CN114230497A - Preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid - Google Patents
Preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid Download PDFInfo
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- CN114230497A CN114230497A CN202111229285.2A CN202111229285A CN114230497A CN 114230497 A CN114230497 A CN 114230497A CN 202111229285 A CN202111229285 A CN 202111229285A CN 114230497 A CN114230497 A CN 114230497A
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- amino
- ethylsulfonyl
- methoxybenzoic acid
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- OJVNCXHGGYYOPH-UHFFFAOYSA-N 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid Chemical compound CCS(=O)(=O)C1=CC(C(O)=O)=C(OC)C=C1N OJVNCXHGGYYOPH-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 127
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims description 21
- 229960004909 aminosalicylic acid Drugs 0.000 claims description 21
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
- YUPQMVSYNJQULF-UHFFFAOYSA-N methyl 4-amino-2-methoxybenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1OC YUPQMVSYNJQULF-UHFFFAOYSA-N 0.000 claims description 16
- BBWJVKZAKHIKRQ-UHFFFAOYSA-N methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate Chemical compound CCS(=O)(=O)C1=CC(C(=O)OC)=C(OC)C=C1N BBWJVKZAKHIKRQ-UHFFFAOYSA-N 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- IRGMWPMUTWZIIJ-UHFFFAOYSA-N methyl 4-amino-2-methoxy-5-thiocyanatobenzoate Chemical compound COC(=O)C1=CC(SC#N)=C(N)C=C1OC IRGMWPMUTWZIIJ-UHFFFAOYSA-N 0.000 claims description 13
- -1 methyl 4-amino-5-ethylthio-2-methoxybenzoate Chemical compound 0.000 claims description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 claims description 10
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 claims description 10
- 229940008406 diethyl sulfate Drugs 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 9
- BVCKAIGDWABZIE-UHFFFAOYSA-N 4-amino-5-ethylsulfanyl-2-methoxybenzoic acid Chemical compound CCSC1=CC(C(O)=O)=C(OC)C=C1N BVCKAIGDWABZIE-UHFFFAOYSA-N 0.000 claims description 8
- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 claims description 8
- 229960003036 amisulpride Drugs 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 150000002978 peroxides Chemical class 0.000 claims description 6
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 6
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012378 ammonium molybdate tetrahydrate Substances 0.000 claims description 5
- FIXLYHHVMHXSCP-UHFFFAOYSA-H azane;dihydroxy(dioxo)molybdenum;trioxomolybdenum;tetrahydrate Chemical compound N.N.N.N.N.N.O.O.O.O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O FIXLYHHVMHXSCP-UHFFFAOYSA-H 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- QWMFKVNJIYNWII-UHFFFAOYSA-N 5-bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine Chemical compound CC1=CC=C(C)N1C1=CC=C(Br)C=N1 QWMFKVNJIYNWII-UHFFFAOYSA-N 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- 229940078916 carbamide peroxide Drugs 0.000 claims description 3
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- MDPFMEGWTZIWDO-UHFFFAOYSA-N 4-amino-2-methoxy-5-thiocyanatobenzoic acid Chemical compound COC1=CC(N)=C(SC#N)C=C1C(O)=O MDPFMEGWTZIWDO-UHFFFAOYSA-N 0.000 claims 2
- 239000002904 solvent Substances 0.000 abstract description 7
- 239000002699 waste material Substances 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 abstract 1
- 230000006203 ethylation Effects 0.000 abstract 1
- 238000006200 ethylation reaction Methods 0.000 abstract 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- 238000007069 methylation reaction Methods 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 50
- 238000001816 cooling Methods 0.000 description 31
- 239000000243 solution Substances 0.000 description 31
- 238000000967 suction filtration Methods 0.000 description 21
- 238000001035 drying Methods 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- 239000012295 chemical reaction liquid Substances 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- 229940125898 compound 5 Drugs 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 229940126214 compound 3 Drugs 0.000 description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QGUALMNFRILWRA-UHFFFAOYSA-M tolmetin sodium Chemical compound [Na+].C1=CC(C)=CC=C1C(=O)C1=CC=C(CC([O-])=O)N1C QGUALMNFRILWRA-UHFFFAOYSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000010413 mother solution Substances 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QOWLKTWQYURQLI-UHFFFAOYSA-N 4-amino-2-methoxy-5-sulfanylbenzoic acid Chemical compound COC1=CC(N)=C(S)C=C1C(O)=O QOWLKTWQYURQLI-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/02—Thiocyanates
- C07C331/14—Thiocyanates having sulfur atoms of thiocyanate groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid. The preparation method comprises five steps of methylation, thiocyanide, ethylation, oxidation and hydrolysis reaction, and the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid is finally prepared. The preparation method provided by the invention can be used for efficiently preparing the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid under mild reaction conditions, only ethanol and water are used as solvents, and the preparation method has the advantages of simplicity in operation, high yield, good product quality, less three wastes, low cost and the like, and is convenient for large-scale production.
