CN102584792B - Method for preparing high-purity esomeprazole - Google Patents
Method for preparing high-purity esomeprazole Download PDFInfo
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- 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 title claims abstract description 44
- 229960004770 esomeprazole Drugs 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 238000003756 stirring Methods 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 238000000746 purification Methods 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 238000005352 clarification Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 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 description 3
- 239000012467 final product Substances 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 claims description 2
- 229960000344 thiamine hydrochloride Drugs 0.000 claims description 2
- 235000019190 thiamine hydrochloride Nutrition 0.000 claims description 2
- 239000011747 thiamine hydrochloride Substances 0.000 claims description 2
- 238000007670 refining Methods 0.000 abstract description 4
- 230000002829 reductive effect Effects 0.000 abstract 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 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 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 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 229960000381 omeprazole Drugs 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229960000496 esomeprazole sodium Drugs 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- FOFFPEFVSRGLOZ-JIDHJSLPSA-N potassium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [K+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C FOFFPEFVSRGLOZ-JIDHJSLPSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- SUBDBMMJDZJVOS-XMMPIXPASA-N (R)-omeprazole Chemical compound C([S@@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-XMMPIXPASA-N 0.000 description 1
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RRFCKCAQHRITRG-UHFFFAOYSA-N sodium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide;hydrate Chemical compound O.[Na+].N=1C2=CC(OC)=CC=C2[N-]C=1S(=O)CC1=NC=C(C)C(OC)=C1C RRFCKCAQHRITRG-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- -1 sulfone compound Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000009466 transformation Effects 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 and refining salt of esomeprazole. According to the method, 2-sulfydryl-5-methoxyl-1H-benzimidazole is used as an initiative raw material for reaction, and a reaction condition is optimized, so that reaction is performed under a mild condition, and the content of impurities in the product is reduced effectively. After the synthesized product is refined further, the purity and enantiomer excess of the product are over 99 percent, so that the effect and safety of administration are improved.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to a kind of synthetic and refining method of esomeprazole salt.
Background technology
Omeprazole (Omeprazole) is the proton pump inhibitor (H of the first gastric acid secretion inhibiting effectively of Astrazeneca AB of Sweden exploitation
+ / K
+ -ATP enzyme), within 1988, first go on the market in Sweden, within 1989, enter American market, trade(brand)name is Losec MUPS, and its indication is stomach ulcer, duodenal ulcer, reflux esophagitis, Zhuo-Emhorn syndrome (zollinger-ellsion) syndrome.First patent EP0005129 has disclosed omeprazole and has obtained chemical structure and preparation method, and patent EP0124495 has disclosed its metal-salt.The people such as PL Lin Debao disclose in US5877192, and omeprazole has dextrorotation (R-) and left-handed (S-) two kinds of isomer, and wherein the drug effect of S-isomer is obviously better than R-omeprazole.
Esomprazole also claims esomeprazole (Esomeprazole, Cas No.:119141-88-7), has the chemical structure shown in following formula:
Result of study shows, esomeprazole and the comparison of omeprazole raceme, and oral artifact availability is higher, and the transformation period is longer, can more effectively reduce acidity, significantly improves the curative ratio of erosive esophagitis, alleviates more quickly and effectively the symptoms such as heartburn.In view of the superiority of esomeprazole, people synthesize and refine and done a large amount of research work esomeprazole.
The method of what prior art had disclosed prepare esomeprazole has following several.
(1), biological synthesis process, utilize the specificity of enzyme or specificity to prepare optically pure esomeprazole.The people such as HOLT ROBERT disclose and have utilized the method for microbial selective oxidation prochirality thioether and selective reduction racemization sulfone compound to prepare esomeprazole in WO9617076, WO9617077, but due to the poor stability of microorganism, purification of products difficulty, therefore and be not suitable for suitability for industrialized production and yield is lower.
(2), chromatogram Split Method, utilize chromatography to break omeprazole to obtain esomeprazole, but this method is because cost is high, yield is low, and is more common in a small amount of preparation in laboratory, have no the report that is applied to large-scale industrial production.
