CN107663192B - A kind of preparation method of Rabeprazole impurity - Google Patents
A kind of preparation method of Rabeprazole impurity Download PDFInfo
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- CN107663192B CN107663192B CN201711068760.6A CN201711068760A CN107663192B CN 107663192 B CN107663192 B CN 107663192B CN 201711068760 A CN201711068760 A CN 201711068760A CN 107663192 B CN107663192 B CN 107663192B
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- 229960004157 rabeprazole Drugs 0.000 title claims abstract description 34
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 239000012535 impurity Substances 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- AYPSHJCKSDNETA-UHFFFAOYSA-N 2-chloro-1h-benzimidazole Chemical compound C1=CC=C2NC(Cl)=NC2=C1 AYPSHJCKSDNETA-UHFFFAOYSA-N 0.000 claims abstract description 5
- MCUYHRNUDDANSO-UHFFFAOYSA-N 4-chloro-2,3-dimethyl-1-oxidopyridin-1-ium Chemical compound CC1=C(C)[N+]([O-])=CC=C1Cl MCUYHRNUDDANSO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 230000035484 reaction time Effects 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 14
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 14
- 150000007529 inorganic bases Chemical class 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 11
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000012286 potassium permanganate Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- GCSVCUMDOQKEMT-UHFFFAOYSA-N butan-1-amine;hydrofluoride Chemical compound [H+].[F-].CCCCN GCSVCUMDOQKEMT-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 208000000718 duodenal ulcer Diseases 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 241000590002 Helicobacter pylori Species 0.000 abstract description 3
- 238000013461 design Methods 0.000 abstract description 3
- 238000011156 evaluation Methods 0.000 abstract description 3
- 229940037467 helicobacter pylori Drugs 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 208000007107 Stomach Ulcer Diseases 0.000 abstract description 2
- 201000005917 gastric ulcer Diseases 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 14
- 238000000926 separation method Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000012216 screening Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 2
- 210000001711 oxyntic cell Anatomy 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- GAILJAVYTROIFN-UHFFFAOYSA-N 4-chloro-2-methyl-1-oxidopyridin-1-ium Chemical compound CC1=CC(Cl)=CC=[N+]1[O-] GAILJAVYTROIFN-UHFFFAOYSA-N 0.000 description 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 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-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
- ALLWOAVDORUJLA-UHFFFAOYSA-N Rebamipida Chemical compound C=1C(=O)NC2=CC=CC=C2C=1CC(C(=O)O)NC(=O)C1=CC=C(Cl)C=C1 ALLWOAVDORUJLA-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229950004535 rebamipide Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000397 ulcer Toxicity 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic methods of Rabeprazole impurity, belong to pharmaceutical synthesis field, and preparation method provided by the invention, technological design is reasonable, and strong operability, reaction condition is milder, and yield height is, it can be achieved that industrialized production.The present invention is with 2,3- dimethyl -4- chloropyridine-N- oxide and 2-Chlorobenzimidazole are raw material, it is reacted by eight steps, realize the synthesis of Rabeprazole impurity, the Rabeprazole impurity that the present invention is prepared, quality, safety and efficiency scientific evaluation are carried out to Rabeprazole and provide important evidence, and Rabeprazole impurity pharmacological activity is good, active duodenal ulcer caused by can developing for treating a variety of causes, benign active gastric ulcer, the helicobacter pylori positive duodenal ulcer drug, have important application value.
Description
Technical field
The invention belongs to pharmaceutical synthesis field more particularly to a kind of preparation methods of Rabeprazole impurity.
Background technique
Proton pump inhibitor is the latest generation acid-suppressing medicine of current clinical use, and Acidinhibitor is powerful and lasting.Proton pump
Act on the last one link during gastric acid secretion, be absorbed into vivo reach after blood parietal cell secretion it is small
Pipe, is changed into active material under acidic environment, acts on H+-K+ATP enzyme simultaneously makes its inactivation, leads to the hydrogen ion in parietal cell
Gastral cavity cannot be transferred to and reduce gastric acid secretion, so that pH value increases in gastric juice, to reach Acidinhibitor.