Description
Technical Field
The invention relates to the technical field of synthesis of amisulpride intermediates, in particular to a preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid.
Background
4-amino-5-ethylsulfonyl-2-methoxybenzoic acid is an important intermediate of Amisulpride (Amisulpride). Amisulpride is chemically known as 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide. Is a broad spectrum antipsychotic drug developed by saint delaburg, sunofir france, and suitable for acute or chronic schizophrenia with positive and negative symptoms, first marketed in grapevine in 1986, marketed in the united states in 1 month in 1997, and marketed in china in 2001. At present, the intermediate synthesis process which has wide market demand in China, high development yield and simple and convenient operation has very far-reaching economic and social significance.
At present, the method for preparing 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid by adopting p-aminosalicylic acid comprises the following steps:
(1) 4-amino-2-methoxy-5-mercaptobenzoic acid method: the method takes 4-amino-2-methoxy-5-mercaptobenzoic acid as a raw material, reacts with strong base and diethyl sulfate to generate 4-amino-5-ethylthio-2-methoxybenzoate, and then is oxidized to obtain 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid. The method has few reaction steps, but has low yield and expensive raw materials.
(2) Chlorosulfonation: the chlorosulfonation method is characterized in that 4-amino-2-methoxy methyl benzoate is used as a raw material, chlorosulfonyl is introduced to the 5 th position of a benzene ring, then disulfide is generated under the action of stannous chloride and hydrochloric acid, then strong alkali is used for hydrolyzing the disulfide into sulfydryl, and the subsequent synthesis method is the same as the method (1) 4-amino-2-methoxy-5-mercaptobenzoic acid method. The method has strong danger of the used raw materials and great difficulty in reaction operation.
(3) 4-amino-2-methoxybenzoic acid methyl ester method: the method takes 4-amino-2-methoxy methyl benzoate as a raw material, firstly introduces thiocyano at 5-position of a benzene ring, then reduces the thiocyano into sulfydryl, and simultaneously hydrolyzes and acidifies ester group into carboxyl under the action of strong alkali to obtain 4-amino-2-methoxy-5-sulfydryl benzoic acid. The subsequent synthesis method is the same as the method (1) 4-amino-2-methoxy-5-mercaptobenzoic acid method. The method reduces the cost of raw materials, has high operability and is the direction of more researches at present.
However, the existing reported reactions have more defects, some methods have harsh reaction conditions, and the reaction solvents in each step are different; some methods need high-boiling-point solvents such as DMF (dimethyl formamide), have high toxicity and complicated post-treatment, and the total yield is only about 50 percent; some methods need acetic acid as a solvent, so that the method has great damage to equipment and lower yield.
In conclusion, aiming at the problems in the prior art, the development of a method for efficiently and quickly synthesizing the amisulpride intermediate 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid is an urgent problem to be solved.
Disclosure of Invention
The invention provides a preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid, which refers to a 4-amino-2-methoxybenzoic acid methyl ester method, synthesizes 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid by taking p-aminosalicylic acid as a starting material through optimizing and improving synthesis conditions, mainly uses low-toxicity solvents such as ethanol, water and the like, and has the total yield of 75 percent.
The invention aims to provide a preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid, which comprises the following steps:
(1) dissolving p-aminosalicylic acid (compound 2) in acetone, adding potassium carbonate, and dropwise adding dimethyl sulfate for reaction to obtain a compound 4-amino-2-methoxybenzoic acid methyl ester (compound 3);
(2) sequentially dissolving the 4-amino-2-methoxy methyl benzoate prepared in the step (1) and ammonium thiocyanate (compound 3) in ethanol, and then dropwise adding liquid bromine dissolved in the ethanol for reaction to obtain a compound 4-amino-2-methoxy-5-thiocyanatobenzoic acid methyl ester (compound 4);
(3) dissolving sodium sulfide in a mixed solvent of ethanol and water, adding the mixed solvent into the methyl 4-amino-2-methoxy-5-thiocyanobenzoate (compound 4) prepared in the step (2), and dropwise adding diethyl sulfate to react to obtain a compound, namely methyl 4-amino-5-ethylthio-2-methoxybenzoate (compound 5);
(4) dissolving the methyl 4-amino-5-ethylthio-2-methoxybenzoate (compound 5) prepared in the step (3) and a catalyst in ethanol, and adding peroxide to react to obtain a compound methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate (compound 6);
(5) and (3) dissolving sodium hydroxide in water to obtain an alkali solution, adding the methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate (compound 6) prepared in the step (4) to react, and adding an acid solution to adjust the pH value to obtain a compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1).
The reaction formula of the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid is as follows:
the preparation method provided by the invention has the advantages of simple operation, mild reaction conditions, high yield, good product quality, less three wastes, low cost and the like, and is convenient for large-scale production. According to the invention, low-toxicity solvents such as ethanol and water are mainly used, part of reaction liquid can be recycled for multiple times, the use of organic solvents is reduced, the waste liquid treatment link is reduced, and the green chemistry concept is met.
