CN116410178A - Preparation method of omeprazole thioether - Google Patents
Preparation method of omeprazole thioether Download PDFInfo
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- CN116410178A CN116410178A CN202111638225.6A CN202111638225A CN116410178A CN 116410178 A CN116410178 A CN 116410178A CN 202111638225 A CN202111638225 A CN 202111638225A CN 116410178 A CN116410178 A CN 116410178A
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- -1 omeprazole thioether Chemical class 0.000 title claims abstract description 30
- 229960000381 omeprazole Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- PVRSIFAEUCUJPK-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine Chemical compound COC1=CC=C(NN)C=C1 PVRSIFAEUCUJPK-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims abstract description 9
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims abstract description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 239000012074 organic phase Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 238000007664 blowing Methods 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- BTVWZWFKMIUSGS-UHFFFAOYSA-N dimethylethyleneglycol Natural products CC(C)(O)CO BTVWZWFKMIUSGS-UHFFFAOYSA-N 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 claims description 2
- LCJDHJOUOJSJGS-UHFFFAOYSA-N 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridin-1-ium;chloride Chemical compound Cl.COC1=C(C)C=NC(CCl)=C1C LCJDHJOUOJSJGS-UHFFFAOYSA-N 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 239000000203 mixture Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- QUVQXQXQRZOCQU-UHFFFAOYSA-N CC=1C(=NC=C(C1OC)C)CSC#N Chemical compound CC=1C(=NC=C(C1OC)C)CSC#N QUVQXQXQRZOCQU-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229940126409 proton pump inhibitor Drugs 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 230000006837 decompression Effects 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000612 proton pump inhibitor Substances 0.000 description 4
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 150000003222 pyridines Chemical class 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- SUBDBMMJDZJVOS-XMMPIXPASA-N (R)-omeprazole Chemical compound C([S@@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-XMMPIXPASA-N 0.000 description 2
- KOFBRZWVWJCLGM-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazole-2-thione Chemical compound COC1=CC=C2NC(S)=NC2=C1 KOFBRZWVWJCLGM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229960000197 esomeprazole magnesium Drugs 0.000 description 2
- 229960000496 esomeprazole sodium Drugs 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- KWORUUGOSLYAGD-WLHYKHABSA-N magnesium;5-methoxy-2-[(r)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Mg+2].C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-WLHYKHABSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical class [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- NMCYSHDHAZKJBA-UHFFFAOYSA-N 1h-benzimidazol-2-yloxymethanethiol Chemical compound C1=CC=C2NC(OCS)=NC2=C1 NMCYSHDHAZKJBA-UHFFFAOYSA-N 0.000 description 1
- BAIWBDZQCQHMJV-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-3,5-dimethylpyridine Chemical compound CC1=CN=C(CCl)C(C)=C1Cl BAIWBDZQCQHMJV-UHFFFAOYSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- XYYYTUCWSSREHK-UHFFFAOYSA-N N1=CC=CC=C1.[N]=O Chemical compound N1=CC=CC=C1.[N]=O XYYYTUCWSSREHK-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of omeprazole thioether; the invention takes 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride as a raw material to react with thiocyanate to obtain an intermediate, then further reacts with p-methoxyphenylhydrazine, and is subjected to post-treatment to obtain the omeprazole thioether. The preparation method is novel, simple to operate, high in product purity and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical synthesis intermediates, and particularly relates to a preparation method of omeprazole thioether.
Background
Proton pump inhibitors (Proton Pump Inhibitor, PPI) are a class of drugs that inhibit gastric acid secretion, also known as H + /K + ATPase inhibitors which act specifically and non-competitively on H on parietal cells + /K + Atpase, blocking gastric acid secretion. The general proton pump inhibitor is benzimidazole derivative, can quickly penetrate through gastric wall cell membrane and accumulate in a gastric secretion tube with strong acidity, and under the acidic condition, acid is catalyzed to generate sulfenamide compounds, and the newly generated sulfenamide compounds can be covalently combined with sulfhydryl of H+/K+ -ATPase to form disulfide bond, so that H is formed + /K + ATPase inactivation, thereby effectively inhibiting peripheral and central mediated gastric acid secretion. Esomeprazole sodium, esomeprazole magnesium and omeprazole are currently marketed via the market.
