CN113845510A - Preparation method of esomeprazole - Google Patents
Preparation method of esomeprazole Download PDFInfo
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- CN113845510A CN113845510A CN202010593529.4A CN202010593529A CN113845510A CN 113845510 A CN113845510 A CN 113845510A CN 202010593529 A CN202010593529 A CN 202010593529A CN 113845510 A CN113845510 A CN 113845510A
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- esomeprazole
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- omeprazole
- ammonia water
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- 229960004770 esomeprazole Drugs 0.000 title claims abstract description 37
- 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 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- -1 omeprazole thioether Chemical class 0.000 claims abstract description 37
- 229960000381 omeprazole Drugs 0.000 claims abstract description 35
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 7
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052719 titanium Inorganic materials 0.000 claims abstract description 5
- 239000010936 titanium Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 114
- 238000003756 stirring Methods 0.000 claims description 53
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 43
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 31
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 22
- 238000001816 cooling Methods 0.000 claims description 22
- 239000000706 filtrate Substances 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 18
- 238000000605 extraction Methods 0.000 claims description 13
- UJMZZAZBRIPOHZ-UHFFFAOYSA-N 2-ethylhexan-1-ol;titanium Chemical compound [Ti].CCCCC(CC)CO UJMZZAZBRIPOHZ-UHFFFAOYSA-N 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 10
- WMKGMCCZGTXXQU-UHFFFAOYSA-N 2,3-benzodioxine-1,4-dione Chemical compound C1=CC=C2C(=O)OOC(=O)C2=C1 WMKGMCCZGTXXQU-UHFFFAOYSA-N 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- XURCIPRUUASYLR-UHFFFAOYSA-N Omeprazole sulfide Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 4
- 239000007864 aqueous solution Substances 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 17
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical group [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 abstract description 16
- 150000003457 sulfones Chemical class 0.000 abstract description 14
- 238000007254 oxidation reaction Methods 0.000 abstract description 7
- 239000000411 inducer Substances 0.000 abstract description 5
- 230000003647 oxidation Effects 0.000 abstract description 5
- 150000002978 peroxides Chemical class 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- 239000010410 layer Substances 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000007788 liquid Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000012362 glacial acetic acid Substances 0.000 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 description 8
- 239000000203 mixture Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 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 5
- 230000000052 comparative effect Effects 0.000 description 5
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 2
- 229960000496 esomeprazole sodium Drugs 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- GDKAXSGMPFSRJY-UHFFFAOYSA-J 2-ethylhexanoate;titanium(4+) Chemical compound [Ti+4].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O GDKAXSGMPFSRJY-UHFFFAOYSA-J 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- IXEQEYRTSRFZEO-UHFFFAOYSA-N Omeprazole sulfone Chemical compound N1C2=CC(OC)=CC=C2N=C1S(=O)(=O)CC1=NC=C(C)C(OC)=C1C IXEQEYRTSRFZEO-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of esomeprazole, which comprises the steps of taking omeprazole thioether as a starting raw material and D-diethyl tartrate and 2-ethyl-1-titanium hexanoate as inducers in a solvent, and carrying out asymmetric oxidation by using phthalic acid based peroxide to obtain the esomeprazole with high yield, wherein the ee% is more than 99.6%, the peroxide impurity 'sulfone' is less than or equal to 0.032%, no titanium residue exists, and the preparation method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of esomeprazole.
Background
Esomeprazole sodium (Esomeprazole sodium), chemically known as S-5-methoxy-2- { [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl } -1H-benzimidazole sodium, is the sodium salt of omeprazole, a single enantiomer of S- (-) -omeprazole developed by astrazeneca. It was the first optically pure proton pump inhibitor marketed in europe in 2003. The medicine is mainly used for treating gastric ulcer, duodenal ulcer, digestive esophagitis and gastritis, is the first choice medicine for treating gastric acid related diseases at present, and has the following structural formula:
esomeprazole is a single enantiomer of omeprazole, S- (-) -omeprazole. The literature reports that there are mainly 3 methods for synthesizing S- (-) -omeprazole:
patents WO2002098423a1, WO2006094904a1 and WO2007013743a1 disclose techniques for obtaining esomeprazole by resolving omeprazole racemates with different chiral resolving agents to obtain esomeprazole inclusion complexes and then dissociating the esomeprazole inclusion complexes. The resolution technology wastes 50% of omeprazole, and the resolution and dissociation steps are complex, so that the method is not suitable for large-scale production.