Preferably, the molar ratio of the potassium carbonate to the p-aminosalicylic acid in the step (1) is 2.0-2.5: 1.0, the molar ratio of the dimethyl sulfate to the p-aminosalicylic acid is 2.0-2.5: 1.0, the mass ratio of the acetone to the p-aminosalicylic acid is 3.0-5.0: 1, the reaction temperature is 20-40 ℃, and the reaction time is 2-4 hours. More preferably, the mass ratio of the acetone to the p-aminosalicylic acid is 3.10-4.13: 1.
Preferably, the molar ratio of ethanol to liquid bromine in the ethanol-dissolved liquid bromine in the step (2) is 13-16: 1, the molar ratio of liquid bromine to methyl 4-amino-2-methoxybenzoate is 1.1-1.5: 1.0, the reaction temperature is 5-25 ℃, and the reaction time is 1-5 hours.
Preferably, the methyl 4-amino-2-methoxybenzoate and the ammonium thiocyanate in the step (2) are sequentially dissolved in ethanol, wherein the molar ratio of the ammonium thiocyanate to the methyl 4-amino-2-methoxybenzoate is 2.2-3.0: 1.0, and the mass ratio of the ethanol to the methyl 4-amino-2-methoxybenzoate is 8.0-15.0: 1.
Preferably, the molar ratio of the sodium sulfide to the methyl 4-amino-2-methoxy-5-thiocyanobenzoate in the step (3) is 1.0-1.8: 1.0; the molar ratio of diethyl sulfate to methyl 4-amino-2-methoxy-5-thiocyanobenzoate is 1.0-1.5: 1.0; the mass ratio of the ethanol to the 4-amino-2-methoxy-5-thiocyanobenzoic acid methyl ester is 2.0-5.0: 1; the mass ratio of the water to the 4-amino-2-methoxy-5-thiocyanobenzoic acid methyl ester is 8.0-20.0: 1, the reaction temperature is 0-20 ℃, and the reaction time is 2-6 hours.
Preferably, the catalyst in the step (4) is sodium tungstate dihydrate or ammonium molybdate tetrahydrate, and the amount of the catalyst is 1-5% of that of the methyl 4-amino-5-ethylthio-2-methoxybenzoate; the peroxide is selected from more than one of hydrogen peroxide, potassium peroxymonosulfonate, carbamide peroxide and m-chloroperoxybenzoic acid, and the molar ratio of the peroxide to the 4-amino-5-ethylthio-2-methoxy methyl benzoate is 2.0-3.0: 1.0.
Preferably, the mass ratio of the ethanol to the 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester in the step (4) is 4.0-8.0: 1, the reaction temperature is 0-40 ℃, and the reaction time is 2-8 hours.
Preferably, the molar ratio of the sodium hydroxide to the methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate in the step (5) is 1.5-3.0: 1.0, the mass ratio of the water to the methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate is 10.0-15.0: 1, the reaction temperature is 40-80 ℃, and the reaction time is 0.5-5 hours.
The invention also provides the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid prepared by the preparation method.
The invention also protects the application of the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid in synthesis of amisulpride.
Compared with the prior art, the invention has the beneficial effects that: aiming at the problems of lower yield, low purity, complex operation, expensive raw materials and the like in the prior art, the provided preparation method has the advantages of easily available raw materials, low cost, high yield, simple operation, mild reaction conditions, good product quality and convenience for large-scale production; meanwhile, the invention only uses low-toxicity solvents such as ethanol, water and the like, and reaction liquid in part of steps can be recycled for multiple times, thereby reducing the use of organic solvents, reducing the link of waste liquid treatment and conforming to the concept of green chemistry.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid prepared in example 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid obtained in example 1;
FIG. 3 is a high resolution mass spectrum of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid prepared in example 1;
FIG. 4 is a high performance liquid chromatography of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid prepared in example 1.
