CN102584792A - Method for preparing high-purity esomeprazole - Google Patents
Method for preparing high-purity esomeprazole Download PDFInfo
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- CN102584792A CN102584792A CN2012100025368A CN201210002536A CN102584792A CN 102584792 A CN102584792 A CN 102584792A CN 2012100025368 A CN2012100025368 A CN 2012100025368A CN 201210002536 A CN201210002536 A CN 201210002536A CN 102584792 A CN102584792 A CN 102584792A
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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 46
- 238000000034 method Methods 0.000 title claims abstract description 35
- 229960004770 esomeprazole Drugs 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 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
- 238000000746 purification Methods 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012141 concentrate Substances 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
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 150000007530 organic bases Chemical class 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
- 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
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 238000005352 clarification Methods 0.000 claims description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000007858 starting material Substances 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 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
- 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
- 229960000381 omeprazole Drugs 0.000 description 9
- 229960000496 esomeprazole sodium Drugs 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000003287 optical effect Effects 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
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000008859 change Effects 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
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000012544 monitoring process Methods 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
- 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
- 238000005303 weighing Methods 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920000858 Cyclodextrin Polymers 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
- 208000007107 Stomach Ulcer Diseases 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
- 230000002950 deficient Effects 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
- 235000019441 ethanol Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 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
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000000813 microbial effect Effects 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
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 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
- 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
- 238000010792 warming Methods 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 purified method of esomeprazole salt.
Background technology
Omeprazole (Omeprazole) is the first excretory of the gastric acid inhibitory effectively proton pump inhibitor (H of Sweden Astrazeneca AB exploitation
+ / K
+ -ATP enzyme), got into American market in 1989 at first in Sweden's listing in 1988, trade(brand)name is Losec MUPS, and its indication is stomach ulcer, duodenal ulcer, reflux esophagitis, Zhuo-Emhorn syndrome (zollinger-ellsion) syndrome.Patent EP0005129 has at first disclosed omeprazole and has got chemical structure and preparation method, and patent EP0124495 has disclosed its metal-salt.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 obviously is superior to the R-omeprazole.
The S-omeprazole is also claimed esomeprazole (Esomeprazole, Cas No.:119141-88-7), has the chemical structure shown in the following formula:
Result of study shows that esomeprazole and omeprazole raceme compare, and oral artifact availability is higher, and the transformation period is longer, can reduce acidity more effectively, significantly improves the curative ratio of erosive esophagitis, alleviates symptoms such as heartburn more quickly and effectively.In view of the meliority of esomeprazole, people are to the synthetic and refining number of research projects of having done of esomeprazole.
The method for preparing esomeprazole that prior art has disclosed has following several kinds.
(1), biological synthesis process, promptly utilize the specificity of enzyme or specificity to prepare optically pure esomeprazole.People such as HOLT ROBERT disclose the method for utilizing microbial selective oxidation prochirality thioether and selective reduction racemization sulfone compound and have prepared esomeprazole in WO9617076, WO9617077; But because the poor stability of mikrobe; The purification of products difficulty; Therefore and be not suitable for suitability for industrialized production and yield is lower.
(2), the chromatogram Split Method, promptly utilize chromatography to break omeprazole obtaining esomeprazole, but this method is because of cost is high, yield is low, and is more common in breadboard a small amount of preparation, do not see the report that is applied to large-scale industrial production.
