CN103288801A - Preparation method for high-purity esomeprazole sodium - Google Patents
Preparation method for high-purity esomeprazole sodium Download PDFInfo
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- CN103288801A CN103288801A CN201310217944XA CN201310217944A CN103288801A CN 103288801 A CN103288801 A CN 103288801A CN 201310217944X A CN201310217944X A CN 201310217944XA CN 201310217944 A CN201310217944 A CN 201310217944A CN 103288801 A CN103288801 A CN 103288801A
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- esomeprazole
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Abstract
The invention discloses a preparation method for high-purity esomeprazole sodium. The preparation method comprises the steps of: including and splitting esomeprazole sodium and D-(-)-diethyl tartrate, titanium iso-propylate, triethylamine and L-(+)-mandelic acid in the presence of a proper amount of water, and separating to obtain an inclusion complex; dissolving the inclusion complex with ethyl acetate, washing inclusion complex with sodium carbonate water solution, carrying out ammonia hydroxide eluting on an ethyl acetate layer, slowly regulating the pH value to 6-7 with glacial acetic acid, then extracting with dichloromethane, and concentrating to obtain crude esomeprazole free alkali product; carrying out silica gel adsorption and elution on the crude product to obtain a pure esomeprazole free alkali product; and enabling the pure product and the methanol-ethanol-acetonitrile solution of sodium hydroxide to form salt, and then crystallizing with isopropyl ether to obtain the high-purity esomeprazole sodium. According to the preparation method, the difficulties that when inclusion and splitting are carried out, the titanium complex suspension body are difficult to split and the ammonia complex of titanium is difficult to remove can be solved, the industrialization production can be realized, the industrialized production cost is low, the product purity is high, the yield is high, and no harmful gas is generated.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to a kind of preparation method of high purity esomeprazole sodium.
Background technology
Esomeprazole sodium (Esomeprazole sodium, C
17H
18N
3NaO
3S), be the S-optically active isomer of omeprazole, be global first isomer proton pump inhibitor (PPI), suppress the parietal cell proton pump by specificity and reduce gastric acid secretion.Confirm through a large amount of clinical experiments and drug research: it keeps pH in the stomach〉time of 4 is longer, and it is higher to press down sour efficient, and curative effect is better than preceding two generation PPI, and individual difference is little.As PPI of new generation, the many acid related disorders of clinical treatment now have been widely used in.
Inclusion is split as the chiral drug resolution method that grows up this year, it occurs titanium complexing suspended matter easily and early produces and influence fractionation effect when producing, we have carried out number of research projects, its complex compound all early occurs and the fractionation poor effect, in the free alkali purifying crude of esomeprazole process, the residual quantity of titanium is big in the product, color is yellow partially, and the finished product optical purity is low, yield is low.
The preparation of esomeprazole sodium at present has two kinds of methods, wherein a kind of method is that Omeprazole Sodium exists down with organic titanium/organic vanadium and resolving agent, get the esomeprazole inclusion complex, inclusion complex is through free, salify and refining esomeprazole sodium finished product, but the residual quantity of its titanium is big, color is yellow partially, and the finished product optical purity is low, yield is low; We are through research, surprised discovery inclusion split in the undue process add suitable quantity of water and by silica gel or carclazyte then the finished product be that the titanium residual quantity is low, color is white, optical purity is high, yield is high.
