CN103044402B - Method for synthesizing esomeprazole sodium - Google Patents
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- 229960000496 esomeprazole sodium Drugs 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 16
- RYXPMWYHEBGTRV-JIDHJSLPSA-N sodium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide Chemical compound [Na+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C RYXPMWYHEBGTRV-JIDHJSLPSA-N 0.000 title claims abstract 17
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000003756 stirring Methods 0.000 claims abstract description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000012043 crude product Substances 0.000 claims abstract description 27
- 238000005406 washing Methods 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 238000001291 vacuum drying Methods 0.000 claims abstract description 12
- 229940043279 diisopropylamine Drugs 0.000 claims abstract description 10
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 claims abstract description 9
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 100
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 17
- 238000000605 extraction Methods 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 13
- 239000012065 filter cake Substances 0.000 claims description 13
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 9
- 239000008367 deionised water Substances 0.000 claims description 9
- 229910021641 deionized water Inorganic materials 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 238000003809 water extraction Methods 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 8
- 238000007670 refining Methods 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 150000003568 thioethers Chemical class 0.000 abstract 2
- FUHSFUQMWWYWSZ-UHFFFAOYSA-N 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-yl)-1-methylsulfanylbenzimidazole Chemical compound N=1C2=CC(OC)=CC=C2N(SC)C=1C1=NC=C(C)C(OC)=C1C FUHSFUQMWWYWSZ-UHFFFAOYSA-N 0.000 abstract 1
- YQHLDYVWEZKEOX-UHFFFAOYSA-N cumene hydroperoxide Chemical compound OOC(C)(C)C1=CC=CC=C1 YQHLDYVWEZKEOX-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 229960004770 esomeprazole Drugs 0.000 description 8
- 238000009835 boiling Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229960000381 omeprazole Drugs 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- LCJDHJOUOJSJGS-UHFFFAOYSA-N 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridin-1-ium;chloride Chemical compound Cl.COC1=C(C)C=NC(CCl)=C1C LCJDHJOUOJSJGS-UHFFFAOYSA-N 0.000 description 2
- KOFBRZWVWJCLGM-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazole-2-thione Chemical compound COC1=CC=C2NC(S)=NC2=C1 KOFBRZWVWJCLGM-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- RBSRVLAVTIXANZ-UHFFFAOYSA-N 1-hydroxy-2-methylpent-1-en-3-one Chemical compound CCC(=O)C(C)=CO RBSRVLAVTIXANZ-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing esomeprazole sodium. The method comprises the steps as follows: preparing 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole, namely prochirality thioether; preparing crude esomeprazole sodium; refining the crude esomeprazole sodium; adding the prepared prochirality thioether and dried methylbenzene into D-(-) diethyl tartrate and water by stirring, adding titanium isopropylate, and stirring; and adding diisopropylamine at constant temperature, stirring, dropwise adding cumyl hydroperoxide with the mass concentration of 80%, ending the reaction, extracting, salifying, concentrating, washing and carrying out vacuum drying to obtain a crude product, and refining the crude product to obtain the esomeprazole sodium. The method is low in cost, toxicity and pollution, easy to operate, short in reaction time, high in product purity and easy for industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, refer in particular to Esomeprazole sodium synthesis production method.
Background technology
Omeprazole is by the one novel proton pump inhibitor class anti-ulcerative drug of Astra Pharma Inc. of Sweden in listing in 1988; omeprazole is the mixture of R type and S type two kinds of optical isomer 1:1; and its S optically active isomer; i.e. S-5-methoxyl group-2-{ [(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline, be namely esomeprazole.
The structural formula of Esomeprazole sodium is as follows:
Molecular formula: C
17h
18n
3naO
3s, molecular weight: 367.4.
Esomeprazole sodium is global first isomer proton pump inhibitor (PPI), and reducing gastric acid secretion by specific targeting mechanism, is the specific inhibitor of proton pump in parietal cell.A new generation's injection PPI Esomeprazole sodium, because having the pharmacokinetic characteristics of uniqueness, its suppress the more oral esomeprazole of sour ability and other injection PPI sooner, more effective.Need to use PPI but cannot the patient of oral administration for clinical, as acute hemorrhage of upper gastrointestinal tract and stress ulcer etc., injection Esomeprazole sodium can provide potent acid suppression and comprehensively protection.Injection Esomeprazole sodium and on March 31st, 2005 are ratified the prescription drugs being used as to treat short-term gastroesophageal reflux disease by FDA.