(3), the inclusion Split Method, promptly the method through inclusion or inclusion forms host-guest inclusion or inclusion compound, and then makes Subjective and Objective separately by all means.Inclusion splits and is invented by Japanization scholar professor Toda; Its principle is to utilize the non covalent bond system; Like hydrogen bond and intermolecular secondary action; Make the enantiomer and the hand shape resolving agent generation inclusion of racemic modification, form stable super molecular complex, again with two enantiomorphs separately through the crystalline method.Because chemical reaction does not take place in main body (Host) and object (Guest) molecule, only has Intermolecular Forces, thus be easy to leave with guest molecule through column chromatography, solvent exchange and distilling step by step etc., and then recycle.WO04/002982 discloses omeprazole sodium salt in the presence of D-diethyl tartrate, titanium complex, L-tonsilla bronsted lowry acids and bases bronsted lowry; Obtain L-tonsilla acid-esomeprazole titanium complex, handled the single enantiomer that just can obtain the optical purity omeprazole through simple alkaline solution; EP1401442 discloses the method for utilizing the beta-cyclodextrin inclusion compound esomeprazole.Because the theoretic yield of inclusion Split Method also has only 50%, the yield in the actual production will be lower, and the isolating cost of inclusion is higher, therefore be inappropriate for suitability for industrialized production.
(4), the method for asymmetric oxidation, promptly use catalyzer or hand shape part to prepare esomeprazole.Disclose first like DE4035455 (WO9208716) and a kind of [(pyridyl-methyl) sulfinyl]-1H-benzoglyoxaline have been separated into the method for single enantiomer; This method adopts chemical process in molecule, to introduce a chirality group; With the raceme omeprazole through stereoselectivity nitrogen for derivatize; Make racemic modification produce stereo disparity, through other separation purification method the chiral radicals of introducing is dissociated again, obtain the sulfoxide class chiral proton pump inhibitor of single enantiomer after the hydrolysis.People such as EM Larsen disclose the method that a kind of improved sharpless asymmetric oxidation legal system is equipped with esomeprazole at WO9602535, but need regulate the pH value times without number among this preparation method, increase the difficulty of operation; And temperature of reaction higher (more than 80 ℃) causes in the product foreign matter content higher; The e.e. value of this method products therefrom can reach 87% simultaneously, but yield has only 40%: these defectives cause this method also not to be suitable for suitability for industrialized production.
Therefore, developing a kind of synthetic and purified method of esomeprazole salt of simple to operate, yield is high, optical purity is high suitable suitability for industrialized production, is very necessary.
Summary of the invention
Synthetic and the purified method that the purpose of this invention is to provide a kind of esomeprazole salt of simple to operate, yield is high, optical purity is high suitable suitability for industrialized production.
This method provides a kind of preparation method of esomeprazole salt; Comprise with shown in the formula
the 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline is as the start material material, concrete steps are:
(1) in 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline, add the organic solvent of its 2～5 times of volumes, stir suspension; Then the aqueous solution of mineral alkali and the mixed solution of organic solvent are added drop-wise in the suspension reaction;
(2) under the temperature control condition; With the 2-chloromethyl-4-methoxyl group-3 shown in the formula
; 5-dimethyl pyrazole thiamine hydrochloride drips of solution is added in (1) the step reaction solution, reaction finish after concentrate, purifying gets the compound shown in the formula
; Reaction process is as follows,
(3) under nitrogen protection; Formula
compound is dissolved in toluene or methylene dichloride; Stir and add D-diethyl tartrate, titanium isopropylate and water down successively; 40～70 ℃ of reactions of controlled temperature; Reaction finishes postcooling to room temperature; Add the organic bases reaction; Reduce temperature of reaction to 0～10 ℃, slow dropping oxidizing agent, reaction finishes that separate the back, recrystallization gets the esomeprazole shown in the formula
; Reaction process is as follows,
(4) with one or more in methyl alcohol, acetone or acetonitrile of the compound dissolution shown in the formula
; Stir; Then to the aqueous solution that wherein adds sodium hydroxide, Pottasium Hydroxide or magnesium chloride; After reaction finished, concentrated, purifying obtained esomeprazole salt.
Further, the organic solvent described in (1) step of aforesaid method is one or more in methyl alcohol, ethanol, Virahol, acetonitrile or the acetone, and described mineral alkali is one or more in sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate or the yellow soda ash.
Further, aforesaid method is in (1) step, and temperature is controlled to be 30～70 ℃.
