CN103880757A - Synthesis method for 5-hydroxyl pyrimidine-2-carboxylic acid - Google Patents
Synthesis method for 5-hydroxyl pyrimidine-2-carboxylic acid Download PDFInfo
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- CN103880757A CN103880757A CN201410149113.8A CN201410149113A CN103880757A CN 103880757 A CN103880757 A CN 103880757A CN 201410149113 A CN201410149113 A CN 201410149113A CN 103880757 A CN103880757 A CN 103880757A
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- carboxylic acid
- cyanopyrimidine
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- hydroxy pyrimidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
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Abstract
The invention discloses a synthesis method for 5-hydroxyl pyrimidine-2-carboxylic acid. The synthesis method comprises the following steps: reacting 5-bromo-2-cyanopyrimidine with phenylcarbinol to generate 5-benzyloxy-2-cyanopyrimidine; then reacting5-benzyloxy-2-cyanopyrimidine in an alkaline condition, dissolving out the product by carrying out an acid adjustment on the reaction solution, and filtering and drying the dissolved solid to obtain the target compound, namely 5-hydroxyl pyrimidine-2-carboxylic acid. The synthesis method disclosed by the invention has the beneficial effects that a synthesis route for 5-hydroxyl pyrimidine-2-carboxylic acid is designed and a preparation method for the compound is provided.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to a kind of synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid.
Background technology
Obesity is the state of excessive accumulation fat in body, generally because triglyceride level in fatty tissue (TG) accumulation causes; And can cause that life style disease is as mixed and disorderly in lipid metabolism, fatty liver, diabetes, hypertension, arteriosclerosis etc.At present, cause that the possibility of these diseases is defined as obesity and treats as a class disease in the future using relating to these diseases or having.
Glyceroyl transferring enzyme (DGAT) is that catalysis diacylglycerol adds that fatty acid acyl forms the enzyme of TG, known two kinds of hypotype DGAT1 and the DGAT2 of existing in DGAT.Wherein, DGAT1 is present in liver, skeletal muscle, adipocyte etc., and the TG participating in each tissue synthesizes.
In addition, DGAT1 also participates in the TG resynthesis of final stage in intestinal epithelial cell.TG is decomposed into lipid acid and monoacylglycerol by steapsase in small intestinal lumen, is then inhaled into intestinal epithelial cell, and resynthesis is to be absorbed after TG in epithelial cell.
Therefore, the medicine that suppresses DGAT1 effect can suppress the synthetic of TG final stage, and its TG that not only can suppress in liver, adipocyte synthesizes, and also can suppress enteral TG resynthesis, reaches thus the morbid state that improves obesity.Obesity or hyperlipidaemia that DGAT1 inhibitor is caused by obesity, hypertriglyceridemia, fat metabolic disturbance, fatty liver, hypertension, arteriosclerosis, diabetes etc. in prevention, treatment have important effect.
5-hydroxy pyrimidine-2-carboxylic acid is an important intermediate in preparation DGAT1 inhibitor.At present, the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid is there are no bibliographical information, but studying its synthetic method has great importance.
Summary of the invention
The object of the invention is to, a kind of synthetic method of medicine intermediate 5-hydroxy pyrimidine-2-carboxylic acid is provided.The technical problem that the present invention solves is: propose first the synthetic schemes of 5-hydroxy pyrimidine-2-carboxylic acid, for the preparation of 5-hydroxy pyrimidine-2-carboxylic acid provides synthetic route.
The technical solution adopted in the present invention is as follows:
A kind of synthetic route of 5-hydroxy pyrimidine-2-carboxylic acid is as follows:
The synthetic method concrete steps of described 5-hydroxy pyrimidine-2-carboxylic acid are: step 1, bromo-5-2-cyanopyrimidine and phenylcarbinol are dissolved in toluene, add cesium carbonate, cuprous iodide, 1,10-phenanthroline, in 80～110 ℃ of reactions, after reacting completely, be cooled to room temperature, obtain 5-benzyloxy-2-cyanopyrimidine after reaction solution is concentrated and purified; Step 2,5-benzyloxy-2-cyanopyrimidine that abovementioned steps is obtained is soluble in water, add highly basic, in 25～100 ℃ of reactions, after reacting completely, be cooled to room temperature, then add acid to regulate its pH value to separate out for acidity makes product to reaction solution, after the solid filtering of separating out is dried, obtain 5-hydroxy pyrimidine-2-carboxylic acid.
Preferably, in described step 1, the reaction times is 4～12 hours.
Preferably, in described step 1, the mol ratio of the bromo-2-cyanopyrimidine of 5-and phenylcarbinol is 1:1.5～1:3.5.
Preferably, the cuprous iodide adding in described step 1 and 1,10-phenanthroline are catalytic amount, and the mass ratio of the bromo-2-cyanopyrimidine of described cuprous iodide and 5-is not less than 10%, described 1, and the mass ratio of the bromo-2-cyanopyrimidine of 10-phenanthroline and 5-is not less than 20%.
