CN103073549A - 3-bromopyrazol[1,5-alpha]pyrimidine-2-formic acid synthesis process - Google Patents
3-bromopyrazol[1,5-alpha]pyrimidine-2-formic acid synthesis process Download PDFInfo
- Publication number
- CN103073549A CN103073549A CN2012103280946A CN201210328094A CN103073549A CN 103073549 A CN103073549 A CN 103073549A CN 2012103280946 A CN2012103280946 A CN 2012103280946A CN 201210328094 A CN201210328094 A CN 201210328094A CN 103073549 A CN103073549 A CN 103073549A
- Authority
- CN
- China
- Prior art keywords
- pyrimidine
- reaction
- alpha
- formic acid
- bromopyrazol
- 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.)
- Withdrawn
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to 3-bromopyrazol[1,5-alpha]pyrimidine-2-formic acid synthesis process, which is characterized in that ethyl 5-amino-1H-pyrazole-3-carboxylate is adopted as a raw material, and is subjected to condensation with 1,1,3,3-tetramethoxypropane to obtain pyrazol[1,5-alpha]pyrimidine-2-acid ethyl ester, the pyrazol[1,5-alpha]pyrimidine-2-acid ethyl ester reacts with NBS to obtain 3-bromopyrazol[1,5-alpha]pyrimidine-2-acid ethyl ester, and the 3-bromopyrazol[1,5-alpha]pyrimidine-2-acid ethyl ester is subjected to hydrolysis in a sodium hydroxide aqueous solution to obtain the 3-bromopyrazol[1,5-alpha]pyrimidine-2-formic acid. The synthesis process has characteristics of simple synthesis route, reasonable process selection, low raw material cost, easily available raw materials, simple operation and post-treatment, high total yield, no use of highly toxic reagents, easy amplification and capability of large scale production. With the synthesis process, disadvantages of expensive and difficultly-obtained raw materials, low yield, requirement of a microwave condition, complex operation, difficult operation, difficult amplification and the like in the processes in the existing literature are solved.
Description
Technical field
The present invention relates to the method for practical synthesizing of a kind of 3-bromine pyrazoline [1,5-α] pyrimidine-2-formic acid.
Background technology
3-bromine pyrazoline [1,5-α] pyrimidine-2-formic acid is synthetic 3-bromine pyrazoline [1,5-α] key intermediate of pyrimidine-2-amine, then it can remove uncle's Boc(oxygen carbonyl through acid treatment with diphenyl phosphate azide (DPPA) reaction in the presence of triethylamine) and generate 3-bromine pyrazoline [1,5-α] pyrimidine-2-amine.By 3-bromine pyrazoline [1,5-α] amino and the various carboxylic acid coupling of pyrimidine-2-amine can generate various acid amides, and these acid amides have very high potassium ion conciliation activity, can reconcile potassium ion by quantity and the speed (US2012122888A1) of cytolemma.And be positioned at 3 bromine atoms, it also is a highly active reaction site, can react with some fragments or transition metal-catalyzed linked reaction such as the Buchwald-Hartwig of intermediate generation, the Heck reaction, the Sonogashira reaction, thereby Still reaction and Suzuki reaction reach prolongation carbochain, the purposes such as structural modification.Just because of 3-bromine pyrazoline [1,5-α] pyrimidine-2-amine has so superior modified characteristic, it has caused widely in organic synthesis circle especially pharmaceutical chemistry circle pays close attention to.From 3-bromine pyrazoline [1,5-α] pyrimidine-2-amine sets out, synthetic molecule with ad hoc structure, then modify by this molecular structures and carry out the SAR(structure activity relationship) research with its research and development that obtains efficient drug candidate molecule also just orderly expansion, also obtained very important achievement (US2012122888A1).
