CN101391993B - Method for preparing S-omeprazole and salt thereof by forming inclusion complex with (S)-(-)-1,1'-dinaphthalene-2,2'-diol - Google Patents
Method for preparing S-omeprazole and salt thereof by forming inclusion complex with (S)-(-)-1,1'-dinaphthalene-2,2'-diol Download PDFInfo
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Abstract
The invention provides a method for preparing S-Omeprazole and salt thereof by the resolution of racemic modification Omeprazole by an inclusion resolution method, the resolution regent of the inclusion resolution method is (S)-(-)-1, 1'-binaphthyl-2, 2'-diphenol, by adding S-Omeprazole and S-1, 1'-binaphthyl-2, 2'-diphenol inclusion complex seed grains at the temperature of 60 to 70 DEG C, the inclusion complex is obtained, then the inclusion complex is processed by the hydroxid aqueous solution of alkali metals to obtain the S-Omeprazole with high ee value, the S-Omeprazole and salt thereof obtained by the method have high ee value which is more than 99.2 percent, and the obtained S-Omeprazole has the color of kind of white, high yield and small pollution to the environment, and is suitable for industrial production.
Description
(1) technical field
The present invention relates to a kind of method for preparing S-omeprazole and salt thereof through inclusion resolution of racemates omeprazole.
(2) background technology
Omeprazole (Omeprazole, trade(brand)name Losec) is the development of Sweden Astra company, and first is applied to clinical proton pump inhibitor in the world, specially treats the specifics of the ulcer of stomach ulcer, duodenal ulcer and reflux esophagitis.
The S-omeprazole is the laevoisomer of racemic modification omeprazole, with respect to racemic modification and R-configuration omeprazole, and the good effect of S-configuration omeprazole, toxic side effect is low.Optical activity S-magnesium salt of omeprazole (trade(brand)name Nexium) in 2000 in Sweden's Initial Public Offering.
The chemical name of S-omeprazole is: (S)-and 5-methoxyl group-2-{ [(4-methoxyl group-3,5-dimethyl--2-pyridyl)-methyl]-sulfoxide }-the 1H-benzoglyoxaline, structural formula is as shown in the formula shown in the I:
Existing at present three pieces of patent documentations disclose with the inclusion Split Method and have split the method that obtains enantiomorph S-omeprazole
The disclosed inclusion resolving agent of Chinese patent notification number CN1087739C is di-phenanthrol and tartaric verivate, and racemic modification omeprazole and resolving agent form inclusion complex, and resolution of omeprazole obtains the S-omeprazole.
The shortcoming that this method exists has:
1. the inclusion complex solid color of gained is a black;
2. the optical purity of S-omeprazole is low in the inclusion complex, need be further purified product;
3. use benzene as solvent, benzene is a kind of high toxicity solvent, and unsuitable suitability for industrialized production is used;
4. adopt chromatography to remove resolving agent, be inappropriate for big production.
PCT patent WO2006094904 adopts and forms (S)-(-)-1,1 '-dinaphthalene-2, the inclusion complex of 2 '-diphenol and omeprazole; When being to form inclusion complex, its difference adds amine; Make the ee value improve a lot, separate and obtain the S-omeprazole through adding alkali at last, but omeprazole with (S)-(-)-1; 1 '-dinaphthalene-2, the mol ratio of 2 '-diphenol are 1: 1.5.
PCT patent WO2007013743 has adopted dissolving (S)-(-)-1 in the mixed solvent of organic solvent that dissolves each other with water and water, 1 '-dinaphthalene-2,2 '-diphenol; Weak base and omeprazole, crystallisation by cooling obtain the S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2; The inclusion complex of 2 '-diphenol; Remove (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol with filtration or method of extraction then; Obtain the S-omeprazole, organic solvent and the water of the mixed solvent that the difference of itself and PCT patent WO2006094904 is to use for dissolving each other with water.
(3) summary of the invention
The objective of the invention is to utilize inclusion Split Method resolution of omeprazole, obtain highly purified S-omeprazole through changing reaction conditions and method; And the color of the S-omeprazole of gained is an off-white color; This process recovery ratio is high, and environmental pollution is little, suitability for industrialized production.