Rabeprazole and Omeprazole, Lansoprazole, Pantoprazole are a kind of current China clinically common novel benzene
And imidazoles proton pump inhibitor, belong to Mucosta, indication has active duodenal ulcer, benign activity stomach to burst
The duodenal ulcer of ulcer, the helicobacter pylori positive.The combination target spot of Rabeprazole is most, pretends with most fast, most lasting, valence
Effect is than best.With the progress in epoch, the raising of scientific and technological level, people to drug to must carry out quality, peace before marketing drugs
Full property and the importance of efficiency scientific evaluation etc., which have, more fully to be recognized, wherein with drug quality it is closely related be drug
The control of impurities.Impurity is often related with drug safety, and also related with efficiency in a few cases.Therefore, it controls
Impurity level is during drug development increasingly by the attention of medical personal.
Rabeprazole impurity is a kind of impurity generated in Rabeprazole synthesis process, carries out phase to Rabeprazole impurity
The pharmacology of pass, pharmacokinetic study can control for the quality of bulk pharmaceutical chemicals Rabeprazole and provide control sample, to promote thunder
The research of shellfish drawing azoles.But about the miscellaneous Quality Research of Rabeprazole, there is not been reported.
Summary of the invention
The present invention provides a kind of preparation methods of Rabeprazole impurity, and this method technological design is reasonable, and yield is high, operation
Process facilitates controllable.
In order to achieve the above object, the present invention uses following scheme:
A kind of preparation method of Rabeprazole impurity, comprising the following steps:
(1) it takes benzyl alcohol to be dissolved in the organic solvent of 10~30 volumes, sodium hydrogen is added under ice bath, stirring 10 under ice bath~
30 minutes, 2,3- dimethyl -4- chloropyridine-N- oxide is added, is stirred 3~15 hours at 30 DEG C -120 DEG C, obtains chemical combination
Object II, structural formula is as follows:
(2) it takes the compound ii to be dissolved in the acetic acid of 5~30 volumes, acetic anhydride is added, is heated to 100 DEG C -140 DEG C and stirs
It mixes 5~20 hours, obtains compound III, structural formula is as follows:
(3) it takes the compound III to be dissolved in the ethyl alcohol of 5~30 volumes, inorganic base, 20~60 DEG C of reactions is added under ice bath
0.5~3 hour, compounds Ⅳ is obtained, structural formula is as follows:
(4) it takes the compounds Ⅳ to be dissolved in the organic solvent of 5~30 volumes, palladium carbon, the compounds Ⅳ and palladium is added
The ratio between amount of substance of carbon be 1:0.1~1:0.2, add hydrogen, 15 DEG C~35 DEG C reaction 8-30 hours, obtain compound V, knot
Structure formula is as follows:
(5) it takes 2-Chlorobenzimidazole to be dissolved in the n,N-Dimethylformamide of 5~30 volumes, 1~2 is added under ice bath and works as
The sodium hydrogen of amount stirs 10~30 minutes under ice bath, is added 2- (trimethylsilyl) ethoxymethyl chlorine of 1~2 equivalent, 10 DEG C~
40 DEG C of reactions obtain compound VII in 8-30 hours；
(6) compound VII of the compound V and 1~2 equivalent is taken to be dissolved in the n,N-Dimethylformamide of 5~30 volumes