In the patent WO96/17076A1 and WO96/17077A1, biological enzymes are used for oxidizing omeprazole thioether or reducing omeprazole sulfone to obtain single enantiomer S- (-) -omeprazole of omeprazole. The technology needs special production devices, the process is strictly controlled and tedious, and the cost is high.
WO96/02535A1 adopts an asymmetric oxidation technology and uses a chiral catalyst to prepare esomeprazole, and compared with the former two technologies, the technology is convenient and easy to implement, and the product has high optical purity but low yield which is lower than 50%.
CN1157614A and WO2010148314A3 use 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole, i.e. omeprazole thioether, as a starting material, and diethyl D-tartrate and tetraisopropyl titanate as inducers to asymmetrically oxidize cumene hydroperoxide to esomeprazole with a calculated yield of over 85%. This process route is uncontrolled on the oxidation product impurity "sulfone", which is structurally similar to the product and difficult to remove in subsequent refining processes.
The technology disclosed in patent CN106366070A also adopts an asymmetric oxidation method, uses omeprazole thioether as an initial raw material, uses diethyl D-tartrate and tetraisopropyl titanate as inducers, and oxidizes cumene hydroperoxide into esomeprazole asymmetrically, and the reaction process uses HPLC detection to control the residual content of omeprazole thioether in the asymmetric oxidation reaction process to be less than or equal to 14%, and the content of peroxidized impurity "sulfone" to be less than or equal to 3%, and stops the reaction, so as to achieve the purpose of controlling peroxidized impurity "sulfone" to meet the requirements of standard bulk drugs, which is cumbersome.
At present, the literature reports that the method for synthesizing S- (-) -omeprazole uses titanate as an inducer, so that the titanium residue in the raw material medicine is high, and certain potential safety hazard is caused.
Therefore, it is urgent to find a new method for increasing the enantiomeric percentage of the chiral compound esomeprazole and simultaneously reducing the impurity content, particularly reducing the titanium residue.
Disclosure of Invention
The invention aims to provide a preparation method of esomeprazole with low specific impurity content, no titanium residue and high enantiomer percentage.
The inventor of the invention unexpectedly finds that the esomeprazole without the characteristic of the asymmetric thioether oxide shows better characteristic of the asymmetric thioether oxide in a specific reaction system, improves the percentage content of enantiomers, reduces the content of impurities, and can also solve the problem of higher titanium residue in the bulk drugs.
The invention provides a preparation method of esomeprazole, which comprises the following technical scheme: omeprazole thioether reacts with phthalic peroxide at 25-35 ℃ in the presence of D- (-) -diethyl tartrate, an organic base and 2-ethyl-1-hexanol titanium to generate esomeprazole.
Specifically, the method comprises the following steps:
mixing D- (-) -diethyl tartrate, 2-ethyl-1-titanium hexanoate and omeprazole thioether at 35-45 ℃, and stirring at a constant temperature; then cooling to 15-25 ℃, adding organic alkali and phthalic peroxide, and stirring while keeping the temperature; and after the reaction is finished, performing extraction treatment to obtain the esomeprazole.
The first heat preservation stirring time is 0.1-2 hours; preferably 0.5-1.5 hours; the second heat preservation stirring time is 0.5 to 3 hours; preferably 1-2.5 hours.
Preferably, the organic solvent is at least one of ethyl acetate, propyl acetate, butyl acetate or isopropyl acetate; more preferably ethyl acetate.
The feeding mass-volume ratio of the omeprazole thioether to the organic solvent is 1: 3-20; in some embodiments, the ratio is 1:8 to 10.