Detailed Description
The following examples are further illustrative of the present invention and are not intended to be limiting thereof. The equipment and reagents used in the present invention are, unless otherwise specified, conventional commercial products in the art.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Example 1
A preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid comprises the following steps:
(1) dissolving 0.65mol of p-aminosalicylic acid (1.0eq) in 500mL of acetone, adding 1.44mol of potassium carbonate (2.2eq), slowly dropwise adding 1.44mol of dimethyl sulfate (2.2eq) at 25-30 ℃, heating to 40 ℃, and continuing to react for 2 h. Distilling under reduced pressure to recover acetone, adding 500mL of ice water, separating out a white solid, carrying out suction filtration while the ice water is cold, washing filter residue with cold water, and drying to obtain a white solid, namely 106g (0.58mol) of the compound 4-amino-2-methoxybenzoic acid methyl ester (compound 3), wherein the yield is 89.6% and the purity is 99.1%;
(2) dissolving 0.55mol of the compound 3(1.0eq) and 1.32mol of ammonium thiocyanate (2.4eq) obtained in the step (1) in 1.0L of ethanol, and cooling to 5-10 ℃ to obtain a reaction solution; taking 0.66mol of liquid bromine (1.2eq), diluting into 500mL of ethanol, slowly dropwise adding into a reaction solution, controlling the reaction temperature to be 5-10 ℃, continuously reacting for 4 hours at 5-10 ℃ after feeding is finished, separating out a white solid, performing suction filtration while the solution is cold, washing filter residue with cold water, separating out a part of white solid in filtrate, collecting the filter residue and the white solid in the filtrate, namely a compound 4-amino-2-methoxy-5-thiocyanobenzoate (compound 4), drying the compound to obtain 124g (0.52mol) in total, wherein the yield is 94.3%, and the purity is 98.5%;
(3) 0.63mol of Na2Dissolving S (1.5eq) in a mixed solvent of water and ethanol, wherein the mixed solvent comprises 2.40L of water and 600mL of ethanol, cooling to 5-10 ℃, adding 0.42mol of the compound 4(1.0eq) obtained in the step (2) in batches, continuing to stir at 5-10 ℃ for 1h, then slowly adding 0.50mol of diethyl sulfate (1.2eq) to gradually generate white solid, continuing to react at 5-10 ℃ for 5h, cooling to 600 ℃, (1.0eq) of the mixture<5 ℃, performing suction filtration while the solution is cold, continuously recycling the mother solution, washing filter residue with cold water, drying to obtain white solid, namely 89.5g (0.37mol) of 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester (compound 5), 88.4% of yield and 97.2% of purity, and repeating the steps (1) - (3) to prepare the compound 5;
(4) dissolving 0.41mol of compound 5(1.0eq) and 0.0041mol of ammonium molybdate tetrahydrate (0.010eq) in 500mL of ethanol, cooling to 5 ℃, slowly dropwise adding 1.04mol of hydrogen peroxide (2.5eq) with the mass fraction of 30%, heating to 30-35 ℃ after dropwise adding, reacting for 5 hours, cooling to below 5 ℃, separating out solids, adding 0.21mol of sodium sulfite (0.5eq) with the mass fraction of 10% until the color of potassium iodide starch test paper does not appear, distilling under reduced pressure to recover ethanol in the solution, cooling to below 5 ℃, carrying out suction filtration while the solution is cold, washing with cold water, and drying to obtain a white solid, namely compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid methyl ester (compound 6)108g (0.39mol), the yield is 95.4%, and the purity is 98.8%;
(5) dissolving 0.72mol of sodium hydroxide (2.0eq) in 1.0L of water to obtain an alkali liquor, suspending 0.36mol of the compound 6(1.0eq) obtained in the step (4) in the alkali liquor, heating to 50 ℃, gradually dissolving the compound 6, continuing to react for 3 hours, stopping the reaction to obtain a reaction liquid, cooling the reaction liquid to less than 5 ℃, adding a hydrochloric acid solution with the mass fraction of 10% to adjust the pH of the reaction liquid to 4.0-4.5, separating out a white solid, carrying out reduced pressure distillation to remove most of water, cooling to less than 5 ℃, carrying out suction filtration while the reaction liquid is cold, washing filter residues with cold water, and drying to obtain the white solid, namely 93.8g (0.36mol) of the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1), wherein the yield is 98.9% and the purity is 99.5%.
The p-aminosalicylic acid (compound 2) is used as a starting material, and the total yield of the 5-step reaction is 70.5 percent. The characterization spectra for compound 1 are shown in fig. 1-4.
The characterization data for 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1) are as follows:1H NMR(400MHz,CDCl3):δ8.50(s,1H,ArH),6.24(s,1H,ArH),8.06(s,2H,ArH),5.70(s,2H,-NH2),4.05(s,3H,-OCH3),3.13(q,J＝7.2Hz,2H,-CH2-),1.29(t,3H,J＝7.2Hz,-CH3).13C NMR(100MHz,CDCl3):δ＝164.1,162.8,152.1,138.6,113.5,107.9,98.3,56.9,49.8,7.2.HRMS:calcd.for C10H13NaNO5S+282.0407,found 282.0415.
the HPLC detection conditions are as follows: a C18 chromatographic column and a UV detector, wherein the detection wavelength is 225 nm; the mobile phase is phosphate buffer (pH 3.0)/acetonitrile 80:20(v/v), the solubility of potassium dihydrogen phosphate in the phosphate buffer is 3.4g/L, and the pH is adjusted to 3.0 by phosphoric acid; the flow rate is 1mL/min, the injection volume is 10 microliters, and the column temperature is 30 ℃.