Preferably, the cesium carbonate adding in described step 1 is reacting weight, and the mol ratio of the bromo-2-cyanopyrimidine of described cesium carbonate and 5-is 1:1～3:1.
Preferably, the highly basic adding in described step 2 is potassium hydroxide.Further preferably, the mol ratio of described potassium hydroxide and 5-benzyloxy-2-cyanopyrimidine is 2:1～4:1.
Preferably, in described step 2, reaction solution is cooled to after room temperature by washed with dichloromethane to remove unreacted raw material and by product, and then adds acid to regulate the pH value of reaction solution.
Preferably, while adding acid to carry out the adjusting of pH value to reaction solution in described step 2, be 3～4 by adding 1N hydrochloric acid to regulate its pH value.
Compared with prior art, beneficial effect of the present invention is as follows:
(1) the present invention has proposed the synthetic route of 5-hydroxy pyrimidine-2-carboxylic acid first, and the preparation technology of synthetic 5-hydroxy pyrimidine-2-carboxylic acid is provided.
(2) synthetic method provided by the invention is 2 step reactions, and yield is respectively 90%, 67%.In the method, reactions steps is few, yield is higher, easy amplification is produced.
Embodiment
By specific embodiment, technical scheme of the present invention is described below.Raw material and all commercially available obtaining of reagent used in the present invention.
Step 1,5-benzyloxy-2-cyanopyrimidine synthetic
Bromo-5-2-cyanopyrimidine (10g, 54mmol) and phenylcarbinol (17.5g, 162mmol) are dissolved in respectively in 100ml toluene, then add respectively cesium carbonate (35g, 108mmol), cuprous iodide (1g, 5.4mmol), 1, (cuprous iodide adding here and 1,10-phenanthroline are as catalyzer for 10-phenanthroline (2g, 11.34mmol), for minimum amount, its add-on be respectively the bromo-2-cyanopyrimidine of 5-10% and 20%).Stirring reaction is after 4 hours at 110 ℃ for reaction solution, and TLC detection reaction is complete.Reaction solution is cooled to room temperature (20-25 ℃), concentration of reaction solution, and column chromatography purification, obtains white solid 5-benzyloxy-2-cyanopyrimidine 10.3g, yield approximately 90%.
1H-NMR（400MHz，DMSO）δ（ppm）：8.79(s,2H)，7.45(d,J=7.1Hz,2H)，7.43-7.34(m,3H)，5.38(s,2H)。In this reactions steps, the product yield that the mol ratio of change reactant, temperature of reaction, reaction times obtain is listed in table 1.
Table 1, the transformation efficiency of synthetic 5-benzyloxy-2-cyanopyrimidine
Step 2,5-hydroxy pyrimidine-2-carboxylic acid synthetic
5-benzyloxy-2-cyanopyrimidine (5.6g, 26.2mmol) that abovementioned steps 1 is made is dissolved in 150ml water, adds potassium hydroxide (4.2g, 52.4mmol) (also can add other highly basic here, as sodium hydroxide etc.), back flow reaction is after 8 hours, and TLC detection reaction is complete.Reaction solution is cooled to after room temperature (20-25 ℃), with methylene dichloride 100ml washing 2 times, in order to remove unreacted raw material and by product in reaction solution, retains water.Then slowly add acid to regulate the pH value of reaction solution to reaction solution, in the time that pH value is acidity, have solid and separate out.Here preferably adopt the hydrochloric acid soln of 1N to regulate the pH value of reaction solution, in the time that reacting liquid pH value is 3-4, will separate out the solid product of maximum, after finally the solid filtering of separating out being dried, obtain white solid 5-hydroxy pyrimidine-2-carboxylic acid, yield is about 67%.
1H-NMR（400MHz，DMSO）δ（ppm）：12.35(s,1H)，8.46(s,2H)。In this reactions steps, the product yield that the mol ratio of change reactant, temperature of reaction, reaction times obtain is listed in table 2.
Table 2, the transformation efficiency of synthetic 5-hydroxy pyrimidine-2-carboxylic acid
The embodiment of the invention described above, is not limited to the present invention.To those skilled in the art, the synthetic method of product of the present invention can change.All in the spirit and principles in the present invention, that does is equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (9)
1. a synthetic method for 5-hydroxy pyrimidine-2-carboxylic acid, is characterized in that described synthetic method is:
Concrete synthesis step is:
Step 1, is dissolved in bromo-5-2-cyanopyrimidine and phenylcarbinol in toluene, adds cesium carbonate, cuprous iodide, 1, and 10-phenanthroline, in 80～110 ℃ of reactions, is cooled to room temperature after reacting completely, and obtains 5-benzyloxy-2-cyanopyrimidine after reaction solution is concentrated and purified;
Step 2,5-benzyloxy-2-cyanopyrimidine that abovementioned steps is obtained is soluble in water, add highly basic, in 25～100 ℃ of reactions, after reacting completely, be cooled to room temperature, then add acid to regulate its pH value to separate out for acidity makes product to reaction solution, after the solid filtering of separating out is dried, obtain 5-hydroxy pyrimidine-2-carboxylic acid.