S-omeprazole through method preparation of the present invention can further be converted into its salt.
For the technical scheme that reaches goal of the invention the present invention employing is:
A) with (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol is dissolved in toluene, under 70～80 ℃ of temperature, adds racemic omeprazole; When being cooled to 60～70 ℃ after the dissolving, add the S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2; 2 '-diphenol inclusion complex crystal seed is cooled to 40～50 ℃ then again, separate out solid obtain the S-omeprazole with (S)-(-)-1; 1 '-dinaphthalene-2,2 '-diphenol inclusion complex, the cooling rate of described twice cooling all is 0.5～1 ℃/min;
B) handle the inclusion complex that obtains in a) step with alkali-metal hydroxide aqueous solution with water unmixing or almost immiscible organic solvent, obtain the form of S-omeprazole freebase or its salt;
C) if what obtain is S-omeprazole freebase form, randomly, be translated into the form of its salt.
Through inspection, a) in the step S-omeprazole that obtains with (S)-(-)-1,1 '-dinaphthalene-2, the enantiomeric excess of 2 '-diphenol inclusion complex (ee value) are greater than 98%, the final S-omeprazole and the ee value of salt thereof are also greater than 99.2%.
Described (S)-(-)-1,1 '-dinaphthalene-2, the structural formula of 2 '-diphenol is suc as formula shown in the II:
Wherein, a) step described in omeprazole with (S)-(-)-1,1 '-dinaphthalene-2, the mol ratio of 2 '-diphenol is 1: 0.8～1.2, is preferably 1: 1; The cooling rate of described twice cooling all is 0.5～1 ℃/min, because the thermo-sensitivity of omeprazole, the speed of cooling rate directly affects the color of the finished product here; If cooling rate is slow, can make the S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2; The blackening of 2 '-diphenol inclusion complex color; Cause the also blackening of color of final S-omeprazole, and this cooling rate of our control, the color of the S-omeprazole that obtains is an off-white color; Described omeprazole and S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2, the mol ratio of 2 '-diphenol inclusion complex crystal seed is 1: 0.001～0.1; And a) in the step we stress omeprazoles all after the dissolving again cooling be because all be dissolved with the S-configuration that is beneficial in the racemic omeprazole with (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol fully combines, and obtains inclusion complex, improves yield and ee value.
B) step described in water unmixing or almost immiscible organic solvent be toluene, YLENE, methylene dichloride, 1,2-ethylene dichloride, ETHYLE ACETATE or isopropyl acetate.Described alkali-metal oxyhydroxide is Pottasium Hydroxide or sodium hydroxide, and the quality percentage composition of this alkali-metal hydroxide aqueous solution is 0.01%～0.05%; Described S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2, the mol ratio of 2 '-diphenol inclusion complex and alkali-metal oxyhydroxide is 1: 1～2
C) being translated into salt in the step can be through handling with the salt of basic metal or earth alkali metal and directly from reaction medium, obtaining; The salt of described basic metal or earth alkali metal is magnesium chloride or sal epsom.
On the other hand, the salt of the S-omeprazole for preparing through method of the present invention is magnesium salts, and described magnesium salts is a S-magnesium salt of omeprazole duohydrate crystal form A, S-magnesium salt of omeprazole duohydrate crystal form B and S-magnesium salt of omeprazole trihydrate crystal formation.
