CN106083819A - A kind of preparation method of omeprazole - Google Patents
A kind of preparation method of omeprazole Download PDFInfo
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- CN106083819A CN106083819A CN201610405440.4A CN201610405440A CN106083819A CN 106083819 A CN106083819 A CN 106083819A CN 201610405440 A CN201610405440 A CN 201610405440A CN 106083819 A CN106083819 A CN 106083819A
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- omeprazole
- methoxyl group
- titanium
- dimethyl
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- 229960000381 omeprazole Drugs 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 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 title description 60
- 238000003756 stirring Methods 0.000 claims abstract description 22
- -1 methoxyl group Chemical group 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- LCKIEQZJEYYRIY-UHFFFAOYSA-N Titanium ion Chemical compound [Ti+4] LCKIEQZJEYYRIY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007800 oxidant agent Substances 0.000 claims abstract description 10
- 230000001590 oxidative effect Effects 0.000 claims abstract description 10
- 238000005352 clarification Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 3
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 claims abstract 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000009413 insulation Methods 0.000 claims description 9
- YQHLDYVWEZKEOX-UHFFFAOYSA-N cumene hydroperoxide Chemical compound OOC(C)(C)C1=CC=CC=C1 YQHLDYVWEZKEOX-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- 230000006837 decompression Effects 0.000 claims description 7
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 25
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical class C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 abstract description 2
- 239000012141 concentrate Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000012535 impurity Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- 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 12
- 230000000052 comparative effect Effects 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 238000001514 detection method Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 2
- 229960004770 esomeprazole Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101000671811 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 37 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 102100040111 Ubiquitin carboxyl-terminal hydrolase 37 Human genes 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002432 hydroperoxides Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000014759 maintenance of location Effects 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000333 poly(propyleneimine) Polymers 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 230000001629 suppression Effects 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses the preparation method of a kind of omeprazole, including: 5 methoxyl group 2 [[(4 methoxyl groups 3,5 dimethyl 2 pyridine radicals) methyl] sulfenyl] 1H benzimidazoles, sour four alkane esters of titanium (IV) are stirred in aprotic organic solvent by (a)；B () dissolves clarification after, lower the temperature and drip oxidant；C () concentrate, stir and wash, filter, be drying to obtain omeprazole.The method is reproducible, easy and simple to handle, and product yield, purity are high, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to the preparation method of a kind of omeprazole.
Background technology
Omeprazole (Omeprazole), chemical entitled 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine
Base) methyl] sulfinyl]-1H-benzimidazole.Omeprazole is the class proton pump inhibitor developed by AstraZeneca
(proton pump inhibitors, PPIs), reduces gastric acid secretion by specificity suppression parietal cell proton pump.In recent years should
Medicine, always situated in the prostatitis of whole world best-selling drugs, has wide market prospect.
Prior art report omeprazole be required for greatly through 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-
2-pyridine radicals)-methyl]-sulfenyl] and-1H-benzimidazole oxidation and prepare.CN91103923.6、CN96199057.0、CN
99811908.3, the Chinese patent such as CN200910118936.3, CN201310167052.3 disclose with metachloroperbenzoic acid,
Peroxy acids oxidation 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl] such as peracetic acid-
1H-benzimidazole and the method for preparing omeprazole.Owing to omeprazole is unstable under acidic condition, produce after peroxy acid reduction
Raw acidic materials can cause product to be degraded, and affects product quality.Therefore said method need to be relatively low in temperature or condition is relatively harsh
Under conditions of carry out, to control the degraded of sample.
The Chinese patents such as CN200480022239.3, CN200710022274.0, CN201510964371.6 or patent Shen
Please disclose with oxidation 5-first such as sodium hypochlorite, 1-hydroxyl-1,2-benzenesulfonyl-3 (1 hydrogen)-one-1-oxide (IBX), hydrogen peroxide
Epoxide-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl]-1H-benzimidazole and prepare omeprazole
Method.Owing to the oxidisability of above-mentioned oxidant is relatively strong, it is easily generated the peroxidating impurity of formula III.This impurity is tied with product
Structure is similar, and character is close, it is more difficult to remove.