Proton pump inhibitors that have been marketed and are being developed today are mostly synthesized from benzimidazole compounds as intermediates. Wherein the compound 5-methoxy-2- [ (4-methoxy-3, 5-dimethylpyridin-2-yl) methylthio ] -1-H benzimidazole (omeprazole thioether) is an important intermediate for synthesizing esomeprazole sodium, esomeprazole magnesium and omeprazole, and the structural formula is shown as follows:
the synthesis of the compound 5-methoxy-2- [ (4-methoxy-3, 5-dimethylpyridin-2-yl) methylthio ] -1-H-benzimidazole (omeprazole thioether) has been reported in relatively large numbers, and is generally the same in that both undergo a substitution reaction with a pyridine derivative, except that the leaving group of the pyridine derivative is different and the sequence of the reaction of the para-position groups of the pyridine ring is different. The main synthetic route is as follows:
1.
the synthesis of this intermediate was first reported by AMCrowe, RJIfe et al, journal of Labelled Compounds and Radiopharmaceuticals,1986, 21-33.
In the route method, the synthesis of the omeprazole thioether uses 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and 5-methoxy-2-mercapto-1H-benzimidazole as starting materials, the omeprazole thioether can be obtained by condensation under alkaline conditions and one-step reaction, the synthesis steps are few, the reaction is simple, the raw materials are easy to obtain, the operation is simple and convenient, and the method is relatively suitable for industrial production. However, the yield and purity are not high, and the subsequent reaction is not affected, and although the prior art improves the post-treatment, the operation steps are complicated.
2.
The pyridine derivative used for synthesizing the CN1233613A omeprazole thioether is p-methoxypyridine mesylate, the hydroxy group is prepared into mesylate which is a good leaving group, and the mesylate and the mercaptomethoxy benzimidazole can smoothly undergo substitution reaction under the action of alkali. However, the synthesis of the p-methoxypyridine methanesulfonate needs to use highly toxic and corrosive methanesulfonyl chloride or methanesulfonic anhydride, is not friendly to the environment, is relatively troublesome in post-treatment of waste liquid, and is not suitable for industrial production.
3.
Condensing 2-chloromethyl-3, 5-dimethyl-4-chloropyridine and 2-mercapto-5-methoxy-1-hydrobenzimidazole, and then substituting chlorine by methoxy under the action of sodium methoxide to obtain omeprazole thioether, wherein the synthetic route is easy to generate side reaction during condensation reaction, and the reaction is not complete when the methoxy substitutes chlorine. The yield and the purity are low, and the method is not suitable for industrial production.
4.
Esfandyari, maryam et al Iranian Journal of Chemistry & Chemical Engineering,36 (4), 21-29;2017 discloses the synthetic route, sulfide nitro is treated, and the yield is 75%. The separation and purification are difficult, the material loss is serious, the cost is high, and the industrial production is not facilitated.
5.
CN 109134354a discloses that pyridine nitrogen oxide III-1 is used as a raw material, ethyl acetate or dichloromethane is used as a solvent, and reacts with trifluoroacetic anhydride to obtain II-1, and toluene or ethyl acetate is used as a solvent, and then reacts with 2-mercapto-5-methoxybenzimidazole to generate omeprazole thioether without purification. Although the reaction process was simple, the post-treatment was column chromatography with a yield of only 60%. Is not beneficial to industrial production.
The above synthetic routes have advantages, but the reaction conditions and production costs used therein remain severe, so that it is necessary to develop a new synthetic route.
Disclosure of Invention
Aiming at a plurality of problems existing in the prior art for preparing the omeprazole thioether compound, the invention provides a novel preparation method of the omeprazole thioether compound. The method has mild reaction conditions, safe and simple operation process, and the prepared target product has higher purity and yield.
