CN100393712C - Improved preparation and separated purification method of benzimidazole type proton pump inhibitors and precursor thereof - Google Patents
Improved preparation and separated purification method of benzimidazole type proton pump inhibitors and precursor thereof Download PDFInfo
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- CN100393712C CN100393712C CNB2006100202066A CN200610020206A CN100393712C CN 100393712 C CN100393712 C CN 100393712C CN B2006100202066 A CNB2006100202066 A CN B2006100202066A CN 200610020206 A CN200610020206 A CN 200610020206A CN 100393712 C CN100393712 C CN 100393712C
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- 238000000034 method Methods 0.000 title claims abstract description 41
- 239000002243 precursor Substances 0.000 title abstract description 11
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title abstract description 8
- 229940126409 proton pump inhibitor Drugs 0.000 title abstract description 5
- 239000000612 proton pump inhibitor Substances 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title description 29
- 238000000746 purification Methods 0.000 title description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 115
- 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 claims abstract description 45
- 229960000381 omeprazole Drugs 0.000 claims abstract description 45
- 239000004094 surface-active agent Substances 0.000 claims abstract description 21
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 14
- 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 claims abstract description 6
- 229960003174 lansoprazole Drugs 0.000 claims abstract description 6
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229960004157 rabeprazole Drugs 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 262
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 80
- 238000003756 stirring Methods 0.000 claims description 70
- 238000001035 drying Methods 0.000 claims description 68
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 54
- 239000012044 organic layer Substances 0.000 claims description 49
- 239000007787 solid Substances 0.000 claims description 43
- 238000000605 extraction Methods 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- 239000013543 active substance Substances 0.000 claims description 24
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 21
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 21
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 21
- -1 methoxyl group Chemical group 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- 150000003568 thioethers Chemical class 0.000 claims description 13
- 150000001556 benzimidazoles Chemical class 0.000 claims description 12
- 230000007935 neutral effect Effects 0.000 claims description 12
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 12
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical group [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 11
- 238000007710 freezing Methods 0.000 claims description 10
- 230000008014 freezing Effects 0.000 claims description 10
- 150000002576 ketones Chemical class 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- 239000013504 Triton X-100 Substances 0.000 claims description 8
- 229920004890 Triton X-100 Polymers 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 239000003093 cationic surfactant Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229960000800 cetrimonium bromide Drugs 0.000 claims description 4
- DVBJBNKEBPCGSY-UHFFFAOYSA-M cetylpyridinium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 DVBJBNKEBPCGSY-UHFFFAOYSA-M 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 4
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 2
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical class ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 229960005019 pantoprazole Drugs 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 230000002349 favourable effect Effects 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000002425 crystallisation Methods 0.000 abstract description 4
- 230000008025 crystallization Effects 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 2
- PQUGCKBLVKJMNT-UHFFFAOYSA-N SC560 Chemical class C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C(F)(F)F)=N1 PQUGCKBLVKJMNT-UHFFFAOYSA-N 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 95
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 74
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 72
- 239000000243 solution Substances 0.000 description 65
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 239000007864 aqueous solution Substances 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 239000011736 potassium bicarbonate Substances 0.000 description 31
- 235000015497 potassium bicarbonate Nutrition 0.000 description 31
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 31
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 31
- 239000000047 product Substances 0.000 description 28
- 229910052938 sodium sulfate Inorganic materials 0.000 description 24
- 235000011152 sodium sulphate Nutrition 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 10
- 229960000344 thiamine hydrochloride Drugs 0.000 description 10
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 10
- 239000011747 thiamine hydrochloride Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- JPMRGPPMXHGKRO-UHFFFAOYSA-N 2-(chloromethyl)pyridine hydrochloride Chemical class Cl.ClCC1=CC=CC=N1 JPMRGPPMXHGKRO-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 159000000011 group IA salts Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000005502 peroxidation Methods 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PNQHTFGZHQFYCW-UHFFFAOYSA-N 2-(chloromethyl)-3-methyl-4-(trifluoromethoxy)pyridine hydrochloride Chemical compound Cl.ClCC1=NC=CC(=C1C)OC(F)(F)F PNQHTFGZHQFYCW-UHFFFAOYSA-N 0.000 description 1
- CJQSCFAGJKQTLM-UHFFFAOYSA-N Cl.ClCC(COC1=NC=CC(=C1)OC)CC Chemical compound Cl.ClCC(COC1=NC=CC(=C1)OC)CC CJQSCFAGJKQTLM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002468 redox effect Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides a method for preparing benzimidazole type proton pump inhibitor and a precursor thereof, such as a method for preparing, separating and purifying omeprazole, rabeprazole, lansoprazole, eprazole, etc. Surfactant or phase transfer catalyst is added into the synthetic process of razole class medicament and the precursor for the first time, which accelerates reaction speed and ensures that the reaction is complete. The method has the advantages of favorable reaction efficiency and selectivity, single product and easy after-treatment of products, overcomes the defects of poor reproducibility and unstable production rate and product purity of original method, and solves the problems of complex post-treatment, difficult crystallization, etc.
Description
Technical field
The invention provides a kind of preparation benzimidazole type proton pump inhibitor and precursor thereof, as omeprazole, rabeprazole, lansoprazole, lY 81149, dissolve the improvement preparation and the separation purification method of Duola's azoles etc.
Background technology
With the compound headed by the omeprazole (Omeprazole) with benzimidazole structure, can suppress to secrete the acid effect by the parietal cell that any stimulation causes, be the good anti-ulcer medicament of a class.
1981, US 4255431 discloses the preparation method of this class benzimidazole compound of omeprazole, reported 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline in dichloromethane solution and-chloroperoxybenzoic acid reaction, generate omeprazole and m-chlorobenzoic acid.There are a plurality of patents that the preparation and the separation purification method of benzimidazole compound improved subsequently.CN 91103923.6 (WO 91/18895) changes the solvent system of oxidation step into methylene dichloride/water, system pH fixes on 8.0-8.6 approximately, its advantage can allow the m-chlorobenzoic acid that generates between the reaction period enter into the aqueous phase that contains buffered soln, the omeprazole of generation is not contacted with acid, solve omeprazole and in acidic medium, decompose rotten problem, in aftertreatment, pass through simultaneously to add alkyl formate the omeprazole Crystallization Separation.CN 96199057.0 (WO9722603) in the three-step reaction of preparation omeprazole, has saved the step of isolated or purified intermediate on the basis of CN 91103923.6 (WO 91/18895).