The invention still further relates to the method for preparing S-magnesium salt of omeprazole duohydrate crystal form A, comprising:
A) with (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol is dissolved in toluene; Under 70～80 ℃ of temperature, add racemic omeprazole, when being cooled to 60～70 ℃ after the dissolving, add the S-omeprazole with (S)-(-)-1; 1 '-dinaphthalene-2,2 '-diphenol inclusion complex crystal seed is cooled to 40～50 ℃ then again; Separate out solid obtain the S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol inclusion complex;
B) handle the inclusion complex that obtains in a) step with the aqueous solution of Pottasium Hydroxide or sodium hydroxide and isopropyl acetate or methylene dichloride, obtain being dissolved in the S-omeprazole freebase in the water layer;
C) water layer use Hydrogen chloride accent pH is 6.5～7.0, uses dichloromethane extraction;
D) organic phase underpressure distillation adds Pottasium Hydroxide that contains methyl alcohol or the potassium methylate that contains methyl alcohol in the distillment, filter to obtain S-omeprazole sylvite;
E) with d) in obtain S-omeprazole sylvite and be dissolved in methyl alcohol, add the methanol solution of magnesium chloride or sal epsom, filter, concentrate if needed, add water and acetone in the filtrating, filter, drying obtains S-magnesium salt of omeprazole duohydrate crystal form A.
Preparing method's beneficial effect of S-omeprazole of the present invention and salt thereof is mainly reflected in: the ee value that obtains S-omeprazole and salt thereof is high; Greater than 99.2%, and the color of the S-omeprazole that obtains is off-white color, and yield is high; Environmental pollution is little, suitability for industrialized production.
(4) embodiment
Below in conjunction with specific embodiment the present invention is described further, but protection scope of the present invention is not limited in this:
The S-magnesium salt of omeprazole duohydrate crystal form A that obtains among the following embodiment, S-magnesium salt of omeprazole duohydrate crystal form B and S-magnesium salt of omeprazole trihydrate crystal formation I, crystal formation separately are to confirm under following condition through the X-ray diffraction method:
X-ray powder diffraction one: Rigaku-D/MAX-2550PC
Power: 40kv, 250Ma
CuK α radiation, sweep limit: 3～50 ° (2 θ)
Go on foot wide: 0.02 °, 5 °/min of sweep velocity
Below embodiment in the S-omeprazole that obtains and salt thereof and S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol inclusion complex, confirm under content separately and the chemical purity condition below:
Chiral column: AD-H (250mm * 4.6mm, 5 μ m) λ=230nmflow=1.0ml/min
Moving phase: normal hexane: Virahol: triethylamine: Glacial acetic acid min. 99.5=85: 15: 0.15: 0.05 (v/v/v/v)
Post: C8 (150mm * 4.6mm, 5 μ m) λ=220nm flow=1.0ml/min
Moving phase: acetonitrile: Ph7.6 10mmol/l Na
2HPO
4=27: 73 (v/v)
Embodiment 1:S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2, the preparation of 2 '-diphenol inclusion complex
(S)-(-)-1 of 249g (0.87mol), 1 '-dinaphthalene-2,2 '-diphenol are dissolved in the 3L toluene, under 80 ℃; In this solution, add 300g (0.87mol) omeprazole, dissolving back time 15min internal cooling to 65 ℃, add 9g S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2; 2 '-diphenol inclusion complex crystal seed is reduced to 45 ℃ then in the 20min, separate out solid; Filter, toluene wash, drying obtain the off-white color crystal.(261.5g, yield 92%, ee value 98.5%)
Embodiment 2:S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2, the preparation of 2 '-diphenol inclusion complex
(S)-(-)-1 of 249g (0.87mol), 1 '-dinaphthalene-2,2 '-diphenol are dissolved in the 3L toluene, under 70 ℃; In this solution, add 300g (0.87mol) omeprazole, dissolving back time 15min internal cooling to 60 ℃, add 9g S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2; 2 '-diphenol inclusion complex crystal seed is reduced to 40 ℃ then in the 20min, separate out solid; Filter, toluene wash, drying obtain the off-white color crystal.(253g, yield 90%, ee value 98.2%)
The preparation of embodiment 3:S-magnesium salt of omeprazole
48.6g (0.87mol) Pottasium Hydroxide is dissolved in the 1.5L water, is configured to potassium hydroxide solution, 300g (0.485mol) the S-omeprazole that adds then with (S)-(-)-1,1 '-dinaphthalene-2; 2 '-diphenol inclusion complex (pressing the method preparation of embodiment 1 or 2) adds isopropyl acetate 1.3L, isolates water layer, and water layer extracts with isopropyl acetate again; Until removing (S)-(-)-1 in the water layer, 1 '-dinaphthalene-2,2 '-diphenol adds configured in advance magnesium chloride brine (magnesium chloride hexahydrate 93.4g well in water layer; Water 240g), forms deposition, filter; Solid is used water washing, obtains wet article 202.6g, (rate of collecting of giving money as a gift is 92%).