Although Chinese patent CN98801797.0 discloses with peroxide alcohol oxidation 5-methoxyl group-2-such as cumyl hydroperoxides
[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl]-1H-benzimidazole and the method for preparing omeprazole,
But the method need to add the additive such as part, organic base, reaction system is more complicated, and post processing is relatively complicated.
Therefore, a kind of reproducible, easy and simple to handle, product yield of exploitation and purity are high, are suitable for the Aomei of industrialized production
Draw the preparation technology of azoles significant.
Summary of the invention
Inventor developed the preparation method of a kind of omeprazole, the method is reproducible, easy and simple to handle, product yield
High with purity, it is suitable for industrialized production.
It is an object of the invention to provide the preparation method of a kind of omeprazole being suitable to industrialization.
In embodiments of the invention, the present invention provides the preparation method of a kind of omeprazole, and the method includes as follows
Step:
A () is by 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl]-1H-benzo
Imidazoles (i.e. compound of formula I), sour four alkane esters of titanium (IV), in aprotic organic solvent, stir at 30-60 DEG C；
(b) dissolve clarification after, lower the temperature-5 DEG C to 25 DEG C and to step (a) gained solution drip oxidant, drip finish after, guarantor
Temperature-5 DEG C to 25 DEG C and stirs 4-8h；
C described aprotic organic solvent decompression in step (b) stirring mixture is steamed by (), residue acetone or second
Nitrile stirs to be washed, and filters, is drying to obtain omeprazole (i.e. Formula II compound)；
Wherein, described oxidant is cumyl hydroperoxide or tert-butyl hydroperoxide.
In embodiments of the invention, 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-first
Base]-sulfenyl]-1H-benzimidazole (i.e. compound of formula I) can be prepared according to methods known in the art, such as Chinese patent
CN201310167052.3。
In a kind of preferred embodiment of the present invention, the preparation method of a kind of omeprazole that the present invention provides, wherein,
In step (a), 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-the sulfenyl]-1H-of 1 gram
Benzimidazole is dissolved in 5-20ml, is preferably dissolved in the aprotic organic solvent of 5-15ml.
In a kind of preferred embodiment of the present invention, the preparation method of a kind of omeprazole that the present invention provides, wherein,
Aprotic organic solvent in described step (a) is toluene, acetone, dichloromethane or ethyl acetate, preferably toluene.
In a kind of preferred embodiment of the present invention, the preparation method of a kind of omeprazole that the present invention provides, wherein,
Sour four alkane esters of titanium (IV) in described step (a) are sour four isopropyl esters of titanium (IV) or titanium (IV) acid orthocarbonate.
In a kind of preferred embodiment of the present invention, the preparation method of a kind of omeprazole that the present invention provides, wherein,
Sour four alkane esters of titanium (IV) and 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-first in described step (a)
Base]-sulfenyl] mol ratio of-1H-benzimidazole is 0.05:1-1:1, preferably 0.1:1-0.6:1, more preferably 0.3:1-
0.5:1。
In a kind of preferred embodiment of the present invention, the preparation method of a kind of omeprazole that the present invention provides, wherein,
System temperature is down to-5 to 25 DEG C and-5 to 25 DEG C of insulations by described step (b), preferably system temperature is down to 0-15 DEG C and
0-15 DEG C of insulation, more preferably 5-10 DEG C.
In a kind of preferred embodiment of the present invention, the preparation method of a kind of omeprazole that the present invention provides, wherein,
In described step (b), the time of dropping oxidant is 10-60 minute, preferably 20-40 minute.
In a kind of preferred embodiment of the present invention, the preparation method of a kind of omeprazole that the present invention provides, wherein,
Oxidant and 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl] in described step (b)-
The mol ratio of 1H-benzimidazole is 1:1-2:1, preferably 1.1:1-1.5:1.