Further, aforesaid method is in (3) step, and described organic bases is one or more in diethylamine, quadrol, triethylamine, diisobutylamine or the diisopropylethylamine.
Further, aforesaid method (3) is in the step, described oxygenant be aqueous hydrogen peroxide solution, metachloroperbenzoic acid or, in tertbutyl peroxide or the hydrogen phosphide cumene one or more.
The present invention also provides the process for purification of esomeprazole salt, comprises the steps:
(1) under the temperature control condition, the bullion that reaction is made adds one or more in absolute ethyl alcohol, methyl alcohol, acetone or the acetonitrile in batches, is stirred to basic dissolving clarification; Filter above-mentioned solution, must clarify light yellow liquid;
(2) ether solvent of its 2～8 times of volumes of adding in above-mentioned yellow solution stirs, and has solid to separate out after leaving standstill, and collects solid, and vacuum-drying promptly gets.
Further, temperature is controlled to be 20～50 ℃ in the above-mentioned purification step (1).
Further, ether solvent is one or more of ether, isopropyl ether, sherwood oil or MTBE in the above-mentioned purification step (2).
The contriver is surprised to find that in research process: after reaction mass and condition are optimized according to above-mentioned method, demonstrated beyond thought advantage:
1. the maintain in the whole process is shorter at lower level, preparation time, can reduce operation easier so on the one hand, reduce cost, and has also reduced foreign matter content in the product on the other hand;
2. through after the 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 specify technical scheme of the present invention.
Embodiment 1 esomeprazole (
) synthetic
Take by weighing the compound 180g (1mol) shown in the formula
; The methyl alcohol that adds 540mL, stir aaerosol solution; Other takes by weighing NaOH 100g (2.5mol) and is dissolved in the 100mL water; Add methyl alcohol 200mL; Get mixed solution; Slowly join in the methanol suspension of above-mentioned imidazoles; Keep about 50 ℃ of temperature of reaction, begin the methanol solution [formula
compound 221g (1mol): methyl alcohol 700mL] of slow dropping formula
compound.Dropwise, holding temperature reaction 0.5～1h, the TLC monitoring (developping agent is a sherwood oil: ETHYLE ACETATE=1:3), react completely, finish reaction.Get the compound shown in the 243g formula
after extraction, suction filtration, the vacuum-drying; HPLC purity is 99.76%, m.p.:119-120 ℃.
Under nitrogen protection, get one and go on foot compound 229g (0.7mol) shown in the formula
that makes and the toluene of 800mL, after stirring, add D-diethyl tartrate (72mL successively; 0.42mol), titanium isopropylate (62mL, 0.22mol), purified water 2mL; Stir, temperature is 50～60 ℃ in slowly being warming up to, all dissolving; Become dark brown clear liquor, it is insulation reaction 1h that interior temperature reaches 55～60 ℃, stirs then and is cooled to room temperature; The adding diisopropylethylamine (35mL, 0.2mol), when being cooled to 0～10 ℃; Beginning slowly drips hydrogen phosphide cumene, and (143mL 0.66mol), is controlled at 2～3h and drips off; Drip off the continued reaction, and the TLC monitoring (developping agent, methylene dichloride: methyl alcohol=25:1); After reaction finishes, through extraction, concentrate, recrystallization and drying and other steps, esomeprazole 172g.
HPLC purity 99.3%, m.p.:156-157 ℃
The preparation of embodiment 2 esomeprazole sodium
35.0g taking esomeprazole with 40mL of methanol was dissolved, stirring until dissolved clarified take another 5.0g of sodium hydroxide dissolved in 5.5mL said water cooled to below room temperature, diluted with methanol and then 5.5mL, was added dropwise to the reaction Fu , 45 ℃ reaction was stirred 0.5h, the reaction was continued heating to 55 ℃ 1h.Concentrate, use anhydrous isopropyl alcohol (25 mL * 2) band water repeatedly, be concentrated into dope, add the 7mL ether and stir, after leaving standstill, have a large amount of solids to separate out, pour the dilution of 20mL ether into, centrifugal, obtain 36.5g esomeprazole sodium bullion.