The feeding molar ratio of the omeprazole thioether to the D- (-) -diethyl tartrate is 1: 0.6-0.8; preferably 1: 0.7.
The feeding molar ratio of the omeprazole thioether to the 2-ethyl-1-hexanol titanium is 1: 0.3-0.5; preferably 1: 0.4. The feeding molar ratio of the omeprazole thioether to the organic base is 1: 1-1.2; preferably 1: 1.1.
The feeding molar ratio of the omeprazole thioether to the phthalic peroxide is 1: 1.0-1.3; preferably 1: 1.2.
Preferably, the temperature of the reaction system is 15-25 ℃ when the organic base is added. In some embodiments, the organic base is one or more of trimethylamine, triethylamine, pyridine, 2, 6-lutidine, N, N-diisopropylethylamine; n, N-diisopropylethylamine is preferred.
The preparation process includes the following specific operations: adding omeprazole thioether into an organic solvent, heating to 35-45 ℃, stirring until the omeprazole thioether is dissolved, sequentially adding D- (-) -diethyl tartrate and 2-ethyl-1-titanium hexanoate, and stirring while keeping the temperature; then cooling to 15-25 ℃, and then sequentially adding organic alkali and phthalic peroxide to stir for reaction; after the reaction is finished, adding an ammonia water solution for extraction twice, combining water phases, adding activated carbon, stirring at room temperature for decoloration, filtering, adding an organic solvent into the water phases, controlling the temperature of the filtrate to be 5-10 ℃, adjusting the pH value to be 7.0-8.0 by using organic acid, extracting, combining organic phases, washing by using a saturated sodium chloride water solution for suction filtration, and concentrating the filtrate under reduced pressure to obtain a viscous oily substance, namely esomeprazole.
Preferably, the ammonia water solution is 15 +/-5% of ammonia water solution, and the mass volume ratio of the omeprazole thioether to the ammonia water solution is 1: 24-27; preferably 1: 25.
Preferably, the temperature is 5-10 ℃ when the pH is adjusted.
Compared with the prior art, the invention has the following remarkable advantages:
an asymmetric oxidation reaction system is innovatively used, diethyl D-tartrate and titanium 2-ethyl-1-hexanoate are used as inducers, and phthalic peroxide participates in asymmetric oxidation of omeprazole thioether to obtain esomeprazole with high optical purity, wherein the ee% is over 99.6%, titanium residues are not detected, and the peroxide impurity 'sulfone' is less than or equal to 0.032%. Mild reaction conditions, low energy consumption and suitability for large-scale production.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which should be understood as being for illustrative purposes only and not limiting the scope of the present invention, and that changes and modifications apparent to those of ordinary skill in the art in light of the present invention are also included within the scope of the present invention.
Example 1
Adding 329mL of ethyl acetate into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating in a water bath to 35-45 ℃, adding 14.43g (0.07mol) of D- (-) -diethyl tartrate and 22.59g (0.04mol) of 2-ethyl-1-hexanol titanium, keeping the temperature and stirring for 1 hour, cooling to 18-22 ℃, adding 14.22g (0.11mol) of N, N-diisopropylethylamine, adding 19.68g (0.12mol) of phthaloyl peroxide, keeping the temperature and reacting for 2-3 hours, adding 274.2mL of 15% ammonia water into the reaction solution after the reaction is finished, stirring for 20 minutes, extracting and separating liquid, extracting an organic layer twice by using 15% ammonia water, extracting 274.2mL each time, combining ammonia water layers, adding 4g of activated carbon, stirring and decolorizing at room temperature for 2 hours, filtering, adding 800mL of ethyl acetate into the ammonia water layer, cooling in an ice bath to 5-10 ℃, and (3) dropwise adding glacial acetic acid to adjust the pH value to 7.0-8.0, separating liquid after dripping, adding 450mL of ethyl acetate into a water layer for secondary extraction, combining ethyl acetate layers, washing for 2 times by using saturated saline solution, drying for 4 hours by using anhydrous sodium sulfate, filtering, controlling the temperature of filtrate to be 35-45 ℃, and concentrating in vacuum until the filtrate is dried to obtain 30.95g of viscous oily matter with the yield of 89.7%. Purity 99.68%, peroxidation impurity "sulfone": 0.006%, no titanium residue was detected, and ee% was 99.9%.