Though enter into the aqueous phase that contains buffered soln by in reaction system, introducing buffered soln, allow the m-chlorobenzoic acid that generates between the reaction period, solve omeprazole and in acidic medium, decompose rotten problem.But we are when repeating the improving one's methods of above-mentioned CN 91103923.6 and CN 96199057.0, but find to be difficult to repeat out the yield of report, be difficult to separate out the omeprazole crystallization, can not get product often by alkyl formate, after reaction scale is amplified, rareer especially to product.Existing reported method circulation ratio is very poor, still has serious deficiency.
Traced it to its cause following some: one, by product m-chlorobenzoic acid can not enter the water of buffered soln very soon in two-phase system, the compound that this is extremely responsive to acid for this class of omeprazole still can influence the stability and the purity of product.They are two years old, the gained target product is a sulfoxide compound, be easy to continue reaction and generate the by product sulfone with metachloroperbenzoic acid, any effectively operation of controlled oxidation dosage, all may cause sulfoxide peroxidation or sulfide oxidation deficiency, make product impure, a large amount of by products generate, low-yield, poor reproducibility.The thioether intermediate does not separate and is directly used in down the step oxidation, may cause oxidant content inaccurate, causes reaction efficiency low, and reaction not exclusively or peroxidation.They are three years old, it separates and the method for purification process employing alkyl formate ester regulation system pH is separated out omeprazole solid, whole process to temperature, pH and add the conditional request harshnesses such as purity of crystal seed, otherwise product extremely difficulty separate out, and slowly, also introduce a large amount of alkyl formate salt simultaneously.This causes poor reproducibility, and the aftertreatment time is longer, technology very complicated, problem such as a large amount of salt are residual.
Based on above problem, still need study preparation new, more effective benzimidazoles compound and separation purification method.
Recently, we have carried out studying (Deng JG etc. to the reaction in the aqueous solution micellar system, J.Org.Chem, 2005,70,9424), the table of discovery surface-active agent forms micella in aqueous phase system, a similar microreactor, what can change reactive component separates ionization potential and redox property, and physical properties, thereby change reactive activity, finally cause the partial concn of reaction system to strengthen, improve the selectivity and the efficient of reaction thus, speed of response becomes geometric growth (comparing with homogeneous reaction) in a lot of reactions, makes reaction more single, more complete, thus degree of purity of production improved.Tascioglu S forms micellar system with regard to tensio-active agent in the system of organic solvent/water, and the many different propertiess that bring thus done detailed narration (Tetrahedron Vol.52,1996,11113-11152).
The preparation feedback system that has earlier of omeprazole is organic solvent/water, adds tensio-active agent therein and can meet the condition that forms micellar system.By in reaction system, adding tensio-active agent, be expected to change the character of system, improve the reaction efficiency of system.Bibliographical information is not seen in the preparation that tensio-active agent is used for the benzimidazole type medicine.
The preparation feedback system that has earlier of omeprazole is organic solvent/water, by adding phase-transfer catalyst, be expected to allow the m-chlorobenzoic acid that generates between the reaction period enter into the aqueous phase that contains buffered soln very soon, solve omeprazole and in acidic medium, decompose rotten problem.Bibliographical information is not seen in the preparation that phase-transfer catalyst is used for the benzimidazole type medicine.
Patent CN 96199057.0 by adding phase-transfer catalyst, impels to be easy in the two-phase system that is reflected at methylene dichloride/water carry out in the reaction of preparation benzimidazole compound precursor thioether.If in the reaction system of its organic solvent/water, add tensio-active agent, can meet the condition that forms micellar system equally, be expected to change the character of system thus, improve the reaction efficiency of system.Bibliographical information is not seen in the preparation that tensio-active agent is used for benzimidazole type medicine thioether precursor yet.
Summary of the invention
The invention provides a kind of by in the solvent system of organic solvent/water, adding tensio-active agent or phase-transfer catalyst, the improvement preparation method of acquisition benzimidazoles compound.Method prepares target product thus, and reaction efficiency and selectivity are good, and product is more single, is easy to the aftertreatment of product.This method has overcome the unsettled shortcoming of method poor reproducibility, productive rate and product purity earlier, has solved problems such as aftertreatment is loaded down with trivial details, crystallization difficulty.
The invention provides a kind of by in the solvent system of organic solvent/water, adding tensio-active agent, the preparation method of acquisition benzimidazole type compound precursor thioether.This method has improved reaction efficiency, and speed of response is accelerated, and reaction yield is higher, and quality product is better.
It below is the advantage of the inventive method.
The present invention provides the preparation method of benzimidazole type compound by add the oxidizing reaction that tensio-active agent carries out thioether in the solvent system of organic solvent/water.An object of the present invention is by adding tensio-active agent in the system efficient of entire reaction obviously to be improved, speed of response is accelerated, and makes reaction more complete.The consumption of controlled oxidation agent effectively makes the selectivity of reaction better thus, avoids the generation of sulfone; Make the product purity height, the post-processing step of reaction is simple.
Another object of the present invention also makes the by product m-chlorobenzoic acid of generation promptly enter water, avoids making degree of purity of production unaffected as far as possible to the extremely decomposition of responsive product benzimidazole type compound of acid.Can improve degree of purity of production thus, simplify post-processing step.
Above-mentioned advantage makes favorable reproducibility of the present invention, and aftertreatment is simple, and the product that directly obtains is without recrystallization, and its purity just can reach 99%.
The present invention provides the preparation method of benzimidazole type compound by add the oxidizing reaction that phase-transfer catalyst carries out thioether in the solvent system of machine solvent/water.Its purpose makes by adding phase-transfer catalyst, make the by product m-chlorobenzoic acid of generation can promptly enter water, avoid the extremely decomposition of responsive product benzimidazole type compound of acid, make degree of purity of production unaffected as far as possible, improved degree of purity of production, made favorable reproducibility of the present invention, aftertreatment is simple, the white solid product that directly obtains is without recrystallization, and its purity just can reach 99%.
