CN113651723A - Synthetic method, intermediate and application of 3- (3-hydroxyphenyl) -1, 1-dimethylurea - Google Patents
Synthetic method, intermediate and application of 3- (3-hydroxyphenyl) -1, 1-dimethylurea Download PDFInfo
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- HQSQPMWCWCOTBH-UHFFFAOYSA-N 3-(3-hydroxyphenyl)-1,1-dimethylurea Chemical compound CN(C)C(=O)NC1=CC=CC(O)=C1 HQSQPMWCWCOTBH-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000010189 synthetic method Methods 0.000 title claims description 8
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 claims abstract description 22
- -1 3-trimethylsiloxy phenylamino Chemical group 0.000 claims abstract description 14
- 229940018563 3-aminophenol Drugs 0.000 claims abstract description 11
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- GSYUIHQMZSVLBA-UHFFFAOYSA-N 3-trimethylsilyloxyaniline Chemical compound C[Si](C)(C)OC1=CC=CC(N)=C1 GSYUIHQMZSVLBA-UHFFFAOYSA-N 0.000 claims description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000012535 impurity Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- ALWKGYPQUAPLQC-UHFFFAOYSA-N neostigmine Chemical compound CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 ALWKGYPQUAPLQC-UHFFFAOYSA-N 0.000 claims description 6
- 229960002362 neostigmine Drugs 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 5
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 239000008399 tap water Substances 0.000 claims description 5
- 235000020679 tap water Nutrition 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- PFTIVKCRALCOLB-UHFFFAOYSA-N [SiH4].[N] Chemical compound [SiH4].[N] PFTIVKCRALCOLB-UHFFFAOYSA-N 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 238000004458 analytical method Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 5
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 206010029333 Neurosis Diseases 0.000 description 1
- 208000033952 Paralysis flaccid Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 208000028331 flaccid paralysis Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- OSZNNLWOYWAHSS-UHFFFAOYSA-M neostigmine methyl sulfate Chemical compound COS([O-])(=O)=O.CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 OSZNNLWOYWAHSS-UHFFFAOYSA-M 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
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- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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- C07F7/02—Silicon compounds
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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Abstract
The invention discloses a synthesis method, an intermediate and application of 3- (3-hydroxyphenyl) -1, 1-dimethylurea, which takes m-aminophenol as a raw material, generates 3-trimethylsiloxy phenylamino under the catalysis of HDMS and phosphotungstic acid, then reacts with dimethylcarbamoyl chloride to obtain 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea, and then removes TMS to obtain 3- (3-hydroxyphenyl) -1, 1-dimethylurea. The method has the advantages of simple synthetic route, simple operation, high yield and no pollution.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthetic method, an intermediate and application of 3- (3-hydroxyphenyl) -1, 1-dimethylurea.
Background
Neostigmine mesylate is a common alloplastic anticholinesterase drug and is commonly used for flaccid paralysis, muscular and neurosis and the like in internal medicine, gynecology and ophthalmology.
3- (3-hydroxyphenyl) -1, 1-dimethylurea is a process impurity generated in the synthesis process of neostigmine mesylate, and the impurity possibly remains in the purification process, so that the impurity brings a great risk to the quality control of the medicine. The synthesis methods of the compounds are reported in patents US41013450, US3383195 and WO2017175258, and m-aminophenol is adopted to directly react with dimethylcarbamoyl chloride, but since the hydroxyl and amino groups on m-aminophenol have obvious competitiveness in the reaction with dimethylcarbamoyl chloride (the reaction equation is as follows), a mixture of three structures can be obtained actually, column chromatography separation is needed, and the operation is complicated, so that the traditional synthesis method of 3- (3-hydroxyphenyl) -1, 1-dimethylurea is required to be improved.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide the synthesis method of the 3- (3-hydroxyphenyl) -1, 1-dimethylurea, which has the advantages of simple synthesis route, simple operation, high yield and no pollution, and the steps directly enter the next reaction without separation.
