be divided into four parts, carry out 32～35 test respectively.
Embodiment 32
Add the 0.3ml butanone, cryosel is bathed and is stirred 1.5hr, adds methyl-formiate and transfers pH=7.5, continues to stir 1.0hr, the solution becomes muddiness, place 5hr, filtration, vacuum-drying 10hr in-5 ℃, obtain the Powdered R-of faint yellow non-crystalline state (+)-lansoprazole 106mg, yield is 41.9%, and chemical purity is 99.1% (area ratio), and the e.e. value is 99.9%; With chemical purity is that 99.1% (area ratio), e.e. value are the Powdered R-of faint yellow non-crystalline state (+)-lansoprazole 100mg of 99.9%, be dissolved in the 0.1ml butanone, add 0.6ml distilled water again, stirred 15 hours in-10 ℃, obtain the optical purity R-(+) with the certain crystalline state-lansoprazole 90mg of white, yield is 90.0%, and chemical purity is 99.9% (area ratio), e.e. value is 99.8%, [α]
D 25 ℃=+143.5 °.
Embodiment 33
Add the 0.3ml butanone, cryosel is bathed and is stirred, and adds methyl-formiate and transfers pH=8.0, continues to stir 1.5hr, solution becomes white pasty liquid, place 10hr, filtration, vacuum-drying 20hr in 0 ℃, obtain the Powdered R-of white non-crystalline state (+)-lansoprazole 548mg, yield is 166%, and chemical purity is 91.2% (area ratio), and the e.e. value is 96.3%.Get the 500mg chemical purity and be R-(+)-lansoprazole of 91.2%, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 4: 1) of 3.0ml 7%, and stir 0.5hr, solution is faint yellow; Then, add 2.0ml distilled water, aqueous-phase concentration is 100mg/1ml, add 0.2ml acetone, transfer pH=8.0 with methyl-formiate again, continue to stir 1.5hr, solution becomes white pasty liquid, and cryosel is bathed and stirred 1.0hr, solution becomes muddiness down, place 10hr, filtration, vacuum-drying 10hr in 0 ℃, obtain the Powdered R-of white non-crystalline state (+)-lansoprazole 83mg, the recrystallization yield is 15.6%, and total recovery is 30%, chemical purity is 99.9% (area ratio), and the e.e. value is 98.7%.
Add the 0.3ml butanone, cryosel is bathed and is stirred, and adds Sodium phosphate dibasic and transfers pH=9.3 (mol ratio of Sodium phosphate dibasic and sodium hydroxide is 1: 1), continues to stir 1.5hr, solution is separated out faint yellow solid, place 18hr, filtration, vacuum-drying 10hr in 5 ℃, obtain the Powdered R-of faint yellow non-crystalline state (+)-lansoprazole 115mg, yield is 45.5%, and chemical purity is 77.4% (area ratio), and the e.e. value is 94.2%; With chemical purity is the Powdered R-of faint yellow non-crystalline state (+)-lansoprazole 110mg of 77.4% (area ratio), be dissolved in the 0.2ml butanone, add 1.6ml distilled water again, stirred 10 hours in-5 ℃, obtain optical purity R-(+)-lansoprazole 99mg that oyster white has certain crystalline state, yield is 89.0%, and chemical purity is 99.9% (area ratio), e.e. value is 99.6%, [α]
D 25 ℃=+143.9 °.
Embodiment 35
Add the 0.3ml butanone, cryosel is bathed and was stirred 1.5 hours, adds sodium bicarbonate and transfers pH=8.0 (mol ratio of sodium bicarbonate and sodium hydroxide is 1: 1), continues to stir 1.5hr, solution is separated out faint yellow solid, place 18hr, filtration, vacuum-drying 10hr in-10 ℃, obtain the Powdered R-of white non-crystalline state (+)-lansoprazole 126mg, yield is 49.8%, and chemical purity is 93.9% (area ratio), and the e.e. value is 98.7%; With chemical purity is that 93.9% (area ratio), e.e. value are the Powdered R-of white non-crystalline state (+)-lansoprazole 120mg of 98.7%, be dissolved in the 0.3ml butanone, add 3.0ml distilled water again, stirred 20 hours in 0 ℃, obtain optical purity R-(+)-lansoprazole 110mg that oyster white has certain crystalline state, yield is 91.7%, and chemical purity is 100.0% (area ratio), e.e. value is 99.1%, [α]
D 25 ℃=+143.1 °.