(3), inclusion resolution method, form host-guest inclusion or inclusion compound by the method for inclusion or inclusion, and then make by all means Subjective and Objective separately.Inclusion resolution is invented by Japanization scholar professor Toda, its principle is to utilize non covalent bond system, as hydrogen bond and intermolecular secondary action, make enantiomer and the hand shape resolving agent generation inclusion of racemic modification, form stable super molecular complex, then by the method for crystallization, two enantiomorphs are separated.Owing to there is not chemical reaction in main body (Host) and object (Guest) molecule, only there is Intermolecular Forces, so be easy to by column chromatography, exchange of solvent and step by step distillation etc. and guest molecule from, and then recycle.WO04/002982 discloses omeprazole sodium salt under the existence of D-diethyl tartrate, titanium complex, L-tonsilla bronsted lowry acids and bases bronsted lowry, obtain L-tonsilla acid-esomeprazole titanium complex, processed the single enantiomer that just can obtain optical purity omeprazole through simple alkaline solution; EP1401442 discloses the method for utilizing beta-cyclodextrin inclusion compound esomeprazole.Because the yield on inclusion resolution law theory also only has 50%, the yield in actual production will be lower, and the cost that inclusion separates is higher, is therefore unsuitable for suitability for industrialized production.
(4), the method for asymmetric oxidation, prepare esomeprazole with catalyzer or hand shape part.As DE4035455(WO9208716) disclose first and a kind of [(pyridyl-methyl) sulfinyl]-1H-benzoglyoxaline has been separated into the method for single enantiomer; the method adopts chemical process in molecule, to introduce a chiral radicals; by raceme omeprazole through stereoselectivity nitrogen for derivatize; make racemic modification produce stereo disparity; by other separation purification method, the chiral radicals of introducing is dissociated again, after hydrolysis, obtain the sulfoxide type chiral proton pump inhibitor of single enantiomer.The people such as EM Larsen disclose the method for a kind of improved sharpless asymmetric oxidation legal system for esomeprazole at WO9602535, but need to regulate repeatedly pH value in this preparation method, increase the difficulty of operation; And temperature of reaction higher (more than 80 DEG C), causes in product foreign matter content higher; The e.e. value of this method products therefrom can reach 87% simultaneously, but yield only has 40%: these defects cause the method not also to be suitable for suitability for industrialized production.
Therefore, developing a kind of synthetic and refining method of esomeprazole salt of simple to operate, yield is high, optical purity is high applicable suitability for industrialized production, is very necessary.
Summary of the invention
The object of this invention is to provide a kind of synthetic and refining method of esomeprazole salt of simple to operate, yield is high, optical purity is high applicable suitability for industrialized production.
The method provides a kind of preparation method of esomeprazole salt, comprises the formula of using
shown 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline is as start material material, and concrete steps are:
(1) to the organic solvent that adds its 2～5 times of volumes in 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline, stir to obtain suspension; Then the mixed solution of the aqueous solution of mineral alkali and organic solvent is added drop-wise in suspension to reaction;
(2) under temperature control condition, by formula
shown 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride solution is added drop-wise in (1) step reaction solution, obtains formula after completion of the reaction through concentrated, purifying
shown compound; Reaction process is as follows,
(3) under nitrogen protection, by formula
compound is dissolved in toluene or methylene dichloride, under stirring, add successively D-diethyl tartrate, titanium isopropylate and water, control 40～70 DEG C of reactions of temperature, after finishing, reaction is cooled to room temperature, add organic bases reaction, reduce temperature of reaction to 0～10 DEG C, slowly drip oxygenant, reaction finishes rear separation, recrystallization obtains formula
shown esomeprazole; Reaction process is as follows,
(4) by formula
one or more in methyl alcohol, acetone or acetonitrile of shown compound dissolution, stir, and then add wherein the aqueous solution of sodium hydroxide, potassium hydroxide or magnesium chloride, and after reaction finishes, concentrated, purifying obtains esomeprazole salt.
Further, the organic solvent described in aforesaid method (1) step is one or more in methyl alcohol, ethanol, Virahol, acetonitrile or acetone, and described mineral alkali is one or more in sodium hydroxide, potassium hydroxide, sodium bicarbonate or sodium carbonate.
Further, in aforesaid method (1) step, temperature control is 30～70 DEG C.
Further, in aforesaid method (3) step, described organic bases is one or more in diethylamine, quadrol, triethylamine, diisobutylamine or diisopropylethylamine.
Further, in aforesaid method (3) step, described oxygenant be aqueous hydrogen peroxide solution, metachloroperbenzoic acid or, one or more in tertbutyl peroxide or hydrogen phosphide cumene.
The present invention also provides the process for purification of esomeprazole salt, comprises the steps:
(1) under temperature control condition, the crude product that reaction is made adds one or more in dehydrated alcohol, methyl alcohol, acetone or acetonitrile in batches, is stirred to basic dissolving clarification; Filter above-mentioned solution, obtain clarification light yellow liquid;
(2) to the ether solvent that adds its 2～8 times of volumes in above-mentioned yellow solution, stir, after leaving standstill, have solid to separate out, collect solid, vacuum-drying and get final product.
