CN114394939A - Synthesis method of cimetidine - Google Patents
Synthesis method of cimetidine Download PDFInfo
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- CN114394939A CN114394939A CN202210100003.7A CN202210100003A CN114394939A CN 114394939 A CN114394939 A CN 114394939A CN 202210100003 A CN202210100003 A CN 202210100003A CN 114394939 A CN114394939 A CN 114394939A
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- cimetidine
- methylamine
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- 229960001380 cimetidine Drugs 0.000 title claims abstract description 34
- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 title claims abstract 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 15
- UBHDUFNPQJWPRQ-UHFFFAOYSA-N (5-methyl-1h-imidazol-3-ium-4-yl)methanol;chloride Chemical compound Cl.CC=1NC=NC=1CO UBHDUFNPQJWPRQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- WTUAWWLVVCGTRG-UHFFFAOYSA-N 4,5-dihydro-1,3-thiazol-2-ylcyanamide Chemical compound N#CNC1=NCCS1 WTUAWWLVVCGTRG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000004970 halomethyl group Chemical group 0.000 claims abstract description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000009835 boiling Methods 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- ZORWZOOZJGMSTE-UHFFFAOYSA-N 1-cyano-2-methyl-3-(2-sulfanylethyl)guanidine Chemical compound N#CNC(=NC)NCCS ZORWZOOZJGMSTE-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 6
- 238000005658 halogenation reaction Methods 0.000 claims description 5
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- -1 alkali metal salts Chemical class 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- UESSEMPSSAXQJC-UHFFFAOYSA-N ethanol;methanamine Chemical compound NC.CCO UESSEMPSSAXQJC-UHFFFAOYSA-N 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 claims description 2
- JHHMSRLTZAUMOJ-UHFFFAOYSA-N methanamine;oxolane Chemical compound NC.C1CCOC1 JHHMSRLTZAUMOJ-UHFFFAOYSA-N 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 8
- 150000007529 inorganic bases Chemical class 0.000 claims 2
- AZGNFIUHXWRRAE-UHFFFAOYSA-N 2-cyano-1-methyl-1-(2-sulfanylethyl)guanidine Chemical compound SCCN(C)C(N)=NC#N AZGNFIUHXWRRAE-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000005576 amination reaction Methods 0.000 abstract 1
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- PDWPOXKSTFGRIT-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-1h-imidazole;hydrochloride Chemical compound Cl.CC=1NC=NC=1CCl PDWPOXKSTFGRIT-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical group NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JEOZNMMOIBLWLV-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethanamine Chemical compound CC=1N=CNC=1CSCCN JEOZNMMOIBLWLV-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- 239000012988 Dithioester Substances 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- WREDNSAXDZCLCP-UHFFFAOYSA-N methanedithioic acid Chemical compound SC=S WREDNSAXDZCLCP-UHFFFAOYSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940106721 tagamet Drugs 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a synthesis method of environment-friendly cimetidine, belonging to the technical field of pharmaceutical chemistry. The synthesis method comprises the following steps: (a) amination of 2-cyanoimino-1, 3-thiazolidine to obtain N-cyano-N '- (2-mercaptoethyl) -N' -methylguanidine (intermediate 1); (b) 4-hydroxymethyl-5-methylimidazole hydrochloride is halogenated to obtain 4- (halomethyl) -5-methyl-1H-imidazole hydrochloride (intermediate 2); (c) the intermediate 1 and the intermediate 2 react under alkaline condition to generate cimetidine. The method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions in each step, simple and easy operation, environmental friendliness, over 90 percent of total yield of the prepared cimetidine and over 99.50 percent of purity, and good industrial production prospect.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a novel synthesis method of environment-friendly cimetidine.
Background
Cimetidine (CAS: 51481-61-9), also known as Cimetidine, is sold under the trade name Tagamet, the Chinese name N' -methyl-N "- [2[ [ (5-methylimidazol-4-yl) methyl]Thio group]Ethyl radical]Guanidine, molecular formula: c10H16N6S; relative molecular mass: 252.34. the structure is as follows:
cimetidine is histamine H2The first marketed antagonist of the receptor treats peptic ulcers by inhibiting gastric acid secretion. The drug is prepared from Smith Kline&Frech was developed and marketed in the United kingdom in 1976 and in the United states by FDA approval in 1979. In recent years, the medicine opens up new clinical application and is commonly used for combined drug research, such as treatment of allergic skin diseases.