The present invention provides the preparation method of benzimidazole type compound precursor thioether by add tensio-active agent in two-phase system.Its purpose has improved reaction efficiency equally, and speed of response is accelerated, and reacts more complete, and aftertreatment is simple, and the product that directly obtains is without recrystallization, and its purity just can reach about 95%.
The invention provides the improvement preparation and the separation purification method of preparation benzimidazole type compound (I) and precursor thioether (II) thereof.
The preparation of benzimidazole type compound (I) is by the sulfoxide derivant of thioether intermediate (II) oxidation transformation for it, and thioether intermediate (II) then by 2-sulfydryl-1H-benzimidizole derivatives (III) and polysubstituted 2-chloromethyl pyridine hydrochloride derivative (IV) linked reaction takes place and makes.
R wherein
1And R
2Mutually the same or be selected from hydrogen, methoxyl group, pyrryl or difluoro-methoxy, R unequally
3, R
4And R
5Mutually the same or be selected from hydrogen, methyl, methoxyl group, methoxy propoxy or trifluoro ethoxy unequally.
It is characterized in that improving one's methods and may further comprise the steps:
1) preparation and the separation purification method of general formula (I).
Will between-chloroperoxybenzoic acid is dissolved in organic solvent such as methylene dichloride or the toluene, can select for use alcohol help between-the chloroperoxybenzoic acid dissolving, in the two-phase buffer system will between-chloroperoxybenzoic acid solution pours into etc. in thioether (II) methylene dichloride or toluene solution of molar equivalent, two-phase buffered soln is made up of organic solvent such as methylene dichloride or toluene and sodium bicarbonate or potassium bicarbonate aqueous solution.In the presence of tensio-active agent or phase-transfer catalyst, be reflected at 0 ℃～25 ℃ and carry out.
After reaction is finished, for the good product of solubleness in used organic solvent, directly add the organic phase of a small amount of triethylamine after the solvent evaporated, the stirring in ketones solvent of gained solid, filtration, drying, obtain the benzimidazole compound (I) of white, content can reach 99%; For the bad product of solubleness in used organic solvent, available the good methylene dichloride of product solvability is extracted organic phase with the product of aqueous phase, the evaporate to dryness organic phase, the stirring in ketones solvent of gained solid, filtration, drying obtain white benzimidazole compound (I).
Suitable tensio-active agent comprises but is not limited to cationic surfactant, as cetrimonium bromide (CTAB), hexadecyl pyridinium bromide (CPB), and aniorfic surfactant, as sodium lauryl sulphate (SDS), and neutral surface active agent, as Triton X-100 (Triton X-100), and amphoterics, as 3-(dimethyl dodecyl ammonium) propyl group-1-sodium sulfonate (DDAPS).Preferably aniorfic surfactant is preferably SDS especially.
Suitable phase-transfer catalyst includes but not limited to quaternary amine, as Tetrabutyl amonium bromide (TBAB).
The amount of suitable tensio-active agent is 1%～16% molar equivalent.The amount of suitable phase-transfer catalyst is 1%～16% molar equivalent.
Suitable organic solvent is and the immiscible organic solvent of water, as haloalkane, and fragrant alkane.Be preferably methylene dichloride, toluene.
Suitable purification solvent is C
3～C
5Straight chain ketone.Be preferably butanone.
The compound of benzimidazole type compound or general formula (I) is meant the neutral form that comprises described compound and the alkaline salt forms of described compound.For example, alkaline salt forms is Mg
2+, Ca
2+, Na
+, K
+Or Li
+Salt, preferred Mg
2+Or Na
+Salt.Below the structural formula of some benzimidazole type proton pump inhibitor is listed in:
2) preparation of general formula (II)
The hydrochloride of 2-sulfydryl-1H-benzimidizole derivatives (III) is dissolved in the ethanol/water solution of sodium hydroxide, add the polysubstituted 2-chloromethyl pyridine hydrochloride of equivalent derivative (IV) again, in the presence of tensio-active agent, stirring and refluxing reaction in 2 hours under alkaline condition.After reaction is finished, filter, transfer pH=7, use dichloromethane extraction, the evaporate to dryness organic layer adds acetone therein, adds sherwood oil again, stirs, and is freezing, filters, and drying gets thioether (II).
Suitable tensio-active agent comprises but is not limited to cationic surfactant, as cetrimonium bromide (CTAB), hexadecyl pyridinium bromide (CPB), or aniorfic surfactant, as sodium lauryl sulphate (SDS), or neutral surface active agent, as Triton X-100 (Triton X-100), amphoterics is as 3-(dimethyl dodecyl ammonium) propyl group-1-sodium sulfonate (DDAPS).Be preferably Triton X-100.
The amount of suitable tensio-active agent is 1%～10% molar equivalent.
Suitable organic solvent is various organic solvents.Be preferably ethanol.
Suitable purification solvent is C
3～C
5Straight chain ketone.Be preferably acetone.
Following non-limiting examples has been described the present invention in more detail.
Omeprazole precursor-5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline synthetic:
The comparative example
According to the method for CN 96199057.0 (WO 9722603), carried out omeprazole precursor-5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-synthesis technique of 1H-benzoglyoxaline.
The comparative example one:
In reaction flask, add 3.62g (0.02 mole) 5-methoxyl group-2-sulfydryl-1H-benzoglyoxaline, 6mL water, (1.63g 0.04 mole) sodium hydroxide, 30mL ethanol, after the stirring and dissolving, add the TBAB of 3% molar equivalent, add 4.44g (0.02 mole) 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride, heated and stirred refluxed 2 hours.Reaction is finished, and filters, and filtrate is added water, acetate with 36% is transferred pH=7, uses dichloromethane extraction, the washing organic layer, the evaporate to dryness organic layer adds acetone, adds sherwood oil again, stir, freezing, filter, drying obtains 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline 3.99g, yield 61.2%, content 95.3%.
