CN115385829A - Preparation method of N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide - Google Patents
Preparation method of N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide Download PDFInfo
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- -1 N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide Chemical compound 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- HKQJXMJGWKDFTA-UHFFFAOYSA-N n-(5-methoxy-2-phenoxyphenyl)methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(OC)=CC=C1OC1=CC=CC=C1 HKQJXMJGWKDFTA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 5
- 238000010693 amine synthesis reaction Methods 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 28
- 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 24
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 11
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 10
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 22
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 5
- 239000002360 explosive Substances 0.000 abstract description 4
- 239000007789 gas Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 abstract description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 abstract description 3
- 239000012044 organic layer Substances 0.000 description 24
- 238000001816 cooling Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 14
- 230000007935 neutral effect Effects 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- ANMATWQYLIFGOK-UHFFFAOYSA-N Iguratimod Chemical compound CS(=O)(=O)NC1=CC=2OC=C(NC=O)C(=O)C=2C=C1OC1=CC=CC=C1 ANMATWQYLIFGOK-UHFFFAOYSA-N 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229950003909 iguratimod Drugs 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
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- 238000000926 separation method Methods 0.000 description 2
- XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- ILFDRUFFPZTDRV-UHFFFAOYSA-N C1=CC(=C(C=C1COCC2=CC(=C(C=C2)Cl)[N+](=O)[O-])[N+](=O)[O-])Cl Chemical class C1=CC(=C(C=C1COCC2=CC(=C(C=C2)Cl)[N+](=O)[O-])[N+](=O)[O-])Cl ILFDRUFFPZTDRV-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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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 N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide, which takes N- (5-methoxyl-2-phenoxyphenyl) methane sulfonamide as a raw material, and obtains N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide through Friedel-crafts acylation reaction and drape Raylen primary amine synthesis reaction, and the whole operation is simple and easy to implement, and the economical practicability is high; by replacing the synthesis route, nitrobenzene is avoided, and the harm to operators and the environment is reduced; reagents used in all steps in the synthesis process are non-explosive chemicals, the reaction conditions are mild, hydrogen chloride gas does not need to be introduced for a long time, and the equipment requirement is reduced.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide.
Background
Rheumatoid Arthritis (RA) is a chronic, inflammatory synovitis-predominant systemic disease of unknown etiology. It is characterized by multiple joints, symmetry and invasive arthritis of small joints of hands and feet, and joint deformity and function loss caused by the fact that the external organs of joints are affected by serum rheumatoid factor positivity. Iguratimod is a novel medicament for treating Rheumatoid Arthritis (RA) and Osteoarthritis (OA), can remarkably reduce inflammatory reaction, can selectively inhibit cyclooxygenase COX-2, can inhibit the generation of inflammatory cytokines, tumor necrosis factors, lymphocytes and immunoglobulin, has an autoimmune regulation effect, takes effect quickly, has better curative effect and less adverse reaction compared with the conventional medicaments, and is also effective for patients with ineffective other medicaments.
The traditional synthesis method of Iguratimod comprises the following steps: the compound is prepared by nucleophilic substitution of 4-chloro-3-nitrobenzyl ether and phenol, and then reduction of nitro group by iron powder, mesylation, gattmann-Koch reaction, formylation, methoxy demethylation and cyclization in 7 steps. In addition, studies on synthesis of iguratimod [ J ]. Wanyanxiang, etc., china new drug journal, 2006, 15 (23): 2043. a novel process for the preparation of iguratimod (compound v) via N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide (compound iv) as an intermediate is reported, the reaction scheme being described in formula 1:
the synthesis process of the N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide comprises the following steps: adding aluminum trichloride and aminoacetonitrile hydrochloride into nitrobenzene as a solvent, heating the reaction to 40 ℃, keeping the temperature and stirring for 1h, then placing the reaction solution into an ice bath, cooling to 10 ℃, stirring, adding 4-phenoxy-3-methylsulfonylaminoaminoanisole, and introducing dry saturated hydrogen chloride gas at the temperature of below 35 ℃ for 10h until the reaction is complete; then, the reaction solution is poured into a certain amount of 4mol/L glacial hydrochloric acid to generate yellow solid, and the yellow solid is sequentially filtered, washed by ethyl acetate and isopropanol and dried to obtain a light yellow target product (compound I)). Among them, nitrobenzene belongs to explosive chemicals, has a strong odor and toxicity, belongs to 2B carcinogens, and has a great pollution to the environment. In view of this, the present invention provides a novel method for preparing iguratimod intermediate N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide, in order to solve the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation method of N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide, wherein N- (5-methoxy-2-phenoxyphenyl) methane sulfonamide is used as a raw material, and is subjected to Friedel-crafts acylation reaction and drape Ruier primary amine synthesis reaction to obtain the N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide, so that the overall operation is simple and feasible, and the economic practicability is high; by replacing the synthesis route, nitrobenzene is avoided, and the harm to operators and the environment is reduced; reagents used in all steps in the synthesis process are non-explosive chemicals, the reaction conditions are mild, long-time introduction of hydrogen chloride gas is not needed, and the equipment requirements are reduced.