Summary of the invention
The objective of the invention is to occur titanium complex suspendible body easily when existing inclusion to split in the prior art and split the deficiency that the ammonia complex difficulty of difficulty, titanium is removed, a kind of preparation method of industrialized high purity esomeprazole sodium is provided.Do not have in the preparation method's of the present invention the finished product that titanium is residual, color is whiter, optical purity of products height, yield height.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
A kind of preparation method of high purity esomeprazole sodium may further comprise the steps:
A, omeprazole sodium salt is added in organic alcohol, omeprazole sodium salt weight and organic pure volume ratio are 1:5～25, stir down to add water, and the weight ratio of water and Omeprazole Sodium is 0.02～0.2, are stirred to solution under the room temperature and clarify;
B, add in the solution of steps A with the omeprazole sodium salt mol ratio be 1:0.8～1.2 D-(-)-diethyl tartrate, with the omeprazole sodium salt mol ratio be the tetraisopropoxy titanium of 1:0.4～1.1, and in 5～30 minutes, add with the omeprazole sodium salt weightmeasurement ratio be 1:0.6～2 triethylamine, with the omeprazole sodium salt mol ratio be L-(+)-amygdalic acid of 1:0.8～2, at 40 ℃ to reflux conditions, reacting by heating 2～4 hours, filter white inclusion complex compound solid;
C, the inclusion complex compound that step B is obtained are dissolved in the ethyl acetate, omeprazole sodium salt weight and ethyl acetate volume ratio are 1:1～20, after inorganic acid salt solution washing, the ethyl acetate layer ammonia scrubbing, gained ammoniacal liquor layer under-5～30 ℃ of temperature with glacial acetic acid slow adjust pH after slightly acidic, use dichloromethane extraction, dichloromethane extraction is through being concentrated into dried esomeprazole free alkali crude product;
D, the esomeprazole free alkali crude product that step C is obtained are dissolved in the ethyl acetate, omeprazole sodium salt weight and ethyl acetate volume ratio are 1:0.5～4), adding with the omeprazole sodium salt weight ratio is that the sorbent material of 1:0.05～1 stirs after-filtration, and filtrate is concentrated into dried the pure product of esomeprazole free alkali;
Behind E, the pure product of esomeprazole free alkali and sodium hydroxide, the organic solvent solution salify, use the isopropyl ether crystallization, make required high purity esomeprazole sodium.
As optimal way, the organic alcohol described in the steps A is C
1～C
8Alkyl alcohol.
As optimal way, the water additional proportion described in the steps A and Omeprazole Sodium weight ratio are 0.05～0.1.
As optimal way, the triethylamine described in the step B, L-(+)-amygdalic acid time of adding are 5～10 minutes.
As optimal way, the reacting by heating time described in the step B is 3.5～4 hours.
As optimal way, the inorganic acid salt described in the step C is selected from one or more in supercarbonate, dihydrogen phosphate, disodium EDTA or the hydrosulphite.
As optimal way, the slightly acidic described in the step C is pH value 6～7.
As optimal way, the organic solvent described in the step e is selected from two or more of ethanol, methyl alcohol, acetonitrile or isopropyl ether.
As optimal way, the sorbent material described in the step e is silica gel or carclazyte.
As optimal way, the sodium hydroxide dosage described in the step e is and omeprazole sodium salt mol ratio 1:0.9～2 that the organic solvent dosage is and omeprazole sodium salt weightmeasurement ratio 1:1～8.
Grope in the process in early-stage Study of the present invention, the contriver has carried out lot of experiments to the solvent species used in the inclusion Split Method, add-on, addition sequence etc., the result all exists D-(-)-diethyl tartrate, tetraisopropoxy titanium and triethylamine namely to produce a large amount of titanium suspended matters in mixing within back 2 minutes, adds the purpose that can't reach fractionation behind L-(+)-amygdalic acid.Through experiment many times, the discovery that we are surprised, after being 0.02～0.2 water and the solution that added triethylamine and L-(+)-amygdalic acid in 5～30 minutes, the weight ratio of adding and Omeprazole Sodium just can realize splitting purpose, and can realize preparation of industrialization, and the finished product chiral purity reaches more than 99.9%, chemical purity reaches more than 99.9% the yield height.
Simultaneously, in the free alkali purifying crude of esomeprazole research process, the residual quantity of titanium is big in the currently available products, product colour is yellow partially.Through experiment many times, the discovery that the contriver is surprised, have only add 5% silica gel or carclazyte after, no longer include in the finished product that titanium is residual, product colour is whiter.
Beneficial effect of the present invention is:
Preparation method of the present invention has solved and has occurred titanium complex suspendible body easily when inclusion splits and split difficulty, and the difficult problem removed of the ammonia complex difficulty of titanium, can realize suitability for industrialized production, and industrial production cost is low, and product purity height, yield height do not produce obnoxious flavour.