The comparative example two:
In reaction flask, add 3.62g (0.02 mole) 5-methoxyl group-2-sulfydryl-1H-benzoglyoxaline, 6mL water, 1.63g (0.04 mole) sodium hydroxide, 30mL ethanol after the stirring and dissolving, adds the PhCH of 3% molar equivalent
2N
+(C
2H
5)
3Cl adds 4.44g (0.02 mole) 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride, and heated and stirred refluxed 2 hours.Reaction is finished, and filters, and filtrate is added water, acetate with 36% is transferred pH=7, uses dichloromethane extraction, the washing organic layer, the evaporate to dryness organic layer adds acetone, adds sherwood oil again, stir, freezing, filter, drying obtains 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline 4.26g, yield 65.3%, content 89.4%.
The comparative example three:
In reaction flask, add 3.70g (0.02 mole) 5-methoxyl group-2-sulfydryl-1H-benzoglyoxaline, 6mL water, (1.63g 0.04 mole) sodium hydroxide, 30mL ethanol, after the stirring and dissolving, add 4.44g (0.02 mole) 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride, heated and stirred refluxed 2 hours.Reaction is finished, and filters, and filtrate is added water, acetate with 36% is transferred pH=7, uses dichloromethane extraction, the washing organic layer, the evaporate to dryness organic layer adds acetone, adds sherwood oil again, stir, freezing, filter, drying obtains 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline 4.20g, yield 64.4%, content 95%.
Embodiment
Embodiment one:
In reaction flask, add 3.62g (0.02 mole) 5-methoxyl group-2-sulfydryl-1H-benzoglyoxaline, 6mL water, (1.63g 0.04 mole) sodium hydroxide, 30mL ethanol, after the stirring and dissolving, add the SDS of 3% molar equivalent, add 4.44g (0.02 mole) 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride, heated and stirred refluxed 2 hours.Reaction is finished, and filters, and filtrate is added water, acetate with 36% is transferred pH=7, uses dichloromethane extraction, the washing organic layer, the evaporate to dryness organic layer adds acetone, adds sherwood oil again, stir, freezing, filter, drying obtains 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline 4.47g, yield 69.7%, content 95.6%.
Embodiment two:
In reaction flask, add 3.62g (0.02 mole) 5-methoxyl group-2-sulfydryl-1H-benzoglyoxaline, 6mL water, (1.63g 0.04 mole) sodium hydroxide, 30mL ethanol, after the stirring and dissolving, add the CTAB of 5% molar equivalent, add 4.44g (0.02 mole) 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride, heated and stirred refluxed 2 hours.Reaction is finished, and filters, and filtrate is added water, acetate with 36% is transferred pH=7, uses dichloromethane extraction, the washing organic layer, the evaporate to dryness organic layer adds acetone, adds sherwood oil again, stir, freezing, filter, drying obtains 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline 4.29g, yield 66.9%, content 94.5%.
Embodiment three:
In reaction flask, add 3.62g (0.02 mole) 5-methoxyl group-2-sulfydryl-1H-benzoglyoxaline, 6mL water, (1.63g 0.04 mole) sodium hydroxide, 30mL ethanol, after the stirring and dissolving, add the neutral surface active agent TritonX-100 of 3% molar equivalent, add 4.44g (0.02 mole) 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride, heated and stirred refluxed 2 hours.Reaction is finished, and filters, and filtrate is added water, acetate with 36% is transferred pH=7, uses dichloromethane extraction, the washing organic layer, the evaporate to dryness organic layer adds acetone, adds sherwood oil again, stir, freezing, filter, drying obtains 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline 5.65g, yield 86.7%, content 98.9%
Embodiment four:
In reaction flask, add 3.62g (0.02 mole) 5-methoxyl group-2-sulfydryl-1H-benzoglyoxaline, 6mL water, (1.61g 0.04 mole) sodium hydroxide, 30mL ethanol, after the stirring and dissolving, add the neutral surface active agent TritonX-100 of 5% molar equivalent, add 4.44g (0.02 mole) 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride, heated and stirred refluxed 2 hours.Reaction is finished, and filters, and filtrate is added water, acetate with 36% is transferred pH=7, uses dichloromethane extraction, the washing organic layer, the evaporate to dryness organic layer adds acetone, adds sherwood oil again, stir, freezing, filter, drying obtains 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline 5.99g, yield 93.4%, content 99.8%.
Embodiment five:
In reaction flask, add 204g (1.12 moles) 5-methoxyl group-2-sulfydryl-1H-benzoglyoxaline, water, 90g (0.04 mole) sodium hydroxide, 1000mL ethanol after the stirring and dissolving, adds the neutral surface active agent TritonX-100 of 1.5% molar equivalent, add 247g (1.12 moles) 2-chloromethyl-4-methoxyl group-3,5-dimethyl pyrazole thiamine hydrochloride is added 500ml ethanol again, and heated and stirred refluxed 2 hours.Reaction is finished, and filters, and filtrate is added water, acetate with 36% is transferred pH=7, uses dichloromethane extraction, the washing organic layer, the evaporate to dryness organic layer adds acetone, adds sherwood oil again, stir, freezing, filter, drying obtains 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-1H-benzoglyoxaline 326g, yield 89.4%, content 99.8%.
Embodiment six:
Rabeprazole precursor-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfo--1H-benzoglyoxaline synthetic:
In reaction flask, add 4.8NaOH (0.12mol), 30mL water, 150mL ethanol, 1.1mLTritonX-100 after the stirring and dissolving, add 2-mercaptobenzimidazole 9g (0.06mol), stirring and dissolving gets the orange reaction solution, add 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride 16g (0.06mol) again, the reaction solution color heated and stirred backflow 0.5h that shoals.The TLC detection reaction finishes, and pressure reducing and steaming ethanol adds the 120mL saturated sodium bicarbonate solution in residue, stir 10 minutes (pH=8-9), has a large amount of white solids to separate out, and uses CH
2Cl
2Extraction 100mL * 2 time, the washing organic layer, drying is filtered, the evaporate to dryness organic solvent gets oily matter, stirs and solidifies, get 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl with the 95mL re-crystallizing in ethyl acetate again] methyl] 16g of sulfo--1H-benzoglyoxaline, yield 78%, content 95%.