In order to achieve the purpose, the technical scheme of the invention is to design N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide, which comprises the following steps:
s1: taking N- (5-methoxy-2-phenoxyphenyl) methane sulfonamide (compound I) and chloroacetyl chloride as raw materials and aluminum trichloride as a catalyst, and carrying out Friedel-crafts acylation reaction in a solvent to prepare a compound II;
s2: taking the compound II prepared in the step S1 and phthalimide as raw materials, and performing a drape Rayleigh primary amine synthesis reaction in a solvent in which an alkaline substance exists to prepare a compound III;
s3: and (3) carrying out hydrolysis reaction on the compound III prepared in the step S2 in an inorganic alkali solution to obtain N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide (compound IV).
The preferable technical scheme is that in the step S1, the molar charge ratio of the N- (5-methoxy-2-phenoxyphenyl) methane sulfonamide, the chloracetyl chloride and the aluminum trichloride is 1: 1-2: 2-3, the reaction temperature is 20-40 ℃, the reaction time is 2-4 h, and the solvent is one of dichloromethane, dichloroethane or chloroform.
Further preferably, in the step S1, the molar ratio of the N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide to the chloroacetyl chloride to the aluminum trichloride is 1: 1.2-1.5: 2-3.
In the preferable technical scheme, in the step S2, the molar charge ratio of the compound II to the phthalimide is 1: 1-2, the reaction temperature is 20-80 ℃, the reaction time is 8-24 h, the alkaline substance is one of potassium tert-butoxide, sodium tert-butoxide and potassium hydroxide, the molar charge ratio of the alkaline substance to the phthalimide is 1: 1, and the solvent is one of DMF and acetonitrile.
In a further preferred technical scheme, in the step S2, the molar charging ratio of the compound II to the phthalimide is 1: 1.1-1.2.
In the preferable technical scheme, in the step S3, the reaction temperature is 20-60 ℃, the reaction time is 2-6 h, the inorganic alkali solution is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and lithium hydroxide aqueous solution, and the solute mass concentration of the inorganic alkali solution is 5-20%.
The invention has the advantages and beneficial effects that:
1. the invention provides a novel method for preparing N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide, which takes N- (5-methoxyl-2-phenoxyphenyl) methane sulfonamide as a raw material, and obtains the N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide through Friedel-crafts acylation reaction and drape Raylen primary amine synthesis reaction.
2. According to the preparation method of the N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide, nitrobenzene is avoided by replacing a synthetic route, and harm to operators and the environment is reduced.
3. According to the preparation method of the N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide, reagents used in all steps in the synthesis process are non-explosive chemicals, the reaction conditions are mild, hydrogen chloride gas does not need to be introduced for a long time, and the equipment requirements are reduced.
Drawings
FIG. 1 is a reaction scheme of a process for preparing N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide according to the present invention;
FIG. 2 is a liquid phase mass spectrum (LC-MS) of N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide prepared in example 1.