In, be added 1~8 equivalent cesium carbonate, 60-140 DEG C reaction 6-30 hours, obtain compound VIII, structure is as follows:
(7) it takes the compound VIII to be dissolved in the tetrahydrofuran of 5~30 volumes, 0.5~6 equivalent is added under condition of ice bath
Tetrabutyl ammonium fluoride, 50-90 DEG C reaction 6-24 hours, obtain compound Ⅸ, structure is as follows:
(8) it takes the compound Ⅸ to be suspended in the water of 5~30 volumes, under condition of ice bath, the hydrogen of 1~3 equivalent is added
The potassium permanganate of sodium oxide molybdena and 1~4 equivalent, 30-100 DEG C reaction 1-15 hours, obtain compound Ⅹ, i.e. Rabeprazole impurity,
Structural formula is as follows:
Organic solvent described in step (1) is dimethyl sulfoxide or dimethylformamide, 2, the 3- bis- in above step
The mass ratio of the material of methyl -4- chloropyridine-N- oxide, benzyl alcohol and sodium hydrogen is 1:1:1~1:2:2, and preferable organic solvent is
The mass ratio of the material of dimethyl sulfoxide, 2, the 3- dimethyl -4- chloropyridine-N- oxide, benzyl alcohol and sodium hydrogen is 1:1.5:
1.5, the reaction temperature is 80 DEG C；Reaction temperature described in step (2) is 120 DEG C, and the reaction time is 15 hours；Step
(3) inorganic base described in is sodium hydroxide or lithium hydroxide, and the mass ratio of the material of the compound III and inorganic base is 1:1~1:
4, preferably inorganic base is sodium hydroxide, and the mass ratio of the material of the compound III and inorganic base is 1:3；Step has described in (4)
Solvent is ethyl acetate, methanol, tetrahydrofuran, and the preferably described organic solvent is ethyl acetate, the compounds Ⅳ and palladium carbon
The ratio between the amount of substance be 1:0.15, the reaction temperature is 25 DEG C, and the reaction time is 20 hours；Described in step (6)
Reaction time is 16 hours, and the reaction temperature is 120 DEG C；Reaction time described in step (7) is 18 hours, the reaction temperature
Degree is 80 DEG C；The ratio between amount of substance of step (8) compound Ⅸ, sodium hydroxide and potassium permanganate is 1:2.2:3.2, described
Reaction temperature is 60 DEG C, and the reaction time is 2.5 hours.
The beneficial effects of the present invention are: the present invention provides a kind of preparation method of Rabeprazole impurity, the preparation method
Technological design is reasonable, and operating method is simple, raw material is easy to get, technique can amplify production, purity is high, reaction process are controllable and environment is protected
It is good, it can be achieved that industrialized production to protect effect, and the Rabeprazole impurity that the present invention is prepared, to Rabeprazole progress matter
Amount, safety and efficiency scientific evaluation provide important evidence, and Rabeprazole impurity pharmacological activity is good, can develop for controlling
Treat 12 positive fingers of active duodenal ulcer caused by a variety of causes, benign active gastric ulcer, helicobacter pylori
The drug of enterelcosis has important application value.
Detailed description of the invention
Fig. 1 is the process flow chart of preparation method of the present invention.