Embodiment seven:
Lansoprazole precursor-2-[3-methyl-4-(2,2, the 2-trifluoromethoxy)-2-pyridine] methylthio group-1H-benzoglyoxaline synthetic:
In reaction flask, add 4.8NaOH (0.12mol), 30mL water, 150mL ethanol, 1.1mLTritonX-100 after the stirring and dissolving, add 2-mercaptobenzimidazole 9.0g (0.06mol), stirring and dissolving gets the orange reaction solution, add 2-chloromethyl-3-methyl-4 trifluoromethoxy pyridine hydrochloride 16.6g (0.0mol) again, the reaction solution color heated and stirred backflow 0.5h that shoals.The TLC detection reaction finishes, pressure reducing and steaming ethanol adds the 120mL saturated sodium bicarbonate solution in residue, stir 10 minutes (pH=8-9), there are a large amount of white solids to separate out, filter crude product 23.4g,, add the 200mL re-crystallizing in ethyl acetate and get 2-[3-methyl-4-(2,2, the 2-trifluoromethoxy)-and the 2-pyridine] methylthio group-1H-benzoglyoxaline 17g, yield: 80%, content 95%.
Table 1. embodiment and comparative example's comparison
A:HPLC measures content.The content that b:NMR measures.
Discussion of results
Result with each embodiment and comparative example as shown in table 1 compares, and the result shows below:
1. with not adding any additives or adding phase-transfer catalyst and compare, add that tensio-active agent can reach with it quite or better result.
2. to different substrates, it is bigger that suitable tensio-active agent can make reaction yield improve.Amphoterics Triton X-100 can make omeprazole thioether precursor keep under the situation of content more than 95%, and reaction yield reaches about 90%, and yield improves more than 20%.
The preparation of omeprazole
Comparative examples
Method according to CN 91103923.6 and CN 96199057.0 (WO 9722603) has repeated the omeprazole synthesis technique, and the result is as follows:
Comparative examples one
Under the room temperature, in 50 milliliters flask, add 1.84 gram 5-methoxyl group-2-sulfydryl-1H-benzoglyoxalines, 0.12 gram TBAB, 2.35 50% aqueous solution of gram sodium hydroxide, 50 milliliters of methylene dichloride in stirring down, add 2.22 gram 2-chloromethyl-4-methoxyl groups-3,5-dimethyl pyrazole thiamine hydrochloride, reflux 2 hours.Stop reaction, be separated two, water is given a baby a bath on the third day after its birth time with methylene dichloride, merges organic phase.
1.05 gram saleratus are dissolved in 9 ml waters, it is added in the above-mentioned organic solution.2.23 gram metachloroperbenzoic acids (77%w/w) are dissolved in 4 milliliters of methylene dichloride and the 1 milliliter of ethanol.Under 0～5 ℃ condition, in the mixing solutions of the methylene dichloride of above-mentioned preparation and potassium bicarbonate aqueous solution, slowly drip metachloroperbenzoic acid solution, the temperature that keeps reaction solution is between 5-10 ℃.Drip and finish, hydro-oxidation sodium is transferred pH to 10, and product is extracted aqueous phase, separates two-phase, and organic phase is washed with alkali aqueous solution, merges water.
Add 1.2 milliliters of methyl-formiates to aqueous phase, not seeing has product to separate out.
Comparative examples two
Under the room temperature, in 50 milliliters flask, add 1.80 gram 5-methoxyl group-2-sulfydryl-1H-benzoglyoxalines, 0.12 gram TBAB, 2.35 50% aqueous solution of gram sodium hydroxide, 50 milliliters of methylene dichloride in stirring down, add 2.22 gram 2-chloromethyl-4-methoxyl groups-3,5-dimethyl pyrazole thiamine hydrochloride, reflux 2 hours.Stop reaction, be separated two, water is given a baby a bath on the third day after its birth time with methylene dichloride, merges organic phase.
1.05 gram saleratus are dissolved in 9 ml waters, it is added in the above-mentioned organic solution.2.23 gram metachloroperbenzoic acids (77%w/w) are dissolved in 4 milliliters of methylene dichloride and the 1 milliliter of ethanol.Under 0～5 ℃ condition, in the mixing solutions of the methylene dichloride of above-mentioned preparation and potassium bicarbonate aqueous solution, slowly dripped metachloroperbenzoic acid solution in 1 hour, the temperature that keeps reaction solution is between 5-10 ℃.Drip and finish, hydro-oxidation sodium is transferred pH to 12, and product is extracted aqueous phase, separates two-phase, and organic phase is washed with alkali aqueous solution, merges water, and this water continues to stir half an hour at 0～5 ℃.
Slowly add 2 milliliters of methyl-formiates to aqueous phase, transfer pH to 10, remove ice bath, make it slowly rise to room temperature, add 0.08 gram crystal seed.Slowly add 1.5 milliliters of methyl-formiates again and transfer pH to 9, continue to stir 2 hours, filter, with 5 milliliter of 0.1% ammoniacal liquor, 3 milliliters methyl alcohol is washed solid, and drying gets product 0.26 gram, productive rate 5.04%, warp
1H-NMR turns out to be omeprazole.
Comparative examples three:
The metachloroperbenzoic acid (72%w/w) of 11.1g (0.046 mole) is dissolved in the 40mL methylene dichloride, and 10mL ethanol is chilled to about 0 ℃, and is standby; The 5.61g saleratus is dissolved in 46mL water, is chilled to 0 ℃, standby; With 15.1g (0.046 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 68mL methylene dichloride, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, slowly drip above-mentioned metachloroperbenzoic acid solution, the temperature that keeps reaction solution is between 5-10 ℃.Reaction is finished, and adds water 46mL, and 50% cold aqueous sodium hydroxide solution 10mL transfers pH to 13.5, stirs 30 minutes at 0～5 ℃, and separatory discards organic layer.Continuation was stirred 1 hour at 0～5 ℃, slowly dripped methyl-formiate simultaneously, transferred pH to 10.7.Remove ice bath, continue to stir, treat that temperature rises to room temperature, add crystal seed 0.23g.In half an hour, slowly drip methyl-formiate, transfer pH to 9.0.This moment, the aqueous solution became redness, had small amount of solid to separate out, and continued to stir two hours.Filter, get off-white powder, wash solid with 40mL0.1% ammonia hydroxide/methanol (1/1) solution, drying gets white solid 5.24g, yield 33.0%, content 96%.