In order to achieve the above object, the present invention adopts the following technical solutions:
a synthetic method of 3- (3-hydroxyphenyl) -1, 1-dimethylurea comprises the following specific steps:
s1, preparation of intermediate compound I: adding raw materials of m-aminophenol, a solvent, HDMS (hexamethyl nitrogen silane) and phosphotungstic acid into a single-mouth round-bottom flask, heating to 55-70 ℃ under stirring, keeping the temperature and stirring for 1-2 hours, cooling to room temperature after the reaction is finished, adding tap water to wash until the pH value is 7.0, taking an organic phase, adding magnesium sulfate to dehydrate, and obtaining a solution of 3-trimethylsiloxy phenylamino, wherein the reaction equation is as follows:
s2, preparation of intermediate compound II: adding organic base into the dehydrated solvent solution of 3-trimethylsiloxyphenylammonia, beginning to dropwise add dimethylcarbamoyl chloride, heating to 55-70 ℃, keeping the temperature and stirring for 6h, filtering to remove solids, washing the organic phase with water for 2 times to obtain a solution of 1,1, -dimethyl-3- (3-trimethylsiloxyphenyl) urea, wherein the reaction equation is as follows:
s3, preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea: adding methanol and TBAF (tetrabutylammonium fluoride) into a solution of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea, heating to 55-70 ℃, keeping the temperature and stirring for 3-6 h, reducing the pressure and distilling to remove the solvent, cooling to 0 ℃, keeping the temperature and crystallizing for 2h, filtering to obtain a wet product, drying the wet product in a vacuum oven at 60 ℃ to obtain a product of 3- (3-hydroxyphenyl) -1, 1-dimethylurea, wherein the reaction equation is as follows:
preferably, in the foregoing step S1, the solvent is one of ethyl acetate, toluene and acetone.
Still preferably, in the foregoing step S1, the molar ratio of m-aminophenol, HDMS and phosphotungstic acid is 1: (1-1.2): (0.0005-0.005).
More preferably, in the step S2, the organic base is one of triethylamine and pyridine.
Further preferably, in the step S2, the molar ratio of 3-trimethylsiloxyphenylammonia, dimethylcarbamoyl chloride and organic base is 1: (1-1.5): (1-1.5).
Specifically, in the foregoing step S3, the molar ratio of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea to TBAF is 1: (0.02-0.2).
Use of 3- (3-hydroxyphenyl) -1, 1-dimethylurea for analysis of neostigmine mesylate kinetics and monitoring of drug impurity residues.
An intermediate compound for the preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea having the formula:
the invention has the advantages that:
(1) the raw materials used in the invention are cheap and easy to obtain, the used reagents belong to conventional reagents, no special reaction condition exists, and the method has the advantages of simple operation process, low energy consumption, low production cost and wide application range, and is suitable for large-scale preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea;
(2) the trimethylsilyl group effectively protects hydroxyl on a benzene ring from being reacted, and products of each step can directly enter the next step for reaction without separation, so that the reaction treatment efficiency and the total yield of the products are greatly improved;
(3) the 3- (3-hydroxyphenyl) -1, 1-dimethylurea prepared by the invention can be used as a reference substance, can effectively carry out quality control on the neostigmine mesylate medicine, and can be used for analyzing neostigmine mesylate kinetics and monitoring impurity residues of the medicine; the intermediate compound 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea in the preparation process provides a standard substance for researching impurities and metabolites of a neostigmine methosulfate process.
Drawings
FIG. 1 is an HPLC plot of 3- (3-hydroxyphenyl) -1, 1-dimethylurea prepared in example 1 of the present invention (retention time 13.837min) in methylthioneostigmine (retention time 18.265 min);
FIG. 2 is a drawing showing the preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea prepared in example 1 of the present invention1H-NMR spectrum.
Detailed Description
The invention is described in detail below with reference to the figures and the embodiments.
Example 1
A synthetic method of 3- (3-hydroxyphenyl) -1, 1-dimethylurea comprises the following specific steps:
s1, preparation of intermediate compound I: adding 20g (0.183mol) of m-aminophenol, 60ml of ethyl acetate, 32g (0.198mol, 1.08eq) of HDMS (hexamethyl-disilazane) and 0.5g (0.17mmol) of phosphotungstic acid into a single-neck round-bottom flask, heating to 55-70 ℃ under stirring, keeping the temperature and stirring for 2 hours, cooling to room temperature after the reaction is finished, adding 100g of tap water to wash until the pH is 7.0, taking an organic phase, adding magnesium sulfate to dehydrate, and obtaining an ethyl acetate solution of 3-trimethylsiloxy aniline, wherein the reaction equation is as follows:
s2, preparation of intermediate compound II: adding 19g (0.187mol, 1.03eq) of triethylamine into the dehydrated ethyl acetate solution of 3-trimethylsiloxyphenylammonia, starting to dropwise add 20g (0.186mol, 1.01eq) of dimethylcarbamoyl chloride, raising the temperature to 55-70 ℃, keeping the temperature and stirring for 6h, filtering to remove solids, washing the organic phase with 100g of water for 2 times to obtain an ethyl acetate solution of 1,1, -dimethyl-3- (3-trimethylsiloxyphenyl) urea, wherein the reaction equation is as follows:
s3, preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea: adding 120g of methanol and 1.4g (0.005mol, 0.03eq) of TBAF (tetrabutylammonium fluoride) into an ethyl acetate solution of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea, heating to 55-70 ℃, keeping the temperature and stirring for 3h, removing the solvent by reduced pressure distillation, cooling to 0 ℃, keeping the temperature and crystallizing for 2h, filtering to obtain a wet product, drying the wet product in a vacuum oven at 60 ℃ to obtain a product, namely 3- (3-hydroxyphenyl) -1, 1-dimethylurea, wherein the reaction equation is as follows:
example 2
A synthetic method of 3- (3-hydroxyphenyl) -1, 1-dimethylurea comprises the following specific steps:
s1, preparation of intermediate compound I: adding 10g (0.092mol) of m-aminophenol, 40ml of toluene, 15.9g (0.10mol, 1.08eq) of HDMS (hexamethyl-disilazane) and 0.26g (0.08mmol) of phosphotungstic acid into a single-neck round-bottom flask, heating to 55-70 ℃ under stirring, keeping the temperature and stirring for 1.5h, cooling to room temperature after the reaction is finished, adding 70g of tap water to wash until the pH value is 7.0, taking an organic phase, adding magnesium sulfate to dehydrate, and obtaining a toluene solution of 3-trimethylsiloxy aniline;
s2, preparation of intermediate compound II: adding 10.1g (0.10mol, 1.09eq) of triethylamine into the dehydrated toluene solution of 3-trimethylsiloxyphenylammonia, starting to dropwise add 10.8g (0.10mol, 1.09eq) of dimethylcarbamoyl chloride, heating to 55-70 ℃, keeping the temperature and stirring for 6h, filtering to remove solids, and washing an organic phase with 80g of water for 2 times to obtain the toluene solution of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea;
s3, preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea: adding 50g of methanol into a toluene solution of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea, stirring, adding 1.42g (0.005mol, 0.06eq) of TBAF (tetrabutylammonium fluoride), heating to 55-70 ℃, keeping the temperature and stirring for 4h, removing the solvent by reduced pressure distillation, cooling to 0 ℃, keeping the temperature and crystallizing for 2h, filtering to obtain a wet product, and drying the wet product in a vacuum oven at 60 ℃ to obtain the product of 3- (3-hydroxyphenyl) -1, 1-dimethylurea.
Example 3
A synthetic method of 3- (3-hydroxyphenyl) -1, 1-dimethylurea comprises the following specific steps:
s1, preparation of intermediate compound I: adding 30g (0.274mol) of m-aminophenol, 150ml of acetone, 50g (0.31mol, 1.13eq) of HDMS (hexamethyl nitrogen silane) and 3g (0.001mol) of phosphotungstic acid into a single-mouth round-bottom flask, heating to 55-70 ℃ under stirring, keeping the temperature and stirring for 1h, cooling to room temperature after the reaction is finished, adding 75g of tap water to wash until the pH value is 7.0, taking an organic phase, adding magnesium sulfate, and dehydrating to obtain an acetone solution of 3-trimethylsiloxy phenylamine;
s2, preparation of intermediate compound II: adding 35g (0.346mol, 1.26eq) of triethylamine into the dehydrated acetone solution of 3-trimethylsiloxyphenylammonia, starting to dropwise add 36g (0.335mol, 1.22eq) of dimethylcarbamoyl chloride, heating to 55-70 ℃, keeping the temperature and stirring for 6h, filtering to remove solids, and washing an organic phase with 350g of water for 2 times to obtain an acetone solution of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea;
s3, preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea: adding 120g of methanol into an acetone solution of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea, stirring, adding 2.5g (0.009mol, 0.03eq) of TBAF (tetrabutylammonium fluoride), heating to 55-70 ℃, keeping the temperature and stirring for 6h, removing the solvent by reduced pressure distillation, cooling to 0 ℃, keeping the temperature and crystallizing for 2h, filtering to obtain a wet product, and drying the wet product in a vacuum oven at 60 ℃ to obtain the product of 3- (3-hydroxyphenyl) -1, 1-dimethylurea.
Comparative example
10.9g (0.1mol) of m-aminophenol, 200ml of dichloromethane, 12.9g (0.12mol, 1.2eq) of dimethylcarbamoyl chloride and 12.6g (0.125mol, 1.25eq) of triethylamine are sequentially added into a four-neck flask, stirred at room temperature overnight, filtered to remove insoluble matters, water is added to wash organic phase and liquid separation is carried out, dichloromethane is concentrated under reduced pressure, petroleum ether and ethyl acetate are used as elution solvents for column chromatography, and the product, namely the 3- (3-hydroxyphenyl) -1, 1-dimethylurea, is obtained after column chromatography purification.
The mass of the product 3- (3-hydroxyphenyl) -1, 1-dimethylurea prepared in examples 1 to 3 and comparative example was weighed, respectively, and the total yield of the product was calculated, and the calculation results are shown in the following table:
| mass/g | Total yield/% | |
| Example 1 | 32.0 | 97 |
| Example 2 | 15.8 | 97 |
| Example 3 | 46.9 | 95 |
| Comparative example | 6.8 | 38 |
As can be seen from the comparison of examples 1-3 and comparative example, the 3- (3-hydroxyphenyl) -1, 1-dimethylurea prepared by the present invention has a high yield.