The preparation of embodiment 4:S-magnesium salt of omeprazole
The method of pressing embodiment 3 replaces magnesium chloride brine with magnesium sulfate solution (sal epsom 49.4g, water 180g)
The preparation of embodiment 5:S-magnesium salt of omeprazole duohydrate crystal form A
According to the method for the embodiment 6 of Chinese patent notification number CN1161351C, the wet article of S-magnesium salt of omeprazole of present embodiment 3 preparations are converted into S-magnesium salt of omeprazole duohydrate crystal form A.
The preparation of embodiment 6:S-magnesium salt of omeprazole duohydrate crystal form B
According to the method for the embodiment 5 of Chinese patent notification number CN1161351C, the wet article of S-magnesium salt of omeprazole of present embodiment 3 preparations are converted into S-magnesium salt of omeprazole duohydrate crystal form B.
The preparation of embodiment 7:S-magnesium salt of omeprazole trihydrate crystal formation I
According to the method for the embodiment 1 of Chinese patent notification number CN1161351C, the wet article of S-magnesium salt of omeprazole of present embodiment 3 preparations are converted into S-magnesium salt of omeprazole trihydrate crystal formation I.
The preparation of embodiment 8:S-omeprazole sylvite
48.6g (0.87mol) Pottasium Hydroxide is dissolved in the 1.5L water, is configured to potassium hydroxide solution, 300g (0.485mol) the S-omeprazole that adds then with (S)-(-)-1,1 '-dinaphthalene-2; 2 '-diphenol inclusion complex adds isopropyl acetate 1.3L extraction, and water layer is again with the isopropyl acetate extraction, until removing (S)-(-)-1 in the water layer; 1 '-dinaphthalene-2,2 '-diphenol adds Hydrogen chloride in water layer, and transferring pH is 6.5～7.0; The 2L that adds methylene chloride extraction, and then methylene dichloride 1.6L extraction, the organic phase underpressure distillation adds methanolic potassium hydroxide solution (26.7g Pottasium Hydroxide in the residue; 710g methyl alcohol), stirred 1 hour, be cooled to 5 ℃ and stir 30min again; Filter, obtain 158g (yield 85%, ee value 99.2%).
The preparation of embodiment 9:S-magnesium salt of omeprazole duohydrate crystal form A
500g (1.3mol) S-omeprazole sylvite (by the method preparation of embodiment 9) is dissolved in the 566g methyl alcohol, adds magnesium chloride methanol solution (magnesium chloride hexahydrate 128.5g, methyl alcohol 425g); Stirred 2 hours, and filtered, filter cake is used the 170g methanol wash; Filtrate decompression is distilled to small volume, adds 857g water and 2090g acetone in the residue, stirs 1 hour; Be cooled to 0～5 ℃ of restir 1 hour, and filtered, filter cake is washed with acetone; The dry S-magnesium salt of omeprazole duohydrate crystal form A 421g (yield 80%, ee value 99.5%) that gets.
The preparation of embodiment 10:S-magnesium salt of omeprazole duohydrate crystal form A
The method of pressing embodiment 9 replaces magnesium chloride brine with sal epsom methanol solution (magnesium chloride 102g, methyl alcohol 350g)
Claims (9)
1. the method for preparing S-omeprazole or its salt is characterized in that described method comprises:
A) with (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol is dissolved in toluene, under 70～80 ℃ of temperature, adds racemic omeprazole; When being cooled to 60～70 ℃ after the dissolving, add the S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2; 2 '-diphenol inclusion complex crystal seed is cooled to 40～50 ℃ then again, separate out solid obtain the S-omeprazole with (S)-1; 1 '-dinaphthalene-2,2 '-diphenol inclusion complex, the cooling rate of described twice cooling all is 0.5～1 ℃/min;
B) handle the inclusion complex that obtains in a) step with alkali-metal hydroxide aqueous solution with water unmixing or almost immiscible organic solvent, obtain the form of S-omeprazole freebase or its salt;
C) if what obtain is S-omeprazole freebase form, randomly, be translated into the form of its salt.