Embodiment
Disclosed all features in this specification sheets, or the step in disclosed all methods or the process except mutually exclusive feature and/or step, all can make up by any way.
Comparative Examples: a kind of preparation method of high purity esomeprazole sodium may further comprise the steps:
With the 1kg Omeprazole Sodium, add in the 10L n-propyl alcohol under stirring, be stirred to the solution clarification, add D-(-)-diethyl tartrate 0.4L, tetraisopropoxy titanium 0.4L, triethylamine 1L then successively, L-(+)-amygdalic acid 0.5kg, in 50 ℃ of following reaction 2h, filter white solid.
White solid and 5L saturated sodium bicarbonate aqueous solution are added in the 5L ethyl acetate, stir 0.5h, water layer is used the back extraction of 2L ethyl acetate once, and the combined ethyl acetate layer is also used saturated sodium bicarbonate aqueous solution 1L*2,1L water washing successively; Collect ethyl acetate layer, add 12.5% ammoniacal liquor 3.5L, stir 20min, leave standstill separatory, ethyl acetate layer washs with 12.5% ammoniacal liquor 1Lx2, merges the ammoniacal liquor layer; The ammoniacal liquor layer is added in the 5L methylene dichloride, with the slow adjust pH to 6 of glacial acetic acid～7, leave standstill separatory under 0 ℃, water layer extracts with methylene dichloride 10L*2, the combined dichloromethane layer also is evaporated to driedly, gets 250g purple oily matter (esomeprazole free alkali), yield 53.2%.
250g esomeprazole free alkali is added in the mixed solvent of 250mL ethanol, 125mL methyl alcohol, 1L acetonitrile, add 30g sodium hydroxide then and be stirred to solid molten entirely, add the 750mL isopropyl ether again, stir the 1h after-filtration, filter cake is with mixed solution washing (ethanol: methyl alcohol: acetonitrile: isopropyl ether=1:0.5:4:3) twice, each 80mL; Merging filtrate, stir and in filtrate, slowly add the 2.5L isopropyl ether down, under ice bath, stirred 2 hours again after 10 hours in 20 ℃～30 ℃ stirrings, filter drying, get the 165.8g white solid, total recovery 33.2%, specific rotatory power+43.7 °, chiral purity 96.43%, chemical pure 97.82%, titanium residual quantity: 986ppm.
Embodiment 1: a kind of preparation method of high purity esomeprazole sodium may further comprise the steps:
0.5L water is added in the 160L n-propyl alcohol, stir and add the 10kg Omeprazole Sodium down, be stirred to the solution clarification, add D-(-)-diethyl tartrate 4.6L, tetraisopropoxy titanium 4.05L, triethylamine 11.3L then successively, L-(+)-amygdalic acid 6.13kg, in 40 ℃ of following reaction 3.5h, filter white solid.
White solid and 60L saturated sodium bicarbonate aqueous solution are added in the 60L ethyl acetate, stir 0.5h, water layer is used the back extraction of 20L ethyl acetate once, and the combined ethyl acetate layer is also used saturated sodium bicarbonate aqueous solution 15L*2,10L water washing successively; Collect ethyl acetate layer, add 12.5% ammoniacal liquor 40L, stir 20min, leave standstill separatory, ethyl acetate layer washs with 12.5% ammoniacal liquor 10Lx2, merges the ammoniacal liquor layer; The ammoniacal liquor layer is added in the 60L methylene dichloride, under 0 ℃ with the slow adjust pH to 6 of glacial acetic acid～7, leave standstill separatory, water layer extracts with methylene dichloride 10L*2, and the combined dichloromethane layer also is evaporated to dried, enriched material adds in 20L ethyl acetate, the 0.5kg silica gel, stirred 30 minutes, and filtered, filtrate decompression is concentrated into dried, get 3.6kg lavender oily matter (esomeprazole free alkali), yield 76.6%.