Further, in above-mentioned purification step (1), temperature control is 20～50 DEG C.
Further, ether solvent is one or more of ether, isopropyl ether, sherwood oil or methyl tertiary butyl ether in above-mentioned purification step (2).
Contriver, in research process, is surprised to find that: after reaction mass and condition are optimized according to above-mentioned method, presented beyond thought advantage:
1. the temperature of reaction in whole process maintains lower level, preparation time is shorter, can reduce operation easier so on the one hand, reduce costs, and has also reduced on the other hand foreign matter content in product;
2. after purification step, the HPLC purity of product and enantiomeric excess (ee) value all reach more than 99%, and this has just improved drug effect and security greatly.
Embodiment
Below in conjunction with specific embodiment, further illustrate technical scheme of the present invention.
embodiment 1 esomeprazole (
) synthetic
Take formula
shown compound 180g(1mol), add the methyl alcohol of 540mL, stir to obtain aaerosol solution; Separately take NaOH 100g(2.5mol) be dissolved in 100mL water, add methyl alcohol 200mL, obtain mixed solution, slowly join in the methanol suspension of above-mentioned imidazoles, maintain 50 DEG C of left and right of temperature of reaction, start slow dropping formula
methanol solution [the formula of compound
compound 221g (1mol): methyl alcohol 700mL].Dropwise, holding temperature reaction 0.5～1h, TLC monitors (developping agent is sherwood oil: ethyl acetate=1:3), reacts completely, and finishes reaction.After extraction, suction filtration, vacuum-drying, obtain 243g formula
shown compound, HPLC purity is 99.76%, m.p.:119-120 DEG C.
Under nitrogen protection, get the formula that previous step makes
shown compound 229g(0.7mol) and the toluene of 800mL, after stirring, add successively D-diethyl tartrate (72mL, 0.42mol), titanium isopropylate (62mL, 0.22mol), purified water 2mL, stir, slowly be warming up to 50～60 DEG C of interior temperature, all dissolve, become dark brown clear liquor, it is insulation reaction 1h that interior temperature reaches 55～60 DEG C, then stir and be cooled to room temperature, add diisopropylethylamine (35mL, 0.2mol), while being cooled to 0～10 DEG C, start slowly to drip hydrogen phosphide cumene (143mL, 0.66mol), being controlled at 2～3h drips off, drip off rear continuation reaction, TLC monitors (developping agent, methylene dichloride: methyl alcohol=25:1), after reaction finishes, through extraction, concentrated, recrystallization and drying and other steps, obtain esomeprazole 172g.
HPLC purity 99.3%, m.p.:156-157 DEG C
the preparation of embodiment 2 Esomeprazole sodiums
Get esomeprazole 35.0g 40mL dissolve with methanol, be stirred to and dissolve clarification, separately claim 5.0g to get sodium hydroxide and be dissolved in 5.5mL water, cool to below room temperature, then with the dilution of 5.5mL methyl alcohol, be added drop-wise in reaction Fu, 45 DEG C of stirring reaction 0.5h, are warming up to 55 DEG C and continue reaction 1h.Concentrated, repeatedly use anhydrous isopropyl alcohol (25 mL × 2) band water, be concentrated into dope, add 7mL ether to stir, after leaving standstill, there are a large amount of solids to separate out, pour the dilution of 20mL ether into, centrifugal, obtain 36.5g Esomeprazole sodium crude product.
The Esomeprazole sodium crude product in batches previous step being made is dissolved in the dehydrated alcohol of 40mL, 35 DEG C of left and right of the hierarchy of control, basic dissolve (clouding a little); Filter above-mentioned solution with the Büchner funnel that contains gac cake and must clarify yellow liquid.Treat that the oily matter in container is slightly chilled to room temperature, add 70mL ether to stir, leave standstill, there are a large amount of solids to separate out, pour the dilution of 20mL ether into, stir evenly suction filtration or centrifugal, collect solid, then by the vacuum-drying at 45-50 DEG C of weight in wet base solid, obtain the highly purified Esomeprazole sodium of 28.5g, yield 78.1%, HPLC purity 99.9%, ee>99.8%.