Present 3-bromine pyrazoline [1,5-α] synthetic method of pyrimidine-2-formic acid is that 3-amino-4-bromine pyrazoles-5-carboxylicesters and 3-dimethylamino acrolein generate 3-bromine pyrazoline [1 by condensation reaction under microwave, 5-α] ester of pyrimidine-2-acid, and then it is sour to obtain 3-bromine pyrazoline [1,5-α] pyrimidine-2-by hydrolysis.There is following problem in the method: (1) raw material 3-amino-4-bromine pyrazoles-5-carboxylicesters is the reagent of a non-commercialization, and it is long to prepare this raw material synthetic route, and cost is high; (2) this condensation reaction need to be carried out under microwave condition, can not fairly largely produce; (3) this process recovery ratio is lower, generally only has about 45%.
Summary of the invention
In order to overcome the shortcoming of existing synthetic method, the object of the present invention is to provide the synthesis technique of 3-bromine pyrazoline [1,5-α] pyrimidine-2-formic acid.
Reaction principle is: 5-amino-pyrazoles-3-ethyl formate is that the raw material process is with 1,1,3, the condensation of 3-tetramethoxy propane obtains pyrazoline [1,5-α] pyrimidine-2-acetoacetic ester, and the NBS reaction obtains 3-bromine pyrazoline [1,5-α] pyrimidine-2-acetoacetic ester, hydrolysis obtains 3-bromine pyrazoline [1,5-α] pyrimidine-2-acid in aqueous sodium hydroxide solution at last.
Reaction formula is as follows:
Concrete technology is:
Step (1) is condensation reaction, and reactant is 5-amino-pyrazoles-3-ethyl formate and 1,1,3, and 3-tetramethoxy propane (both equimolar ratios), reaction solvent are 2M hydrochloric acid, and temperature of reaction is 70 ℃, 10 minutes reaction times;
Step (2) is the bromo-reaction of aromatic heterocycle, and agents useful for same is N-bromo-succinimide (NBS), and reaction solvent is DMF, and the reaction times is stirred overnight at room temperature; Pyrazoline [1,5-α] pyrimidine-2-ethyl formate and NBS equimolar ratio;
Step (3) is the hydrolysis of ester, and reaction soln is MeOH and 2M aqueous solution of sodium oxide equal-volume mixed-shaped resulting mixture, and temperature of reaction is room temperature, and the reaction times is for spending the night.
Beneficial effect: the invention provides a kind of 3-bromine pyrazoline [1 take 5-amino-pyrazoles-3-ethyl formate as raw material, 5-α] synthetic method of pyrimidine-2-formic acid, route is succinct, technique is reasonable, raw material be simple and easy to, cost is low, operation and convenient post-treatment, total recovery is high, do not use poisonous reagent, be easy to amplify, can be used for scale operation.It is low to have solved the expensive rare yield of existing document technique Raw, needs microwave condition, complicated operation, and the aftertreatment difficulty is difficult for the shortcomings such as amplification.
Embodiment
All raw materials all reach auspicious fine chemicals company limited available from Shanghai.
Embodiment
The first step: pyrazoline [1,5-α] pyrimidine-2-ethyl formate synthetic
With 1, Isosorbide-5-Nitrae, 4-tetramethoxy propane (10.5g, 64.5mmol) join in the 2M aqueous hydrochloric acid (120mL) of 5-amino-pyrazoles-3-ethyl formate (10g, 64.5mmol) under 70 ℃, mixture cooling after stirring 10 minutes under this temperature.Add saturated sodium bicarbonate aqueous solution solution ethyl acetate extraction to the pH=8, organic phase is spin-dried for after with anhydrous sodium sulfate drying, and residue obtains pyrazoline [1,5-α] pyrimidine-2-ethyl formate (4.4g, 34%) behind column chromatography.
1HNMR(400MHz,CDCl
3):1.45(t,3H),4.50(m,2H),6.95(m,1H),7.25(s,12H),8.57(m,1H),8.76(m,1H)。
Second step: 3-bromine pyrazoline [1,5-α] pyrimidine-2-ethyl formate synthetic
With pyrazoline [1,5-α] pyrimidine-2-ethyl formate (1g, 5.24mmol), NBS(0.93g, 5.24mmol) and the mixed solution of DMF (10mL) at room temperature stir and spend the night, mixture is filtered after adding large water gaging, obtain 3-bromine pyrazoline [1 behind the gained solid drying, 5-α] pyrimidine-2-ethyl formate (1.2g, 88%).