The invention is realized by the following technical scheme:
the preparation method of omeprazole thioether compound I comprises the steps of reacting SM-1 serving as a starting material with thiocyanate under an alkaline condition to prepare an intermediate SM-2, and then reacting p-methoxy phenylhydrazine with SM-2 to prepare a target product I, wherein the reaction formula is as follows:
a preparation method of an omeprazole thioether compound shown in a formula I, which comprises the following steps:
step 1: adding SM-1 and alkali into a reaction solvent, and controlling the temperature T 1 Stirring, adding thiocyanate, maintaining the temperature, stirring until the reaction is finished, and performing post-treatment to obtain an intermediate SM-2, wherein the synthetic route is as follows:
preferably, the molar ratio of SM-1 to thiocyanate in step 1 is: 1:1.0 to 1.2, more preferably 1:1.05.
Preferably, the molar ratio of SM-1 to base fed in step 1 is: 1:1.0 to 2.0, more preferably 1:1.2.
Preferably, the base described in step 1 is NaOH, KOH, na 2 CO 3 、K 2 CO 3 、NaHCO 3 、KHCO 3 One of them.
Preferably, the reaction solvent in the step 1 is one of ethanol, methanol and isopropanol.
Preferably, the thiocyanate in step 1 is one of NaSCN, KSCN, ammonium thiocyanate.
Preferably, T as described in step 1 1 20 to 30℃and preferably 25 ℃. The room temperature in the present invention was 25 ℃.
Preferably, the reaction time described in step 1 is: 1 to 2 hours, more preferably 1.5 hours.
In a preferred embodiment, the post-treatment step in step 1 is: after the reaction is finished, adding an extractant into the feed liquid, washing with water and saturated saline respectively, organically drying, and concentrating until the mixture is dried to obtain SM-2.
Preferably, the extractant is one of dichloromethane, chloroform, toluene, ethyl acetate and butyl acetate, and further preferably dichloromethane.
Step 2: adding an intermediate SM-2 and p-methoxy phenylhydrazine into a reaction solvent, and controlling the temperature T 2 After the reaction is detected, the target compound I is prepared through post-treatment, and the synthetic route is as follows:
preferably, the reaction solvent in the step 2 is one or a combination of tetrahydrofuran, N dimethylformamide, N dimethylacetamide, dimethyl sulfoxide, 1, 4-dioxane, 2-methyltetrahydrofuran, water, ethylene glycol dimethyl ether and ethylene glycol monoether, and further preferably tetrahydrofuran: the volume ratio of water is 1:1.
Preferably, the feeding mole ratio of SM-2 to p-methoxyphenylhydrazine in the step 2 is 1:1.0 to 1.2, and more preferably 1:1.05.
Preferably, the reaction temperature in step 2 is 60 to 100 ℃, more preferably 60 to 80 ℃.
Preferably, the reaction time described in step 2: from 6 to 10 hours, more preferably 8 hours.
In a preferred embodiment, the post-treatment step of step 2 is as follows: after the reaction is finished, cooling to room temperature, adding an extractant, washing an organic phase with water, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness under reduced pressure to obtain oily substance, adding acetonitrile, stirring until no crystal is separated out, cooling to 0-5 ℃ for crystallization, filtering, leaching a filter cake with acetonitrile, and drying by blowing to obtain the compound I. Preferably, the extractant is one of dichloromethane, chloroform and ethyl acetate, and more preferably dichloromethane.
The invention has the beneficial effects that:
1. the invention provides a simple and efficient method for preparing omeprazole thioether, and the target product prepared by the process has higher yield and purity, and is suitable for industrial mass production. Meanwhile, the problems of exceeding the standard of the water content of the omeprazole thioether are avoided, and the water content is less than 0.01 percent or even less through detection.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Example 1
100g (0.45 mol) of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride, 21.6g (0.54 mol) of sodium hydroxide and 500ml of ethanol are added into a 1L three-necked flask, stirred at room temperature for 30min, 38.3g (0.47 mol) of sodium thiocyanate is added, stirring reaction is continued for 1.5 hours at room temperature, after detection, the reaction is completed, the feed liquid is transferred to a 2L separating funnel, 500ml of dichloromethane is added, the mixture is washed twice with 500ml of water and then washed once with 500ml of saturated saline, the organic phase is dried with anhydrous sodium sulfate, and the organic phase is concentrated until the dried product is 92.7g of (4-methoxy-3, 5-dimethylpyridine-2-yl) methylthiocyanate, and the yield is 98.9% and the HPLC is 98.5%.