Example 2
The same as example 1, except that:
in the step (3), 0.42mol of Na is added2S (1.0eq) is dissolved in a mixed solvent of water and ethanol, the mixed solvent comprises 2.40L of water and 600mL of ethanol, the temperature is reduced to 5-10 ℃, 0.42mol of compound 4(1.0eq) is added in batches, stirring is continued for 1h at 5-10 ℃, and then 0.42mol of diethyl sulfate (1.0eq) is slowly added to obtain whiteAnd (4) gradually generating a solid, and continuously reacting for 5 hours at the temperature of 5-10 ℃. Cooling to<And (3) carrying out suction filtration while the solution is cold at 5 ℃, continuously recycling the mother solution, washing filter residues with cold water, and drying to obtain a white solid, namely 95.7g (0.40mol) of the compound 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester (compound 5), wherein the yield is 94.5% and the purity is 99.0%.
And (3) continuously carrying out the circular reaction for 3 times by taking the mother liquor as a solvent to obtain 90.0-95.5 g of white solid, wherein the yield is 88.7-94.3%, and the purity is 98.2-99.1%.
The other reaction steps are the same as the example 1, the target product 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1) is finally obtained, p-aminosalicylic acid (compound 2) is used as a starting material, and the total yield of the 5 steps is 70.7-75.3%.
Example 3
The same as example 1, except that:
in the step (4), 0.41mol of compound 5(1.0eq) and 0.0041mol of sodium tungstate dihydrate (0.010eq) are dissolved in 500mL of ethanol, the temperature is reduced to 5 ℃, 1.04mol of hydrogen peroxide (2.5eq) is slowly dripped, the mass fraction of the hydrogen peroxide is 30%, and the temperature is increased to 30-35 ℃ after the dripping is finished to react for 3 hours. Cooling to below 5 deg.C, separating out solid, adding 0.21mol sodium sulfite (0.5eq) with mass fraction of 10% until no color is developed on starch potassium iodide paper. And (3) after ethanol in the solution is recovered by reduced pressure distillation, the temperature is reduced to less than 5 ℃, the filtration is carried out while the solution is cold, filter residue is washed by cold water, and the white solid, namely the compound methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate (compound 6), is 97.0g, the yield is 85.6 percent, and the purity is 97.4 percent.
The other reaction steps are the same as example 1, and the target product 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1) is finally obtained, the p-aminosalicylic acid (compound 2) is used as a starting material, and the total yield of the 5-step reaction is 67.6%.
Example 4
A preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid comprises the following steps:
(1) dissolving 0.50mol of p-aminosalicylic acid (1.0eq) in 400mL of acetone, adding 1.0mol of potassium carbonate (2.0eq), slowly dropwise adding 1.0mol of dimethyl sulfate (2.0eq) at 35-40 ℃, and continuing to react for 4 hours. Distilling under reduced pressure to recover acetone, adding 400mL of ice water, separating out a white solid, carrying out suction filtration while the ice water is cold, washing filter residue with cold water, and drying to obtain a white solid, namely 76g (0.42mol) of the compound 4-amino-2-methoxybenzoic acid methyl ester (compound 3), wherein the yield is 84.3%, and the purity is 96.8%;
(2) dissolving 0.4mol of compound 3(1.0eq) and 0.88mol of ammonium thiocyanate (2.2eq) obtained in the step (1) in 800mL of ethanol, and cooling to 5-10 ℃ to obtain a reaction solution; taking 0.44mol of liquid bromine (1.1eq), diluting the liquid bromine into 400mL of ethanol, slowly dropwise adding the liquid bromine into a reaction solution, controlling the reaction temperature to be 10-20 ℃, continuously reacting for 5 hours after the material is added, separating out a white solid, carrying out suction filtration while the solution is cold, washing filter residues with cold water, separating out a part of white solid from a filtrate, collecting the filter residues and the white solid in the filtrate, namely a compound 4-amino-2-methoxy-5-thiocyanobenzoate (compound 4), drying the filter residues and the white solid in the filtrate to obtain 86g (0.36mol) in total, wherein the yield is 90.2%, and the purity is 95.5%;
(3) 0.36mol of Na2S (1.0eq) is dissolved in a mixed solvent of water and ethanol, the mixed solvent comprises 1.60L of water and 400mL of ethanol, the temperature is controlled to 15-20 ℃, 0.36mol of the compound 4(1.0eq) obtained in the step (2) is added in batches, the mixture is continuously stirred for 1h at 15-20 ℃, then 0.36mol of diethyl sulfate (1.0eq) is slowly added, white solid is gradually generated, the reaction is continuously carried out for 2h at 15-20 ℃, the temperature is reduced to 400mL of ethanol, the temperature is controlled to be 15-20 ℃, and the reaction is continuously carried out for 1h<5 ℃, performing suction filtration while the solution is cold, continuously recycling the mother solution, washing filter residue with cold water, and drying to obtain a white solid, namely 65g (0.27mol) of the compound 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester (compound 5), wherein the yield is 75.4% and the purity is 93.9%;