2. method according to claim 1, it is characterized in that a) omeprazole described in the step with (S)-(-)-1,1 '-dinaphthalene-2, the mol ratio of 2 '-diphenol is 1: 0.8～1.2.
3. method according to claim 2, it is characterized in that a) omeprazole described in the step with (S)-(-)-1,1 '-dinaphthalene-2, the mol ratio of 2 '-diphenol is 1: 1.
4. method according to claim 1 is characterized in that b) step described in alkali-metal oxyhydroxide be Pottasium Hydroxide or sodium hydroxide.
5. method according to claim 1 is characterized in that b) step described in water unmixing or almost immiscible organic solvent be toluene, YLENE, methylene dichloride, 1,2-ethylene dichloride, ETHYLE ACETATE or isopropyl acetate.
6. according to any described method of claim 1～5, the salt that it is characterized in that preparing the S-omeprazole is through handling with the salt of basic metal or earth alkali metal and directly from reaction medium, obtaining.
7. method according to claim 6, the salt that it is characterized in that described basic metal or earth alkali metal is magnesium chloride or sal epsom.
8. according to any one or 7 described methods in the claim 1～5, the salt of the S-omeprazole for preparing is magnesium salts, and described magnesium salts is a S-magnesium salt of omeprazole duohydrate crystal form A, S-magnesium salt of omeprazole duohydrate crystal form B.
9. the method for preparing S-magnesium salt of omeprazole duohydrate crystal form A is characterized in that described method comprises:
A) with (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol is dissolved in toluene; Under 80 ℃ of temperature, add racemic omeprazole, during dissolving back fast cooling to 65 ℃, add the S-omeprazole with (S)-(-)-1; 1 '-dinaphthalene-2,2 '-diphenol inclusion complex crystal seed, fast cooling to 45 ℃ again then; Separate out solid obtain the S-omeprazole with (S)-(-)-1,1 '-dinaphthalene-2,2 '-diphenol inclusion complex;
B) handle the inclusion complex that obtains in a) step with potassium hydroxide aqueous solution and isopropyl acetate or methylene dichloride, obtain being dissolved in the S-omeprazole freebase in the water layer;
C) water layer use Hydrogen chloride accent pH is 6.5～7.0, uses dichloromethane extraction;
D) organic phase underpressure distillation adds Pottasium Hydroxide that contains methyl alcohol or the potassium methylate that contains methyl alcohol in the residue, filter to obtain S-omeprazole sylvite;
E) with d) in obtain S-omeprazole sylvite and be dissolved in methyl alcohol, add the methanol solution of magnesium chloride or sal epsom, filter, filtrating concentrates if needed, adds water and acetone in the filtrating, filters, drying obtains S-magnesium salt of omeprazole duohydrate crystal form A.
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| EP2499125B1 (en) * | 2009-11-12 | 2016-01-27 | Hetero Research Foundation | Process for the resolution of omeprazole |
| CN102241668B (en) * | 2010-05-11 | 2015-11-25 | 中国科学院成都有机化学有限公司 | Esomprazole salt |
| WO2011144994A1 (en) * | 2010-05-21 | 2011-11-24 | Lupin Limited | Pharmaceutical compositions of nsaid and acid inhibitor |
| CN102924435B (en) * | 2011-11-25 | 2014-06-25 | 成都自豪药业有限公司 | Novel crystal form of S-omeprazole magnesium salt and preparing method thereof |
| CN102898418B (en) * | 2012-08-28 | 2014-03-12 | 南京优科制药有限公司 | Preparation method of esomeprazole magnesium |
| CN103467453A (en) * | 2013-09-13 | 2013-12-25 | 上海海虹实业(集团)巢湖今辰药业有限公司 | Preparation method of omeprazole magnesium crude medicine |
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