Detailed Description
The following description of the embodiments of the present invention will be made with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
The method for preparing the N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide has the reaction flow shown in the attached figure 1, and comprises the following specific operation steps:
s1: adding 10g of N- (5-methoxy-2-phenoxyphenyl) methane sulfonamide, 50mL of dichloromethane and 9.1g of aluminum trichloride into a 150mL reaction bottle, cooling to below 20 ℃ under stirring, dropwise adding 3.9g of chloroacetyl chloride, reacting at 20 ℃ for 4h after dropwise adding is finished, and cooling to room temperature. Pouring the reaction solution into 50mL 10% hydrochloric acid solution, stirring for separating liquid, extracting a water layer for 3 times by using 20mL dichloromethane, combining organic layers, washing the organic layers to be neutral, drying the organic layers by using anhydrous sodium sulfate, filtering, concentrating to obtain 12g of a crude compound II product, adding 120mL ethanol, heating to reflux for 1h, cooling to room temperature for crystallization, filtering, and pumping a filter cake to obtain 8.4g of a pure compound II product with the yield: 66.7% (based on N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide);
s2: adding 2g of phthalimide and 10mL of DMF into a 100mL reaction bottle, cooling to 20 ℃, adding 1.51g of potassium tert-butoxide, dropwise adding a solution prepared from 5g of compound II prepared in the step S1 and 25mL of DMF at the temperature of below 20 ℃, and reacting at 20 ℃ for 24 hours after dropwise adding. Transferring the reaction solution into 300mL of ice water, extracting for 3 times by using 50mL of ethyl acetate, combining organic layers, washing to be neutral, separating a clear water layer, concentrating the organic layer until the organic layer is dried to obtain 5.5g of a crude compound III, adding 33mL of ethanol, heating to reflux and dissolving, stirring for 30min, cooling to room temperature for crystallization, filtering, and drying to obtain 4.6g of a pure compound III, wherein the yield is as follows: 70.8% (calculated as compound II);
s3: adding 2g of the compound III and 80mL of a 5% sodium hydroxide solution into a 100mL reaction bottle, stirring for 6h at 20 ℃, adjusting the pH to 1-2 by using hydrochloric acid, separating out a solid, filtering, washing with water to be neutral, and drying to obtain 1.4g of N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide (compound IV), wherein the purity is as follows: 99.7%, yield: 96.5% (based on compound III). As shown in the liquid phase mass spectrum chart of FIG. 2, the mass spectrum data of the compound IV is MS (ESI) m/z:351.1 (M + H) +, in agreement with the theoretical mass spectrometric data for N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide.
Example 2
The method for preparing the N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide has the reaction flow shown in the attached figure 1, and comprises the following specific operation steps:
s1: adding 10g of N- (5-methoxy-2-phenoxyphenyl) methane sulfonamide, 50mL of dichloromethane and 18.2g of aluminum trichloride into a 150mL reaction bottle, cooling to below 20 ℃ under stirring, dropwise adding 7.8g of chloroacetyl chloride, reacting at 40 ℃ for 2h after dropwise adding, and cooling to room temperature. Pouring the reaction solution into 50mL 10% hydrochloric acid solution, stirring for separating liquid, extracting a water layer for 3 times by using 20mL dichloromethane, combining organic layers, washing the organic layers to be neutral, drying the organic layers by using anhydrous sodium sulfate, filtering, concentrating to obtain 14g of a crude compound II, adding 120mL ethanol, heating to reflux for 1h, cooling to room temperature for crystallization, filtering, and pumping a filter cake to obtain 10.2g of a pure compound II, wherein the yield is as follows: 81% (based on N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide);
s2: adding 4g of phthalimide and 10mL of acetonitrile into a 100mL reaction bottle, cooling to below 20 ℃, adding 1.51g of potassium hydroxide, dropwise adding a solution prepared by 5g of the compound II prepared in the step S1 and 25mL of DMF at below 20 ℃, and reacting for 24 hours at 20 ℃ after dropwise adding. Transferring the reaction solution into 300mL of ice water, extracting for 3 times by using 50mL of ethyl acetate, combining organic layers, washing to be neutral, separating a clear water layer, concentrating the organic layer until the organic layer is dried to obtain 5g of a crude compound III, adding 30mL of ethanol, heating to reflux and dissolving clear, stirring for 30min, cooling to room temperature for crystallization, filtering, and drying to obtain 4.2g of a pure compound III, wherein the yield is as follows: 64.6% (calculated as compound II);
s3: adding 2g of the compound III and 80mL of 10% potassium hydroxide solution into a 100mL reaction bottle, stirring for 2h at 60 ℃, adjusting the pH to 1-2 by using hydrochloric acid, separating out a solid, filtering, washing with water to be neutral, and drying to obtain 1.2g of N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide (compound IV), wherein the purity is as follows: 99.8%, yield: 82.8% (based on compound III). Mass spectrum data of the compound IV is MS (ESI) m/z:351.1 (M + H) +, in agreement with the theoretical mass spectrometric data for N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide.