(4) dissolving 0.27mol of compound 5(1.0eq) and 0.0054mol of sodium tungstate dihydrate (0.020eq) in 600mL of ethanol, cooling to 0-5 ℃, slowly dropwise adding 0.68mol of m-chloroperoxybenzoic acid (2.5eq), heating to 35-40 ℃ after dropwise adding, reacting for 8 hours, cooling to the temperature of less than 5 ℃, separating out solids, adding 0.14mol of sodium sulfite (0.5eq) with the mass fraction of 10% until potassium iodide starch test paper does not develop color, distilling under reduced pressure to recover ethanol in a filter residue solution, cooling to the temperature of less than 5 ℃, carrying out suction filtration while the solution is cold, washing with cold water, and drying to obtain a white solid, namely compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid methyl ester (compound 6)66g (0.24mol), wherein the yield is 90.5%, and the purity is 97.1%;
(5) dissolving 0.36mol of sodium hydroxide (1.5eq) in 800mL of water to obtain an alkali liquor, suspending 0.24mol of the compound 6(1.0eq) obtained in the step (4) in the alkali liquor, heating to 80 ℃, gradually dissolving the compound 6, continuously reacting for 0.5h, stopping the reaction to obtain a reaction liquid, cooling the reaction liquid to less than 5 ℃, adding a hydrochloric acid solution with the mass fraction of 10% to adjust the pH of the reaction liquid to 4.0-4.5, separating out a white solid, carrying out reduced pressure distillation to remove most of water, cooling to less than 5 ℃, carrying out suction filtration while cooling, washing filter residues with cold water, and drying to obtain a white solid, namely 61g (0.236mol) of the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1), wherein the yield is 98.5% and the purity is 98.9%;
the p-aminosalicylic acid (compound 2) is used as a starting material, and the total yield of the 5-step reaction is 51.1%.
Example 5
A preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid comprises the following steps:
(1) dissolving 0.50mol of p-aminosalicylic acid (1.0eq) in 300mL of acetone, adding 1.25mol of potassium carbonate (2.5eq), slowly dropwise adding 1.25mol of dimethyl sulfate (2.5eq) at 20-25 ℃, and continuing to react for 3 hours. Distilling under reduced pressure to recover acetone, adding 300mL of ice water, separating out a white solid, carrying out suction filtration while the ice water is cold, washing filter residue with cold water, and drying to obtain a white solid, namely 80g (0.44mol) of the compound 4-amino-2-methoxybenzoic acid methyl ester (compound 3), wherein the yield is 88.2% and the purity is 97.8%;
(2) dissolving 0.4mol of compound 3(1.0eq) and 1.2mol of ammonium thiocyanate (3.0eq) obtained in the step (1) in 1.2L of ethanol, and cooling to 5-10 ℃ to obtain a reaction solution; taking 0.60mol of liquid bromine (1.5eq), diluting the liquid bromine into 500mL of ethanol, slowly dropwise adding the liquid bromine into a reaction solution, controlling the reaction temperature to be 20-25 ℃, continuously reacting for 1h after the material is added, separating out a white solid, carrying out suction filtration while the solution is cold, washing filter residues with cold water, separating out a part of white solid from a filtrate, collecting the filter residues and the white solid in the filtrate, namely the compound 4-amino-2-methoxy-5-thiocyanobenzoate (compound 4), drying the filter residues and the white solid in the filtrate, wherein the total amount of 88g (0.37mol) of the white solid is 93.2 percent in yield and 98.3 percent in purity;
(3) 0.67mol of Na2S(1.8eq) is dissolved in a mixed solvent of water and ethanol, the mixed solvent comprises 2.0L of water and 500mL of ethanol, the temperature is controlled to be 0-5 ℃, 0.37mol of the compound 4(1.0eq) obtained in the step (2) is added in batches, the mixture is continuously stirred at 0-5 ℃ for 1h, then 0.56mol of diethyl sulfate (1.5eq) is slowly added, white solid is gradually generated, the mixture is continuously reacted at 0-5 ℃ for 6h, the mixture is subjected to suction filtration while cold, mother liquor is continuously recycled, filter residue is washed by cold water and dried to obtain 75g (0.31mol) of the compound 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester (compound 5), the yield is 84.6%, and the purity is 96.7%;
(4) dissolving 0.31mol of compound 5(1.0eq) and 0.0062mol of ammonium molybdate tetrahydrate (0.020eq) in 400mL of ethanol, cooling to 0-5 ℃, slowly dropwise adding 0.93mol of carbamide peroxide (3.0eq), heating to 35-40 ℃ after dropwise adding, reacting for 4 hours, cooling to less than 5 ℃, separating out solids, adding 0.16mol of sodium sulfite (0.5eq) with the mass fraction of 10% until no color is developed in potassium iodide starch test paper, distilling under reduced pressure to recover ethanol in the solution, cooling to less than 5 ℃, performing suction filtration while cold, washing filter residues with cold water, and drying to obtain a white solid, namely 78g (0.29mol) of compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid methyl ester (compound 6), wherein the yield is 92.1% and the purity is 97.3%;
(5) dissolving 0.87mol of sodium hydroxide (3.0eq) in 1.1L of water to obtain an alkali liquor, suspending 0.29mol of the compound 6(1.0eq) obtained in the step (4) in the alkali liquor, heating to 40 ℃, gradually dissolving the compound 6, continuing to react for 5 hours, stopping the reaction to obtain a reaction liquid, cooling the reaction liquid to less than 5 ℃, adding a hydrochloric acid solution with the mass fraction of 10% to adjust the pH of the reaction liquid to 4.0-4.5, separating out a white solid, reducing the pressure, distilling to remove most of water, cooling to less than 5 ℃, carrying out suction filtration while cooling, washing filter residues with cold water, and drying to obtain a white solid, namely 75g (0.29mol) of the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1), wherein the yield is 99.8% and the purity is 98.7%;
the p-aminosalicylic acid (compound 2) is used as a starting material, and the total yield of the 5-step reaction is 63.9 percent.