Comparative examples four:
The metachloroperbenzoic acid (72%w/w) of 11.2g (0.046 mole) is dissolved in the 40mL methylene dichloride, and 10mL ethanol is chilled to about 0 ℃, and is standby; The 5.61g saleratus is dissolved in 46mL water, is chilled to 0 ℃, standby; With 15.4g (0.046 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 68mL methylene dichloride, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, slowly drip above-mentioned metachloroperbenzoic acid solution, the temperature that keeps reaction solution is between 5-10 ℃.Reaction is finished, and adds water 46mL, and 50% cold aqueous sodium hydroxide solution 10mL transfers pH to 13.5, stirs 30 minutes at 0～5 ℃, and separatory discards organic layer.Continuation was stirred 1 hour at 0～5 ℃, slowly dripped methyl-formiate simultaneously, transferred pH to 10.7.Remove ice bath, continue to stir, treat that temperature rises to room temperature, add crystal seed 0.23g.In half an hour, slowly drip methyl-formiate, transfer pH to 9.0.This moment, the aqueous solution became redness, had small amount of solid to separate out, and continued to stir two hours.Filter, get off-white powder, wash solid with 40mL0.1% ammonia hydroxide/methanol (1/1) solution, drying gets white solid 2.70g, yield 17.0%, content 91.3%.
Comparative examples five:
The metachloroperbenzoic acid (86%w/w) of 37.2g (0.184 mole) is dissolved in the 160mL methylene dichloride, and 40mL ethanol is chilled to about 0 ℃, and is standby; The 22.5g saleratus is dissolved in 184mL water, is chilled to 0 ℃, standby; With 60.6g (0.184 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 272mL methylene dichloride, add above-mentioned potassium bicarbonate aqueous solution, be chilled to 0～5 ℃, slowly drip above-mentioned metachloroperbenzoic acid solution, the temperature that keeps reaction solution is between 5-10 ℃.Reaction is finished, and adds water 184mL, and 50% cold aqueous sodium hydroxide solution 10mL transfers pH to 13.5, stirs 30 minutes at 0～5 ℃, and separatory discards organic layer.Continuation was stirred 1 hour at 0～5 ℃, slowly dripped methyl-formiate simultaneously, transferred pH to 10.7.Remove ice bath, continue to stir, treat that temperature rises to room temperature, add crystal seed 0.83g.In half an hour, slowly drip methyl-formiate, transfer pH to 9.0.This moment, the aqueous solution became redness, had small amount of solid to separate out, and continued to stir two hours.Filter, get off-white powder, wash solid with 160mL0.1% ammonia hydroxide/methanol (1/1) solution, drying gets white solid 8.51g, yield 13.4%, content 74.9%.
Comparative examples six:
In the mixing solutions of 9mL toluene and 4mLEtOH, add 4.03g (002 mole) metachloroperbenzoic acid (86%w/w), after the dissolving, be cooled to 0 ℃, standby; In reaction flask, add 6.58g (1.0 moles) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline, after 60mL toluene/6mL ethanol mixture solution dissolving, add 2.8g KHCO
3With the buffered soln of 24mL water preparation, cool off reaction flask to 5-10 ℃ with ice bath again, slowly drip above-mentioned mCPBA solution again, the temperature that keeps reaction solution is between 5-10 ℃.Drip and finish, under ice bath, add 20mL water again.With 4N NaOH regulator solution pH value is 13-14, and separatory, water layer use methyl-formiate (5mL) to regulate about pH to 9 stirring at room 3h again, filter, filter cake washs with less water, steams empty drying at room temperature 3h, again at 60 ℃ of following vacuum-drying 1.5h, get 5.0 gram solids, yield 71%, content 98%.
Embodiment
Embodiment one:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the TritonX-100 of 3% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.14g, yield 52.5%, content 96.7%.
Embodiment two:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the DDPS of 3% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.45g, yield 63.9%, content 102.0%.
Embodiment three:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, standby the 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, and is standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the CPB of 3% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, and separatory is used dichloromethane extraction 5mL3 time, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.54g, yield 68.8%, content 96.7%.
Embodiment four:
The metachloroperbenzoic acid (86%w/w) of 4.05g (0.02 mole) is dissolved in the 20mL methylene dichloride, and 5mL ethanol is chilled to about 0 ℃, and is standby; The 2.42g saleratus is dissolved in 20mL water, is chilled to 0 ℃, standby; With 6.52g (0.02 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 30mL methylene dichloride, adds the neutral surface active agent CTAB of 1% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 10mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 15mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 4.47g, yield 64.7%, content 96.9%.
Embodiment five:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the CTAB of 2% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.69g, yield 74.5%, content 90.6%.
Embodiment six:
The metachloroperbenzoic acid (86%w/w) of 4.05g (0.02 mole) is dissolved in the 20mL methylene dichloride, and 5mL ethanol is chilled to about 0 ℃, and is standby; The 2.42g saleratus is dissolved in 20mL water, is chilled to 0 ℃, standby; With 6.52g (0.02 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 30mL methylene dichloride, adds the neutral surface active agent CTAB of 3% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 10mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 15mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 5.74g, yield 83.2%, content 101.8%.
Embodiment seven:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water } standby; Be chilled to 0 ℃.With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the CTAB of 4% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.69g, yield 74.5%, content 86.7%.
Embodiment eight:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the SDS of 1% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.90g, yield 83.8%, content 94.5%.
Embodiment nine:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the SDS of 2% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.86g, yield 82.1%, content 95.7%.
Embodiment ten:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the SDS of 3% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.86g, yield 82.1%, content 95.9%.
Embodiment 11:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the SDS of 4% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.86g, yield 82.1%, content 96.2%.
Embodiment 12:
The m-chloro peroxide benzene first (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the SDS of 5% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.94g, yield 85.4%, content 95.3%.