Example 3
The method for preparing the N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide has the following specific operation steps, and the reaction flow is shown in the attached figure 1:
s1: adding 10g of N- (5-methoxy-2-phenoxyphenyl) methane sulfonamide, 50mL of dichloromethane and 13.6g of aluminum trichloride into a 150mL reaction bottle, cooling to below 20 ℃ under stirring, dropwise adding 5.9g of chloroacetyl chloride, reacting at 40 ℃ for 3 hours after dropwise adding is finished, and cooling to room temperature. Pouring the reaction solution into 50mL 10% hydrochloric acid solution, stirring for liquid separation, extracting a water layer for 3 times by using 20mL dichloromethane, combining organic layers, washing the organic layers to be neutral, drying the organic layers by using anhydrous sodium sulfate, filtering, concentrating to obtain 14g of a crude compound II product, adding 135mL ethanol, heating the mixture to reflux for 1 hour, cooling the mixture to room temperature for crystallization, filtering, and drying a filter cake to obtain 10g of a pure compound II product, wherein the yield is as follows: 79.4% (calculated as N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide);
s2: adding 4g of phthalimide and 20mL of DMF into a 100mL reaction bottle, cooling to below 20 ℃, adding 2.6g of sodium tert-butoxide, dropwise adding a solution prepared from 5g of compound II prepared in the step S1 and 25mL of DMF at below 20 ℃, and reacting for 24 hours at 40 ℃ after dropwise adding. Transferring the reaction solution into 300mL of ice water, extracting for 3 times by using 50mL of ethyl acetate, combining organic layers, washing to be neutral, separating a clear water layer, concentrating the organic layer until the organic layer is dried to obtain 6g of a crude product of the compound III, adding 36mL of ethanol, heating to reflux and dissolving clear, stirring for 30min, cooling to room temperature for crystallization, filtering, and drying to obtain 5.5g of a pure product of the compound III, wherein the yield is as follows: 84.6% (calculated as compound II);
s3: adding 2g of the compound III and 80mL of a lithium hydroxide solution with the mass concentration of 15% into a 100mL reaction bottle, stirring for 2h at 40 ℃, adjusting the pH to 1-2 by using hydrochloric acid, separating out a solid, filtering, washing with water to be neutral, and drying to obtain 1.3g of N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide (compound IV) with the purity: 99.6%, yield: 89.7% (based on compound III). Mass spectrum data of the compound IV is MS (ESI) m/z:351.1 (M + H) +, in agreement with the theoretical mass spectrometric data for N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide.