1HNMR(400MHz,CDCl
3):1.50(t,3H),4.55(m,2H),7.05(t,1H),8.68(m,1H),8.76(m,1H)。
The 3rd step: 3-bromine pyrazoline [1,5-α] pyrimidine-2-formic acid synthetic
3-bromine pyrazoline [1,5-α] pyrimidine-2-ethyl formate (10g, 37.2mmol) is dissolved in the mixed solvent of MeOH (200mL) and 2M aqueous sodium hydroxide solution (200mL) and with the mixed solution stirred overnight at room temperature.1M hydrochloric acid is added to solution is after the acidity mixture is filtered, obtain 3-bromine pyrazoline [1,5-α] pyrimidine-2-formic acid (7.2g, 80%) behind the gained solid drying
1HNMR (400MHz, DMSO-d
6): 7.29 (m, 1H), 8.73 (m, 1H), 9.22 (m, 1H), 12.52 (s, 1H).
Claims (4)
1.3-the synthesis technique of bromine pyrazoline [1,5-α] pyrimidine-2-formic acid is characterized in that reaction formula is as follows:
2. according to claim 11,3-bromine pyrazoline [1,5-α] synthesis technique of pyrimidine-2-formic acid, it is characterized in that step (1) is condensation reaction, reactant is 5-amino-pyrazoles-3-ethyl formate and 1,1,3, the 3-tetramethoxy propane, reaction solvent is 2M hydrochloric acid, and temperature of reaction is 70 ℃, 10 minutes reaction times.
3. according to claim 11,3-bromine pyrazoline [1,5-α] synthesis technique of pyrimidine-2-formic acid, it is characterized in that step (2) is the bromo-reaction of aromatic heterocycle, agents useful for same is the N-bromo-succinimide, reaction solvent is DMF, and the reaction times is stirred overnight at room temperature.
4. the synthesis technique of according to claim 11,3-bromine pyrazoline [1,5-α] pyrimidine-2-formic acid is characterized in that step (3) is the hydrolysis reaction of ester, and reaction soln is the 2M aqueous sodium hydroxide solution, and temperature of reaction is room temperature, and the reaction times is for spending the night.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103280946A CN103073549A (en) | 2012-09-07 | 2012-09-07 | 3-bromopyrazol[1,5-alpha]pyrimidine-2-formic acid synthesis process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103280946A CN103073549A (en) | 2012-09-07 | 2012-09-07 | 3-bromopyrazol[1,5-alpha]pyrimidine-2-formic acid synthesis process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103073549A true CN103073549A (en) | 2013-05-01 |
Family
ID=48150268
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012103280946A Withdrawn CN103073549A (en) | 2012-09-07 | 2012-09-07 | 3-bromopyrazol[1,5-alpha]pyrimidine-2-formic acid synthesis process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103073549A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586464A (en) * | 2018-04-12 | 2018-09-28 | 苏州康润医药有限公司 | A kind of synthetic method of 3- bromines pyrazolo [1,5- α] pyrimidine -6- formic acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101316847A (en) * | 2005-10-06 | 2008-12-03 | 先灵公司 | Pyrazolo(1, 5A) pyrimidines as protein kinase inhibitors |
| CN101932583A (en) * | 2007-12-19 | 2010-12-29 | 沃泰克斯药物股份有限公司 | Pyrazolo [1,5-a] pyrimidines useful as jak2 inhibitors |
| WO2011003065A2 (en) * | 2009-07-02 | 2011-01-06 | Genentech, Inc. | Pyrazolopyrimidine jak inhibitor compounds and methods |
| US20120122888A1 (en) * | 2010-11-16 | 2012-05-17 | Abbott Laboratories | Potassium Channel Modulators |
-
2012
- 2012-09-07 CN CN2012103280946A patent/CN103073549A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101316847A (en) * | 2005-10-06 | 2008-12-03 | 先灵公司 | Pyrazolo(1, 5A) pyrimidines as protein kinase inhibitors |
| CN101932583A (en) * | 2007-12-19 | 2010-12-29 | 沃泰克斯药物股份有限公司 | Pyrazolo [1,5-a] pyrimidines useful as jak2 inhibitors |