With 377mg (1.01mmol) pale yellow powder shape R-(+)-lansoprazole, the e.e. value is 99.4%, and chemical purity is 99.7% (area ratio), [α]
D 25 ℃=+143.4 °, under 110 ℃, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 1.5: 1) of 1.0ml 3%, add 3.0ml water again, 0.6ml butanone, and stirring 0.5hr, solution is faint yellow, and aqueous-phase concentration is 94mg/1.0ml, transfers pH=7.5 with methyl-formiate, place 10hr in 0 ℃, filter, vacuum-drying 10hr obtains R-(+)-lansoprazole 344mg that oyster white has certain crystalline state, yield is 87.5%, chemical purity is 99.9% (area ratio), and the e.e. value is 100%, [α]
D 25 ℃=+143.7 °.
Embodiment 37
With 581mg (1.58mmol) off-white powder shape S-(-)-lansoprazole, the e.e. value is 97.7%, and chemical purity is 98.9% (area ratio), [α]
D 25 ℃=-142.2 °, under 120 ℃, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 1.5: 1) of 1.3ml 7%, add 2.7ml water again, 0.5ml butanone, and stirring 1.0hr, solution is faint yellow, and aqueous-phase concentration is 145.3mg/1.0ml, transfers Ph=8.0 with methyl-formiate, place 18hr in-5 ℃, filter, vacuum-drying 10hr obtains S-(-)-lansoprazole 477mg that oyster white has certain crystalline state, yield is 93.9%, chemical purity is 99.7% (area ratio), and the e.e. value is 98.7%, [α]
D 25 ℃=-143.0 °.
With 206mg (0.56mmol) incarnadine syrupy shape R-(+)-lansoprazole, the e.e. value is 99.9%, and chemical purity is 99.8% (area ratio), [α]
D 25 ℃=+143.4 °, under 90 ℃, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 2.5: 1) of 1.3ml 4%, and stir 0.5hr, solution is faint yellow, aqueous-phase concentration is 158mg/1.0ml, places 10hr, filtration in-5 ℃, vacuum-drying 20hr, obtain the sodium salt 130mg of the Powdered R-of oyster white non-crystalline state (+)-Lan Suola, yield is 63%, and chemical purity is 99.7% (area ratio), e.e. value is 99.4%, [α]
D 25 ℃=+104.5 °.
With 200mg (0.54mmol) incarnadine syrupy shape R-(+)-lansoprazole, the e.e. value is 99.9%, and chemical purity is 99.8% (area ratio), [α]
D 25 ℃=+143.4 °, under 100 ℃, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 2.0: 1) of 1.3ml 3%, and stir 1.0hr, solution is faint yellow, aqueous-phase concentration is 154mg/1.0ml, places 15hr, filtration in 0 ℃, vacuum-drying 10hr, obtain the sodium salt 171mg of the Powdered R-of oyster white non-crystalline state (+)-lansoprazole, yield is 85.5%, and chemical purity is 100% (area ratio), e.e. value is 100%, [α]
D 25 ℃=+105.1 °.
Embodiment 40
With 200mg (0.54mmol) incarnadine syrupy shape R-(+)-lansoprazole, the e.e. value is 99.9%, and chemical purity is 99.8% (area ratio), [α]
D 25 ℃=+143.4 °, under 120 ℃, be dissolved in the NaOH solution (mol ratio of NaOH and lansoprazole is 1.5: 1) of 1.0ml 3%, and stir 2.0hr, solution is faint yellow, aqueous-phase concentration is 200mg/1.0ml, places 18hr, filtration in 5 ℃, vacuum-drying 10hr, obtain the Powdered R-of oyster white non-crystalline state (+)-lansoprazole sodium salt 162mg, yield is 81%, and chemical purity is 99.9% (area ratio), e.e. value is 99.6%, [α]
D 25 ℃=+104.4 °.