Embodiment 13:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the SDS of 6% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.84g, yield 81.0%, content 99.3%.
Embodiment 14:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the SDS of 7% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.83g, yield 82.1%, content 99.3%.
Embodiment 15:
The metachloroperbenzoic acid (86%w/w) of 42.3g (0.21 mole) is dissolved in the 150mL methylene dichloride, and 75mL ethanol is chilled to about 0 ℃, and is standby; The 24g saleratus is dissolved in 150mL water, is chilled to 0 ℃, standby; With 65.8g (0.2 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 250mL methylene dichloride, adds the SDS of 6% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 100mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 150mL, stir 1.5 in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 60.2g, yield 87.2%, content 99.09%.
Embodiment 16:
The metachloroperbenzoic acid (86%w/w) of 84.6g (0.42 mole) is dissolved in the 300mL methylene dichloride, and 150mL ethanol is chilled to about 0 ℃, and is standby; The 48g saleratus is dissolved in 300mL water, is chilled to 0 ℃, standby; With 131.6g (0.4 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 500mL methylene dichloride, adds the SDS of 6% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, and usefulness dichloromethane extraction 200mL * 3 times merges organic layer, adds a small amount of triethylamine, the evaporate to dryness organic phase adds butanone 300mL, stirs 1.5h in 0 ℃ of left and right sides lucifuge, filters, drying obtains white omeprazole solid 120.7g, yield 87.4%, content 99.23%.
Embodiment 17:
In the mixing solutions of 9mL toluene and 4mLEtOH, add 4.03g (0.02moL) metachloroperbenzoic acid (86%w/w), after the dissolving, be cooled to 0 ℃, standby; In reaction flask, add 6.58g (0.02moL) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline, surfactant SDS 0.348 gram (6% molar equivalent) after 60mL toluene/6mL ethanol mixture solution dissolving, adds 2.8g KHCO
3With the buffered soln of 24mL water preparation, cool off reaction flask to 5-10 ℃ with ice bath again, slowly drip above-mentioned mCPBA solution again, the temperature that keeps reaction solution is between 5-10 ℃.Drip and finish, under ice bath, add 20mL water again.With 4N NaOH regulator solution pH value is 13-14, separatory, separatory, the water layer dichloromethane extraction, 30mL * 2 time merge organic layer, evaporate to dryness adds the 15mL butanone, stirs 2-3h, filter, with a small amount of butanone washing leaching cake, vacuum-drying 1.5h gets 6.3 gram white solids, yield 91.3%, content 99.5%.
Embodiment 18:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the TBAB of 1% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.58g, yield 70.0%, content 92.4%.
Embodiment 19:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the TBAB of 2% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.57g, yield 69.1%, content 97.9%.
Embodiment 20:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the TBAB of 3% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.59g, yield 70.0%, content 101.0%.
Embodiment 21:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the TBAB of 4% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.64g, yield 72.0%, content 97.1%.
Embodiment 22:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the TBAB of 6% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.59g, yield 70.0%, content 95.0%.
Embodiment 23:
The metachloroperbenzoic acid (86%w/w) of 1.35g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.80g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.17g (0.006 mole) 5-methoxyl group-2-[(4-methoxyl group-3,5-dimethyl-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds the TBAB of 7% molar equivalent, adds above-mentioned potassium bicarbonate aqueous solution.0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white omeprazole solid 1.62g, yield 72.3%, content 95.7%.
Synthesizing of rabeprazole:
Embodiment 24:
The metachloroperbenzoic acid (86%w/w) of 1.110g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.72g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.01g (0.006 mole) 2-[(3-dimethyl-4-3 '-methoxyl group-propoxy--2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds 6%SDS, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to-45 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds acetone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white rabeprazole solid 1.2g, yield 57%, content 95.5%.
Synthesizing of lansoprazole:
Embodiment 25:
The metachloroperbenzoic acid (86%w/w) of 1.110g (0.006 mole) is dissolved in the 6mL methylene dichloride, and 1.5mL ethanol is chilled to about 0 ℃, and is standby; The 0.72g saleratus is dissolved in 3mL water, is chilled to 0 ℃, standby; With 2.11g (0.006 mole) 2-[(3-dimethyl-4-2 ', 2 ', 2 '-trifluoro ethoxy-2-pyridyl)-methylthio group]-the 1H-benzoglyoxaline is dissolved in the 10mL methylene dichloride, adds 6%mgSDS, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times, merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying, remove by filter anhydrous sodium sulphate, evaporate to dryness adds butanone 5mL, stir 1.5h in 0 ℃ of left and right sides lucifuge, filter, drying obtains white lansoprazole solid 1.53g, yield 70%, content 94.1%.
Synthesizing of lY 81149:
Embodiment 26:
The metachloroperbenzoic acid (86%w/w) of 0.263g (0.00143 mole) is dissolved in the 3mL methylene dichloride, and 0.75mL ethanol is chilled to about 0 ℃, and is standby; The 0.172g saleratus is dissolved in 1.5mL water, is chilled to 0 ℃, standby; With 0.500g (0.00143 mole) 5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] methylthio group]-1-hydrogen-benzoglyoxaline is dissolved in the 5mL methylene dichloride, adds 6%SDS, adds above-mentioned potassium bicarbonate aqueous solution.Be chilled to 0～5 ℃, drip above-mentioned metachloroperbenzoic acid solution.Reaction is finished, separatory, usefulness dichloromethane extraction 5mL * 3 times; merge organic layer, add a small amount of triethylamine, anhydrous sodium sulfate drying; remove by filter anhydrous sodium sulphate, evaporate to dryness adds acetone 5mL; stir 1.5h in 0 ℃ of left and right sides lucifuge; filter, drying obtains white 5-(1H-pyrroles-1-yl)-2-[[(4-methoxyl group-3-methyl-2-pyridyl)-methyl] sulfinyl]-1-hydrogen-benzoglyoxaline solid 0.292g; yield 56%, content 85.4%.
Table 2. embodiment and comparative example's comparison
A: by compound (III) is starting raw material, not separating intermediate carries out-and the footwork reaction.