2. the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid as claimed in claim 1, is characterized in that: in described step 1, the reaction times is 4～12 hours.
3. the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid as claimed in claim 1, is characterized in that: in described step 1, the mol ratio of the bromo-2-cyanopyrimidine of 5-and phenylcarbinol is 1:1.5～1:3.5.
4. the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid as claimed in claim 1, it is characterized in that: the cuprous iodide adding in described step 1 and 1,10-phenanthroline is catalyzer, its add-on is respectively: the mass ratio of the bromo-2-cyanopyrimidine of described cuprous iodide and 5-is not less than 10%, described 1, the mass ratio of the bromo-2-cyanopyrimidine of 10-phenanthroline and 5-is not less than 20%.
5. the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid as claimed in claim 1, is characterized in that: the cesium carbonate adding in described step 1 is reacting weight, the mol ratio of the bromo-2-cyanopyrimidine of described cesium carbonate and 5-is 1:1～3:1.
6. the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid as claimed in claim 1, is characterized in that: the highly basic adding in described step 2 is potassium hydroxide.
7. the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid as claimed in claim 6, is characterized in that: the mol ratio of described potassium hydroxide and 5-benzyloxy-2-cyanopyrimidine is 2:1～4:1.
8. the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid as claimed in claim 1, is characterized in that: in described step 2, reaction solution is cooled to after room temperature by washed with dichloromethane to remove unreacted raw material and by product, and then adds acid to regulate the pH value of reaction solution.
9. the synthetic method of 5-hydroxy pyrimidine-2-carboxylic acid as claimed in claim 1, is characterized in that: while adding acid to carry out the adjusting of pH value to reaction solution in described step 2, be 3～4 by adding 1N hydrochloric acid to regulate its pH value.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829712A (en) * | 2003-07-25 | 2006-09-06 | 辉瑞大药厂 | Nicotinamide derivatives useful as PDE4 inhibitors |
| CN102498103A (en) * | 2009-06-19 | 2012-06-13 | 阿斯利康(瑞典)有限公司 | Pyrazine carboxamides as inhibitors of DGAT1 |
| CN102639135A (en) * | 2009-10-08 | 2012-08-15 | 先灵公司 | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| WO2012162129A1 (en) * | 2011-05-20 | 2012-11-29 | Glaxosmithkline Llc | Novel compounds as diacylglycerol acyltransferase inhibitors |
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2014
- 2014-04-15 CN CN201410149113.8A patent/CN103880757B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829712A (en) * | 2003-07-25 | 2006-09-06 | 辉瑞大药厂 | Nicotinamide derivatives useful as PDE4 inhibitors |
| CN102498103A (en) * | 2009-06-19 | 2012-06-13 | 阿斯利康(瑞典)有限公司 | Pyrazine carboxamides as inhibitors of DGAT1 |
| CN102639135A (en) * | 2009-10-08 | 2012-08-15 | 先灵公司 | Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| WO2012162129A1 (en) * | 2011-05-20 | 2012-11-29 | Glaxosmithkline Llc | Novel compounds as diacylglycerol acyltransferase inhibitors |
Non-Patent Citations (4)
| Title |
|---|
| DEREK A. PRATT等: "5-Pyrimidinols: Novel Chain-Breaking Antioxidants More Effective than Phenols", 《J. AM. CHEM. SOC.》, vol. 123, 18 April 2001 (2001-04-18), XP009062480, DOI: doi:10.1021/ja005679l * |
| FREDRIK K. WALLNER等: "Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxyphenoxy) acetic acid as a linker in solid-phase synthesis monitored by gel-phase 19F NMR spectroscopy", 《ORGANIC & BIOMOLECULAR CHEMISTRY》, no. 5, 28 June 2007 (2007-06-28), pages 2465 * |
| SUSHEEL J. NARA等: "A Simple Cu-Catalyzed Coupling Approach to Substituted 3-Pyridinol and 5-Pyrimidinol Antioxidants", 《J. ORG. CHEM.》, vol. 73, 1 November 2008 (2008-11-01) * |
| 武钦佩等: "《保护基化学》", 30 April 2007, article "保护基化学", pages: 50-54 * |
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Address after: 200433 Room 101, block a, building 11, 128 Xiangyin Road, Yangpu District, Shanghai Patentee after: Shanghai bide Medical Technology Co.,Ltd. Address before: Room A50, building 031, 1076 Jungong Road, Yangpu District, Shanghai 200090 Patentee before: BIDE PHARMATECH Ltd. |
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