With 200mg (0.54mmol) incarnadine syrupy shape S-(-)-lansoprazole, the e.e. value is 97.7%, and chemical purity is 98.9% (area ratio), [α]
D 25 ℃=-142.2 °, under 50 ℃, be dissolved in the KOH solution (mol ratio of KOH and lansoprazole is 2.0: 1) of 1.0ml 5%, and stir 1.0hr, solution is faint yellow, aqueous-phase concentration is 200mg/1.0ml, places 20hr, filtration in-10 ℃, vacuum-drying 10hr, obtain the Powdered S-of oyster white non-crystalline state (-)-lansoprazole sylvite 146.6mg, yield is 73.3%, and chemical purity is 99.8% (area ratio), e.e. value is 99.5%, [α]
D 25 ℃=-97.5 °.
With 200mg (0.54mmol) incarnadine syrupy shape R-(+)-lansoprazole, the e.e. value is 99.7%, and chemical purity is 99.5% (area ratio), [α]
D 25 ℃=+143.0 °, under 120 ℃, be dissolved in the KOH solution (mol ratio of NaOH and lansoprazole is 3.0: 1) of 2.5ml 3%, and stir 2.0hr, solution is faint yellow, aqueous-phase concentration is 80mg/1.0ml, places 10hr, filtration in-15 ℃, vacuum-drying 10hr, obtain the Powdered R-of oyster white non-crystalline state (+)-lansoprazole sylvite 154mg, yield is 77%, and chemical purity is 99.9% (area ratio), e.e. value is 99.1%, [α]
D 25 ℃=+97.1 °.
Claims (7)
1. the preparation method of an optical purity lansoprazole, it is characterized in that with optically pure binaphthol compounds be the inclusion main body, with racemic lansoprazole is object, adopt the inclusion method for splitting to prepare optically pure lansoprazole, make oily or syrupy shape optical purity S-(-)-or R-(+)-lansoprazole; Oily that fractionation is obtained or syrupy shape optical purity S-(-)-or R-(+)-lansoprazole is prepared into more stable white powder and has certain crystalline state or amorphous optical purity lansoprazole or its salt in basic solution or water/a small amount of organic solvent again; Wherein:
(a) with racemic lansoprazole and 1: 2 in molar ratio～1: 6 ratio of optically pure binaphthol compounds, under 60～160 ℃, be dissolved in the organic solvent, perhaps under 10～80 ℃, in organic solvent, stirred 12～72 hours, organic solvent is an aromatic hydrocarbon, or the mixture of aromatic hydrocarbon/normal hexane, the volume ratio of mixture is aromatic hydrocarbon/normal hexane of 1: 1～10: 1; Quantity of solvent is every gram object 10～80ml; Placed 5～48 hours down in 10～30 ℃ then, filter, obtain the solid inclusion complex compound and the dominant filtrate of another configuration lansoprazole of optical purity main body and a certain configuration lansoprazole; Again solid inclusion complex compound is separated with conventional chromatography method respectively with filtrate, with the inclusion subject and object separately, can obtain two kinds of configurations dominant oilies or syrupy shape optical purity S-(-)-or R-(+)-lansoprazole respectively;
(b) with the oily that obtains among the above-mentioned preparation method or syrupy shape optical purity S-(-)-or R-(+)-lansoprazole under 50～120 ℃, be dissolved in the aqueous solution of mineral alkali, the concentration of solution is 1～10%, and the mol ratio of mineral alkali and optical purity lansoprazole is 1: 1～5: 1; Stir after 5 minutes to 2 hours, the pH value is 10～13, obtain colourless or faint yellow optical purity lansoprazole solution, with the solution cooling, bathe stirring down 1-3 hour in cryosel, placed 5～20 hours in-20～10 ℃, filter, washing, vacuum drying at room temperature 10～20 hours can make the salt of oyster white or white non-crystalline state lansoprazole; Perhaps in colourless or faint yellow optical purity lansoprazole solution, add dissolving each other with water or the organic solvent of partial miscibility of 0.1～1 times of aqueous solution volume, add inorganic acid salt or methyl-formiate again, the mol ratio of itself and alkali is 0.5: 1～2: 1, control final pH value is 7～10, continues to stir after 0.5～6 hour, places 5～20 hours in-20～10 ℃, filter, washing, vacuum drying at room temperature 10～20 hours makes that optical purity white is amorphous, the neutral lansoprazole; Again with resulting optical purity white amorphous S-(-)-R-(+)-lansoprazole be dissolved in dissolve each other with water or the organic solvent of partial miscibility in, quantity of solvent is 0.5～2.5ml/ gram optical purity lansoprazole, in every gram optical purity lansoprazole, add 5～25ml distilled water again, stirred 0.5～20 hour in-20～10 ℃, make the certain crystalline state of optical purity white, neutral S-(-)-or R-(+)-lansoprazole.