In prior art, the synthetic method of esomeprazole, by different raw materials and route, is mainly divided into asymmetric oxidation method and Split Method two kinds.Asymmetric oxidation method is divided into by starting raw material difference: 1, be starting raw material with acetaldehyde; 2, with 2-methyl-acetoacetic ester for raw material; 3, with 1-hydroxy-2-methyl-1-penten-3-one for raw material.Split Method mainly from the omeprazole of preparation through inclusion resolution, or divide through simulated moving bed chromatography separation and obtain esomeprazole.In existing synthetic route, there is raw materials cost high, and material toxicity is comparatively large, the defects such as operational condition is severe.Due to esomeprazole poor stability, place very easily by the catalyzed oxidation such as oxygen, illumination for a long time, therefore yield is low, purity is low, cannot reach other requirement of pharmaceutical grade, and long reaction time, not easily industry's enlarging production.
Summary of the invention
In order to overcome defect of the prior art, the object of the present invention is to provide that a kind of product yield is high, purity is high, the reaction times is short and toxicity is low, the Esomeprazole sodium of energy-conserving and environment-protective synthesis production method.
The invention provides a kind of Esomeprazole sodium synthesis production method based on above-mentioned purpose, its reaction principle is:
The synthesis production method of Esomeprazole sodium provided by the invention, comprises the steps:
(A) 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline is prepared;
(B) by prepared 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline toluene dissolves, add D-(-) diethyl tartrate, water, titanium isopropylate and diisopropylamine, form chiral catalytic system; Add hydrogen phosphide cumene again and carry out chiral oxidization reaction; Add sodium hydroxide after reaction terminates, obtain Esomeprazole sodium crude product;
(C) the Esomeprazole sodium crude product of said process gained is refined.
Further, in (B) step, the temperature of above-mentioned chiral oxidization reaction is 20-30 DEG C; The mass concentration of the hydrogen phosphide cumene added is 80%, and the reaction times is 1 hour-5 hours.
Further, in (B) step, the temperature of chiral oxidization reaction is 25 ± 2 DEG C.
Further, in (B) step, the reaction times is 2.5 hours-3.5 hours.
Further, in (B) step, the ratio adding the amount of hydrogen phosphide cumene and the molar weight of 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline is 0.8:1 ~ 1:1.
Further, also comprise: in (C) step by Esomeprazole sodium dissolving crude product in dehydrated alcohol, add after activated carbon decolorizing filters, filtrate concentrates evaporate to dryness, and adds acetone to this system or ethyl acetate stirs and filters; Again with acetone or ethyl acetate drip washing filter cake and crude product, preferably use ethyl acetate drip washing filter cake and crude product, obtain the Esomeprazole sodium refined thus.
Preparation 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline (also known as pro-chiral sulphide or intermediate in presents) concrete steps are:
(I) by after 2-chloromethyl-3,5 dimethyl-4-methoxypyridine hydrochloride, methyl alcohol (boiling point 64.7 DEG C) stirring and dissolving, the clarification of solution yellow, adds sodium hydroxide and the aqueous solution, and settled solution becomes muddy.Then 2-sulfydryl-5-methoxybenzimidazol is added.
(II), after temperature rising reflux, drip and the sodium hydroxide of step (I) identical amount and the aqueous solution (darkening).After dropwising, keep backflow.
(III) cooling suction filtration, filtrate decompression is distilled, and removes about part methyl alcohol, then uses water and dichloromethane extraction.Water layer again with dichloromethane extraction once.Combined dichloromethane layer, washing, then with after saturated common salt washing, dry, suction filtration, uses washed with dichloromethane filter cake.
(IV) underpressure distillation, removes methylene dichloride, obtains oily matter.Oily matter acetonitrile (boiling point 81.1 DEG C) reflux, naturally cooling stirred crystallization, suction filtration, with acetonitrile wash filter cake or filter residue, dry, obtain white or off-white color product.