250ml of water and 62g (0.45 mol) of p-methoxyphenylhydrazine are added into a 1L three-necked flask, 89.3g (0.43 mol) of SM-2 compound is dissolved by 250ml of tetrahydrofuran and then added into the three-necked flask, reflux reaction is carried out for 8 hours, the reaction is completed, the temperature is reduced, 500ml of dichloromethane is added, stirring is carried out for 15 minutes, liquid separation is carried out, an organic phase is washed by 200ml of water for 2 times, the organic phase is dried by 100g of anhydrous sodium sulfate for 1 hour, decompression and evaporation are carried out until oily substances are obtained, 400ml of acetonitrile are added for stirring, the temperature is reduced to 0-5 ℃ for 6 hours, filtration is carried out, a filter cake is leached by 50ml of acetonitrile once, and air blast drying is carried out to obtain white solid compound I, namely omeprazole thioether 135.6g, the yield is 95.7%, the purity is 99.8%, and the moisture content is less than 0.01%.
Example 2
100g (0.45 mol) of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride, 21.6g (0.54 mol) of sodium hydroxide and 500ml of ethanol are added into a 1L three-necked flask, stirred at room temperature for 30min, 43.8g (0.54 mol) of sodium thiocyanate is added, stirring reaction is continued for 2 hours at room temperature, after detection reaction is finished, the feed liquid is transferred to a 2L separating funnel, 500ml of dichloromethane is added, the mixture is washed twice with 500ml of water and then washed once with 500ml of saturated saline, the organic phase is dried with anhydrous sodium sulfate, and the organic phase is concentrated until the organic phase is dried to obtain 91.4g of (4-methoxy-3, 5-dimethylpyridine-2-yl) methyl thiocyanate, and the yield is 97.5%, and the HPLC is 98.0%.
250ml of water and 62g (0.45 mol) of p-methoxyphenylhydrazine are added into a 1L three-port bottle, 78.1g (0.38 mol) of SM-2 compound is dissolved by 250ml of tetrahydrofuran and then added into the three-port bottle, reflux reaction is carried out for 6 hours, the reaction is completed, the temperature is reduced, 500ml of dichloromethane is added, stirring is carried out for 15 minutes, liquid separation is carried out, an organic phase is washed by 200ml of water for 2 times, the organic phase is dried by 100g of anhydrous sodium sulfate for 1 hour, decompression and evaporation are carried out until oily substances are obtained, 400ml of acetonitrile are added for stirring, the temperature is reduced to 0-5 ℃ for 7 hours, filtration is carried out, a filter cake is leached by 50ml of acetonitrile for one time, and blast drying is carried out to obtain white solid compound I, namely omeprazole thioether 121.2g, the yield is 96.8%, purity is 99.3%, and moisture content is less than 0.01%.
Example 3
100g (0.45 mol) of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride, 21.6g (0.54 mol) and 500ml of ethanol are added into a 1L three-necked flask, the mixture is stirred at room temperature for 30min, 36.5g (0.45 mol) of sodium thiocyanate is added, the mixture is continuously stirred at room temperature for reaction for 1 hour, after detection, the feed liquid is transferred to a 2L separating funnel, 500ml of dichloromethane is added, the mixture is washed twice with 500ml of water and then washed once with 500ml of saturated saline, the organic phase is dried with anhydrous sodium sulfate, and the organic phase is concentrated until the organic phase is dried to obtain 89.6g of (4-methoxy-3, 5-dimethylpyridine-2-yl) methylthiocyanate, and the yield is 95.6% and the HPLC is 99.0%.