Specific embodiment
Embodiment 1
(1) it takes benzyl alcohol to be dissolved in the dimethyl sulfoxide of 10~30 volumes, sodium hydrogen is added under ice bath, stirs 10 under ice bath
Minute, 2,3- dimethyl -4- chloropyridine-N- oxide is added, is stirred at 30 DEG C -120 DEG C, obtains compound ii, compound
I, the screening experiment data of the ratio between benzyl alcohol and the amount of substance of sodium hydrogen, reaction dissolvent are as follows:
It is as follows that reaction temperature changes experimental data:
(2) 0.31mol compound ii is taken to be dissolved in 360mL acetic acid, be added 360mL acetic anhydride, heating stirring, reaction solution by
Pale red solution becomes dark red solution.Reaction solution is cooled to room temperature, concentration is evaporated to obtain red solid compound III, reacts
Temperature, the experimental data are shown in the following table for reaction time variation:
(3) it takes compound III to be dissolved in 595mL ethyl alcohol, inorganic base is added portionwise under condition of ice bath, reaction solution is by dark red
Color solution becomes pale red turbid solution, and 20 DEG C are reacted 1 hour, reaction solution is filtered to remove to extra sodium hydroxide, filtrate is dense
Contracting removes ethyl alcohol, and 500mL water is added and is then extracted with ethyl acetate, and organic phase merges, and after drying, passes through column color after being evaporated again
Spectrum separating-purifying obtains compound as white solid IV, inorganic base type, the reality of the ratio between amount of substance of compound III and inorganic base
It is as follows to test data:
(4) it takes compounds Ⅳ to be dissolved in ethyl acetate, palladium carbon is added under the conditions of nitrogen protection, by hydrogen balloon plus hydrogen,
It is reacted 20 hours at 25 DEG C, reaction solution is black suspension, filters under the conditions of nitrogen protection and removes palladium carbon, and filtrate concentration is evaporated
Afterwards, purify to obtain compound as white solid V by pillar layer separation, organic solvent, the optimisation substance of compounds Ⅳ and palladium carbon
The screening experiment data of the ratio between amount are as follows:
Reaction temperature and reaction time experimental data are as follows:
(5) 0.078mol 2-Chlorobenzimidazole is taken to be dissolved in the dry n,N-Dimethylformamide of 90mL, in ice bath and nitrogen
Under the conditions of gas shielded, 60% sodium hydrogen of 0.079mol is added portionwise, is stirred 30 minutes under the conditions of ice bath and nitrogen protection, is added
0.079mol 2- (trimethylsilyl) ethoxymethyl chlorine, 20 DEG C are reacted 16 hours, and reaction solution becomes yellow suspension, ice bath
Under cooling, it being slowly added to 200mL water, is extracted with ethyl acetate, organic phase merges, after drying, stone in a volume ratio of 10:1
Oily ether: ethyl acetate as eluent, pillar layer separation obtain 16g compound as white solid VII, yield 71.93%；
(6) 0.056mol compound V and 0.056mol compound VII is taken to be dissolved in 160mL n,N-Dimethylformamide,
0.085mol cesium carbonate is added, reacts at a certain temperature, forms yellow suspension, reaction solution is cooled to room temperature, under ice bath
400mL water is added, is extracted with ethyl acetate, organic phase merges, after drying, the methylene chloride for being 25:1 with volume ratio: methanol
Make eluant, eluent, pillar layer separation obtains compound as white solid VIII, and reaction temperature and the screening experiment data in reaction time are as follows:
(7) it takes 0.020mol compound VIII to be dissolved in 234mL tetrahydrofuran, under condition of ice bath, 0.101mol is added
The tetrabutyl ammonium fluoride tetrahydrofuran solution of 1mol/L, reacts at a certain temperature, forms pale red suspension, will react liquid cooling
But to room temperature, concentration is evaporated removing tetrahydrofuran, and 280mL water is added, is adjusted to reacting liquid pH value with saturated aqueous sodium carbonate
9, it is stirred at room temperature 0.5 hour, is extracted with ethyl acetate, organic phase merges, after drying, the dichloromethane for being 20:1 with volume ratio
