CN102633803A - Synthetic method of 5,7-dichloro pyrazole [1,5-a] pyrimidine - Google Patents
Synthetic method of 5,7-dichloro pyrazole [1,5-a] pyrimidine Download PDFInfo
- Publication number
- CN102633803A CN102633803A CN2012101339536A CN201210133953A CN102633803A CN 102633803 A CN102633803 A CN 102633803A CN 2012101339536 A CN2012101339536 A CN 2012101339536A CN 201210133953 A CN201210133953 A CN 201210133953A CN 102633803 A CN102633803 A CN 102633803A
- Authority
- CN
- China
- Prior art keywords
- pyrimidine
- pyrazolo
- dichloro
- pyrazole
- glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses a synthetic method of 5,7-dichloro pyrazole [1,5-a] pyrimidine. According to the synthetic method, 1H-pyrazole amine serves as a raw material and is processed by dimethyl malonate, alkali and methanol to obtain pyrazole [1,5-a] pyrimidine-5,7-glycol; the pyrazole [1,5-a] pyrimidine-5,7-glycol is subjected to reflow process by phosphorus oxychloride and triethylamine so as to be converted to the 5,7-dichloro pyrazole [1,5-a] pyrimidine; and during the purification, only the phosphorus oxychloride and the triethylamine need to be removed through decompression rotating evaporation, and obtained residues directly pass by a silicagel column to obtain a pure product of 5,7-dichloro pyrazole [1,5-a] pyrimidine. The preparation method has the advantages of simplicity in operation, short reaction period and high yield.
Description
Technical field
The present invention relates to a kind ofly 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine belongs to medicine, chemical technology field.
Background technology
5,7-dichloro pyrazolo [1,5-a] pyrimidine is a kind of faint yellow solid, is a kind of important medicinal intermediates.
Summary of the invention
The present invention is being under the prerequisite of raw material with 1H-pyrazoles amine, attempted two circuits after, finally confirmed the technology circuit of this patent.Two lines are at synthesizing pyrazole [1,5-a] pyrimidine-5 also, and method therefor all is to be raw material with 1H-pyrazoles amine in the process of 7-glycol; Resultant with ethyl malonate pass ring through the alkaline processing in methanol solution, different is: article one route is pyrazolo [1, a 5-a] pyrimidine-5; The 7-glycol refluxes resultant in sulfur oxychloride; This method byproduct of reaction is too many, and productive rate is not high, and the purifying difficulty is big.The second route is pyrazolo [1, a 5-a] pyrimidine-5, the 7-glycol gained that in POCl3, refluxes, and this method has only a product to generate, and the by product that only need remove reaction solvent and solvolysis generation gets final product.Through the comparison of two lines, finally selected the used route of this patent.
According to the invention 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine is that to adopt 1H-pyrazoles amine be initial raw material; In methyl alcohol, close ring through alkaline processing and ethyl malonate and obtain pyrazolo [1,5-a] pyrimidine-5, the 7-glycol is with resulting pyrazolo [1; 5-a] pyrimidine-5, the 7-glycol has obtained 5,7-dichloro pyrazolo [1 through the processing of POCl3 and triethylamine; 5-a] bullion of pyrimidine, 5,7-dichloro pyrazolo [1; 5-a] bullion of pyrimidine just can obtain through the silicagel column simple process flaxen 5, the pure article of 7-dichloro pyrazolo [1,5-a] pyrimidine.
Above-mentioned 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine is characterized in that: sodium methylate that described highly basic refers to.
Above-mentioned 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine is characterized in that: use POCl3 to replace sulfur oxychloride.
Above-mentioned 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine is characterized in that: said 5; The compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine makes: in the 5L there-necked flask, drop into 3500 ml methanol, 110 gram sodium are cut into small pieces to join in the methanol solution in batches, has a large amount of hydrogen to emit; And emit big calorimetric and make methanol eddy, connect a prolong, after the sodium piece adds; 1H-pyrazoles amine, ethyl malonate are added respectively in the methanol solution, and reflux is spent the night, and raw material reaction is complete.Cool to room temperature filters, and filter cake is soluble in water, about concentrated hydrochloric acid acid adjustment degree to 2, separates out solid, filters, and washes with 1 liter of ethanol again, and filtering drying gets pyrazolo [1,5-a] pyrimidine-5,7-glycol 280 grams.In the there-necked flask of 5L, drop into 280 gram pyrazolo [1,5-a] pyrimidines-5, the 7-glycol, 3000 milliliters of POCl3s, nitrogen protection drips 600 milliliters of triethylamines, and after the dropping fully, reflux reacts completely.Revolve steaming and spin off POCl3 and triethylamine, the silicagel column purifying obtains 5, pure article 227 grams of 7-dichloro pyrazolo [1,5-a] pyrimidine.