Specific rotation: [ɑ]
20 d=+36(0.3%, H
2o)
m.p.：249℃
Nuclear-magnetism (DMSO): δ 8.2379(s, 1H, 16-H); δ 7.3246-7.3418(d, 1H, J=8.6,7-H); δ 6 .9926-6.9971(d, 1H, J=2.25,4-H); δ 6.5470-6.5691(m, 1H, J=2.4,8.6,6-H); δ 4.4019-4.4278 (d, 1H, 17-H), δ 4.6026-4.6285 (d, 1H, 17-H); δ 3.7265(s, 3H, 10-H), 3.6940(s, 3H, 19-H); δ 2.2150(s, 3H, 20-H), 2.1820(s, 3H, 18-H).
D
2after O exchange, hydrogen spectrum does not change
δ 11.216, primary carbon, 18-C; δ 12.847, primary carbon, 20-C; δ 39.001-40.002, DMSO; δ 55.135,10-C; δ 59.618,19-C; δ 60.274,17-C; δ 99.458,4-H; δ 108.684,6-H; δ 117.280,7-C; δ 148.933,16-C; δ 163.299,14-C; δ 161.583,2-C; δ 153.417,5-C; δ 151.762,12-C; δ 141.620,8-C; δ 146.995,9-C.
Mass spectrum: [M+H]
+be 368.1.
the preparation of embodiment 3 Esomeprazole sodiums
Get esomeprazole 35.0g 40mL dissolve with methanol, be stirred to and dissolve clarification, separately claim 5.0g to get sodium hydroxide and be dissolved in 5.5mL water, cool to below room temperature, then with the dilution of 5.5mL methyl alcohol, be added drop-wise in reaction Fu, 45 DEG C of stirring reaction 0.5h, are warming up to 50 DEG C and continue reaction 1h.Concentrated, repeatedly use anhydrous isopropyl alcohol (25 mL × 2) band water, be concentrated into dope, add 7mL petroleum ether and stirring even, after leaving standstill, there are a large amount of solids to separate out, pour the dilution of 20mL sherwood oil into, centrifugal, obtain 35.7g Esomeprazole sodium crude product.
The Esomeprazole sodium crude product in batches previous step being made is dissolved in the methyl alcohol of 40mL, 35 DEG C of left and right of the hierarchy of control, basic dissolve (clouding a little); Filter above-mentioned solution with the Büchner funnel that contains gac cake and must clarify yellow liquid.Treat that the oily matter in container is slightly chilled to room temperature, add 140mL petroleum ether and stirring even, leave standstill, there are a large amount of solids to separate out, pour the dilution of 20mL sherwood oil into, stir evenly suction filtration or centrifugal, collect solid, then by the vacuum-drying at 45-50 DEG C of weight in wet base solid, obtain the highly purified Esomeprazole sodium of 27.4g, yield 76.7%, yield HPLC purity 99.8%, ee>99.8%.
the preparation of embodiment 4 esomeprazole potassium
Get esomeprazole 35.0g 40mL acetone solution, be stirred to and dissolve clarification, separately claim 5.0g to get potassium hydroxide and be dissolved in 5.5mL water, cool to below room temperature, then with the dilution of 5.5mL methyl alcohol, be added drop-wise in reaction Fu, 45 DEG C of stirring reaction 0.5h, are warming up to 50 DEG C and continue reaction 1h.Concentrated, repeatedly use anhydrous isopropyl alcohol (20 mL × 2) band water, be concentrated into dope, add 7mL methyl tertiary butyl ether to stir, after leaving standstill, there are a large amount of solids to separate out, pour the dilution of 20mL methyl tertiary butyl ether into, centrifugal, obtain 35.7g esomeprazole potassium crude product.
The esomeprazole potassium crude product in batches previous step being made is dissolved in the dehydrated alcohol of 40mL, 35 DEG C of left and right of the hierarchy of control, basic dissolve (clouding a little); Filter above-mentioned solution with the Büchner funnel that contains gac cake and must clarify yellow liquid.Treat that the oily matter in container is slightly chilled to room temperature, add 210mL methyl tertiary butyl ether to stir, leave standstill, there are a large amount of solids to separate out, pour the dilution of 20mL methyl tertiary butyl ether into, stir evenly suction filtration or centrifugal, collect solid, then by the vacuum-drying at 45-50 DEG C of weight in wet base solid, obtain the highly purified esomeprazole potassium of 27.4g, yield 77.4%, yield HPLC purity 99.4%, ee>99.2%.
It should be noted that the above embodiments are only for illustrating instead of limiting technical scheme of the present invention, any replacement being equal to or change, all should be considered as being included within the scope of the present invention.