3.6kg esomeprazole free alkali is added in the mixed solvent of 3.6L ethanol, 1.8L methyl alcohol, 14.4L acetonitrile, add 0.58kg sodium hydroxide then and be stirred to solid molten entirely, add the 10.8L isopropyl ether again, stir the 1h after-filtration, filter cake is with mixed solution washing (ethanol: methyl alcohol: acetonitrile: isopropyl ether=1:0.5:4:3) twice, each 1L; Merging filtrate, stir and in filtrate, slowly add the 36L isopropyl ether down, under ice bath, stirred 2 hours again after 10 hours in 20 ℃～30 ℃ stirrings, filter drying, get the 3.3kg white solid, total recovery 66%, specific rotatory power+46 °, chiral purity 99.94%, chemical pure 99.92%, titanium residual quantity: do not detect.
Embodiment 2: a kind of preparation method of high purity esomeprazole sodium may further comprise the steps:
0.5L water is added in the 150L n-propyl alcohol, stir and add the 10kg Omeprazole Sodium down, be stirred to the solution clarification, add D-(-)-diethyl tartrate 4.6L, tetraisopropoxy titanium 4.05L, triethylamine 11.3L then successively, L-(+)-amygdalic acid 6.13kg, in 40 ℃ of following reaction 3.5h, filter white solid.
White solid and 60L saturated sodium bicarbonate aqueous solution are added in the 60L ethyl acetate, stir 0.5h, water layer is used the back extraction of 20L ethyl acetate once, and the combined ethyl acetate layer is also used saturated sodium bicarbonate aqueous solution 15L*2,10L water washing successively; Collect ethyl acetate layer, add 12.5% ammoniacal liquor 40L, stir 20min, leave standstill separatory, ethyl acetate layer washs with 12.5% ammoniacal liquor 10Lx2, merges the ammoniacal liquor layer; The ammoniacal liquor layer is added in the 60L methylene dichloride, under 0 ℃ with the slow adjust pH to 6 of glacial acetic acid～7, leave standstill separatory, water layer extracts with methylene dichloride 8L*2, and the combined dichloromethane layer also is evaporated to dried, enriched material adds in 15L ethyl acetate, the 1.0kg silica gel, stirred 30 minutes, and filtered, filtrate decompression is concentrated into dried, get 3.2kg lavender oily matter (esomeprazole free alkali), yield 68.1%.
3.2kg esomeprazole free alkali is added in the mixed solvent of 3.2L ethanol, 1.6L methyl alcohol, 12.8L acetonitrile, add 0.5kg sodium hydroxide then and be stirred to solid molten entirely, add the 9.6L isopropyl ether again, stir the 1h after-filtration, filter cake is with mixed solution washing (ethanol: methyl alcohol: acetonitrile: isopropyl ether=1:0.5:4:3) twice, each 1L; Merging filtrate, stir and in filtrate, slowly add the 32L isopropyl ether down, under ice bath, stirred 2 hours again after 10 hours in 20 ℃～30 ℃ stirrings, filter drying, get the 2.7kg white solid, total recovery 54%, specific rotatory power+45.8 °, chiral purity 99.13%, chemical pure 99.72%, titanium residual quantity: do not detect.
Can find out obviously that from above-mentioned data product parameters such as the esomeprazole sodium yield, purity of preparation are all far above Comparative Examples in the embodiment of the invention 1,2, and it is residual not detect titanium, and product colour is white, has improved quality product significantly.
Simultaneously, the change of every processing parameter of preparation method of the present invention all can produce directly influence to the finished product, and the selection of any parameter is not random.
