CN104744282A - Preparation process of insulin sensitizer - Google Patents
Preparation process of insulin sensitizer Download PDFInfo
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- CN104744282A CN104744282A CN201510086842.8A CN201510086842A CN104744282A CN 104744282 A CN104744282 A CN 104744282A CN 201510086842 A CN201510086842 A CN 201510086842A CN 104744282 A CN104744282 A CN 104744282A
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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
The invention relates to a kind of preparation technology of euglycemic agent, is more particularly a kind of preparation technology utilizing the euglycemic agent of Methanesulfonyl chloride activated hydroxyl groups.
Background technology
In recent years, domestic and international diabetic subject increases with surprising rapidity year by year, and this disease has been listed in three large diseases of the serious harm human health after cardiovascular and cerebrovascular, cancer.Wherein diabetes B accounts for more than 90% of diabetes cases, and the feature of this metabolic disturbance acute disease is hyperglycemia, and can produce mental diseases, the metabolic syndrome such as ephrosis, retinopathy, hypertriglyceridemia, obesity and other cardiovascular diseasess.
The medicine of diabetes B includes sulfonylurea or biguanides.But it is not high to take sulfonylureas efficiency, and there is many side effects, such as, be directed at hypoglycemia and obesity.Take biguanides and then can cause the side effects such as emulsion acidismus, vomiting and diarrhoea.Therefore concerning diabetes B, developing a kind of blood sugar concentration that controls does not have again the medicament of larger side effect significant.
In recent years, the compound of another kind of thiazolidinediones by name has hypoglycemic effect by improving insulin sensitivity, and it does not impel pancreas excreting insulin, can not cause undesirable hypoglycemia yet, even if it is also like this for increasing dosage.Thiazolidinedione is the activator of PPAR γ, and it is by bringing out and regulating the differentiation of adipocyte to produce above-mentioned effect.The compound of this Class Activation PPAR γ has proved to be used for the treatment of diabetes B clinically.The activation of PPAR γ and glucose metabolism really cutting link are also completely not obvious.Free fatty acid in what it played link effect is fat tissue instead of muscle cell.Activate PPAR γ by it, then produce lipoprotein lipase, fatty acid transport protein and acetyl-CoA-synthetase.Because substrate competition and metabolic pathway compensate, this can show the concentration reducing free fatty acid in blood plasma conversely, thus realization is from the conversion being oxidized to the oxidation of glucose of lipid acid.
The oxidation of glucose mainly occur in be in hypermetabolism state tissue as in skeletal muscle, this will reduce the resistibility of these tissues to Regular Insulin.In addition, activate some genes of PPAR γ energy regulable control glucose energy balance, this also will make blood sugar concentration reduce.Although thiazolidinediones is good anti-diabetes B preparation, its severe side effect such as heart hypertrophy, hemodilution and liver poison have limited its clinical application.
It is reported, there occurs in the U.S. and Japan and a lot ofly caused liver injury or lethal event because medicine is harmful to liver.In addition, selective PPAR γ part impels Adipocyte Differentiation and white adipose to pile up, the generation of thus causeing fat.Fat closely related with diabetes B, it can bring out diabetes B, also can produce because of diabetes B.These adverse consequencess finally can damage the susceptibility of body to Regular Insulin.Therefore, diabetes B needs of patients one safely and effectively preparation treats this disease, this preparation should have double activity, both can improve the susceptibility of body to Regular Insulin, the deposition again by regulating the content of free fatty acid and triglyceride level to reduce white adipose.
PPAR γ is a member in nuclear receptor superfamily, and it mainly expresses in fatty tissue.Another member PPAR α in this family mainly expresses in liver organization, can be produced the effect reducing triglyceride level and cholesterol level by a class the ligand activation of fibrates.
PPAR α can stimulate the propagation of peroxidase, accelerates the oxidation of lipid acid, thus the fatty acid content reduced in blood has report to point out recently, and PPAR δ has widely the effect of " burning " fat as lipometabolic attemperator.In experiment in vitro, in fat and Skeletal Muscle Cell, activate oxidation and utilization that PPAR δ contributes to lipid acid.In the fatty tissue that PPAR alpha expression amount is very low, activation PPAR δ can induce the expression with Fatty Acid Oxidation and energy expenditure genes involved specifically, thus reaches the effect improving lipid content and fat-reducing.The more important thing is, these animals that have activated PPAR δ have resistant function completely to the obesity that high fat diet and inherited genetic factors (Lepr (db/db)) are induced.Can make the fat consumption of accumulation after process Lepr (db/db) mouse of short duration in PPAR δ activator, the mouse of PPAR δ defect then can cause fat PPAR α, PPAR γ and PPAR δ all to form heterodimer with retinoic acid receptor X with high fat diet process.Therefore RXR/PPAR heterodimer also plays vital role in control cell sugar, fat balance and Adipocyte Differentiation.