The concrete steps preparing Esomeprazole sodium crude product are:
(I) by 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline and dry toluene stirring and dissolving, heat up, add D-(-) diethyl tartrate and water, stir, more slowly add titanium isopropylate, continue to stir;
(II) above-mentioned reaction solution is cooled to 20-30 DEG C, constant temperature adds diisopropylamine, stirs, and Slow Isothermal drips mass concentration 80% hydrogen phosphide cumene, and after dropwising, constant temperature stirs 1 hour-5 hours;
(III) under above-mentioned reaction solution constant temperature, add strong aqua and deionized water, stir, extraction of ammonia water layer; Use strong aqua and deionized water extraction reaction solution again, extraction of ammonia water layer, merge ammoniacal liquor layer, by toluene wash; Be placed in ice bath by the ammoniacal liquor after washing, add methylene dichloride, slowly drip glacial acetic acid, during dropping, temperature is no more than 15 DEG C, and solution ph is greater than 7, and best pH value controls between 7-8.Drip off stirring, extraction dichloromethane layer, ammoniacal liquor layer adds methylene dichloride again, extraction dichloromethane layer, combined dichloromethane layer;
(IV) add sodium hydrogen carbonate solution to dichloromethane layer, temperature controls as the temperature in (II), and stir, separatory, gets dichloromethane layer; Deionized water washing dichloromethane layer, filter after adding anhydrous sodium sulfate drying, filtrate concentrates evaporate to dryness and obtains oily matter;
(V) use dissolve with methanol oily matter, add sodium hydroxide, stirring at room temperature, activated carbon decolorizing, filter, concentrated evaporate to dryness, add 40 DEG C of hot acetones, stirring and refluxing, is down to room temperature, and filter, drip washing, vacuum-drying obtains crude product.
The detailed process of Esomeprazole sodium crude product refining is:
(I) crude product is dissolved in dehydrated alcohol, and crude product and dehydrated alcohol mass volume ratio are 1:8, and temperature 30 DEG C of-40 DEG C of stirring and dissolving, add gac, decolouring;
(II) by above-mentioned reacting liquid filtering, temperature is 45 DEG C of-50 DEG C of concentrated evaporates to dryness;
(III) in upper step gained material, add ethyl acetate or acetone, mass volume ratio is 1:8, and at 40 DEG C-50 DEG C, constant temperature stirs;
(IV) be cooled to less than 25 DEG C, filter; With acetone or ethyl acetate drip washing filter cake;
(V) 50 DEG C of vacuum-drying, obtains fine work Esomeprazole sodium.
In summary it can be seen, the beneficial effect of Esomeprazole sodium synthesis production method provided by the invention is:
1, preparing in Esomeprazole sodium crude product process, adopting Diisopropylamine to replace diisopropyl ethyl amine, not only effectively reduce production cost; And the toxicity greatly reduced in reaction process, reduce the pollution to production environment.
Furtherly, the beneficial effect that the present invention also comprises is:
2, preparing in Esomeprazole sodium crude product process, determine chiral oxidization reaction (namely dripping and drip off the reaction after 80% hydrogen phosphide cumene) temperature range 20-30 DEG C, optimum chooses 25 ± 2 DEG C, this reaction compared with prior art, easy control of temperature, do not need cold condition (the most temperature of prior art controls at 10 DEG C, even less than 0 DEG C), energy-saving and cost-reducing.
3, determine 1 hour-5 hours chiral oxidization reaction times, preferably get 2.5 hours-3.5 hours, shorten the reaction times.
4, chiral oxidization single step reaction products therefrom enantiomer-pure angle value is higher, reaches as high as 97%; And reaction yield is high, chiral oxidization reacts a step yield and reaches more than 80%.
5, by with ethyl acetate drip washing filter cake, under the prerequisite of equal quality standard-required can be met, make the yield of product higher.
6, simplify treating process operation steps, do not need recrystallization process.
7, refining to obtain product yield high, can reach more than 85%; After refining, final product quality is high, content more than 98%, enantiomer-pure angle value more than 99.5%, purity more than 99.5%.