Example 2
Adding 263.2mL of ethyl acetate into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating in a water bath to 35-45 ℃, adding 12.37g (0.06mol) of D- (-) -diethyl tartrate and 16.94g (0.03mol) of 2-ethyl-1-hexanol titanium, keeping the temperature and stirring for 1 hour, cooling to 18-22 ℃, adding 12.93g (0.1mol) of N, N-diisopropylethylamine, adding 16.4g (0.1mol) of phthalic acid peroxide, keeping the temperature and reacting for 2-3 hours, adding 15% ammonia water 263.2mL into the reaction solution after the reaction is finished, stirring for 20min, extracting and separating liquid, extracting the organic layer twice by 15% ammonia water, each time of 263.2mL, combining ammonia water layers, adding 4g of activated carbon, stirring and decolorizing for 2 hours at room temperature, filtering, adding 800mL of ethyl acetate into the ammonia water layer, cooling to 5-10 ℃, and (3) dropwise adding glacial acetic acid to adjust the pH value to 7.0-8.0, separating liquid after dripping, adding 450mL of ethyl acetate into a water layer for secondary extraction, combining ethyl acetate layers, washing for 2 times by using saturated saline solution, drying for 4 hours by using anhydrous sodium sulfate, filtering, controlling the temperature of filtrate to be 35-45 ℃, and concentrating in vacuum until the filtrate is dried to obtain 30.46g of viscous oily matter, wherein the yield is 88.3%. The purity was 99.61%, the content of the peroxidated impurity "sulfone" was 0.018%, no titanium remained, and the ee% was 99.7%.
Example 3
Adding 329mL of butyl acetate into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating in a water bath to 35-45 ℃, adding 14.43g (0.07mol) of D- (-) -diethyl tartrate and 22.59g (0.04mol) of 2-ethyl-1-hexanol titanium, keeping the temperature and stirring for 1 hour, cooling to 18-22 ℃, adding 14.22g (0.11mol) of N, N-diisopropylethylamine, adding 21.34g (0.13mol) of phthaloyl peroxide, keeping the temperature and reacting for 2-3 hours, adding 274.2mL of 15% ammonia water into the reaction solution after the reaction is finished, stirring for 20 minutes, extracting and separating liquid, extracting an organic layer twice by using 15% ammonia water, extracting 274.2mL each time, combining ammonia water layers, adding 4g of activated carbon, stirring and decolorizing at room temperature for 2 hours, filtering, adding 800mL of ethyl acetate into the ammonia water layer, cooling in an ice bath to 5-10 ℃, and (3) dropwise adding glacial acetic acid to adjust the pH value to 7.0-8.0, separating liquid after dripping, adding 450mL of ethyl acetate into a water layer for secondary extraction, combining ethyl acetate layers, washing for 2 times by using saturated saline solution, drying for 4 hours by using anhydrous sodium sulfate, filtering, controlling the temperature of filtrate to be 35-45 ℃, and concentrating in vacuum until the filtrate is dried to obtain 28.95g of viscous oily matter with the yield of 83.9%. The purity was 98.93%, the content of peroxidized impurity "sulfone" was 0.021%, no titanium residue was detected, and ee% was 99.6%.