To go up one in batches and go on foot the absolute ethyl alcohol that the esomeprazole sodium bullion that makes is dissolved in 40mL, about 35 ℃ of the hierarchies of control, basic dissolving (clouding a little); Filter above-mentioned solution with the B that contains the gac cake and must clarify yellow liquid.Treat that the oily matter in the container is chilled to room temperature slightly, add the 70mL ether and stir, leave standstill, have a large amount of solids to separate out; Pour the dilution of 20mL ether into, stir suction filtration or centrifugal; Collect solid, then with the weight in wet base solid 45-50 ℃ of following vacuum-drying, promptly get 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, and .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
2O exchange back 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 sodium
35.0g taking esomeprazole with 40mL of methanol was dissolved, stirring until dissolved clarified take another 5.0g of sodium hydroxide dissolved in 5.5mL said water cooled to below room temperature, diluted with methanol and then 5.5mL, was added dropwise to the reaction Fu , 45 ℃ reaction was stirred 0.5h, the reaction was continued heating to 50 ℃ 1h.Concentrate, use anhydrous isopropyl alcohol (25 mL * 2) band water repeatedly, be concentrated into dope, adding 7mL petroleum ether and stirring is even, after leaving standstill, has a large amount of solids to separate out, and pours the dilution of 20mL sherwood oil into, and is centrifugal, obtains 35.7g esomeprazole sodium bullion.
To go up one in batches and go on foot the methyl alcohol that the esomeprazole sodium bullion that makes is dissolved in 40mL, about 35 ℃ of the hierarchies of control, basic dissolving (clouding a little); Filter above-mentioned solution with the B that contains the gac cake and must clarify yellow liquid.Treat that the oily matter in the container is chilled to room temperature slightly, adding 140mL petroleum ether and stirring is even, leaves standstill, and has a large amount of solids to separate out; Pour the dilution of 20mL sherwood oil into, stir suction filtration or centrifugal; Collect solid, then with the weight in wet base solid 45-50 ℃ of following vacuum-drying, promptly get 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
Taking esomeprazole with 40mL of acetone was dissolved 35.0g, stir until dissolved clear, otherwise known to take 5.0g of potassium hydroxide dissolved in 5.5mL water, cooled to below room temperature, diluted with methanol and then 5.5mL, was added dropwise to the reaction Fu , 45 ℃ reaction was stirred 0.5h, the reaction was continued heating to 50 ℃ 1h.Concentrate, use anhydrous isopropyl alcohol (20 mL * 2) band water repeatedly, be concentrated into dope, add the 7mL MTBE and stir, after leaving standstill, have a large amount of solids to separate out, pour the dilution of 20mL MTBE into, centrifugal, obtain 35.7g esomeprazole potassium bullion.
To go up one in batches and go on foot the absolute ethyl alcohol that the esomeprazole potassium bullion that makes is dissolved in 40mL, about 35 ℃ of the hierarchies of control, basic dissolving (clouding a little); Filter above-mentioned solution with the B that contains the gac cake and must clarify yellow liquid.Treat that the oily matter in the container is chilled to room temperature slightly, add the 210mL MTBE and stir, leave standstill, have a large amount of solids to separate out; Pour the dilution of 20mL MTBE into, stir suction filtration or centrifugal; Collect solid, then with the weight in wet base solid 45-50 ℃ of following vacuum-drying, promptly get the highly purified esomeprazole potassium of 27.4g; Yield 77.4%, yield HPLC purity 99.4%, ee>99.2%.
Should be noted that the above embodiments only are used for explanation rather than limit technical scheme of the present invention, any replacement that is equal to or change all should be regarded as being included within the scope of the present invention.