Have been reported and show, two activator of activator and PPAR α/PPAR γ that some new compounds comprise PPAR γ have good effect (WO00/08002 in the metabolic syndrome of prevention and therapy humans and animals, WO01/57001A1, US6054453, EP088317B1, WO97/25042, WO02/26729A2 and US6353018B1).Therefore, screen the new complex therapy of compound to metabolic disturbance diseases with PPAR α, PPAR γ and PPAR δ activator performance and have very important meaning.These metabolic disturbance diseases comprise the metabolic syndromes such as diabetes, hypertension, obesity, insulin resistant, hypertriglyceridemia, hyperglycemia, hypercholesterolemia, the sample sclerosis of artery week, coronary heart disease and other cardiovascular diseasess.
But, in Chinese issued patents CN1562970A exposure, there is the aryl alkyl amino acid PPAR full activator that ester activity falls in excellent hypoglycemic, disclosed preparation technology, when utilizing 1, when 2-ethylene dibromide and 2-(1-methyl-3-oxo-3-(4-fluorophenyl) allylamine)-3-(4-hydroxy phenyl)-methyl propionate prepare 2-(1-methyl-3-oxo-3-(4-fluorophenyl) allylamine)-3-(4-(2-bromine oxethyl) phenyl)-methyl propionate, its consumption reaches 10 equivalents, and its yield mutually extremely low (27%), also just represent that the preparation technology disclosed by above-mentioned this section of document lacks the actual application value of suitability for industrialized production.
Summary of the invention
Based on the demand, main purpose of the present invention provides one to utilize 2-(4-fluoro benzoyl) pimelinketone as raw material, and utilizes Methanesulfonyl chloride activated hydroxyl groups, with the productive rate of the rate of utilization and final product that improve raw material.
For reaching above-mentioned purpose; the present invention adopts a kind of preparation technology of euglycemic agent; its step comprises: 2-(4-fluoro benzoyl) pimelinketone, TYR methyl esters, dioxane and toluene mix by (1); and pass into nitrogen carry out building-up reactions in mixed solution, after reaction completes, obtain the first reaction intermediates.Then, distillation sequence is carried out to the first reaction intermediates, methyl-phenoxide is added and concentration is the palladium/carbon of 10% and carries out back flow reaction again in the first reaction intermediates, to obtain the first product, it is yellow oil 2-[2-(4-fluoro benzoyl) aniline]-3-(4-hydroxy phenyl)-methyl propionate, and yield is 45%, (2) the first product and methylene dichloride are mixed to form mixed solution, and the temperature of mixed solution is cooled to 3 degree to 8 degree, again Methanesulfonyl chloride and pyridine are added mixed solution and carry out building-up reactions, to obtain the second reaction intermediates, then the second reaction intermediates is distilled to remove the methylene dichloride that the second reaction intermediates comprises, and obtain the second product, 2-[2-(4-fluoro benzoyl) aniline]-3-(4-first sulphur ester group phenyl)-methyl propionate, yield is 95%, (3) the second product is added tetrahydrofuran (THF) and 1,2-ethylene dibromide mixes, and building-up reactions is carried out between temperature 45 C-55 DEG C, to obtain the 3rd reaction intermediates, described 3rd reaction intermediates is diluted to separate out third product by recycling water, 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-bromine oxethyl) phenyl]-methyl propionate, and (4) are by third product, salt, cuprous chloride, carbazole, oxine and methyl-sulphoxide mixing, and temperature of reaction is increased to 115 DEG C-120 DEG C and carries out building-up reactions, and obtain the 4th reaction intermediates, with water, the 4th reaction intermediates is diluted again, recycling ethyl acetate extracts to be extracted liquid to the 4th reaction intermediates of having diluted, the ethyl acetate that recycling distillation removing extraction liquid comprises, to obtain the 4th product, 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-carbazyl oxyethyl group) phenyl]-methyl propionate, its yield is 47%, by the preparation technology disclosed by the present invention, in step (4), in the docking of 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-bromine oxethyl) phenyl]-methyl propionate and carbazole, utilize new preparation technology, and improve the yield of final product, the situation that the building-up reactions of novel insulin sensitizer chiglitazar simultaneously can be avoided easily to be hydrolyzed as the ester disclosed in No. CN1562970Ath, Chinese issued patents occurs.