Accompanying drawing explanation
Fig. 1 is that the embodiment of the present invention one dropwises rear maintenance backflow TLC analysis chart after 2 hours.
In figure: 1 2-sulfydryl-5-methoxybenzimidazol
2 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochlorides
3 reaction solution 4 mixed solutions (1+2+3)
embodiment
For making the object, technical solutions and advantages of the present invention clearly understand, below in conjunction with specific embodiment, the present invention is described in more detail.
Embodiment 1
After 3080g2-chloromethyl-3,5 dimethyl-4-methoxypyridine hydrochloride, 25L methyl alcohol (boiling point 64.7) stirring and dissolving (yellow clarification), add the solution of 575g sodium hydroxide and 2250ml water, settled solution becomes muddy.Then 2500g2-sulfydryl-5-methoxybenzimidazol is added.Heat up after 65 DEG C of backflows, in 15min, drip the sodium hydroxide solution (575g sodium hydroxide+2250ml water) (darkening) of identical amount again.Dropwise rear maintenance backflow after 2 hours TLC analyze (developping agent: methylene dichloride: ethyl acetate=25:1).
Be down to 25 DEG C of suction filtrations, filtrate (reddish-brown) 45 DEG C removes about 1/2 methyl alcohol (having solid to separate out) under reduced pressure, then uses 12L water and 12L methylene dichloride (boiling point 39.8) extraction.Water layer uses 8L dichloromethane extraction once again.Combined dichloromethane layer 5L washes, after the washing of 5L saturated common salt, with 2000g anhydrous sodium sulfate drying 2 hours, suction filtration, and washed with dichloromethane filter cake.Remove methylene dichloride under reduced pressure and obtain oily matter.Oily matter 10L acetonitrile (boiling point 81.1 DEG C) 85 DEG C of reflux 30min, naturally cooling stirred crystallization (is spent the night, at least 3.5 hours) suction filtration (centrifuging) afterwards, 2L acetonitrile wash filter cake (filter residue), at 30 DEG C, vacuum (air blast) dry (more than 4 hours) obtains product pro-chiral sulphide (white or off-white color, fusing point: 118 ~ 119 DEG C) 3882.8g, yield 85%(product yield=actual value/theoretical value * 100%).
First add pro-chiral sulphide 3880g prepared by said process, use 15L toluene (boiling point 110.6 again, with anhydrous sodium sulfate drying, or it is qualified to detect moisture) slow stirring and dissolving, 1500g D-(-) diethyl tartrate is added after being warming up to 50 DEG C (being as the criterion 50-55 DEG C with thermometer), add 30ml water again and stir 0.5 hour, slowly add 1010g titanium isopropylate, continue to stir 50min.
Then be cooled to 25 ± 2 DEG C, add diisopropylamine 500g and stir 5min, (during dropping, temperature controls at 25 ± 2 DEG C, and rate of addition wants slow, and 1.5 hours drip off then to drip 2050g mass concentration 80% hydrogen phosphide cumene.Drip 0.9 times that hydrogen phosphide cumene substantial amount is intermediate and 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline molar weight).Drip and finish rear 25 ± 2 DEG C of stirring reactions 3 hours, TLC per hour detects once.
Add 4L strong aqua and 4L deionized water in 25 DEG C of downhill reaction liquid, stir 30min, then extracting and demixing (lower floor is ammoniacal liquor layer).Use 8L strong aqua and 8L deionized water extraction reaction solution 2 times again.Merge ammoniacal liquor layer, 15L toluene wash once.Getting ammoniacal liquor is placed in ice bath, then adds 15L methylene dichloride, and slowly drip glacial acetic acid (about 9L), during dropping, temperature does not exceed 15 DEG C.PH regulator is to 7.0-8.0.Drip off and stir 30min, extraction dichloromethane layer, ammoniacal liquor layer 10L methylene dichloride extracts once again.
Get dichloromethane layer and add 25L 5% sodium hydrogen carbonate solution, 25 DEG C are stirred 2 hours, separatory is (as density adds water close to not stratified, object washing dichloromethane layer), 20L × 4 deionized water is washed 4 times (to two-layer adhesion), dry 2 hours of dichloromethane layer anhydrous sodium sulphate (2kg), filter, filtrate concentrates evaporate to dryness and obtains oily matter.