250ml of water and 55.3g (0.40 mol) of p-methoxyphenylhydrazine are added into a 1L three-necked flask, 83.3g (0.40 mol) of the SM-2 compound is dissolved by 250ml of tetrahydrofuran and then added into the three-necked flask, reflux reaction is carried out for 6 hours, the reaction is completed, the temperature is reduced to room temperature, 500ml of dichloromethane is added, stirring is carried out for 15 minutes, liquid separation is carried out, an organic phase is washed by 200ml of water for 2 times, the organic phase is dried by 100g of anhydrous sodium sulfate for 1 hour, decompression and evaporation are carried out until oily substances are obtained, 350ml of acetonitrile are added for stirring, the temperature is reduced to 0-5 ℃ for crystallization for 6 hours, filtration is carried out, a filter cake is leached by 40ml of acetonitrile once, and a white solid compound I, namely omeprazole thioether 123.1g is obtained after forced air drying, the yield is 93.4%, purity is 99.1%, and the moisture content is less than 0.01%.
Example 4
100g (0.45 mol) of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride, 57.3g (0.54 mol) of sodium carbonate and 500ml of ethanol are added into a 1L three-necked flask, stirred at room temperature for 30min, 47.4g (0.59 mol) of sodium thiocyanate is added, stirring reaction is continued for 1 hour at room temperature, after detection reaction is finished, the feed liquid is transferred to a 2L separating funnel, 500ml of dichloromethane is added, washing is carried out twice with 500ml of water, washing is carried out once with 500ml of saturated saline solution, the organic phase is dried with anhydrous sodium sulfate, and the organic phase is concentrated until the dry compound SM-2 is 89.8g of (4-methoxy-3, 5-dimethylpyridine-2-yl) methyl thiocyanate, and the yield is 95.8%, and the HPLC is 97.8%.
250ml of N, N-dimethylformamide and 62g (0.45 mol) of p-methoxyphenylhydrazine are added into a 1L three-necked flask, 89.3g (0.43 mol) of the SM-2 compound is dissolved by 250ml of N, N-dimethylformamide and then added into the three-necked flask, the reaction is carried out for 8 hours at 100 ℃, the reaction is cooled to room temperature, 500ml of dichloromethane is added, stirring is carried out for 15 minutes, the organic phase is washed for 2 times by 200ml of water, the organic phase is dried by 100g of anhydrous sodium sulfate for 1 hour, the organic phase is evaporated to an oil under reduced pressure, the mixture is added into 400ml of acetonitrile and stirred and cooled to 0-5 ℃ for crystallization for 6 hours, filtration is carried out, a filter cake is leached once by 50ml of acetonitrile, and the white solid compound I, namely omeprazole thioether 133.6g, is obtained in 94.3% yield, the purity is 98.7% and the moisture content is less than 0.01% by air blast drying.
Example 5
100g (0.45 mol) of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride, 57.3g (0.54 mol) of sodium carbonate and 500ml of ethanol are added into a 1L three-necked flask, the mixture is stirred for 30min at 30 ℃, 36.0g (0.47 mol) of ammonium thiocyanate is added, the mixture is continuously stirred for reaction for 1 hour at 30 ℃, after detection, the reaction is completed, the feed liquid is transferred to a 2L separating funnel, 500ml of dichloromethane is added, the mixture is washed twice with 500ml of water, the mixture is washed once with 500ml of saturated saline, the organic phase is dried with anhydrous sodium sulfate, and the organic phase is concentrated until the dry compound SM-2 is 90.8g of (4-methoxy-3, 5-dimethylpyridine-2-yl) methyl thiocyanate, the yield is 96.9%, and the HPLC is 98.2%.