Alkane: methanol makees eluant, eluent, and pillar layer separation obtains compound as white solid Ⅸ, the screening experiment data of reaction temperature and reaction time
It is as follows:
(8) it takes 0.005mol compound Ⅸ to be suspended in 70mL water, under condition of ice bath, sodium hydroxide and permanganic acid is added
Potassium reacts at a certain temperature, forms red suspension, reaction solution is cooled to room temperature, and 20mL methanol is added, and filters, filter cake
Washed with methanol, the methylene chloride for being 5:1 with volume ratio after filtrate is evaporated: methanol makees eluant, eluent, and pillar layer separation obtains white
Solid chemical compound Ⅹ, sodium hydroxide, potassium permanganate substance magnitude relation experimental data it is as follows:
Reaction temperature and the experimental data in reaction time are as follows:
Embodiment 2
(1) it takes benzyl alcohol to be dissolved in the dimethylformamide of 10~30 volumes, sodium hydrogen is added under ice bath, is stirred under ice bath
10 minutes, 2,3- dimethyl -4- chloropyridine-N- oxide is added, is stirred at 30 DEG C -120 DEG C, obtains compound ii, chemical combination
The screening experiment data of the ratio between object I, benzyl alcohol and amount of substance of sodium hydrogen, reaction dissolvent are as follows:
It is as follows that reaction temperature changes experimental data:
(2) 0.31mol compound ii is taken to be dissolved in 360mL acetic acid, be added 360mL acetic anhydride, heating stirring, reaction solution by
Pale red solution becomes dark red solution.Reaction solution is cooled to room temperature, concentration is evaporated to obtain red solid compound III, reacts
Temperature, the experimental data are shown in the following table for reaction time variation:
(3) it takes compound III to be dissolved in 595mL ethyl alcohol, sodium hydroxide is added portionwise under condition of ice bath, reaction solution is by depth
Red solution becomes pale red turbid solution, and 20 DEG C are reacted 1 hour, and reaction solution is filtered to remove to extra sodium hydroxide, filtrate
Concentration removes ethyl alcohol, and 500mL water is added and is then extracted with ethyl acetate, and organic phase merges, and after drying, passes through column after being evaporated again
Chromatographic purification obtains compound as white solid IV, inorganic base type, the ratio between amount of substance of compound III and inorganic base
Experimental data is as follows:
(4) it takes compounds Ⅳ to be dissolved in ethyl acetate, palladium carbon is added under the conditions of nitrogen protection, by hydrogen balloon plus hydrogen,
It is reacted 20 hours at 25 DEG C, reaction solution is black suspension, filters under the conditions of nitrogen protection and removes palladium carbon, and filtrate concentration is evaporated
Afterwards, purify to obtain compound as white solid V by pillar layer separation, organic solvent, the optimisation substance of compounds Ⅳ and palladium carbon
The screening experiment data of the ratio between amount are as follows:
Reaction temperature and reaction time experimental data are as follows:
(5) 0.078mol 2-Chlorobenzimidazole is taken to be dissolved in the dry n,N-Dimethylformamide of 90mL, in ice bath and nitrogen
Under the conditions of gas shielded, 60% sodium hydrogen of 0.079mol is added portionwise, is stirred 30 minutes under the conditions of ice bath and nitrogen protection, is added
0.079mol 2- (trimethylsilyl) ethoxymethyl chlorine, 20 DEG C are reacted 16 hours, and reaction solution becomes yellow suspension, ice bath
Under cooling, it being slowly added to 200mL water, is extracted with ethyl acetate, organic phase merges, after drying, stone in a volume ratio of 10:1
Oily ether: ethyl acetate as eluent, pillar layer separation obtain 16g compound as white solid VII, yield 71.93%；
(6) 0.056mol compound V and 0.056mol compound VII is taken to be dissolved in 160mL n,N-Dimethylformamide,
0.085mol cesium carbonate is added, reacts at a certain temperature, forms yellow suspension, reaction solution is cooled to room temperature, under ice bath
400mL water is added, is extracted with ethyl acetate, organic phase merges, after drying, the methylene chloride for being 25:1 with volume ratio: methanol