Example 4
Adding 296.1mL of ethyl acetate into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating in a water bath to 35-45 ℃, adding 16.50g (0.08mol) of D- (-) -diethyl tartrate and 28.24g (0.05mol) of 2-ethyl-1-hexanol titanium, keeping the temperature and stirring for 1 hour, cooling to 15-18 ℃, adding 15.51g (0.12mol) of N, N-diisopropylethylamine, adding 21.34g (0.13mol) of phthalic acid peroxide, keeping the temperature and reacting for 2-3 hours, adding 296.1mL of 15% ammonia water into the reaction solution after the reaction is finished, stirring for 20 minutes, extracting and separating liquid, extracting the organic layer twice by 15% of ammonia water, each time of 296.1mL, combining the ammonia water layers, adding 4g of activated carbon, stirring and decolorizing at room temperature for 2 hours, filtering, adding 800mL of ethyl acetate into the ammonia water layer, cooling to 5-10 ℃, and dropwise adding glacial acetic acid to adjust the pH value to 7.0-8.0, separating liquid after dripping, adding 450mL of ethyl acetate into a water layer for secondary extraction, combining ethyl acetate layers, washing for 2 times by using saturated saline solution, drying for 4 hours by using anhydrous sodium sulfate, filtering, controlling the temperature of filtrate to be 35-45 ℃, and concentrating in vacuum until the filtrate is dried to obtain 28.39g of viscous oily matter with the yield of 82.3%. The purity was 98.27%, the content of the peroxidated impurity "sulfone" was 0.032%, no titanium residue was detected, and ee% was 99.6%.
Comparative example 1
Adding 329mL of toluene into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating in a water bath to 35-45 ℃, adding 14.43g (0.07mol) of D- (-) -diethyl tartrate and 11.37g (0.04mol) of tetraisopropyl titanate, keeping the temperature and stirring for 1 hour, cooling to 28-32 ℃, adding 14.22g (0.11mol) of N, N-diisopropylethylamine, adding 18.24g (0.12mol) of cumene hydroperoxide, keeping the temperature and reacting for 2-3 hours, adding 274.2mL of 15% ammonia water into a reaction solution after the reaction is finished, stirring for 20 minutes, extracting and separating liquid, extracting an organic layer twice by using 15% ammonia water, extracting 74.2mL each time, combining an ammonia water layer, adding 4g of activated carbon, stirring and decolorizing at room temperature for 2 hours, filtering, adding 800mL of ethyl acetate into the ammonia water layer, cooling to 5-10 ℃ in an ice bath, dropwise adding glacial acetic acid, adjusting the pH to 7.0-8.0, after the liquid is completely dropped, 450mL of ethyl acetate is added into the water layer for secondary extraction, the ethyl acetate layers are combined, the mixture is washed for 2 times by saturated saline solution, dried for 4 hours by anhydrous sodium sulfate, filtered, and the filtrate is controlled to be 35-45 ℃ and concentrated to be dry in vacuum, so that 26.67g of viscous oily matter is obtained, and the yield is 77.3%. The purity was 95.31%, the content of peroxidized impurity "sulfone" was 2.21%, the titanium residue was 480ppm, and the ee% was 97.2%.
Comparative example 2
Adding 329mL of toluene into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating the mixture in a water bath to 35-45 ℃, adding 14.43g (0.07mol) of D- (-) -diethyl tartrate and 22.59g (0.04mol) of 2-ethyl-1-hexanol titanium, keeping the temperature and stirring the mixture for 1 hour, cooling the mixture to 22-25 ℃, adding 14.22g (0.11mol) of N, N-diisopropylethylamine, adding 18.24g (0.12mol) of cumene hydroperoxide, keeping the temperature and reacting the mixture for 2-3 hours, adding 274.2mL of 15% ammonia water into the reaction solution after the reaction is finished, stirring the mixture for 20 minutes, extracting the separated liquid, extracting the organic layer twice by 15% and 274.2mL each time, combining the ammonia water layers, adding 4g of activated carbon, stirring