Claims (1)
1. a preparation method for esomeprazole salt, comprises the preparation of esomeprazole and the salt-forming reaction of esomeprazole and purification step, it is characterized in that, described " salt-forming reaction of esomeprazole and purification step " comprises the steps:
(1) esomeprazole is dissolved in methyl alcohol or acetone, stirs, then add wherein the aqueous solution of sodium hydroxide, potassium hydroxide or magnesium chloride, after reaction finishes, concentrated, purifying obtains esomeprazole salt;
(2) under 20～50 DEG C of conditions of temperature control, the crude product that reaction is made adds in methyl alcohol or ethanol in batches, is stirred to basic dissolving clarification, filters above-mentioned solution, obtains clarification light yellow liquid;
(3) to the sherwood oil or the methyl tert-butyl ether solvent that add its 2～8 times of volumes in above-mentioned light yellow liquid, stir, after leaving standstill, have solid to separate out, collect solid, vacuum-drying and get final product,
Wherein, described " esomeprazole " is to prepare and get in accordance with the following steps:
(a) in 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline (formula I), add the methyl alcohol of its 2～5 times of volumes, stir to obtain suspension, then the mixed solution of the aqueous solution of sodium hydroxide and methyl alcohol is added drop-wise in suspension, reaction, temperature control is 30～70 DEG C;
(b) under temperature control condition, by 2-chloromethyl-4-methoxyl group-3 shown in formula II, 5-dimethyl pyrazole thiamine hydrochloride solution is added drop-wise in step (a) reaction solution, obtains formula III compound (reacting as follows) after completion of the reaction through concentrated, purifying,
(c) under nitrogen protection; formula III compound is dissolved in to toluene; under stirring, add successively D-diethyl tartrate, titanium isopropylate and water; control 40～70 DEG C of reactions of temperature, after reaction finishes, be cooled to room temperature, add diisopropylethylamine reaction; reduce temperature of reaction to 0～10 DEG C; slowly drip hydrogen phosphide cumene, reaction finishes rear separation, recrystallization obtains the esomeprazole shown in formula IV (reacting as follows)
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| CN103275064B (en) * | 2012-11-06 | 2014-08-06 | 寿光富康制药有限公司 | Preparation method of Esomeprazole and preparation method of Esomeprazole sodium |
| CN102993177B (en) * | 2012-11-29 | 2015-05-06 | 科贝源(北京)生物医药科技有限公司 | Preparation method of high-purity esomeprazole sodium salt |
| CN103896917B (en) * | 2012-12-27 | 2018-06-05 | 鲁南贝特制药有限公司 | A kind of process for purification of Esomeprazole sodium |
| CN103896916B (en) * | 2012-12-27 | 2016-08-17 | 鲁南贝特制药有限公司 | A kind of preparation method of Esomeprazole sodium |
| CN103044402B (en) * | 2012-12-31 | 2015-01-14 | 康普药业股份有限公司 | Method for synthesizing esomeprazole sodium |
| CN104098545B (en) * | 2013-04-15 | 2016-03-23 | 北大方正集团有限公司 | The preparation method of Esomeprazole sodium |
| CN104098546B (en) * | 2013-04-15 | 2016-06-08 | 北大方正集团有限公司 | The preparation method of esomeprazole |
| CN103265528B (en) * | 2013-05-10 | 2015-05-06 | 湖南千金湘江药业股份有限公司 | Esomeprazole magnesium preparation method |
| 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 |
| CN103570686B (en) * | 2013-10-14 | 2015-04-01 | 哈药集团技术中心 | Method for synthesizing and refining esomeprazole sodium |
| CN103936714A (en) * | 2014-04-15 | 2014-07-23 | 北京华禧联合科技发展有限公司 | Preparation method of esomeprazole magnesium |
| CN103936715B (en) * | 2014-04-17 | 2016-08-24 | 哈尔滨珍宝制药有限公司 | The process for purification of a kind of Esomeprazole sodium and synthetic method |
| 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 |
| CN104030997B (en) * | 2014-06-25 | 2016-07-06 | 寿光富康制药有限公司 | A kind of catalyst for esomeprazole asymmetric synthesis |
| CN104496964A (en) * | 2014-12-18 | 2015-04-08 | 合肥远志医药科技开发有限公司 | Industrial production method of esomeprazole |
| CN104557867A (en) * | 2015-01-16 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of esomeprazole sodium salt |
| 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 |
| CN113698389A (en) * | 2021-08-26 | 2021-11-26 | 安徽鼎旺医药有限公司 | Synthetic method of esomeprazole |
| CN116496250A (en) * | 2023-04-18 | 2023-07-28 | 新沂大江化工有限公司 | Esomeprazole sodium synthesis process |
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