In embodiments of the invention, the preparation method of a kind of omeprazole that the present invention provides, obtain in step (c)
Purification step is included further after omeprazole:
Omeprazole is dissolved in methanol/water (volume ratio is 1:1) and sodium hydrate aqueous solution；Then solution is cooled to
0-5 DEG C, it is maintained at less than 5 DEG C, drips acetic acid, when adjusting pH to 10.5-11.0, add crystal seed omeprazole (the inventive method system
Standby and purity ＞ 99.5%), continue to adjust pH to 9.0, insulated and stirred is after 30 minutes, filters, 10ml methanol/water used successively by filter cake
(volume ratio 1:1), methanol wash, and be vacuum dried, obtain white solid at 30-35 DEG C.
Compared with prior art, the chromatographic purity of the omeprazole tool more than 99% that said method of the present invention prepares, formula III
The content of Peroxidation Product is about 0.5%.
Therefore, the invention provides the preparation method of a kind of omeprazole, the method have reproducible, easy and simple to handle,
Product yield and purity are high, are suitable for the advantages such as industrialized production.
Detailed description of the invention
The present invention is further illustrated below by embodiment.Should correct understanding: in embodiments of the invention
Method is only used for illustrating that the present invention provides rather than limitation of the present invention, so, under the method premise of the present invention
The simple modifications of the present invention is all belonged to the scope of protection of present invention.
Following prepare this omeprazole time, 5-methoxyl group-2-[[(4-methoxyl group-3, the 5-dimethyl-2-pyridine of use
Base)-methyl]-sulfenyl]-1H-benzimidazole (omeprazole thioether) is referred to patent CN201310167052.3 embodiment 1
Method prepare, and purification process can be used to make its chromatographic purity more than 98%, in order to for the preparation of omeprazole.
In the present invention, omeprazole Related substance method, with reference to USP37 and EP8.0, analyzes method as follows:
There is a related substance HPLC detection method:
Fixing phase: C8 post (4.6 × 150mm × 5 μm)
Flowing phase: phosphate buffer (weighs in five water sodium dihydrogen phosphate 3.58g to 1000ml water, adjusts pH=with phosphoric acid
7.9)-acetonitrile (73:27)
Detection wavelength: 280nm
Flow velocity: 1.0ml/min
Sample size: 20 μ l
Measure: take this product appropriate, adding flowing and make dissolving mutually and be diluted in every 1ml the solution containing about 0.2mg, as examination
Product solution；Precision measures 1ml, puts in 100ml measuring bottle, add flowing phase dilution to scale, shake up, as contrast solution.According to efficiently
Liquid chromatography for measuring, takes contrast solution 20 μ l and injects chromatograph of liquid, regulate detection sensitivity, make the peak of main constituent chromatographic peak
The 10%～25% of a height of full scale；Precision measures need testing solution and each 20 μ l of contrast solution, is injected separately into chromatograph of liquid,
Record chromatogram is to 3 times of main constituent peak retention time.
The preparation of embodiment 1 omeprazole
By 10g omeprazole thioether, 0.43g tetraisopropyl titanate in 200ml toluene, stir to dissolving clear at 40 DEG C
Clearly.It is cooled to-5 DEG C, insulation dropping 4.6g cumyl hydroperoxide, within 10 minutes, drip off, drip after finishing ,-5 DEG C of insulated and stirred 8h.Will
Organic solvent decompression steams, and residue acetone stirs to be washed, and filters, is dried, obtains white solid 8.9g, molar yield 85%, chromatograph
Purity 99.39%, formula III peroxidating impurity content is 0.46%.
The preparation of embodiment 2 omeprazole
By 10g omeprazole thioether, 8.6g tetraisopropyl titanate in 50ml toluene, stir to dissolving clarification at 30 DEG C.