Comparative example 1
(1) Dissolving 0.50mol of p-aminosalicylic acid (1.0eq) in 300mL of acetone, adding 1.25mol of potassium hydroxide (2.5eq) and 0.023mol of tetrabutyl ammonium bromide (0.046eq), slowly adding 1.0mol of dimethyl sulfate (2.0eq) dropwise at 20-25 ℃, reacting for 0.5h, then adding 0.23mol (0.46eq) of potassium hydroxide and 0.18mol (0.36eq) of dimethyl sulfate, and continuing to react for 1 h. Distilling under reduced pressure to recover acetone, adding 300mL of ice water, separating out a white solid, carrying out suction filtration while the ice water is cold, washing filter residue with cold water, and drying to obtain a white solid, namely 70g (0.38mol) of the compound 4-amino-2-methoxybenzoic acid methyl ester (compound 3), wherein the yield is 76.8% and the purity is 95.4%;
(2) dissolving 0.3mol of compound 3(1.0eq) and 0.72mol of ammonium thiocyanate (2.4eq) obtained in the step (1) in 0.6L of methanol, and cooling to 0-5 ℃ to obtain a reaction solution; taking 0.36mol of liquid bromine (1.2eq), diluting the liquid bromine into 150mL of methanol, slowly dropwise adding the liquid bromine into a reaction solution, controlling the reaction temperature to be 5-10 ℃, continuously reacting for 2.5 hours after the charging is finished, separating out white solids, carrying out suction filtration while the solution is cold, washing filter residues with cold water, separating out partial white solids from a filtrate, collecting the filter residues and the white solids in the filtrate, namely a compound 4-amino-2-methoxy-5-thiocyanobenzoate (compound 4), drying the filter residues and the white solids in the filtrate, obtaining 65g (0.27mol) in total, wherein the yield is 90.5%, and the purity is 96.1%;
(3) 0.43mol of Na2Dissolving S (1.6eq) in 400mL of DMF, controlling the temperature to 15-20 ℃, adding 0.27mol of the compound 4(1.0eq) obtained in the step (2) in batches, continuing to stir at 20-25 ℃ for 0.5h, then slowly adding 0.32mol of diethyl sulfate (1.2eq), continuing to react at 20-25 ℃ for 1h, adding 500mL of ice water into the reaction solution, stirring, performing suction filtration, washing filter residue with cold water, and drying to obtain light yellow solid, namely 52g (0.22mol) of the compound methyl 4-amino-5-ethylthio-2-methoxybenzoate (compound 5), wherein the yield is 79.8% and the purity is 93.3%;
(4) dissolving 0.22mol of compound 5(1.0eq) and 0.73mmol of ammonium molybdate tetrahydrate (0.0033eq) in 200mL of methanol, cooling to 5-10 ℃, slowly dropwise adding 0.66mol of hydrogen peroxide (3.0eq) with the mass fraction of 30%, heating to 30-35 ℃ after dropwise adding, reacting for 1h, cooling to less than 5 ℃, adding 0.22mol of sodium sulfite (0.5eq) with the mass fraction of 10% until no color is developed in potassium iodide starch test paper, distilling under reduced pressure to recover methanol in a filter residue solution, cooling to less than 5 ℃, carrying out suction filtration while the solution is cold, washing with cold water, and drying to obtain a white solid, namely compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid methyl ester (compound 6)53g (0.19mol), wherein the yield is 88.5%, and the purity is 98.1%;
(5) dissolving 0.38mol of sodium hydroxide (2.0eq) in 150mL of water to obtain an alkali liquor, suspending 0.19mol of the compound 6(1.0eq) obtained in the step (4) in the alkali liquor, heating to 50 ℃, gradually dissolving the compound 6, continuing to react for 1h, stopping the reaction to obtain a reaction liquid, cooling the reaction liquid to less than 10 ℃, adding a hydrochloric acid solution with the mass fraction of 10% to adjust the pH of the reaction liquid to 4.0-4.5, separating out a white solid, reducing the pressure, distilling to remove most of water, cooling to less than 5 ℃, carrying out suction filtration while cooling, washing filter residues with cold water, and drying to obtain a white solid, namely 48g (0.18mol) of the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (compound 1), wherein the yield is 97.2% and the purity is 97.5%;
the p-aminosalicylic acid (compound 2) is used as a starting material, and the total yield of the 5 steps is 47.7%.