and decoloring the organic layer at room temperature for 2 hours, filtering the ammonia water layer, adding 800mL of ethyl acetate into the ammonia water layer, cooling the ice bath to 5-10 ℃, and dropwise adding glacial acetic acid to adjust the pH value to 7.0-8.0, after liquid dripping, adding 450mL of ethyl acetate into a water layer for secondary extraction, combining ethyl acetate layers, washing for 2 times by using saturated saline solution, drying for 4 hours by using anhydrous sodium sulfate, filtering, controlling the temperature of filtrate to be 35-45 ℃, and performing vacuum concentration until the filtrate is dried to obtain 26.91g of viscous oily matter, wherein the yield is 78.0%. The purity was 96.03%, the content of the oxidized impurity "sulfone" was 2.19%, the titanium residue was 350ppm, the ee% was 97.5%
Comparative example 3
Adding 329mL of ethyl acetate into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating in a water bath to 35-45 ℃, adding 14.43g (0.07mol) of D- (-) -diethyl tartrate and 11.37g (0.04mol) of tetraisopropyl titanate, keeping the temperature and stirring for 1 hour, cooling to 18-22 ℃, adding 14.22g (0.11mol) of N, N-diisopropylethylamine, adding 19.68g (0.12mol) of phthalic peroxide, keeping the temperature and reacting for 2-3 hours, adding 74.2mL of 15% ammonia water into the reaction solution after the reaction is finished, stirring for 20 minutes, extracting and separating liquid, extracting an organic layer twice by 15% ammonia water, each time extracting by 274.2mL, combining an ammonia water layer, adding 4g of activated carbon, stirring and decoloring for 2 hours at room temperature, filtering, adding 800mL of ethyl acetate into the ammonia water layer, cooling to 5-10 ℃ in an ice bath, dropwise adding glacial acetic acid to adjust the pH to 7.0-8.0, after the liquid is completely dropped, 450mL of ethyl acetate is added into the water layer for secondary extraction, the ethyl acetate layers are combined, the mixture is washed for 2 times by saturated saline solution, dried for 4 hours by anhydrous sodium sulfate, filtered, and the filtrate is controlled to be 35-45 ℃ and concentrated to be dry in vacuum, so that 27.32g of viscous oily matter is obtained, and the yield is 79.2%. The purity was 96.80%, the content of peroxidized impurity "sulfone" was 1.05%, the titanium residue was 340ppm, the ee% was 97.9%.
Comparative example 4
Adding 329mL of ethyl acetate into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating in a water bath to 35-45 ℃, adding 14.43g (0.07mol) of D- (-) -diethyl tartrate and 22.59g (0.04mol) of 2-ethyl-1-hexanol titanium, keeping the temperature and stirring for 1 hour, cooling to 18-22 ℃, adding 14.22g (0.11mol) of N, N-diisopropylethylamine, adding 15.36g (0.12mol) of cyclopropane peroxide, keeping the temperature and reacting for 2-3 hours, adding 274.2mL of 15% ammonia water into the reaction solution after the reaction is finished, stirring for 20min, extracting and separating liquid, extracting an organic layer twice by 15% and 274.2mL each time, combining an ammonia water layer, adding 4g of activated carbon, stirring and decolorizing at room temperature for 2 hours, filtering, adding 800mL of ethyl acetate into the ammonia water layer, cooling to 5-10 ℃, and dropwise adding glacial acetic acid to adjust the pH value to 7.0-8.0, after liquid dripping, adding 450mL of ethyl acetate into a water layer for secondary extraction, combining ethyl acetate layers, washing for 2 times by using saturated saline solution, drying for 4 hours by using anhydrous sodium sulfate, filtering, controlling the temperature of filtrate to be 35-45 ℃, and performing vacuum concentration until the filtrate is dried to obtain 27.01g of viscous oily matter, wherein the yield is 78.3%. The purity was 96.47%, the content of peroxidized impurity "sulfone" was 1.94%, the titanium residue was 310ppm, the ee% was 97.8%.