Example 4
The method for preparing the N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide has the reaction flow shown in the attached figure 1, and comprises the following specific operation steps:
s1: adding 10g of N- (5-methoxy-2-phenoxyphenyl) methane sulfonamide, 50mL of dichloromethane and 9.1g of aluminum trichloride into a 150mL reaction bottle, cooling to below 20 ℃ under stirring, dropwise adding 4.7g of chloroacetyl chloride, reacting at 30 ℃ for 4 hours after dropwise adding, and cooling to room temperature. Pouring the reaction solution into 50mL 10% hydrochloric acid solution, stirring for liquid separation, extracting a water layer for 3 times by using 20mL dichloromethane, combining organic layers, washing the organic layers to be neutral, drying the organic layers by using anhydrous sodium sulfate, filtering, concentrating to obtain 14g of a crude compound II product, adding 138mL ethanol, heating to reflux for 1 hour, cooling to room temperature for crystallization, filtering, and drying a filter cake to obtain 10.1g of a pure compound II product, wherein the yield is as follows: 80.2% (calculated as N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide);
s2: adding 2.4g of phthalimide and 12mL of DMF into a 100mL reaction bottle, cooling to below 20 ℃, adding 1.8g of potassium tert-butoxide, dropwise adding a solution prepared from 5g of the compound II prepared in the step S1 and 25mL of DMF below 20 ℃, and reacting at 80 ℃ for 8 hours after dropwise adding. Transferring the reaction solution into 300mL of ice water, extracting for 3 times by using 50mL of ethyl acetate, combining organic layers, washing to be neutral, separating a clear water layer, concentrating the organic layer until the organic layer is dried to obtain 6.3g of a crude compound III, adding 35mL of ethanol, heating to reflux and dissolving, stirring for 30min, cooling to room temperature for crystallization, filtering, and drying to obtain 5.6g of a pure compound III, wherein the yield is as follows: 86.2% (based on compound II);
s3: adding 2g of the compound III and 80mL of 20% sodium hydroxide solution into a 100mL reaction bottle, stirring for 2h at 20 ℃, adjusting the pH to 1-2 by using hydrochloric acid, separating out a solid, filtering, washing with water to be neutral, and drying to obtain 1.3g of N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methane sulfonamide (compound IV), wherein the purity is as follows: 99.7%, yield: 89.7% (based on compound III). Mass spectrum data of the compound IV is MS (ESI) m/z:351.1 (M + H) +, in agreement with the theoretical mass spectrometric data for N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, it is possible to make various improvements and modifications without departing from the technical principle of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention.
Claims (6)
1. A preparation method of N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide is characterized by comprising the following steps:
s1: taking N- (5-methoxy-2-phenoxyphenyl) methane sulfonamide (compound I) and chloroacetyl chloride as raw materials and aluminum trichloride as a catalyst, and carrying out Friedel-crafts acylation reaction in a solvent to prepare a compound II;
s2: taking the compound II prepared in the step S1 and phthalimide as raw materials, and performing a drape Rayleigh primary amine synthesis reaction in a solvent in which an alkaline substance exists to prepare a compound III;
s3: and (3) carrying out hydrolysis reaction on the compound III prepared in the step S2 in an inorganic alkali solution to obtain N- (3-glycyl-2-methoxyl-5-phenoxyphenyl) methane sulfonamide (compound IV).
2. The method for preparing N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide according to claim 1, wherein in the step S1, the molar charge ratio of the N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide, the chloroacetyl chloride and the aluminum trichloride is 1: 1-2: 2-3, the reaction temperature is 20-40 ℃, the reaction time is 2-4 h, and the solvent is one of dichloromethane, dichloroethane or chloroform.
3. The method for producing N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide according to claim 2, wherein the molar ratio of N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide to chloroacetyl chloride to aluminum trichloride in step S1 is 1: 1.2 to 1.5: 2 to 3.
4. The method for preparing N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide according to claim 1, wherein in step S2, the molar charge ratio of the compound II to phthalimide is 1: 1-2, the reaction temperature is 20-80 ℃, the reaction time is 8-24 h, the alkaline substance is one of potassium tert-butoxide, sodium tert-butoxide and potassium hydroxide, the molar charge ratio of the alkaline substance to phthalimide is 1: 1, and the solvent is one of DMF and acetonitrile.
5. The method for producing N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide according to claim 4, wherein the molar charge ratio of the compound II to phthalimide in step S2 is 1: 1.1 to 1.2.
6. The method for preparing N- (3-glycyl-2-methoxy-5-phenoxyphenyl) methanesulfonamide according to claim 1, wherein in step S3, the reaction temperature is 20 ℃ to 60 ℃, the reaction time is 2 to 6 hours, the inorganic alkali solution is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and lithium hydroxide aqueous solution, and the solute mass concentration of the inorganic alkali solution is 5 to 20%.
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