2. the preparation method of optical purity lansoprazole according to claim 1, it is characterized in that the solid inclusion complex compound that obtains also can be under 60～160 ℃, ratio in every gram inclusion complex compound 10～70ml solvent is dissolved in the aromatic hydrocarbon solvent, then, the alkane that adds 0～3 times of volume again, placed 5～48 hours down in-10～30 ℃, filter, obtain the higher inclusion complex compound of e.e. value, this process can repeat repeatedly, till to obtain the high main body/object of e.e. value be 2: 1 solid inclusion complex compound, again solid inclusion complex compound is separated with conventional chromatography method respectively with filtrate, with the inclusion subject and object separately, can obtain two kinds of configurations dominant oilies or syrupy shape optical purity S-(-)-or R-(+)-lansoprazole respectively.
3. the preparation method of optical purity lansoprazole according to claim 1 and 2, it is characterized in that if oily or syrupy shape optical purity S-(-)-or the color of R-(+)-lansoprazole is darker, obtain deep yellow solution after being dissolved in alkaline solution, then use activated carbon decolorizing, operation steps is as follows: the water that adds every gram optical purity lansoprazole 2～15ml, the gac that adds 0.3～1 times of optical purity lansoprazole weight again, under 80～120 ℃, stir decolouring 0.5～2 hour, filter, obtain colourless extremely faint yellow optical purity lansoprazole solution, carry out subsequent step again.
4. the preparation method of optical purity lansoprazole according to claim 1 and 2 is characterized in that used alkali is meant NaOH, KOH, K
2CO
3, Na
2CO
3
5. the preparation method of optical purity lansoprazole according to claim 1 and 2, it is characterized in that resulting optical purity S-(-)-or the salt of R-(+)-lansoprazole be meant sodium salt or sylvite.
6. the preparation method of optical purity lansoprazole according to claim 1 and 2 is characterized in that used inorganic acid salt is meant a kind of or how several in hydrosulfate, supercarbonate, the dihydrogen phosphate.
7. the preparation method of optical purity lansoprazole according to claim 1 and 2, it is characterized in that organic solvent that dissolve each other with water or partial miscibility is meant alkyl alcohol, alkyl ketone or the ethyl acetate below the C5, alcohol is one or more in methyl alcohol, ethanol, Virahol, propyl carbinol or the sec-butyl alcohol, and ketone is one or more of acetone, butanone or cyclopentanone.
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| TWI289557B (en) * | 1999-06-17 | 2007-11-11 | Takeda Chemical Industries Ltd | A crystal of a hydrate of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole |
| KR100887912B1 (en) * | 2000-12-01 | 2009-03-12 | 다케다 야쿠힌 고교 가부시키가이샤 | Process for the crystallization of r- or s-lansoprazole |
| US8697094B2 (en) * | 2002-10-16 | 2014-04-15 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
| ES2259269B1 (en) * | 2005-03-03 | 2007-11-01 | Esteve Quimica, S.A. | PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF 2- (2-PIRIDILMETILSULFINIL) -BENCIMIDAZOL OPTICALLY ACTIVE. |
| AU2008346115A1 (en) * | 2007-12-18 | 2009-07-16 | Watson Pharma Private Limited | A process for preparation of stable amorphous R-lansoprazole |
| AU2009336561A1 (en) | 2008-05-14 | 2010-07-15 | Watson Pharma Private Limited | Stable R-(+)-lansoprazole amine salt and a process for preparing the same |
| CN103788068B (en) * | 2014-02-26 | 2016-04-06 | 南京海融医药科技有限公司 | Dystectic chiral benzimidazole compound sodium salt, preparation method and its usage |
| 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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