Since cimetidine is on the market, a large number of synthetic methods have been developed, but most of the methods have the problems of low yield, serious environmental pollution, complex production process and the like. The preparation method disclosed in CN 101838241 comprises the following steps: 4-hydroxymethyl-5-methylimidazole hydrochloride is prepared by reacting 4-methylimidazole with paraformaldehyde; 4- [ [ (2-aminoethyl) thio ] methyl ] -5-methylimidazole is prepared by condensing 4-hydroxymethyl-5-methylimidazole hydrochloride and cysteamine hydrochloride and is commonly called a condensate; the first condensate and cyanoimido dithioformic acid dimethyl ester are condensed to prepare N' -cyano-N- [2- [ [ (5-methyl-1-H-imidazole-4-yl) methyl ] thio ] ethyl ] -S-methylisothiourea which is commonly called as a second condensate; the two-condensed product is aminated to prepare cimetidine. The cimetidine prepared by the method has high purity, but long production period, and simultaneously generates the methyl mercaptan with foul smell, thereby causing pollution to the environment to a certain extent.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a synthesis method of environment-friendly cimetidine, which can solve the problem of environmental pollution caused by foul-smelling thiol byproducts in the existing cimetidine production process, and the method has the advantages of easily available raw materials, mild reaction conditions, simple operation, total yield of the prepared compound of more than 90 percent and purity of more than 99.50 percent.
The invention is realized by adopting the following technical scheme:
a synthetic method of cimetidine comprises the following steps:
(1) dissolving 2-cyanoimino-1, 3-thiazolidine in an organic solvent, and adding methylamine to perform a methylaminoylation reaction; after the reaction is finished, carrying out suction filtration, washing and drying to obtain N-cyano-N '- (2-mercaptoethyl) -N' -methylguanidine (intermediate 1);
(2) dissolving 4-hydroxymethyl-5-methylimidazole hydrochloride in an organic solvent, and adding a halogenating reagent to perform halogenation reaction; after the reaction is finished, 4- (halomethyl) -5-methyl-1H-imidazole hydrochloride (intermediate 2) is obtained by post-treatment;
(3) and dissolving the intermediate 1 in an organic solvent, adding the intermediate 2 and alkali, adjusting the pH of a reaction solution to 7-8 by using acid after the reaction is finished, extracting, washing and drying to obtain cimetidine.
In the step (1), methylamine is one or more of methylamine gas, methylamine aqueous solution and methylamine organic solution; the methylamine organic solution comprises methylamine-methanol solution, methylamine-ethanol solution, methylamine-tetrahydrofuran solution, etc.
In the step (1), the organic solvent refers to one or more of methanol, ethanol, isopropanol and acetonitrile.
In the step (1), the molar ratio of 2-cyanoimino-1, 3-thiazolidine: methylamine gas, aqueous methylamine solution, organic methylamine solution, where 1: 1-5, preferably 1: 1.5-3.
In the step (1), the temperature of the methylamine reaction is 0 ℃ to the boiling point temperature of the solvent, and preferably 40 ℃ to the boiling point temperature of the solvent.
And (2) in the step (1), after the reaction is finished, carrying out suction filtration, washing with absolute ethyl alcohol, and drying.
In the step (2), the halogenating reagent refers to one or more of thionyl chloride, sulfuryl chloride, methylsulfonyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and hydrobromic acid.
In the step (2), the organic solvent is one or more of benzene, toluene, dioxane, tetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, chloroform, DMF, N-dimethylaniline and N, N-diisopropylethylamine.
In the step (2), the molar ratio of 4-hydroxymethyl-5-methylimidazolium hydrochloride: halo reagent ═ 1: 1-10, preferably 1: 1.5-3.
In the step (2), the halogenation temperature is 0 ℃ to the boiling point temperature of the solvent, and preferably 25 ℃ to 40 ℃.