Claims (10)
1. the preparation method of a high purity esomeprazole sodium is characterized in that may further comprise the steps:
A, omeprazole sodium salt is added in organic alcohol, omeprazole sodium salt weight and organic pure volume ratio are 1:5～25, stir down to add water, and the weight ratio of water and Omeprazole Sodium is 0.02～0.2, are stirred to solution under the room temperature and clarify;
B, add in the solution of steps A with the omeprazole sodium salt mol ratio be 1:0.8～1.2 D-(-)-diethyl tartrate, with the omeprazole sodium salt mol ratio be the tetraisopropoxy titanium of 1:0.4～1.1, and in 5～30 minutes, add with the omeprazole sodium salt weightmeasurement ratio be 1:0.6～2 triethylamine, with the omeprazole sodium salt mol ratio be L-(+)-amygdalic acid of 1:0.8～2, at 40 ℃ to reflux conditions, reacting by heating 2～4 hours, filter white inclusion complex compound solid;
C, the inclusion complex compound that step B is obtained are dissolved in the ethyl acetate, omeprazole sodium salt weight and ethyl acetate volume ratio are 1:1～20, after inorganic acid salt solution washing, the ethyl acetate layer ammonia scrubbing, gained ammoniacal liquor layer under-5～30 ℃ of temperature with glacial acetic acid slow adjust pH after slightly acidic, use dichloromethane extraction, dichloromethane extraction is through being concentrated into dried esomeprazole free alkali crude product;
D, the esomeprazole free alkali crude product that step C is obtained are dissolved in the ethyl acetate, omeprazole sodium salt weight and ethyl acetate volume ratio are 1:0.5～4), adding with the omeprazole sodium salt weight ratio is that the sorbent material of 1:0.05～1 stirs after-filtration, and filtrate is concentrated into dried the pure product of esomeprazole free alkali;
Behind E, the pure product of esomeprazole free alkali and sodium hydroxide, the organic solvent solution salify, use the isopropyl ether crystallization, make required high purity esomeprazole sodium.
2. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the organic alcohol described in the steps A is C
1～C
8Alkyl alcohol.
3. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the water additional proportion described in the steps A and Omeprazole Sodium weight ratio are 0.05～0.1.
4. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the triethylamine described in the step B, L-(+)-amygdalic acid time of adding are 5～10 minutes.
5. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the reacting by heating time described in the step B is 3.5～4 hours.
6. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the inorganic acid salt described in the step C is selected from one or more in supercarbonate, dihydrogen phosphate, disodium EDTA or the hydrosulphite.
7. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the slightly acidic described in the step C is pH value 6～7.
8. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the organic solvent described in the step e is selected from two or more of ethanol, methyl alcohol, acetonitrile or isopropyl ether.
9. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the sorbent material described in the step e is silica gel or carclazyte.
10. the preparation method of a kind of high purity esomeprazole sodium as claimed in claim 1, it is characterized in that: the sodium hydroxide dosage described in the step e is and omeprazole sodium salt mol ratio 1:0.9～2 that the organic solvent dosage is and omeprazole sodium salt weightmeasurement ratio 1:1～8.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570687A (en) * | 2013-11-15 | 2014-02-12 | 悦康药业集团有限公司 | Crystalline compound of omeprazole sodium |
| CN104926791A (en) * | 2015-07-02 | 2015-09-23 | 山东金诃药物研究开发有限公司 | Preparation method of esomeprazole sodium |
| CN105669648A (en) * | 2014-11-21 | 2016-06-15 | 北大方正集团有限公司 | Preparation method of high-purity esomeprazole sodium |
| CN107698515A (en) * | 2017-09-07 | 2018-02-16 | 拉萨泰达医药科技有限公司 | A kind of preparation method of benzimidazole complex compound |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2616663A (en) * | 2022-03-18 | 2023-09-20 | Alkaloid Ad Skopje | Pharmaceutical formulation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993184A (en) * | 2013-01-08 | 2013-03-27 | 湖南方盛制药股份有限公司 | Esomeprazole and preparation method of magnesium trihydrate of esomeprazole |
-
2013
- 2013-06-04 CN CN201310217944.XA patent/CN103288801B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993184A (en) * | 2013-01-08 | 2013-03-27 | 湖南方盛制药股份有限公司 | Esomeprazole and preparation method of magnesium trihydrate of esomeprazole |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570687A (en) * | 2013-11-15 | 2014-02-12 | 悦康药业集团有限公司 | Crystalline compound of omeprazole sodium |
| CN105669648A (en) * | 2014-11-21 | 2016-06-15 | 北大方正集团有限公司 | Preparation method of high-purity esomeprazole sodium |
| CN104926791A (en) * | 2015-07-02 | 2015-09-23 | 山东金诃药物研究开发有限公司 | Preparation method of esomeprazole sodium |
| CN107698515A (en) * | 2017-09-07 | 2018-02-16 | 拉萨泰达医药科技有限公司 | A kind of preparation method of benzimidazole complex compound |
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