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Preparation process of insulin sensitizer

An insulin sensitizer and a technology for the preparation process are applied in the field of preparation technology of the insulin sensitizer, and can solve the problems that the preparation process lacks practical application value in industrialized production and the yield is relatively low.

Inactive Publication Date: 2015-07-01
NANTONG HENGSHENG FINE CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, the Chinese patent publication No. CN1562970A discloses an aralkyl amino acid PPAR full activator with excellent hypoglycemic and lipid-lowering activity. The disclosed preparation process, when using 1,2-dibromoethane and 2-(1-methyl Preparation of 2-(1-methyl-3-oxo-3- (4-fluorophenyl) allylamine)-3-(4-(2-bromoethoxy) phenyl)-propionic acid methyl ester, its consumption reaches 10 equivalents, and its yield is extremely low (27% ), it also means that the preparation process disclosed in the above-mentioned document lacks the practical application value of industrialized production

Method used

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  • Preparation process of insulin sensitizer
  • Preparation process of insulin sensitizer
  • Preparation process of insulin sensitizer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Embodiment 1: preparation 2-[2-(4-fluorobenzoyl) aniline]-3-(4-hydroxyphenyl)-propionic acid methyl ester

[0014]

[0015] Add 2.2 g of 2-(4-fluorobenzoyl) cyclohexanone, 1.96 g of L-tyrosine methyl ester, 30 ml of dioxane and 30 ml of toluene into a 100 ml reaction flask, and mix with an inert gas, such as Nitrogen was replaced three times, and the reflux reaction was performed for at least 5 hours to obtain the first reaction intermediate. After the reaction is complete, the first reaction intermediate is subjected to vacuum distillation, the purpose of which is to completely distill the solvent of the first reaction intermediate. Then, 50 ml of anisole and 1.5 g of palladium / carbon (Pd / C) with a concentration of 10% were added to the first reaction intermediate, and the reflux reaction was carried out for at least 3 hours. After the reaction was complete, the solvent of the first reaction intermediate was removed by distillation again, and the obtained crude pro...

Embodiment 2

[0016] Embodiment 2: Preparation 2-[2-(4-fluorobenzoyl) aniline]-3-(4-methylsulfonyl phenyl)-propionic acid methyl ester

[0017]

[0018] Add the first product prepared in Example 1, 2-[2-(4-fluorobenzoyl)aniline]-3-(4-hydroxyphenyl)-propionic acid methyl ester, 3.93 g and 30ml of dichloromethane are mixed, and the mixture is cooled to 3 to 8 degrees, and the optimum cooling temperature is 5 degrees. Then, slowly drop 3.5 g of methanesulfonyl chloride and a small amount of pyridine into the mixed solution, keep the reaction temperature of the mixed solution at a cooling temperature, and carry out the synthesis reaction for at least 2 hours. It should be noted here that the "trace" in the dropwise addition of a trace amount of pyridine here refers to the amount of dropping one drop of pyridine after the dropper absorbs pyridine, which is called a trace amount. After the reaction, a second reaction intermediate is obtained, which is a liquid, and then the second reaction in...

Embodiment 3

[0019] Embodiment 3: Preparation 2-[2-(4-fluorobenzoyl)aniline]-3-[4-(2-bromoethoxy)phenyl]-propionic acid methyl ester

[0020]

[0021]In a 100ml reaction flask, add the second product prepared in Example 2, 2-[2-(4-fluorobenzoyl)aniline]-3-(4-methylsulfonylphenyl)-propionic acid methyl Esters, 4.46g and solvent tetrahydrofuran 20ml, after stirring and dissolving, add 1.88g of 1,2-dibromoethane dropwise, and raise the reaction temperature to 45°C-55°C, the optimum reaction temperature is 50°C, and react here Synthesis is carried out at temperature for at least 2.5 hours to 3 hours. Obtain the 3rd reaction intermediate after reaction is complete, and this 3rd reaction intermediate is liquid, and it is diluted with the water of 100ml, makes it have a large amount of yellow solids to separate out in the process of diluting, then these separated yellow solids are separated out. The solid is dried to obtain the third product, 2-[2-(4-fluorobenzoyl)aniline]-3-[4-(2-bromoethoxy...

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Abstract

The invention discloses a preparation process of an insulin sensitizer. The preparation process comprises the following steps: mixing 2-(4-fluorobenzoyl) cyclohexanone, L-tyrosine methyl ester, dioxane and methylbenzene, filling nitrogen and reacting, carrying out a distilling procedure, and reacting with the addition of anisole and palladium / carbon so as to obtain a first product; mixing the first product with dichloromethane, adding methylsufonyl chloride and pyridine, reacting, distilling and removing dichloromethane so as to obtain a second product; mixing for reacting the second product with tetrahydrofuran and 1,2-dibromoethane, and thinning with water so as to obtain a third product; and mixing for reacting the third product with salt, cuprous chloride, carbazole, 8-hydroxyquinoline and dimethyl sulfoxide, thinning with water and extracting with ethyl acetate, distilling and removing ethyl acetate so as to obtain a final product, namely 2-[2-(4-fluorobenzoyl) aniline]-3-[4-(2-carbazolyl ethyoxyl) phenyl] methyl propionate. The yield of the final product is 47%; and in the process of joining the final product and carbazole, the circumstance of ester hydrolysis in a synthesis reaction of the novel insulin sensitizer, namely chiglitazar, is avoided.

Description

technical field [0001] The invention relates to a preparation process of an insulin sensitizer, more specifically to a preparation process of an insulin sensitizer using methylsulfonyl chloride to activate a hydroxyl group. Background technique [0002] In recent years, the number of diabetic patients at home and abroad is increasing year by year at an astonishing rate, and the disease has been listed as the three major diseases that seriously endanger human health after cardiovascular and cerebrovascular diseases and cancer. Among them, type 2 diabetes accounts for more than 90% of diabetes cases. This metabolic abnormal emergency is characterized by hyperglycemia and can cause metabolic syndrome such as mental illness, nephropathy, retinopathy, hypertriglyceridemia, obesity and other cardiovascular diseases. [0003] Treatment for type 2 diabetes includes sulfonylureas or biguanides. However, the efficiency of taking sulfonylureas is not high, and there are many side effe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/36C07C227/18C07C309/70C07C303/28C07D209/86
Inventor 钟天桂申伟成陈均鸿
Owner NANTONG HENGSHENG FINE CHEM
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