Claims (8)
1. the preparation method of an esomeprazole salt; Comprise with the 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline shown in the formula
as the start material material; It is characterized in that method also comprises:
(1) in 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline, add the organic solvent of its 2～5 times of volumes, stir suspension; Then the aqueous solution of mineral alkali and the mixed solution of organic solvent are added drop-wise in the suspension reaction;
(2) under the temperature control condition; With the 2-chloromethyl-4-methoxyl group-3 shown in the formula
; 5-dimethyl pyrazole thiamine hydrochloride drips of solution is added in (1) the step reaction solution, reaction finish after concentrate, purifying gets the compound shown in the formula
; Reaction process is as follows,
(3) under nitrogen protection; Formula
compound is dissolved in toluene or methylene dichloride; Stir and add D-diethyl tartrate, titanium isopropylate and water down successively; 40～70 ℃ of reactions of controlled temperature; Reaction finishes postcooling to room temperature; Add the organic bases reaction; Reduce temperature of reaction to 0～10 ℃, slow dropping oxidizing agent, reaction finishes that separate the back, recrystallization gets the esomeprazole shown in the formula
; Reaction process is as follows,
(4) with one or more in methyl alcohol, acetone or acetonitrile of the compound dissolution shown in the formula
; Stir; Then to the aqueous solution that wherein adds sodium hydroxide, Pottasium Hydroxide or magnesium chloride; After reaction finished, concentrated, purifying obtained esomeprazole salt.
2. the preparation method of esomeprazole salt according to claim 1; It is characterized in that; Organic solvent described in (1) step is one or more in methyl alcohol, ethanol, Virahol, acetonitrile or the acetone, and described mineral alkali is one or more in sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate or the yellow soda ash.
3. the preparation method of esomeprazole salt according to claim 1 is characterized in that, in (1) step, temperature is controlled to be 30～70 ℃.
4. the preparation method of esomeprazole salt according to claim 1 is characterized in that, in (3) step, described organic bases is one or more in diethylamine, quadrol, triethylamine, diisobutylamine or the diisopropylethylamine.
5. the preparation method of esomeprazole salt according to claim 1; It is characterized in that; In (3) step, described oxygenant be aqueous hydrogen peroxide solution, metachloroperbenzoic acid or, in tertbutyl peroxide or the hydrogen phosphide cumene one or more.
6. according to the preparation method of each described esomeprazole salt in the claim 1～5, it is characterized in that this method also comprises purification step:
(1) under the temperature control condition, the bullion that reaction is made adds one or more in methyl alcohol, ethanol, acetone or the acetonitrile in batches, is stirred to basic dissolving clarification; Filter above-mentioned solution, must clarify light yellow liquid;
(2) ether solvent of its 2～8 times of volumes of adding in above-mentioned yellow solution stirs, and has solid to separate out after leaving standstill, and collects solid, and vacuum-drying promptly gets.
7. according to the preparation method of right 6 described esomeprazole salt, it is characterized in that temperature is controlled to be 20～50 ℃ in the purification step (1).
8. according to the preparation method of right 6 described esomeprazole salt, it is characterized in that ether solvent is one or more of ether, isopropyl ether, sherwood oil or MTBE in the purification step (2).
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| CN102993177A (en) * | 2012-11-29 | 2013-03-27 | 郑祖爽 | Preparation method of high-purity esomeprazole sodium salt |
| CN103044402A (en) * | 2012-12-31 | 2013-04-17 | 康普药业股份有限公司 | Method for synthesizing esomeprazole sodium |
| CN103242295A (en) * | 2013-05-14 | 2013-08-14 | 山东罗欣药业股份有限公司 | Esomeprazole sodium crystal-form compound and synthesis method thereof |
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| CN116496250A (en) * | 2023-04-18 | 2023-07-28 | 新沂大江化工有限公司 | A kind of synthetic technique of esomeprazole sodium |
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