| WO2011003065A2 (en) * | 2009-07-02 | 2011-01-06 | Genentech, Inc. | Pyrazolopyrimidine jak inhibitor compounds and methods |
| US20120122888A1 (en) * | 2010-11-16 | 2012-05-17 | Abbott Laboratories | Potassium Channel Modulators |
Non-Patent Citations (3)
| Title |
|---|
| A. MAQUESTIAU 等: "Preparation and characterization of pyrazolo[1,5-a]pyrimidines", 《BULLETIN DES SOCIETES CHIMIQUES BELGES》, vol. 101, no. 2, 31 December 1992 (1992-12-31) * |
| ALEXANDRE V. IVACHTCHENKO 等: "Synthesis and SAR of 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines as potent serotonin 5-HT6 receptor antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 19, no. 4, 5 January 2011 (2011-01-05) * |
| 邢其毅 等: "《基础有机化学（第三版）》", 30 June 2005, article "第14章 羧酸衍生物", pages: 605-606 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108586464A (en) * | 2018-04-12 | 2018-09-28 | 苏州康润医药有限公司 | A kind of synthetic method of 3- bromines pyrazolo [1,5- α] pyrimidine -6- formic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108424388A (en) | A kind of preparation method of chronic anaemia drug | |
| CN103724329A (en) | Preparation method of 4-[5-(pyridyl-4-yl)-1H-[1,2,4]triazolyl-3-yl]pyridyl-2-formonitrile | |
| Shi et al. | General rhodium-catalyzed oxidative cross-coupling reactions between anilines: synthesis of unsymmetrical 2, 2′-diaminobiaryls | |
| CN104447547A (en) | Synthesis method of 4-aminoisoquinoline-8-methyl formate | |
| CN102775358B (en) | Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide | |
| CN103965191A (en) | Synthesis method of 6-bromoimidazo[1,2-alpha]pyridyl-3-formic acid | |
| CN103626697B (en) | A kind of preparation method of the cyanopyridine of 2 chlorine, 4 trifluoromethyl 3 | |
| CN103073549A (en) | 3-bromopyrazol[1,5-alpha]pyrimidine-2-formic acid synthesis process | |
| CN107233344B (en) | Preparation method of antitumor drug ibrutinib | |
| CN109553532B (en) | Preparation method of 4-bromoacetyl-2-methyl benzoic acid methyl ester | |
| CN102464661A (en) | Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester | |
| CN103965190A (en) | Synthesis method of imidazo[1,2-alpha]pyridyl-3-formic acid | |
| CN108558758A (en) | A kind of synthetic method of 4- fluorine isoquinolin -5- amine | |
| CN107935996A (en) | A kind of 3,4 dihydro-pyrimidin 2 (1H) (sulphur) ketone compounds and preparation method thereof | |
| CN105237337B (en) | The synthetic method of new 5 [10 (9 carboxyl anthryl)] M-phthalic acid | |
| CN103058921A (en) | Synthesis method of 3-bromo-6-chloropyridyl-2-formic acid | |
| CN104447543A (en) | 3-amino-7,8-difluoroquinoline and synthesis method of intermediate body of 3-amino-7,8-difluoroquinoline | |
| CN103864786A (en) | Method for synthesizing 6-fluoroimidazo-[1,2-a]-pyridine-3-formic acid | |
| CN106008336A (en) | Preparation method of 4-chloro-6,7-dimethoxyquinoline | |
| CN101921235A (en) | Preparation method of telmisartan | |
| CN104163798A (en) | Synthesis method of 3-amino-8-trifluoromethyl quinoline | |
| CN102887858B (en) | Method for synthesizing 3-chloro-5-amino-1H-pyrazolyl-4-ethyl formate | |
| CA2612419C (en) | Process for preparing benzimidazole compounds | |
| CN110372600A (en) | A kind of synthetic method of the chloro- 4- cyanopyrimidine of 2- | |
| CN104876917B (en) | The synthetic method of triazolone as fatty acid sythetase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C04 | Withdrawal of patent application after publication (patent law 2001) | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20130501 |