Get oily matter 20L dissolve with methanol, then add sodium hydroxide 380g, stirring at room temperature 2 hours, gac 100g decolours, filter, concentrated evaporate to dryness, adds 20L hot acetone (40 DEG C) stirring and refluxing 30min, is down to stirring at room temperature 2 hours, filter, drip washing, 50 DEG C of vacuum-dryings obtain Esomeprazole sodium crude product 2167.5g, yield 50%.
Esomeprazole sodium crude product 2160g prepared by said process, is dissolved in dehydrated alcohol 15L(mass volume ratio and is about 1:8), 35 DEG C of stirring and dissolving, 75g gac 35 DEG C decolouring 1 hour; Filter, 45-50 DEG C of concentrated evaporate to dryness; Add 17L ethyl acetate (mass volume ratio is about 1:8) 45 DEG C of insulated and stirred 30min; Be cooled to 25 DEG C of filtrations, 3L ethyl acetate drip washing filter cake; 50 DEG C of vacuum-dryings obtain white solid (fusing point: 247 ~ 249 DEG C), actually obtain Esomeprazole sodium fine work 1728g, and product yield is 80%.
In following embodiment, correlation step is omitted, and implements with reference to correlation step concrete in embodiment 1.
Embodiment 2
1568g esomeprazole intermediate (5-methoxyl group-2-(4-methoxyl group-3 is added in 20L reactor, 5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline), use the slow stirring and dissolving of 6.4L toluene again, 600g D-(-) diethyl tartrate is added after being warming up to 50 DEG C-55 DEG C, add 40ml purified water again and stir 0.5 hour, after add 410g titanium isopropylate, continue stir 50min.Be cooled to 25 ± 2 DEG C, add diisopropylamine 190g and stir 5min, drip 820g mass concentration 80% hydrogen phosphide cumene (during dropping, temperature controls at 25 ± 2 DEG C).Drip and finish rear 25 ± 2 DEG C of stirring reactions 3 hours, TLC per hour detects once.React complete, in reaction solution, add 3L strong aqua and 3L purified water, stir 30 min, then extraction of ammonia water layer.Sub-water extractive reaction liquid 1 time is purified again with 3L strong aqua and 3L.Merge ammoniacal liquor layer, with 7L toluene wash once, add 10L methylene dichloride to ammoniacal liquor layer, stir and be cooled to less than 10 DEG C, slowly drip glacial acetic acid and regulate pH to 7.0-8.0, during dropping, temperature does not exceed 15 DEG C.Drip off and stir 30min, extraction dichloromethane layer, adds 10L 5% sodium hydrogen carbonate solution, 25 ± 5 DEG C are stirred 2 hours, and get dichloromethane layer, 10L × 4 purified water washes 4 times, dichloromethane layer anhydrous sodium sulfate drying 2 hours, filter, filtrate 35 ± 5 DEG C of concentrated evaporates to dryness obtain oily matter.Get oily matter 10L dissolve with methanol, then add sodium hydroxide 150g, 25 DEG C-30 DEG C are stirred 2 hours, add gac 50g decolouring 30min, filter, filtrate 45 ± 5 DEG C of concentrated evaporates to dryness, add 10L hot acetone (40 DEG C) 50 DEG C of stirring and refluxing 30min, be cooled to 25 ± 5 DEG C to stir 2 hours, filter, 1L acetone drip washing filter cake, 50 DEG C of vacuum-dryings obtain crude product 1497.8g, yield 84.9%, enantiomeric purity 98.4%.
Embodiment 3
1568g esomeprazole intermediate (5-methoxyl group-2-(4-methoxyl group-3 is added in 20L reactor, 5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline), use the slow stirring and dissolving of 6.4L toluene again, 600g D-(-) diethyl tartrate is added after being warming up to 50 DEG C-55 DEG C, add 40ml purified water again and stir 0.5 hour, after add 410g titanium isopropylate, continue stir 50min.Be cooled to 20 DEG C, add diisopropylamine 190g and stir 5min, drip 820g mass concentration 80% hydrogen phosphide cumene (during dropping, temperature controls at 20 ± 2 DEG C).Drip and finish rear 20 ± 2 DEG C of stirring reactions 5 hours.React complete, obtain crude product 1362.3g, yield 77.2% through steps such as extraction, salify, concentrated, washing, vacuum-dryings, enantiomeric purity is 99.3%.