It is cooled to 25 DEG C, insulation dropping 9.2g cumyl hydroperoxide, within 60 minutes, drip off, drip after finishing, 25 DEG C of insulated and stirred 4h.By organic
Solvent under reduced pressure steams, and residue acetone stirs to be washed, and filters, is dried, obtains white solid 9.2g, molar yield 88%, chromatographic purity
99.35%, formula III peroxidating impurity content is 0.52%.
The preparation of embodiment 3 omeprazole
By 10g omeprazole thioether, 3.4g metatitanic acid orthocarbonate in 100ml toluene, stir to dissolving clarification at 60 DEG C.Fall
Temperature is to 10 DEG C, and insulation drips 4.1g tert-butyl hydroperoxide, within 30 minutes, drips off, and drips after finishing, 10 DEG C of insulated and stirred 6h.By organic molten
Agent decompression steams, and residue acetone stirs to be washed, and filters, is dried, obtains white solid 9.0g, molar yield 86%, chromatographic purity
99.42%, formula III peroxidating impurity content is 0.40%.
The preparation of embodiment 4 omeprazole
By 10g omeprazole thioether, 2.6g tetraisopropyl titanate in 100ml dichloromethane, at 35 DEG C, stirring is to dissolving
Clarification.It is cooled to 5 DEG C, insulation dropping 5.5g cumyl hydroperoxide, within 30 minutes, drip off, drip after finishing, 5 DEG C of insulated and stirred 5h.Will
Organic solvent decompression steams, and residue acetone stirs to be washed, and filters, is dried, obtains white solid 9.1g, molar yield 87%, chromatograph
Purity 99.46%, formula III peroxidating impurity content is 0.43%.
The preparation of embodiment 5 omeprazole
By 10g omeprazole thioether, 2.6g tetraisopropyl titanate in 120ml ethyl acetate, at 38 DEG C, stirring is to dissolving
Clarification.It is cooled to 5 DEG C, insulation dropping 5.0g cumyl hydroperoxide, within 25 minutes, drip off, drip after finishing, 5 DEG C of insulated and stirred 6h.Will
Organic solvent decompression steams, and residue acetone stirs to be washed, and filters, is dried, obtains white solid 9.0g, molar yield 86%, chromatograph
Purity 99.48%, formula III peroxidating impurity content is 0.44%.
The preparation of embodiment 6 omeprazole
By 10g omeprazole thioether, 3.6g tetraisopropyl titanate in 100ml acetone, stir to dissolving clarification at 40 DEG C.
It is cooled to 0 DEG C, insulation dropping 5.0g cumyl hydroperoxide, within 30 minutes, drip off, drip after finishing, 0 DEG C of insulated and stirred 8h.By organic molten
Agent decompression steams, and residue acetonitrile stirs to be washed, and filters, is dried, obtains white solid 8.8g, molar yield 84%, chromatographic purity
99.52%, formula III peroxidating impurity content is 0.35%.
The preparation of embodiment 7 omeprazole fine work
With reference to the process for purification in patent CN 99811908.3 embodiment 2, at 20 DEG C, 10g is prepared by embodiment 1
Omeprazole be dissolved in the sodium hydroxide of 73ml methanol/water (1:1) and 2.6ml 50%.Then solution is cooled to 3 DEG C, protects
Hold below 5 DEG C, dropping 25% acetic acid, adjust pH to 10.7 time, add crystal seed omeprazole (embodiment of the present invention 6 prepare and
Purity ＞ 99.5%) 0.5g, continue to adjust pH to 9.0, insulated and stirred is after 30 minutes, and 10ml methanol/water used successively by filtration, filter cake
(1:1), the methanol washing of pre-cooling at 10ml 5 DEG C, be vacuum dried at 35 DEG C, obtain white solid 9.3g, molar yield 93%, color
Spectral purity 99.89%, formula III peroxidating impurity content is 0.05%.