89.3g (0.43 mol) and 62g (0.45 mol) of the SM-2 compound are added into a 1L three-necked flask, 500ml of 1, 4-dioxane is added, the reaction is carried out for 6 hours at 80 ℃, the reaction is completed, the room temperature is cooled, 500ml of dichloromethane is added, the mixture is stirred for 15 minutes, the liquid is separated, the organic phase is washed 2 times by 200ml of water, the organic phase is dried by 100g of anhydrous sodium sulfate for 1 hour, the mixture is evaporated to oil under reduced pressure, 400ml of acetonitrile is added, the mixture is stirred and cooled to 0-5 ℃ for 6 hours, the mixture is filtered, the filter cake is washed once by 50ml of acetonitrile, and the mixture is dried by blast to obtain 132.7g of the white solid compound I, namely omeprazole thioether with 93.7%, the purity of 99.4% and the moisture content of which is less than 0.01%.
Example 6
Step 1. The procedure is as in example 1.
250ml of water and 62g (0.45 mol) of p-methoxy phenylhydrazine are added into a 1L three-port bottle, 89.3g (0.43 mol) of SM-2 compound is dissolved by 250ml of tetrahydrofuran and then added into the three-port bottle for reaction for 8 hours at 50 ℃, after the reaction is finished, the temperature is reduced to room temperature, 500ml of dichloromethane is added, stirring is carried out for 15 minutes, liquid separation is carried out, an organic phase is washed by 200ml of water for 2 times, the organic phase is dried by 100g of anhydrous sodium sulfate for 1 hour, decompression and evaporation are carried out until oily matter is obtained, 400ml of acetonitrile is added for stirring, the temperature is reduced to 0-5 ℃ for crystallization for 6 hours, filtration is carried out, a filter cake is leached by 50ml of acetonitrile for one time, and blast drying is carried out to obtain a white solid compound I, namely omeprazole thioether 129.8g, the yield is 91.6%, the purity is 95.8%, and the moisture content is less than 0.01%.
Claims (10)
1. The preparation method of omeprazole thioether is characterized in that SM-1 is used as a starting material and reacts with thiocyanate under an alkaline condition to prepare an intermediate SM-2, and then p-methoxy phenylhydrazine reacts with SM-2 to prepare a target product I, wherein the reaction formula is as follows:
2. the method of manufacturing according to claim 2, comprising the steps of:
step 1: adding SM-1 and alkali into a reaction solvent, and controlling the temperature T 1 Stirring, adding thiocyanate, maintaining the temperature, stirring until the reaction is finished, and performing post-treatment to obtain an intermediate SM-2, wherein the synthetic route is as follows:
step 2: adding an intermediate SM-2 and p-methoxy phenylhydrazine into a reaction solvent, and controlling the temperature T 2 After the reaction is detected, the target compound I is prepared through post-treatment, and the synthetic route is as follows:
3. the preparation method according to claim 1 or 2, wherein the molar ratio of SM-1 to thiocyanate is: 1:1.0-1.2; the feeding mole ratio of SM-1 to alkali is as follows: 1:1.0-2.0.
4. The method according to claim 1 or 2, wherein the thiocyanate is one of NaSCN, KSCN and ammonium thiocyanate.
5. The process according to claim 2, wherein T is as defined in step 1 1 20 to 30℃and preferably 25 ℃.
6. The method according to claim 2, wherein the reaction solvent in step 1 is one of ethanol, methanol and isopropanol.
7. The method according to claim 2, wherein the reaction solvent in the step 2 is one or a combination of tetrahydrofuran, N dimethylformamide, N dimethylacetamide, dimethylsulfoxide, 1, 4-dioxane, 2-methyltetrahydrofuran, water, ethylene glycol dimethyl ether, and ethylene glycol monoether.
8. The preparation method according to claim 2, wherein the feeding molar ratio of SM-2 to p-methoxyphenylhydrazine in the step 2 is 1:1.0-1.2.
9. The preparation process according to claim 2, wherein the reaction temperature in step 2 is 60 to 100 ℃, more preferably 60 to 80 ℃.
10. The method of claim 2, wherein the post-treatment step of step 2 is as follows: after the reaction is finished, cooling to room temperature, adding an extractant, washing an organic phase with water, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness under reduced pressure to obtain oily substance, adding acetonitrile, stirring until no crystal is separated out, cooling to 0-5 ℃ for crystallization, filtering, leaching a filter cake with acetonitrile, and drying by blowing to obtain the compound I.
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