Embodiment
Embodiment 1: preparation 2-[2-(4-fluoro benzoyl) aniline]-3-(4-hydroxy phenyl)-methyl propionate
In the reaction flask of 100ml, add 2-(4-fluoro benzoyl) pimelinketone 2.2g, TYR methyl esters 1.96g, dioxane 30ml and toluene 30ml mix; and pass into rare gas element; such as nitrogen, carry out displacement three times, back flow reaction obtains the first reaction intermediates at least 5 hours.After reacting completely, underpressure distillation is carried out to the first reaction intermediates, its objective is by the distillation of the solvent of the first reaction intermediates completely.Then by methyl-phenoxide 50ml and concentration be again 10% palladium/carbon (Pd/C) 1.5g add the first reaction intermediates, carry out back flow reaction at least 3 hours.After reacting completely; utilize the solvent of distillation removal first reaction intermediates again; crude product recycling column chromatography for separation (PE/EA=3:2) obtained; obtain the first product; 2-[2-(4-fluoro benzoyl) aniline]-3-(4-hydroxy phenyl)-methyl propionate; this first product is yellow oil, and yield is 45%.
Embodiment 2: preparation 2-[2-(4-fluoro benzoyl) aniline]-3-(4-first sulphur ester group phenyl)-methyl propionate
The first product prepared by embodiment 1 is added in the reaction flask of 100ml; 2-[2-(4-fluoro benzoyl) aniline]-3-(4-hydroxy phenyl)-methyl propionate; 3.93g and methylene dichloride 30ml mixes; and its mixed solution is cooled to 3 degree to 8 degree, best cooling temperature is 5 degree.Then, the temperature of reaction of mixed solution, in mixed solution, is remained on cooling temperature, and carries out building-up reactions at least 2 hours by the pyridine slowly dripping Methanesulfonyl chloride 3.5g and trace." trace " in this is noted that the pyridine dripping trace herein refers to, after pyridine drawn by dropper, the amount dripping a pyridine is called trace.After reaction; obtain the second reaction intermediates; this second reaction intermediates is liquid; and then wash the second reaction intermediates with the saturated saleratus solution of 10ml; then anhydrous sodium sulfate drying is utilized, the methylene dichloride that recycling distillation removal second reaction intermediates comprises, to obtain the second product; 2-[2-(4-fluoro benzoyl) aniline]-3-(4-first sulphur ester group phenyl)-methyl propionate, its yield is about 95%.
Embodiment 3: preparation 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-bromine oxethyl) phenyl]-methyl propionate
The second product prepared by embodiment 2 is added in the reaction flask of 100ml; 2-[2-(4-fluoro benzoyl) aniline]-3-(4-first sulphur ester group phenyl)-methyl propionate; 4.46g and solvents tetrahydrofurane 20ml; 1 is dripped after stirring and dissolving; 2-ethylene dibromide 1.88g; and temperature of reaction is increased to 45 DEG C-55 DEG C, optimal reaction temperature is 50 DEG C, carries out synthesis anti-at least 2.5 hours-3 hours under this temperature of reaction.The 3rd reaction intermediates is obtained after reacting completely; this the 3rd reaction intermediates is liquid; and used the water of 100ml to dilute; make it in the process of dilution, have a large amount of yellow solids to separate out; then again these yellow solids of separating out are dried and namely obtain third product; 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-bromine oxethyl) phenyl]-methyl propionate, its yield is about 95%.
Embodiment 4: preparation 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-carbazyl oxyethyl group) phenyl]-methyl propionate
The third product prepared by previous embodiment 3 is added in the reaction flask of 100ml; 2-[2-(4-fluoro benzoyl) aniline)-3-[4-(2-bromine oxethyl) phenyl]-methyl propionate; 5g, salt, such as salt of wormwood; 2.8g, cuprous chloride 0.05g, oxine 0.07g, carbazole 1.7g and methyl-sulphoxide (DMSO; Dimethyl sulfoxide) 20ml mixing; and temperature of reaction is warming up to 115 DEG C-130 DEG C; optimal reaction temperature is 120 DEG C, and carries out building-up reactions at least 8 hours in this temperature.After reacting completely, obtain the 4th reaction intermediates, this 4th reaction intermediates is liquid, and utilizes the water of 100ml to dilute the 4th reaction intermediates.Then, utilize ethyl acetate to extract the 4th reaction intermediates of having diluted, at least extract three times, the amount of ethyl acetate is 50ml each time, after extraction step terminates, and combining extraction liquid, then wash with the saturated aqueous common salt of 30ml, then use anhydrous sodium sulfate drying.Then recycling distillation is to remove ethyl acetate to obtain yellow solid; chromatography (PE/EA=5:1) is separated via post; to obtain the 4th product; 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-carbazyl oxyethyl group) phenyl]-methyl propionate, its yield is 47%.