Above-mentioned with 1H-pyrazoles amine, ethyl malonate is that raw material synthesizes 5, and the chemical reaction and the reaction formula of 7-dichloro pyrazolo [1,5-a] pyrimidine are following:
(1) synthesizing pyrazole [1,5-a] pyrimidine-5 also, the reaction equation of 7-glycol is:
(2) reaction is accomplished, and the reaction equation of handling later and phosphorus oxychloride reaction is:
(3) react completely after, directly revolve to steam and spin off POCl3 and triethylamine 100-200 order silica gel is directly done appearance, sherwood oil ETHYLE ACETATE is that developping agent directly washes silicagel column and just can obtain 5, the pure article of 7-dichloro pyrazolo [1,5-a] pyrimidine.
Embodiment
Embodiment:
Said 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine makes: in the 5L there-necked flask, drop into 3500 ml methanol; 110 gram sodium are cut into small pieces and join in the methanol solution in batches, have a large amount of hydrogen to emit, and emit big calorimetric and make methanol eddy; Connect a prolong, after the sodium piece adds, add 200 gram 1H-pyrazoles amine, 636 gram ethyl malonates in the methanol solution respectively; Reflux is spent the night, and raw material reaction is complete.Cool to room temperature filters, and filter cake is dissolved in 6000 ml waters, about concentrated hydrochloric acid acid adjustment degree to 2, separates out solid; Filter, solid with 1000 milliliters washing is once washed filtration again with 1000 milliliters ethanol; Dry pyrazolo [1,5-a] pyrimidine-5,7-glycol 280 gram, productive rate is 76.76%.With 280 gram pyrazolo [1,5-a] pyrimidines-5 of gained, the 7-glycol is put in 3000 milliliters the there-necked flask, and mechanical stirring adds 1500 milliliters of POCl3s again, and nitrogen protection drips 300 milliliters of triethylamines, drip complete after, reflux reacts completely.Revolve steaming and spin off POCl3 and triethylamine, the silicagel column purifying obtains 5, and the pure article 227 gram productive rates of 7-dichloro pyrazolo [1,5-a] pyrimidine are 80.7%.
Claims (5)
1.5 the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine is that employing 1H-pyrazoles amine is raw material; In methyl alcohol, close ring and obtain pyrazolo [1,5-a] pyrimidine-5,7-glycol, pyrazolo [1 through alkaline processing and ethyl malonate; 5-a] pyrimidine-5, the 7-glycol just can obtain 5,7-dichloro pyrazolo [1 through the processing of POCl3 and triethylamine again; 5-a] pyrimidine, 5,7-dichloro pyrazolo [1; 5-a] pyrimidine bullion through silicagel column handle just can obtain flaxen 5, the pure article of 7-dichloro pyrazolo [1,5-a] pyrimidine.
2. as claimed in claim 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine is characterized in that: said new initial feed is meant that with 1H-pyrazoles amine be raw material.
3. as claimed in claim 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine, it is characterized in that: employed highly basic is sodium methylate.
4. as claimed in claim 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine; It is characterized in that: said 5, the compound method of 7-dichloro pyrazolo [1,5-a] pyrimidine makes: in the 5L there-necked flask, drop into 3500 ml methanol; 110 gram sodium are cut into small pieces and join in the methanol solution in batches, have a large amount of hydrogen to emit, and emit big calorimetric and make methanol eddy; Connect a prolong, after the sodium piece adds, add 1H-pyrazoles amine, ethyl malonate in the methanol solution respectively; Reflux is spent the night, and raw material reaction is complete.