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (10)
1. A preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid is characterized by comprising the following steps:
(1) dissolving p-aminosalicylic acid in acetone, adding potassium carbonate, and dropwise adding dimethyl sulfate for reaction to obtain a compound 4-amino-2-methoxybenzoic acid methyl ester;
(2) sequentially dissolving the 4-amino-2-methoxy methyl benzoate prepared in the step (1) and ammonium thiocyanate in ethanol, and then dropwise adding liquid bromine dissolved in the ethanol for reaction to obtain a compound, namely 4-amino-2-methoxy-5-thiocyanobenzoate;
(3) dissolving sodium sulfide in a mixed solvent of ethanol and water, adding the mixed solvent into the 4-amino-2-methoxy-5-thiocyanobenzoate prepared in the step (2), and dropwise adding diethyl sulfate to react to obtain a compound, namely 4-amino-5-ethylthio-2-methoxybenzoate;
(4) dissolving the 4-amino-5-ethylthio-2-methoxybenzoic acid methyl ester prepared in the step (3) and a catalyst in ethanol, and adding peroxide for reaction to obtain a compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid methyl ester;
(5) and (3) dissolving sodium hydroxide in water to obtain an alkali liquor, adding the methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate prepared in the step (4) to react, and adding an acid solution to adjust the pH value to obtain the compound 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid.
2. The preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid according to claim 1, wherein the molar ratio of potassium carbonate to p-aminosalicylic acid in step (1) is 2.0-2.5: 1.0, the molar ratio of dimethyl sulfate to p-aminosalicylic acid is 2.0-2.5: 1.0, the mass ratio of acetone to p-aminosalicylic acid is 3.0-5.0: 1, the reaction temperature is 20-40 ℃, and the reaction time is 2-4 hours.
3. The preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid according to claim 1, wherein the molar ratio of ethanol to liquid bromine in the liquid bromine dissolved in ethanol in step (2) is 13-16: 1, the molar ratio of liquid bromine to methyl 4-amino-2-methoxybenzoate is 1.1-1.5: 1.0, the reaction temperature is 5-25 ℃, and the reaction time is 1-5 hours.
4. The preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid according to claim 1 or 3, characterized in that the methyl 4-amino-2-methoxybenzoate and ammonium thiocyanate are sequentially dissolved in ethanol, wherein the molar ratio of ammonium thiocyanate to methyl 4-amino-2-methoxybenzoate is 2.2-3.0: 1.0, and the mass ratio of ethanol to methyl 4-amino-2-methoxybenzoate is 8.0-15.0: 1.
5. The method for preparing 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid according to claim 1, wherein the molar ratio of sodium sulfide to methyl 4-amino-2-methoxy-5-thiocyanobenzoate in step (3) is 1.0-1.8: 1.0; the molar ratio of diethyl sulfate to methyl 4-amino-2-methoxy-5-thiocyanobenzoate is 1.0-1.5: 1.0; the mass ratio of the ethanol to the 4-amino-2-methoxy-5-thiocyanobenzoic acid methyl ester is 2.0-5.0: 1; the mass ratio of the water to the 4-amino-2-methoxy-5-thiocyanobenzoic acid methyl ester is 8.0-20.0: 1, the reaction temperature is 0-20 ℃, and the reaction time is 2-6 hours.
6. The method for preparing 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid according to claim 1, wherein the catalyst in step (4) is sodium tungstate dihydrate or ammonium molybdate tetrahydrate, and the amount of the catalyst is 1% to 5% of the amount of the methyl 4-amino-5-ethylthio-2-methoxybenzoate; the peroxide is selected from more than one of hydrogen peroxide, potassium peroxymonosulfonate, carbamide peroxide and m-chloroperoxybenzoic acid, and the molar ratio of the peroxide to the 4-amino-5-ethylthio-2-methoxy methyl benzoate is 2.0-3.0: 1.0.
7. The method for preparing 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid according to claim 1, wherein the mass ratio of ethanol to methyl 4-amino-5-ethylthio-2-methoxybenzoate in the step (4) is 4.0-8.0: 1, the reaction temperature is 0-40 ℃, and the reaction time is 2-8 hours.
8. The preparation method of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid according to claim 1, characterized in that the molar ratio of sodium hydroxide to methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate in step (5) is 1.5-3.0: 1.0, the mass ratio of water to methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate is 10.0-15.0: 1, the reaction temperature is 40-80 ℃, and the reaction time is 0.5-5 h.
9. The process according to claim 1, wherein the 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid is obtained.
Application of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid in synthesis of amisulpride.
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