Embodiment 4
1568g esomeprazole intermediate (5-methoxyl group-2-(4-methoxyl group-3 is added in 20L reactor, 5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline), use the slow stirring and dissolving of 6.4L toluene again, 600g D-(-) diethyl tartrate is added after being warming up to 50 DEG C-55 DEG C, add 40ml purified water again and stir 0.5 hour, after add 410g titanium isopropylate, continue stir 50min.Be cooled to 30 DEG C, add diisopropylamine 190g and stir 5min, drip 820g mass concentration 80% hydrogen phosphide cumene (during dropping, temperature controls at 30 ± 2 DEG C).Drip after finishing, temperature controls 30 ± 2 DEG C of stirring reactions 1 hour.React complete, obtain crude product 902.8g, yield 51.2% through steps such as extraction, salify, concentrated, washing, vacuum-dryings, enantiomeric purity is 95.6%.
Embodiment 5
Esomeprazole sodium crude product 700g(enantiomeric purity 98.4%), be dissolved in 6L dehydrated alcohol, 35 ± 5 DEG C of stirring and dissolving, 35g gac 35 ± 5 DEG C decolouring 1 hour; Filter, 45-50 DEG C of concentrated evaporate to dryness; Add 6L ethyl acetate 45 ± 5 DEG C of insulated and stirred 30min; Be cooled to less than 25 DEG C filtrations, 1L ethyl acetate drip washing filter cake; 50 DEG C of vacuum-dryings obtain white or off-white color solid 606.8g, yield 86.7%, enantiomeric purity 99.8%, content 98.7%.
Embodiment 6
Esomeprazole sodium crude product 700g(enantiomeric purity 98.4%), be dissolved in 7L dehydrated alcohol, 35 ± 5 DEG C of stirring and dissolving, 35g gac 35 ± 5 DEG C decolouring 1 hour; Filter, 45-50 DEG C of concentrated evaporate to dryness; Add 7L acetone 45 ± 5 DEG C of insulated and stirred 30min; Be cooled to less than 25 DEG C filtrations, 1L acetone filter wash cake; 50 DEG C of vacuum-dryings obtain white or off-white color solid 509.7g, yield 72.8%, and enantiomeric purity is 99.9%, content 99.4%.
Those of ordinary skill in the field are to be understood that: the foregoing is only specific embodiments of the invention; be not limited to the present invention; within the spirit and principles in the present invention all, any amendment made, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (7)
1. an Esomeprazole sodium synthesis production method, comprises the steps:
(A) 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline is prepared;
(B) by prepared 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline toluene dissolves, add D-(-) diethyl tartrate, water, titanium isopropylate and diisopropylamine, form chiral catalytic system; Add hydrogen phosphide cumene again and carry out chiral oxidization reaction; Add sodium hydroxide after reaction terminates, obtain Esomeprazole sodium crude product;
(C) the Esomeprazole sodium crude product of said process gained is refined;
Wherein, described (B) step specifically comprises following steps:
(I) by 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline and dry toluene stirring and dissolving, heat up, add D-(-) diethyl tartrate and water, stir, more slowly add titanium isopropylate, continue to stir;
(II) above-mentioned reaction solution is cooled to 25 ± 2 DEG C, constant temperature adds diisopropylamine, stirs, and Slow Isothermal drips mass concentration 80% hydrogen phosphide cumene, and after dropwising, constant temperature stirs 1 hour-5 hours;
(III) under above-mentioned reaction solution constant temperature, add strong aqua and deionized water, stir, extraction of ammonia water layer; Use strong aqua and deionized water extraction reaction solution again, extraction of ammonia water layer, merge ammoniacal liquor layer, by toluene wash; Be placed in ice bath by the ammoniacal liquor after washing, add methylene dichloride, slowly drip glacial acetic acid, during dropping, temperature is no more than 15 DEG C, solution ph is greater than 7, drips off stirring, extraction dichloromethane layer, ammoniacal liquor layer adds methylene dichloride again, extraction dichloromethane layer, combined dichloromethane layer;
(IV) add sodium hydrogen carbonate solution to dichloromethane layer, temperature controls as the temperature in (II), and stir, separatory, gets dichloromethane layer; Deionized water washing dichloromethane layer, filter after adding anhydrous sodium sulfate drying, filtrate concentrates evaporate to dryness and obtains oily matter;
(V) use dissolve with methanol oily matter, add sodium hydroxide, stirring at room temperature, activated carbon decolorizing, filter, concentrated evaporate to dryness, add 40 DEG C of hot acetones, stirring and refluxing, is down to room temperature, and filter, drip washing, vacuum-drying obtains crude product.