5. cool to room temperature filters, and filter cake is soluble in water, about concentrated hydrochloric acid acid adjustment degree to 2, separates out solid; Filter, wash with 1 liter of ethanol, filtering drying gets pyrazolo [1,5-a] pyrimidine-5,7-glycol 280 grams; In the there-necked flask of 5L, drop into 280 grams 5,7-dichloro pyrazolo [1,5-a] pyrimidine, 3000 milliliters of POCl3s, nitrogen protection; Drip 600 milliliters of triethylamines, after the dropping fully, reflux reacts completely; Revolve steaming and spin off POCl3 and triethylamine, the silicagel column purifying obtains 5, pure article 227 grams of 7-dichloro pyrazolo [1,5-a] pyrimidine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101339536A CN102633803A (en) | 2012-05-03 | 2012-05-03 | Synthetic method of 5,7-dichloro pyrazole [1,5-a] pyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101339536A CN102633803A (en) | 2012-05-03 | 2012-05-03 | Synthetic method of 5,7-dichloro pyrazole [1,5-a] pyrimidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102633803A true CN102633803A (en) | 2012-08-15 |
Family
ID=46618396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101339536A Pending CN102633803A (en) | 2012-05-03 | 2012-05-03 | Synthetic method of 5,7-dichloro pyrazole [1,5-a] pyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102633803A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204855A (en) * | 2013-03-26 | 2013-07-17 | 内蒙古医科大学 | Compound I tetrazole (1, 5-a) pyrimidine-5, 7-diol and synthetic route thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1701073A (en) * | 2002-09-04 | 2005-11-23 | 先灵公司 | Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors |
| WO2007063934A1 (en) * | 2005-12-02 | 2007-06-07 | Mitsubishi Tanabe Pharma Corporation | Alicyclic heterocyclic compound |
| JP2009007342A (en) * | 2007-06-01 | 2009-01-15 | Mitsubishi Tanabe Pharma Corp | Medicinal composition |
| WO2012027240A1 (en) * | 2010-08-23 | 2012-03-01 | Schering Corporation | Fused tricyclic inhibitors of mammalian target of rapamycin |
| WO2012044562A2 (en) * | 2010-09-30 | 2012-04-05 | Merck Sharp & Dohme Corp. | Pyrazolopyrimidine pde10 inhibitors |
| WO2012047570A1 (en) * | 2010-09-28 | 2012-04-12 | Schering Corporation | Fused tricyclic inhibitors of mammalian target of rapamycin |
| WO2012047569A1 (en) * | 2010-09-28 | 2012-04-12 | Schering Corporation | Fused tricyclic inhibitors of mammalian target of rapamycin |
-
2012
- 2012-05-03 CN CN2012101339536A patent/CN102633803A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1701073A (en) * | 2002-09-04 | 2005-11-23 | 先灵公司 | Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors |
| WO2007063934A1 (en) * | 2005-12-02 | 2007-06-07 | Mitsubishi Tanabe Pharma Corporation | Alicyclic heterocyclic compound |
| JP2009007342A (en) * | 2007-06-01 | 2009-01-15 | Mitsubishi Tanabe Pharma Corp | Medicinal composition |
| WO2012027240A1 (en) * | 2010-08-23 | 2012-03-01 | Schering Corporation | Fused tricyclic inhibitors of mammalian target of rapamycin |
| WO2012047570A1 (en) * | 2010-09-28 | 2012-04-12 | Schering Corporation | Fused tricyclic inhibitors of mammalian target of rapamycin |
| WO2012047569A1 (en) * | 2010-09-28 | 2012-04-12 | Schering Corporation | Fused tricyclic inhibitors of mammalian target of rapamycin |
| WO2012044562A2 (en) * | 2010-09-30 | 2012-04-05 | Merck Sharp & Dohme Corp. | Pyrazolopyrimidine pde10 inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| TETSUJI SAITO，等: "Pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and their tricyclic derivatives as corticotropin-releasing factor 1 (CRF1) receptor antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 赵临襄: "《化学制药工艺学》", 31 January 2003, 中国医药科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204855A (en) * | 2013-03-26 | 2013-07-17 | 内蒙古医科大学 | Compound I tetrazole (1, 5-a) pyrimidine-5, 7-diol and synthetic route thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101993087A (en) | Method for preparing water glass by using fly ash | |
| CN103664912B (en) | A kind of synthesis technique of prucalopride | |
| CN101193866A (en) | Process for the synthesis of 5- (methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) -benzeneamine | |
| CN103923083A (en) | Adenine synthesis technology | |
| CN108358929A (en) | Refining method of tofacitinib citrate | |
| CN106146560B (en) | A kind of refining methd of high-purity phosphoric acid specially azoles amine | |
| CN102633803A (en) | Synthetic method of 5,7-dichloro pyrazole [1,5-a] pyrimidine | |
| CN103435651A (en) | Synthesis method and process of riboflavin sodium phosphate | |
| CN101560210B (en) | Method for synthesizing diprophylline | |
| CN103664952A (en) | Preparation method of zopiclone | |
| CN102786543A (en) | Preparation methods for imidazole[1,2-a]pyridine-6-boric acid pinacol ester and derivatives thereof | |
| CN102786541A (en) | Preparation method and application of potassium (iso)quinoline thifluoroborate | |
| CN103992238B (en) | The preparation method of 3-aminosallcylic acid | |
| CN108033962B (en) | A method of synthesis (6S) -5-methyltetrahydrofolate salt | |
| CN103408495B (en) | The synthesis technique of phentolamine mesilate | |
| CN104004044A (en) | Highly pure fluticasone propionate preparation method | |
| CN102001973A (en) | Method for preparing and refining 1,3-propanedisulfonate | |
| CN105237529A (en) | Refining method for high-purity anhydrous dasatinib | |
| CN101830938B (en) | Preparation method of N-acetyl-D-glucosamine | |
| CN104447468A (en) | Deep processing method of lutein extract | |
| CN105601545B (en) | A kind of synthetic method of sulphoamidine | |
| CN103012100B (en) | The purification process of tetradecylic acid | |
| CN105294620A (en) | Synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid | |
| CN103113441A (en) | Method for preparing capecitabine | |
| CN105669539A (en) | Preparation method of 2-amino-3-fluoropyridine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120815 |