In the step (2), the reaction is directly distilled after the reaction is finished.
In the step (3), the used alkali is inorganic alkali or organic alkali, and the inorganic alkali comprises: sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium bicarbonate, potassium carbonate; the organic base includes: alkali metal salts of triethylamine, DIEA, pyridine, alcohols.
In the step (3), the organic solvent refers to one or more of methanol, ethanol, propanol, butanol, tetrahydrofuran, dichloromethane, acetonitrile, DMF and DMSO.
In the step (3), the molar ratio of the intermediate 1: intermediate 2 ═ 1: 1-2, preferably 1: 1.0-1.5.
In the step (3), the reaction temperature is 0 ℃ to the boiling point of the solvent after the alkali is added, and preferably 10 ℃ to the boiling point of the solvent is lower than the boiling point of the solvent.
And (3) after the reaction is finished, extracting, washing with water, washing with saturated saline solution, and drying to obtain the target compound.
Specifically, the reaction scheme of the invention is as follows:
the invention can also comprise conventional purification means such as pulping, recrystallization and the like.
The raw materials and reagents used in the present invention are commercially available.
The beneficial effect of the invention is to provide a preparation route of cimetidine, which is not reported so far. In addition, the method has the advantages of cheap and easily obtained used reagents, simple and convenient operation, no use of cyanamide dithio ester with mucosa irritation, no generation of volatile methyl mercaptan with foul smell, no pollution caused by the methyl mercaptan, great improvement of environmental protection and safety, over 90 percent of total yield of the prepared cimetidine, over 99.50 percent of purity and good industrial production prospect.
Detailed Description
In order to obtain the optimal reaction parameters, the invention adopts a single control variable method to screen the experimental parameters with larger influence on the final yield.
1. In the step (1), ethanol is used as a solvent, and the molar ratio of 2-cyanoimino-1, 3-thiazolidine to methylamine in a 40% methylamine water solution is 1: 1.5, the temperature of the methylamine reaction and the product yield are as follows:
TABLE 1
Temperature (. degree.C.) for methylamination | Step (1) yield of product/% |
0 | 89.81 |
25 | 92.37 |
40 | 98.10 |
60 | 97.80 |
80 | 98.02 |
2. In the step (1), ethanol is used as a solvent at 40 ℃, the dosage of methylamine (1 eq is 2-cyanoimino-1, 3-thiazolidine) in 40% methylamine water solution and the yield of the product are as follows:
TABLE 2
3. In the step (2), dichloroethane is used as a solvent, and the molar ratio of 4-hydroxymethyl-5-methylimidazole hydrochloride to thionyl chloride is 1: 1.5, the chlorination reaction temperature and the product yield are as follows:
TABLE 3
Temperature of chlorination reaction (. degree.C.) | Step (2) yield of product/% |
0 | 87.15 |
25 | 99.28 |
40 | 95.70 |
60 | 93.80 |
80 | 94.02 |
4. In the step (2), dichloroethane is used as a solvent at 30 ℃, the dosage of thionyl chloride (1 eq of 4-hydroxymethyl-5-methylimidazole hydrochloride) and the product yield are as follows:
TABLE 4
5. In the step (3), methanol is used as a solvent, triethylamine is used as an alkali, and the molar ratio of the intermediate 1 to the intermediate 2 is 1: 1.1, the reaction temperature and the product yield after adding the alkali are as follows:
TABLE 5
Reaction temperature (. degree.C.) after addition of base | Yield of the product of step (3)/%) |
0 | 72.62 |
25 | 82.30 |
40 | 90.85 |
50 | 92.97 |
64 | 92.34 |
6. In the step (3), at 50 ℃, methanol is used as a solvent, triethylamine is used as a base, and the dosage of the intermediate 2 (the intermediate 1 is 1eq) and the product yield are as follows:
TABLE 6
Intermediate 1: intermediate 2 | Step (2) yield of product/% |
1:1.0 | 92.09 |
1:1.5 | 91.43 |
1:2.0 | 82.32 |
1:5.0 | 70.43 |
The following optimum process parameters were determined: in the step (1), the reaction temperature of the methylamine reaction is 40-solvent boiling point temperature, the molar ratio of 2-cyanoimino-1, 3-thiazolidine to methylamine in 40% methylamine water solution is 1: 1.5-3; in the step (2), the halogenation reaction temperature is 25-40 ℃, and the molar ratio of the 4-hydroxymethyl-5-methylimidazole hydrochloride to the halogenating reagent is 1: 1.5-3; the reaction temperature after adding the alkali in the step (3) is 10 ℃ lower than the boiling point temperature of the solvent to the boiling point temperature of the solvent, and the molar ratio of the intermediate 1 to the intermediate 2 is 1: 1.0-1.5.