The preparation (preparing by the method " illustrated " in CN98801797.0) of comparative example 1 omeprazole
15.4g omeprazole thioether is dissolved in 70ml toluene.Solution is heated to 50 DEG C, and add water 0.03ml.Mix to this
Thing adds 8ml and contains the toluene solution of 2.02g diethyl tartrate. and the tetraisopropyl titanate of 1.33g.Mixture is cooled to
30 DEG C, successively add 0.962g N, N-diisopropyl ethyl amine and 8.21g cumyl hydroperoxide.At 30 DEG C, mixture quilt
Stir 5 hours, leach precipitated product, wash with 12ml toluene, obtain off-white color solid 12.6g, molar yield 78%, chromatographic purity
98.30%, formula III peroxidating impurity content is 1.5%.
The preparation of comparative example 2 omeprazole fine work
With reference to the process for purification in patent CN 99811908.3 embodiment 2, at 20 DEG C, 10g is prepared by comparative example 1
Omeprazole be dissolved in the sodium hydroxide of 73ml methanol/water (1:1) and 2.6ml 50%.Then solution is cooled to 3 DEG C, protects
Hold below 5 DEG C, dropping 25% acetic acid, adjust pH to 10.7 time, add crystal seed omeprazole (embodiment of the present invention 6 prepare and
Purity ＞ 99.5%) 0.5g, continue to adjust pH to 9.0, insulated and stirred is after 30 minutes, and 10ml methanol/water used successively by filtration, filter cake
(1:1), the methanol washing of pre-cooling at 10ml 5 DEG C, be vacuum dried at 35 DEG C, obtain white solid 9.2g, molar yield 92%, color
Spectral purity 99.48%, formula III peroxidating impurity content is 0.56%.
Prepare sample by embodiment 1-7 and comparative example 1-2 method thereof and carry out every detection, the results are shown in Table 1.
Table 1: embodiment 1-7 and comparative example 1-2 method thereof prepare sample detection result
From the data in table 1, the molar yield of the omeprazole product prepared by embodiment of the present invention 1-6 exists
84%-88%, prepares the omeprazole of gained according to comparative example 1 (preparing by the method " illustrated " in CN98801797.0) method
Yield about 78%；By embodiment of the present invention 1-6 prepare omeprazole product the equal ＞ of chromatographic purity 99%, formula
The equal ＜ of content 1% of III peroxidating impurity, and the chromatographic purity of the omeprazole product that comparative example 1 prepares is about 98%, formula
The content of III peroxidating impurity is about 1.5%.
The above results shows, the omeprazole prepared according to embodiment 1-6 compares the omeprazole prepared by comparative example 1,
There is higher chromatographic purity and more effective formula III peroxidating Control of Impurities, illustrate that the reaction condition of the present invention can be effective
Control to have related substance, improve product quality.
By the equal ＞ of yield 90% of the omeprazole fine work that the embodiment of the present invention 7 and comparative example 2 prepare；Implement by the present invention
The omeprazole fine work that example 7 prepares chromatographic purity be up to 99.89%, the content ＜ 0.1% of formula III peroxidating impurity, and
The chromatographic purity of the omeprazole fine work that comparative example 2 prepares is about 99.48%, and the content of formula III peroxidating impurity exists
About 0.56%.
The above results shows, the omeprazole prepared by the embodiment of the present invention 1 compares the omeprazole that comparative example 1 prepares,
Use process for purification disclosed in CN 99811908.3 to refine simultaneously, more can obtain meeting the omeprazole of medicinal requirements.
Additionally, the S configurational isomer (esomeprazole) of omeprazole can be prepared by the chiral separation of omeprazole.Therefore, this
The preparation method of bright omeprazole is to realize meeting medicinal requirements omeprazole or the industrialized production of esomeprazole crude drug
Lay the foundation.