Comparative example 5
Adding 329mL of ethyl acetate into a 1000mL three-neck round-bottom flask, adding 32.9g (0.1mol) of omeprazole thioether under stirring, heating in a water bath to 35-45 ℃, adding 14.43g (0.07mol) of D- (-) -diethyl tartrate and 22.59g (0.04mol) of 2-ethyl-1-hexanol titanium, keeping the temperature and stirring for 1 hour, cooling to 22-25 ℃, adding 14.22g (0.11mol) of N, N-diisopropylethylamine, adding 10.81g (0.12mol) of tert-butyl hydroperoxide, keeping the temperature and reacting for 2-3 hours, adding 274.2mL of 15% ammonia water into the reaction solution after the reaction is finished, stirring for 20min, extracting the separated liquid, extracting the organic layer twice by 15% ammonia water, extracting 274.2mL each time, combining the ammonia water layers, adding 4g of activated carbon, stirring and decolorizing at room temperature for 2 hours, filtering, adding 800mL of ethyl acetate into the ammonia water layer, cooling to 5-10 ℃ in an ice bath, and dropwise adding glacial acetic acid to adjust the pH value to 7.0-8.0, after liquid dripping, adding 450mL of ethyl acetate into a water layer for secondary extraction, combining ethyl acetate layers, washing for 2 times by using saturated saline solution, drying for 4 hours by using anhydrous sodium sulfate, filtering, controlling the temperature of filtrate to be 35-45 ℃, and performing vacuum concentration until the filtrate is dried to obtain 27.08g of viscous oily matter with the yield of 78.5%. The purity was 96.29%, the content of peroxidized impurity "sulfone" was 2.05%, the titanium residue was 320ppm, the ee% was 97.6%.
Claims (10)
1. The preparation method of esomeprazole is characterized by comprising the following steps: mixing D- (-) -diethyl tartrate, 2-ethyl-1-titanium hexanoate and omeprazole thioether at 35-45 ℃, and stirring at a constant temperature; then cooling to 15-25 ℃, adding organic alkali and phthalic peroxide, and stirring while keeping the temperature; and after the reaction is finished, performing extraction treatment to obtain the esomeprazole.
2. The process for preparing esomeprazole according to claim 1, wherein the first stirring with heat preservation is carried out for 0.1-2 hours; the second heat preservation stirring time is 0.5-3 hours.
3. The process for preparing esomeprazole according to claim 1, wherein the reaction is carried out in an organic solvent, which is one or more of ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate.
4. The preparation method of esomeprazole according to claim 3, wherein the feeding mass volume ratio of the omeprazole sulfide to the organic solvent is 1: 3-20.
5. The preparation method of esomeprazole of claim 1, wherein the feeding molar ratio of omeprazole thioether to diethyl D- (-) -tartrate is 1: 0.6-0.8.
6. The preparation method of esomeprazole according to claim 1, wherein the feeding molar ratio of omeprazole thioether to 2-ethyl-1-hexanol titanium is 1: 0.3-0.5.
7. The process for preparing esomeprazole according to claim 1, wherein the organic base is one or more of trimethylamine, triethylamine, pyridine, 2, 6-lutidine, N, N-diisopropylethylamine.
8. The preparation method of esomeprazole according to claim 1, wherein the feeding molar ratio of omeprazole thioether to phthalyl peroxide is 1: 1-1.3.
9. The preparation method of esomeprazole according to claim 1, which comprises the specific steps of: adding an organic solvent into a reaction bottle, adding omeprazole thioether under stirring, heating to 35-45 ℃, stirring until the omeprazole thioether is dissolved, sequentially adding D- (-) -diethyl tartrate and 2-ethyl-1-hexanol titanium, stirring for reaction, cooling to 15-25 ℃, sequentially adding an organic base and phthalic acid peroxide, stirring for reaction, adding an ammonia water solution for extraction, combining water phases, adding activated carbon, stirring and decoloring at room temperature, filtering, adding ethyl acetate into the water phase, regulating the temperature to 5-10 ℃, adjusting the pH value to 7.0-8.0 with an organic acid, extracting with ethyl acetate, combining organic phases, washing with a saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, carrying out suction filtration, and concentrating the filtrate under reduced pressure to obtain esomeprazole.
10. The preparation method of esomeprazole of claim 9, wherein the ammonia water solution is 15 ± 5% of the ammonia water solution, and the mass volume ratio of the omeprazole sulfide to the ammonia water solution is 1: 24-27.
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