The invention is further described below by means of specific examples.
Example 1
(1) Synthesis of N-cyano-N' - (2-mercaptoethyl) -N "-methylguanidine (intermediate 1)
Weighing 10g (0.0786mol) of 2-cyanoimino-1, 3-thiazolidine into a 100mL three-necked flask, adding 50mL of absolute ethyl alcohol, stirring, heating to dissolve, adding 12.45g (0.1572mol) of 40% methylamine aqueous solution, heating to 60 ℃, reacting for 12h, monitoring by TLC to ensure that the reaction is basically complete, stopping the reaction, cooling to room temperature, performing suction filtration to obtain a white solid, washing with absolute ethyl alcohol, and performing vacuum drying to obtain an intermediate 1: N-cyano-N' - (2-mercaptoethyl) -N "-methylguanidine 12.42g, yield 98%.
(2) Synthesis of 4- (chloromethyl) -5-methyl-1H-imidazole hydrochloride
Weighing 12.5g (0.084mol) of 4-hydroxymethyl-5-methylimidazole hydrochloride into a 250mL single-neck bottle, adding 100mL of dichloromethane, stirring, adding 20g (0.168mol) of thionyl chloride solution at 0 ℃, after dropwise addition, heating to 40 ℃, and stirring for 12 hours. TLC is used for monitoring the completion of the basic reaction, the reaction is stopped, a normal pressure distillation device is arranged, and thionyl chloride is distilled off at 80 ℃. The yield of pure 4- (chloromethyl) -5-methyl-1H-imidazole hydrochloride in the reaction flask was 98% at 10.78 g. Can be directly used for the next reaction.
(3) Synthesis of cimetidine
Weighing 10g (0.063mol) of N-cyano-N '- (2-mercaptoethyl) -N' -methylguanidine into a 100mL three-necked bottle, adding 50mL of methanol, stirring, adding 50mL of 1M NaOH aqueous solution after dissolving, stirring for 30min, adding 9.90g (0.076mol) of 4- (chloromethyl) -5-methyl-1H-imidazole hydrochloride, heating to 60 ℃ for reaction for 6H, monitoring by TLC for complete basic reaction, stopping the reaction, cooling to room temperature, adjusting the pH of the reaction solution to be neutral by using dilute hydrochloric acid, extracting by using ethyl acetate, washing by using saturated saline, drying, recrystallizing by using absolute ethyl alcohol to obtain a cimetidine pure product, wherein the yield is 94%, the total yield is 90.28%, and the purity is 99.705%.
Example 2
(1) Synthesis of N-cyano-N' - (2-mercaptoethyl) -N "-methylguanidine (intermediate 1)
Weighing 10g (0.0786mol) of 2-cyanoimino-1, 3-thiazolidine into a 100mL three-necked flask, adding 50mL of absolute ethyl alcohol, stirring, heating to dissolve, adding 15.22g (0.1965mol) of 40% methylamine aqueous solution, heating to 40 ℃, reacting for 12h, monitoring by TLC to ensure that the reaction is basically complete, stopping the reaction, cooling to room temperature, performing suction filtration to obtain a white solid, washing with absolute ethyl alcohol, and performing vacuum drying to obtain an intermediate 1: N-cyano-N' - (2-mercaptoethyl) -N "-methylguanidine 12.67g, yield 99%.
1H NMR(500MHz,DMSO-d6)
δ7.12-7.02(m,2H),3.39(dt,J=7.7,5.9Hz,2H),2.85(dd,J=7.8,6.2Hz,2H),2.67(d,J=4.6Hz,3H).