Make eluant, eluent, pillar layer separation obtains compound as white solid VIII, and reaction temperature and the screening experiment data in reaction time are as follows:
(7) it takes 0.020mol compound VIII to be dissolved in 234mL tetrahydrofuran, under condition of ice bath, 0.101mol is added
The tetrabutyl ammonium fluoride tetrahydrofuran solution of 1mol/L, reacts at a certain temperature, forms pale red suspension, will react liquid cooling
But to room temperature, concentration is evaporated removing tetrahydrofuran, and 280mL water is added, is adjusted to reacting liquid pH value with saturated aqueous sodium carbonate
9, it is stirred at room temperature 0.5 hour, is extracted with ethyl acetate, organic phase merges, after drying, the dichloromethane for being 20:1 with volume ratio
Alkane: methanol makees eluant, eluent, and pillar layer separation obtains compound as white solid Ⅸ, the screening experiment data of reaction temperature and reaction time
It is as follows:
(8) it takes 0.005mol compound Ⅸ to be suspended in 70mL water, under condition of ice bath, sodium hydroxide and permanganic acid is added
Potassium reacts at a certain temperature, forms red suspension, reaction solution is cooled to room temperature, and 20mL methanol is added, and filters, filter cake
Washed with methanol, the methylene chloride for being 5:1 with volume ratio after filtrate is evaporated: methanol makees eluant, eluent, and pillar layer separation obtains white
Solid chemical compound Ⅹ, sodium hydroxide, potassium permanganate substance magnitude relation experimental data it is as follows:
Reaction temperature and the experimental data in reaction time are as follows:
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (11)
1. a kind of preparation method of Rabeprazole impurity, which comprises the following steps:
(1) it takes benzyl alcohol to be dissolved in the organic solvent of 10~30 volumes, sodium hydrogen is added under ice bath, stirs 10~30 points under ice bath
Clock is added 2,3- dimethyl -4- chloropyridine-N- oxide, stirs 3~15 hours at 30 DEG C -120 DEG C, obtain compound ii,
Structural formula is as follows:
(2) it takes the compound ii to be dissolved in the acetic acid of 5~30 volumes, acetic anhydride is added, be heated to 100 DEG C of -140 DEG C of stirrings 5
~20 hours, compound III is obtained, structural formula is as follows:
(3) it takes the compound III to be dissolved in the ethyl alcohol of 5~30 volumes, is added inorganic base under ice bath, 20~60 DEG C of reactions 0.5~
3 hours, compounds Ⅳ is obtained, structural formula is as follows:
(4) it takes the compounds Ⅳ to be dissolved in the organic solvent of 5~30 volumes, palladium carbon is added, the compounds Ⅳ and palladium carbon
The ratio between amount of substance be 1:0.1~1:0.2, add hydrogen, 15 DEG C~35 DEG C reaction 8-30 hours, obtain compound V, structural formula
It is as follows:
(5) it takes 2-Chlorobenzimidazole to be dissolved in the n,N-Dimethylformamide of 5~30 volumes, 1~2 equivalent is added under ice bath
Sodium hydrogen stirs 10~30 minutes under ice bath, is added 2- (trimethylsilyl) ethoxymethyl chlorine of 1~2 equivalent, and 10 DEG C~40 DEG C
Reaction obtains compound VII in 8-30 hours；
(6) it takes the compound VII of the compound V and 1~2 equivalent to be dissolved in the n,N-Dimethylformamide of 5~30 volumes, adds
Enter the cesium carbonate of 1~8 equivalent, 60-140 DEG C reaction 6-30 hours, obtain compound VIII, structure is as follows:
(7) it takes the compound VIII to be dissolved in the tetrahydrofuran of 5~30 volumes, the four of 0.5~6 equivalent is added under condition of ice bath
Butyl ammonium fluoride, 50-90 DEG C reaction 6-24 hours, obtain compound Ⅸ, structure is as follows:
(8) it takes the compound Ⅸ to be suspended in the water of 5~30 volumes, under condition of ice bath, the hydroxide of 1~3 equivalent is added
The potassium permanganate of sodium and 1~4 equivalent, 30-100 DEG C reaction 1-15 hours, obtain compound Ⅹ, i.e. Rabeprazole impurity, structure
Formula is as follows:
2. the preparation method of Rabeprazole impurity according to claim 1, which is characterized in that organic described in step (1)
Solvent is dimethyl sulfoxide or dimethylformamide, 2, the 3- dimethyl -4- chloropyridine-N- oxide, benzyl alcohol and sodium hydrogen
The mass ratio of the material be 1:1:1~1:2:2.