B: with toluene is solvent.
C:HPLC measures content.
Discussion of results
Result with each embodiment and comparative example as shown in table 2 compares, and the result shows below:
1. repeat patent CN 91103923.6 and CN 96199057.0, in different reaction scale, when being solvent with the methylene dichloride, common yield is not more than 33%, can't obtain the yield of the described 75%-90% of patent, and during fairly large reaction, yield is lower.
2. when adding tensio-active agent in the reaction, in different solvent systems, the yield of reaction is significantly improved.
3. by the present invention, product is easy to get, and aftertreatment is simple, the reaction favorable reproducibility, and the yield of product is at 52-91%, and content is greater than 92%.
4. add anion surfactant SDS in system, the yield of product is greater than 81%, and content is greater than more than 94.5%.
5. when being solvent with the methylene dichloride, in system, add phase-transfer catalyst, can obtain the yield about 70%, content greater than 90%.And product is easy to get, and aftertreatment is simple, the reaction favorable reproducibility.
Claims (14)
1. method for preparing general formula (I) benzimidazole type compound,
R wherein
1And R
2Mutually the same or be selected from hydrogen, methoxyl group, pyrryl or difluoro-methoxy, R unequally
3, R
4And R
5It is mutually the same or be selected from hydrogen, methyl, methoxyl group, methoxy propoxy or trifluoro ethoxy unequally,
It is characterized in that described this method may further comprise the steps:
Step 1:
Make general formula (II) compound and a chloroperoxybenzoic acid reaction, it is characterized in that in the mixing solutions of organic solvent and water, the tensio-active agent or the phase-transfer catalyst that add 1%～16% molar equivalent, the pH of solution remains under 7.5～8.5 the condition, with general formula (II) compound and etc. molar equivalent between chloroperoxybenzoic acid reaction, after above-mentioned reaction is finished, separatory, use the dichloromethane extraction water, merge organic layer, directly evaporate to dryness adds the organic phase of a small amount of triethylamine, and the gained solid stirs in ketones solvent, filter, drying obtains the benzimidazoles derivative of general formula (I);
Step 2:
2-sulfydryl-1H-benzimidizole derivatives (III) and etc. the polysubstituted 2-chloromethylpyridine acid salt derivative (IV) of molar equivalent, in the presence of 1%～10% molar equivalent tensio-active agent, under alkaline condition in the mixing solutions of organic solvent and water stirring and refluxing 2 hours, after reaction is finished, filter, transfer pH=7, use the dichloromethane extraction water, the evaporate to dryness organic layer adds straight chain ketone therein, add sherwood oil again, stir, freezing, filter, drying, the sulfide derivative of general formula (II).
2. method according to claim 1 is characterized in that the tensio-active agent of described step 1 selects in cationic surfactant, aniorfic surfactant, neutral surface active agent or amphoterics.
3. method according to claim 2, it is characterized in that cationic surfactant is cetrimonium bromide or hexadecyl pyridinium bromide, aniorfic surfactant is a sodium lauryl sulphate, the neutral surface active agent is a Triton X-100, and amphoterics is 3-(dimethyl dodecyl ammonium) propyl group-1-sodium sulfonate.
4. method according to claim 1, the phase-transfer catalyst that it is characterized in that described step 1 is a Tetrabutyl amonium bromide.
5. method according to claim 1, the organic solvent that it is characterized in that described step 1 is a haloalkane, fragrant alkane.
6. method according to claim 5 is characterized in that described organic solvent is a methylene dichloride.
7. method according to claim 5 is characterized in that described organic solvent is a toluene.
8. method according to claim 1 is characterized in that described step 1 is to carry out at-5 ℃ to 20 ℃.
9. method according to claim 1 is characterized in that the used ketones solvent of described step 1 is C
3～C
5Straight chain ketone.
10. method according to claim 9 is characterized in that described ketones solvent is a butanone.
11. method according to claim 1 is characterized in that the benzimidazole type compound of described its formula of (I) is selected from omeprazole, lansoprazole, rabeprazole, lY 81149 and pantoprazole.
12. method according to claim 1 is characterized in that the tensio-active agent of described step 2 selects in cationic surfactant, aniorfic surfactant, neutral surface active agent or amphoterics.
13. method according to claim 12, it is characterized in that cationic surfactant is cetrimonium bromide or hexadecyl pyridinium bromide, aniorfic surfactant is a sodium lauryl sulphate, the neutral surface active agent is a Triton X-100, and amphoterics is 3-(dimethyl dodecyl ammonium) propyl group-1-sodium sulfonate.
14. method according to claim 1, the straight chain ketone that it is characterized in that described step 2 is acetone.
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| CN103664885A (en) * | 2013-12-12 | 2014-03-26 | 武汉工程大学 | Preparation method of benzimidazole proton pump inhibitor intermediate |
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| CN104610226A (en) * | 2014-12-31 | 2015-05-13 | 广东东阳光药业有限公司 | Asymmetric oxidation method for dexlansoprazole |
| CN105859685A (en) * | 2016-05-12 | 2016-08-17 | 山东裕欣药业有限公司 | Method for preparing dexrabeprazole sodium |
| CN106543146A (en) * | 2016-11-10 | 2017-03-29 | 石家庄市度智医药科技有限公司 | A kind of preparation method of R-lansoprazole |
| CN112707889B (en) * | 2020-06-15 | 2024-02-06 | 江苏中邦制药有限公司 | Synthesis method of lansoprazole |
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| CN103664885A (en) * | 2013-12-12 | 2014-03-26 | 武汉工程大学 | Preparation method of benzimidazole proton pump inhibitor intermediate |
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Effective date of registration: 20090904 Address after: Four, nine South Renmin Road, Sichuan, Chengdu Province, China: 610041 Co-patentee after: Zhejiang Jinhua Conba Bio-pharm. Co., Ltd. Patentee after: Chengdu Organic Chemistry Co., Ltd., Chinese Academy of Sciences Address before: Four, nine South Renmin Road, Sichuan, Chengdu Province, China: 610041 Patentee before: Chengdu Organic Chemicals Co., Ltd., Chinese Academy of Sciences |