(2) Synthesis of 4- (chloromethyl) -5-methyl-1H-imidazole hydrochloride
12.5g (0.084mol) of 4-hydroxymethyl-5-methylimidazole hydrochloride was weighed into a 250mL single-neck flask, 100mL of dichloroethane was added and stirred, 25g (0.210mol) of thionyl chloride solution was added at 0 ℃ and after the dropwise addition was completed, the mixture was transferred to room temperature and stirred for 12 hours. TLC monitoring the basic reaction, stopping reaction, installing normal pressure distillation device, distilling out thionyl chloride and dichloroethane at 80 ℃, and recycling. The pure 4- (chloromethyl) -5-methyl-1H-imidazole hydrochloride in the reaction flask was 10.89g, with a yield of 99%. Can be directly used for the next reaction.
(3) Synthesis of cimetidine
Weighing 10g (0.063mol) of N-cyano-N '- (2-mercaptoethyl) -N' -methylguanidine into a 100mL three-necked bottle, adding 100mL of methanol, stirring, adding triethylamine after dissolution, stirring for 30min, adding 8.67g (0.066mol) of 4- (chloromethyl) -5-methyl-1H-imidazole hydrochloride, heating to 50 ℃ for reaction for 4H, monitoring by TLC for complete basic reaction, stopping the reaction, cooling to room temperature, adjusting the pH of a reaction solution to be neutral by using dilute hydrochloric acid, extracting by using ethyl acetate, washing by using water, washing by using saturated saline, drying, recrystallizing by using absolute ethyl alcohol to obtain a cimetidine pure product, wherein the yield is 92%, the total yield is 90.99%, the purity is 99.779%, the maximum impurity content is 0.049%, and the product meets the standard of European pharmacopoeia.1H NMR (400MHz, DMSO-d6, ppm) delta-11.75 (bs,1H),7.44(s, H),7.15(s,2H),3.63(s,2H),3.21(m,2H),2.70(d,3H),2.54(t2H),2.11(s, 3H). The characterization results are consistent with literature reports, indicating that the product is cimetidine.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and it will be apparent to those skilled in the art that various modifications and variations can be made within the spirit and principle of the present invention, and these equivalent modifications and substitutions are included in the scope of the present invention.
Claims (10)
1. The synthesis method of cimetidine is characterized by comprising the following steps:
(1) dissolving 2-cyanoimino-1, 3-thiazolidine in an organic solvent, then adding methylamine to carry out a methylaminoylation reaction, and after the reaction is finished, carrying out suction filtration, washing and drying to obtain an intermediate 1: N-cyano-N' - (2-mercaptoethyl) -N "-methylguanidine;
(2) dissolving 4-hydroxymethyl-5-methylimidazole hydrochloride in an organic solvent, adding a halogenating reagent for halogenation, and performing post-treatment after the reaction to obtain an intermediate 2: 4- (halomethyl) -5-methyl-1H-imidazole hydrochloride;
(3) and dissolving the intermediate 1 in an organic solvent, adding the intermediate 2 and alkali, adjusting the pH of a reaction solution to 7-8 by using acid after the reaction is finished, extracting, washing and drying to obtain cimetidine.
2. A method of synthesizing cimetidine as claimed in claim 1, wherein: in the step (1), the methylamine used is one or more of methylamine gas, methylamine water solution and methylamine organic solution; wherein the methylamine organic solution comprises methylamine-methanol solution, methylamine-ethanol solution and methylamine-tetrahydrofuran solution.
3. A method of synthesizing cimetidine as claimed in claim 1, wherein: in the step (1), the organic solvent refers to one or more of methanol, ethanol, isopropanol and acetonitrile; the temperature of the methylamine reaction is 0-boiling point temperature of the solvent, preferably 40-boiling point temperature of the solvent.
4. A method of synthesizing cimetidine as claimed in claim 1, wherein: in the step (1), the molar ratio of the 2-cyanoimino-1, 3-thiazolidine to methylamine in methylamine gas, methylamine water solution or methylamine organic solution is 1: 1-5, preferably 1: 1.5-3.