The HPLC profile of 3- (3-hydroxyphenyl) -1, 1-dimethylurea prepared in example 1 (retention time 13.837min) in methionineopsin (retention time 18.265min) is shown in FIG. 1, and 3- (3-hydroxyphenyl) -1, 1-dimethylurea prepared in example 11The H-NMR spectrum is shown in FIG. 2.
As can be seen from FIG. 1, the impurity 3- (3-hydroxyphenyl) -1, 1-dimethylurea in the methioninemine is strictly localized by HPLC, and can be used for providing a standard substance for the detection and research of the pharmaceutical impurities of the methioninemine, and the use of the impurity research can be clarified by HPLC.
As can be seen from FIG. 2, the target product 3- (3-hydroxyphenyl) -1, 1-dimethylurea was synthesized in example 1,1the H-NMR spectrum can correspond to the hydrogen peak and hydrogen data of the substance.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. It should be understood by those skilled in the art that the above embodiments do not limit the present invention in any way, and all technical solutions obtained by using equivalent alternatives or equivalent variations fall within the scope of the present invention.
Claims (8)
1. A synthetic method of 3- (3-hydroxyphenyl) -1, 1-dimethylurea is characterized by comprising the following specific steps:
s1, preparation of intermediate compound I: adding raw materials of m-aminophenol, a solvent, HDMS (hexamethyl nitrogen silane) and phosphotungstic acid into a single-mouth round-bottom flask, heating to 55-70 ℃ under stirring, keeping the temperature and stirring for 1-2 hours, cooling to room temperature after the reaction is finished, adding tap water to wash until the pH value is 7.0, taking an organic phase, adding magnesium sulfate to dehydrate, and obtaining a solution of 3-trimethylsiloxy phenylamino, wherein the reaction equation is as follows:
s2, preparation of intermediate compound II: adding organic base into the dehydrated solvent solution of 3-trimethylsiloxyphenylammonia, beginning to dropwise add dimethylcarbamoyl chloride, heating to 55-70 ℃, keeping the temperature and stirring for 6h, filtering to remove solids, washing the organic phase with water for 2 times to obtain a solution of 1,1, -dimethyl-3- (3-trimethylsiloxyphenyl) urea, wherein the reaction equation is as follows:
s3, preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea: adding methanol and TBAF (tetrabutylammonium fluoride) into a solution of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea, heating to 55-70 ℃, keeping the temperature and stirring for 3-6 h, reducing the pressure and distilling to remove the solvent, cooling to 0 ℃, keeping the temperature and crystallizing for 2h, filtering to obtain a wet product, drying the wet product in a vacuum oven at 60 ℃ to obtain a product of 3- (3-hydroxyphenyl) -1, 1-dimethylurea, wherein the reaction equation is as follows:
2. the method for synthesizing 3- (3-hydroxyphenyl) -1, 1-dimethylurea as claimed in claim 1, wherein the solvent is one of ethyl acetate, toluene and acetone in step S1.
3. The method for synthesizing 3- (3-hydroxyphenyl) -1, 1-dimethylurea as claimed in claim 1, wherein in step S1, the molar ratio of m-aminophenol, HDMS and phosphotungstic acid is 1: (1-1.2): (0.0005-0.005).
4. The method for synthesizing 3- (3-hydroxyphenyl) -1, 1-dimethylurea as claimed in claim 1, wherein in step S2, the organic base is one of triethylamine and pyridine.
5. The method for synthesizing 3- (3-hydroxyphenyl) -1, 1-dimethylurea as claimed in claim 1, wherein the molar ratio of 3-trimethylsiloxyphenylamine, dimethylcarbamoyl chloride and organic base in step S2 is 1: (1-1.5): (1-1.5).
6. The method for synthesizing 3- (3-hydroxyphenyl) -1, 1-dimethylurea according to claim 1, wherein in step S3, the molar ratio of 1, 1-dimethyl-3- (3-trimethylsiloxyphenyl) urea to TBAF is 1: (0.02-0.2).
7. Use of 3- (3-hydroxyphenyl) -1, 1-dimethylurea according to any one of claims 1 to 6 for the analysis of neostigmine mesylate kinetics and monitoring of residual pharmaceutical impurities.
8. An intermediate compound for the preparation of 3- (3-hydroxyphenyl) -1, 1-dimethylurea having the formula:
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| CN115353466A (en) * | 2022-10-24 | 2022-11-18 | 云南先施药业有限公司 | Preparation and purification method of neostigmine methosulfate |
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