3. the preparation method of Rabeprazole impurity according to claim 1 or 2, which is characterized in that step has described in (1)
Solvent is dimethyl sulfoxide, the mass ratio of the material of 2, the 3- dimethyl -4- chloropyridine-N- oxide, benzyl alcohol and sodium hydrogen
For 1:1.5:1.5, the reaction temperature is 80 DEG C.
4. the preparation method of Rabeprazole impurity according to claim 1, which is characterized in that reaction described in step (2)
Temperature is 120 DEG C, and the reaction time is 15 hours.
5. the preparation method of Rabeprazole impurity according to claim 1, which is characterized in that inorganic described in step (3)
Alkali is sodium hydroxide or lithium hydroxide, and the mass ratio of the material of the compound III and inorganic base is 1:1~1:4.
6. the preparation method of Rabeprazole impurity according to claim 1 or 5, which is characterized in that nothing described in step (3)
Machine alkali is sodium hydroxide, and the mass ratio of the material of the compound III and inorganic base is 1:3.
7. the preparation method of Rabeprazole impurity according to claim 1, which is characterized in that organic described in step (4)
Solvent is ethyl acetate, methanol, tetrahydrofuran.
8. the preparation method of Rabeprazole impurity according to claim 1 or claim 7, which is characterized in that step has described in (4)
Solvent is ethyl acetate, and the ratio between amount of substance of the compounds Ⅳ and palladium carbon is 1:0.15, and the reaction temperature is 25 DEG C,
The reaction time is 20 hours.
9. the preparation method of Rabeprazole impurity according to claim 1, which is characterized in that reaction described in step (6)
Time is 16 hours, and the reaction temperature is 120 DEG C.
10. the preparation method of Rabeprazole impurity according to claim 1, which is characterized in that reaction described in step (7)
Time is 18 hours, and the reaction temperature is 80 DEG C.
11. the preparation method of Rabeprazole impurity according to claim 1, which is characterized in that step (8) described compound
Ⅸ, the ratio between amount of substance of sodium hydroxide and potassium permanganate is 1:2.2:3.2, and the reaction temperature is 60 DEG C, when the reaction
Between be 2.5 hours.
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| EP0167943A2 (en) * | 1984-07-05 | 1986-01-15 | Beecham Group Plc | Benzimidazole derivatives, process for their preparation, and their use as pharmaceuticals |
| CN1856490A (en) * | 2003-07-28 | 2006-11-01 | 詹森药业有限公司 | Benzimidazole, benzthiazole and benzoxazole derivatives and their use as lta4h modulators |
| JP2012167027A (en) * | 2011-02-10 | 2012-09-06 | Shionogi & Co Ltd | Condensed heterocyclic derivative having npy y5 receptor antagonism |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0167943A2 (en) * | 1984-07-05 | 1986-01-15 | Beecham Group Plc | Benzimidazole derivatives, process for their preparation, and their use as pharmaceuticals |
| CN1856490A (en) * | 2003-07-28 | 2006-11-01 | 詹森药业有限公司 | Benzimidazole, benzthiazole and benzoxazole derivatives and their use as lta4h modulators |
| JP2012167027A (en) * | 2011-02-10 | 2012-09-06 | Shionogi & Co Ltd | Condensed heterocyclic derivative having npy y5 receptor antagonism |
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| Structure-Activity Relationship of 2-[[(2-Pyridyl)methyl]thio]-1H-benzimidazoles as Anti Helicobacter pylori Agents in Vitro and Evaluation of their in Vivo Efficacy;Thomas C. Kuhler et al.;《Journal of Medicinal Chemistry》;19980429;第41卷(第11期);1777-1788 |
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