5. A method of synthesizing cimetidine as claimed in claim 1, wherein: in the step (2), the halogenating reagent is one or more of thionyl chloride, sulfuryl chloride, methylsulfonyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and hydrobromic acid, and the organic solvent is one or more of benzene, toluene, dioxane, tetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, chloroform, DMF, N-dimethylaniline and N, N-diisopropylethylamine; the halogenation reaction temperature is 0 ℃ to the boiling point temperature of the solvent, and preferably 25 ℃ to 40 ℃.
6. A method of synthesizing cimetidine as claimed in claim 1, wherein: in the step (2), the molar ratio of the 4-hydroxymethyl-5-methylimidazole hydrochloride to the halogenating reagent is 1: 1-10, preferably 1: 1.5-3.
7. A method of synthesizing cimetidine as claimed in claim 1, wherein: in the step (3), the organic solvent refers to one or more of methanol, ethanol, propanol, butanol, tetrahydrofuran, dichloromethane, acetonitrile, DMF and DMSO; the base used is an inorganic base or an organic base, and the inorganic base comprises: sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium bicarbonate, potassium carbonate; the organic base includes: alkali metal salts of triethylamine, DIEA, pyridine, alcohols.
8. A method of synthesizing cimetidine as claimed in claim 1, wherein: in the step (3), the reaction temperature is 0 ℃ to the boiling point of the solvent after the alkali is added, and preferably 10 ℃ to the boiling point of the solvent is lower than the boiling point of the solvent.
9. A method of synthesizing cimetidine as claimed in claim 1, wherein: the molar ratio of the intermediate 1 to the intermediate 2 in the step (3) is 1: 1-2, preferably 1: 1.0-1.5.
10. Use of the synthesis according to any one of claims 1 to 9 for the preparation of cimetidine.
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH627747A5 (en) * | 1977-12-12 | 1982-01-29 | Crc Ricerca Chim | Process for the preparation of 4(5)-alkylthioalkylguanidine derivatives of imidazole |
US4365067A (en) * | 1980-11-26 | 1982-12-21 | Fujimoto Pharmaceutical Corporation | Method for preparing pharmacologically active cyanoguanidine derivative |
JPS59128375A (en) * | 1983-01-10 | 1984-07-24 | Tokawa Tetsuo | Preparation of imidazole compound |
JPS60100557A (en) * | 1983-11-04 | 1985-06-04 | Fujimoto Seiyaku Kk | Preparation of guanidine derivative |
WO2015009882A2 (en) * | 2013-07-18 | 2015-01-22 | The Hamner Institutes | Cyano derivatives and their uses |
CN112830896A (en) * | 2021-02-24 | 2021-05-25 | 盐城凯利药业有限公司 | Preparation method of cimetidine |
CN112979555A (en) * | 2021-02-24 | 2021-06-18 | 盐城凯利药业有限公司 | Process for synthesizing cimetidine |
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Publication number | Priority date | Publication date | Assignee | Title |
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CH627747A5 (en) * | 1977-12-12 | 1982-01-29 | Crc Ricerca Chim | Process for the preparation of 4(5)-alkylthioalkylguanidine derivatives of imidazole |
US4365067A (en) * | 1980-11-26 | 1982-12-21 | Fujimoto Pharmaceutical Corporation | Method for preparing pharmacologically active cyanoguanidine derivative |
JPS59128375A (en) * | 1983-01-10 | 1984-07-24 | Tokawa Tetsuo | Preparation of imidazole compound |
JPS60100557A (en) * | 1983-11-04 | 1985-06-04 | Fujimoto Seiyaku Kk | Preparation of guanidine derivative |
WO2015009882A2 (en) * | 2013-07-18 | 2015-01-22 | The Hamner Institutes | Cyano derivatives and their uses |
CN112830896A (en) * | 2021-02-24 | 2021-05-25 | 盐城凯利药业有限公司 | Preparation method of cimetidine |
CN112979555A (en) * | 2021-02-24 | 2021-06-18 | 盐城凯利药业有限公司 | Process for synthesizing cimetidine |
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