2. Esomeprazole sodium synthesis production method according to claim 1, it is characterized in that, in (B) step, the reaction times is 2.5 hours-3.5 hours.
3. Esomeprazole sodium synthesis production method according to claim 1, it is characterized in that, in (B) step, the ratio adding the amount of hydrogen phosphide cumene and the molar weight of 5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl thio-1H-benzoglyoxaline is 0.8:1 ~ 1:1.
4. Esomeprazole sodium synthesis production method according to claim 1, it is characterized in that, (C) step also comprises: by Esomeprazole sodium dissolving crude product in dehydrated alcohol, after adding activated carbon decolorizing filtration, filtrate concentrates evaporate to dryness, adds acetone or ethyl acetate stirs and filters in gained material; Again with acetone or ethyl acetate drip washing filter cake, obtain the Esomeprazole sodium refined thus.
5. Esomeprazole sodium synthesis production method according to claim 4, is characterized in that, use ethyl acetate washing leaching cake.
6. Esomeprazole sodium synthesis production method according to claim 1, it is characterized in that, in described (III) step, solution ph is 7 ~ 8.
7. Esomeprazole sodium synthesis production method according to claim 1, it is characterized in that, described (C) step specifically comprises following steps:
(I) crude product is dissolved in dehydrated alcohol, and crude product and dehydrated alcohol mass volume ratio are 1:8, and temperature 30 DEG C of-40 DEG C of stirring and dissolving, add gac, decolouring;
(II) by above-mentioned reacting liquid filtering, temperature is 45 DEG C of-50 DEG C of concentrated evaporates to dryness;
(III) in upper step gained material, add acetone or ethyl acetate, mass volume ratio is 1:8, and at 40 DEG C-50 DEG C, constant temperature stirs;
(IV) be cooled to less than 25 DEG C, filter; With ethyl acetate or acetone drip washing filter cake;
(V) 50 DEG C of vacuum-drying, obtains fine work Esomeprazole sodium.
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| CN103242295B (en) * | 2013-05-14 | 2015-11-04 | 山东罗欣药业集团股份有限公司 | Esomeprazole sodium crystal-form compound and synthetic method thereof |
| CN104693177A (en) * | 2013-12-09 | 2015-06-10 | 北大方正集团有限公司 | Refining method of esomeprazole sodium |
| CN103755685B (en) * | 2014-01-16 | 2015-03-25 | 山东科源制药有限公司 | Purifying and refining method of esomeprazole sodium |
| CN103739592A (en) * | 2014-01-24 | 2014-04-23 | 山东科源制药有限公司 | Method for producing esomeprazole sodium |
| CN104163814B (en) * | 2014-05-27 | 2016-08-24 | 浙江新东港药业股份有限公司 | A kind of high-purity 5-methoxyl group-2-((S)-((4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl) sulfinyl)-1H-benzimidazole sodium preparation method |
| CN105418589B (en) * | 2016-01-17 | 2017-09-26 | 青岛市中心医院 | A kind of esomeprazole magnesium trihydrate preparation method for treating disease of digestive system |
| CN106366070B (en) * | 2016-08-10 | 2019-06-11 | 上海万巷制药有限公司 | A kind of preparation method of high-purity esomeprazole sodium |
| CN107987058A (en) * | 2017-11-28 | 2018-05-04 | 江苏中邦制药有限公司 | A kind of synthetic method of esomeprazole sodium impurity I |
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