Claims (8)
1. a preparation method for omeprazole, described preparation method comprises the following steps:
(a) by 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl]-1H-benzimidazole,
Sour four alkane esters of titanium (IV), in aprotic organic solvent, stir at 30-60 DEG C；
(b) dissolve clarification after, be cooled to-5 to 25 DEG C and to step (a) gained solution drip oxidant, drip finish after, insulation-5 to
25 DEG C of stirring 4-8h；
C described aprotic organic solvent decompression in step (b) stirring mixture is steamed by (), residue acetone or acetonitrile stir
Wash, filter, be drying to obtain omeprazole；
Wherein, oxidant described in step (b) is cumyl hydroperoxide or tert-butyl hydroperoxide.
Preparation method the most according to claim 1, wherein, in described step (a), the 5-methoxyl group-2-[[(4-of 1 gram
Methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl]-1H-benzimidazole is dissolved in 5-20ml, is preferably dissolved in 5-
In the described aprotic organic solvent of 15ml.
Preparation method the most according to claim 1, wherein, the described aprotic organic solvent in described step (a) is first
Benzene, acetone, dichloromethane or ethyl acetate, preferably toluene.
Preparation method the most according to claim 1, wherein, sour four alkane esters of titanium (IV) in described step (a) are titanium
(IV) sour four isopropyl esters or titanium (IV) acid orthocarbonate.
Preparation method the most according to claim 1, wherein, sour four alkane esters of titanium (IV) and 5-methoxy in described step (a)
The mol ratio of base-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl]-1H-benzimidazole is 0.05:
1-1:1, preferably 0.1:1-0.6:1, more preferably 0.3:1-0.5:1.
Preparation method the most according to claim 1, wherein, system temperature is down to 0-15 DEG C and at 0-by described step (b)
15 DEG C of insulations, more excellent for 5-10 DEG C.
Preparation method the most according to claim 1, wherein, the time dripping described oxidant in described step (b) is 10-
60 minutes, preferably 20-40 minute.
Preparation method the most according to claim 1, wherein, oxidant described in described step (b) and 5-methoxyl group-2-
The mol ratio of [[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-methyl]-sulfenyl]-1H-benzimidazole is 1:1-2:1, excellent
Elect 1.1:1-1.5:1 as.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114209697A (en) * | 2021-12-14 | 2022-03-22 | 重庆大学附属三峡医院 | Proton pump inhibitor, preparation method and application |
| CN116444487A (en) * | 2022-01-07 | 2023-07-18 | 重庆莱美药业股份有限公司 | Intermediate composition of omeprazole, and preparation method and application thereof |
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| CN1381443A (en) * | 2001-04-20 | 2002-11-27 | 中国医学科学院药物研究所 | Process for preparing sulfoxide group contained medicine by catalytic oxidization of thioether compounds |
| CN1426406A (en) * | 2000-04-28 | 2003-06-25 | 武田药品工业株式会社 | Process for producing optically active sulfoxide devivative' |
| US20080319195A1 (en) * | 2005-12-22 | 2008-12-25 | Ratiopharm Gmbh | Enantioselective Preparation of Benzimidazole Derivatives and Their Salts |
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| CN1243512A (en) * | 1997-11-14 | 2000-02-02 | 阿斯特拉公司 | new method |
| CN1426406A (en) * | 2000-04-28 | 2003-06-25 | 武田药品工业株式会社 | Process for producing optically active sulfoxide devivative' |
| CN1381443A (en) * | 2001-04-20 | 2002-11-27 | 中国医学科学院药物研究所 | Process for preparing sulfoxide group contained medicine by catalytic oxidization of thioether compounds |
| US20080319195A1 (en) * | 2005-12-22 | 2008-12-25 | Ratiopharm Gmbh | Enantioselective Preparation of Benzimidazole Derivatives and Their Salts |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114209697A (en) * | 2021-12-14 | 2022-03-22 | 重庆大学附属三峡医院 | Proton pump inhibitor, preparation method and application |
| CN116444487A (en) * | 2022-01-07 | 2023-07-18 | 重庆莱美药业股份有限公司 | Intermediate composition of omeprazole, and preparation method and application thereof |
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