Can know according to upper art; compared to existing preparation technology; in step of the present invention (4); in the docking of 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-bromine oxethyl) phenyl]-methyl propionate and carbazole; utilize new preparation technology; and the yield of final product can be improve, the situation that the building-up reactions of novel insulin sensitizer chiglitazar simultaneously can be avoided easily to be hydrolyzed as the ester disclosed in No. CN1562970Ath, Chinese issued patents occurs.
The above embodiment, just preferred embodiment of the present invention, not be used for limiting the scope of the present invention, therefore all equivalences done according to structure, feature and the principle described in the present patent application the scope of the claims change or modify, and all should be included in patent claim of the present invention.The reagent used in the various embodiments described above, as not dated especially, is all buied by open channel.
Claims (7)
1. a preparation technology for euglycemic agent, is characterized in that, described preparation technology comprises the following steps:
(1) 2-(4-fluoro benzoyl) pimelinketone, TYR methyl esters, dioxane and toluene are mixed, and pass into rare gas element and carry out building-up reactions, to obtain the first reaction intermediates, after described first reaction intermediates distillation, add methyl-phenoxide and palladium/carbon and carry out back flow reaction again, to obtain the first product after described first reaction intermediates mixing;
(2) described first product is mixed to form mixed solution with methylene dichloride, and the temperature of described mixed solution is cooled to 3 degree to 8 degree, again Methanesulfonyl chloride and pyridine are added described mixed solution and carry out building-up reactions, to obtain the second reaction intermediates, described second reaction intermediates is distilled to remove the described methylene dichloride that described second reaction intermediates comprises, to obtain the second product;
(3) described second product is added tetrahydrofuran (THF) and glycol dibromide mixing, between temperature 45 C-55 DEG C, carry out building-up reactions, to obtain the 3rd reaction intermediates, described 3rd reaction intermediates is diluted to separate out third product by recycling water; And
(4) described third product, salt, cuprous chloride, carbazole, oxine and methyl-sulphoxide mixed and temperature of reaction be increased to 115 DEG C-120 DEG C to carry out building-up reactions, and obtain the 4th reaction intermediates, with water, described 4th reaction intermediates is diluted again, recycling ethyl acetate extracts to be extracted liquid to described 4th reaction intermediates of having diluted, the described ethyl acetate that the described extraction liquid of recycling distillation removing comprises, to obtain the 4th product.
2. preparation technology as claimed in claim 1, it is characterized in that, be nitrogen in step (1) described rare gas element.
3. preparation technology as claimed in claim 1, it is characterized in that, described first product is 2-[2-(4-fluoro benzoyl) aniline]-3-(4-hydroxy phenyl)-methyl propionate.
4. preparation technology as claimed in claim 1, it is characterized in that, described second product is 2-[2-(4-fluoro benzoyl) aniline]-3-(4-first sulphur ester group phenyl)-methyl propionate.
5. preparation technology as claimed in claim 1, is characterized in that, described tri-Productivity thing As 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-bromine oxethyl) phenyl]-methyl propionate.
6. preparation technology as claimed in claim 1, it is characterized in that, be salt of wormwood in step (4) described salt.
7. preparation technology as claimed in claim 1, is characterized in that, described tetra-Productivity thing As 2-[2-(4-fluoro benzoyl) aniline]-3-[4-(2-carbazyl oxyethyl group) phenyl]-methyl propionate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107868033A (en) * | 2016-09-27 | 2018-04-03 | 深圳微芯生物科技有限责任公司 | A kind of preparation method of phenylalanine class compound |
| CN110934866A (en) * | 2018-09-25 | 2020-03-31 | 深圳微芯生物科技股份有限公司 | Use of sitagliptin and related compounds |
| CN112479977A (en) * | 2016-09-27 | 2021-03-12 | 深圳微芯生物科技股份有限公司 | Substituted phenylpropionic acid compound enantiomer, and preparation method, composition and application thereof |
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| CN112479977A (en) * | 2016-09-27 | 2021-03-12 | 深圳微芯生物科技股份有限公司 | Substituted phenylpropionic acid compound enantiomer, and preparation method, composition and application thereof |
| KR102264868B1 (en) | 2016-09-27 | 2021-06-14 | 쉔젠 칩스크린 바이오사이언스 씨오., 엘티디. | Method for producing phenylalanine compound |
| CN110934866A (en) * | 2018-09-25 | 2020-03-31 | 深圳微芯生物科技股份有限公司 | Use of sitagliptin and related compounds |
| CN110934866B (en) * | 2018-09-25 | 2023-12-01 | 深圳微芯生物科技股份有限公司 | Use of sitagliptin carboxylic acids and related compounds |
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Application publication date: 20150701 |