CN102399196A - Synthesizing method of 4,6-dihydroxy-2-methylpyrimidine - Google Patents
Synthesizing method of 4,6-dihydroxy-2-methylpyrimidine Download PDFInfo
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- CN102399196A CN102399196A CN2011103715144A CN201110371514A CN102399196A CN 102399196 A CN102399196 A CN 102399196A CN 2011103715144 A CN2011103715144 A CN 2011103715144A CN 201110371514 A CN201110371514 A CN 201110371514A CN 102399196 A CN102399196 A CN 102399196A
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Abstract
The invention discloses a synthesizing method of 4,6-dihydroxy-2-methylpyrimidine. The method comprises the following steps of adding sodium methoxide, dimethyl malonate and acetamidine hydrochloride in methanol under an ice-bath condition; removing the ice-bath; heating the mixture to 18-25 DEG C; reacting the mixture for 3-5 hours, distilling the reactant in reduced pressure to remove the methanol; adding water to dissolve the reactant; adjusting the PH value of the reactant to 1-2; and agitating the reactant at a temperature of 0 DEG C and devitrifying the reactant for 3-5 hours; filtering, washing and drying the product, obtaining white solid 4,6-dihydroxy-2-methylpyrimidine. In the invention, triphosgene is adopted to replace reagents such as POC13, phosgene and the like severely polluting the environment and with high toxicity, so that the synthesizing method provided by the invention is safe and easy to operate, the synthesizing process is simple and the synthesizing method is applicable to industrialization production.
Description
Technical field
The present invention relates to the medicine intermediate field, relate in particular to a kind of 4, the compound method of 6-dihydroxyl-2-methylpyrimidine.
Background technology
4,6-dihydroxyl-2-methylpyrimidine is the important intermediate of cancer therapy drug Dasatinib, and Dasatinib is the medicine that first approval is used for previously treating adult's stage chronic myeloid leukemia of failing or not tolerating.In the prior art, 4, the compound method of 6-dihydroxyl-2-methylpyrimidine has multiple, but the reagent environmental pollution of selecting for use is serious, and toxicity is bigger, and synthesis route is all complicated, is not suitable for suitability for industrialized production.
Summary of the invention
In order to overcome above-mentioned deficiency, technical problem to be solved provides a kind of safety, technology and simply is fit to 4 of suitability for industrialized production, the compound method of 6-dihydroxyl-2-methylpyrimidine just in the present invention.
For solving the problems of the technologies described above, the technical scheme that the present invention adopted is following:
A kind of 4, the compound method of 6-dihydroxyl-2-methylpyrimidine, it comprises the steps:
In reactor drum, add methyl alcohol, under condition of ice bath, add sodium methylate while stirring; Treat to add methyl-malonate and B amidine hydrochloric acid salt after its dissolving finishes, remove ice bath then and be warming up to 18～25 ℃ of reaction 3～5h, methyl alcohol is removed in underpressure distillation; Add water dissolution, regulate pH value to 1～2, stirring and crystallizing 3～5h under 0 ℃ of condition; Suction filtration, washing, drying obtain white solid 4,6-dihydroxyl-2-methylpyrimidine;
Reaction formula is as follows:
Described washing methods is to wash through mixture of ice and water earlier, washs under 0～5 ℃ of condition through ice methyl alcohol then.
The volume of said methyl alcohol and the mass ratio of methyl-malonate are: 10～12: 1, and ml/g.
The mol ratio of said sodium methylate and methyl-malonate is: 2.5～4.5: 1, and mol/mol.
The mol ratio of said methyl-malonate and B amidine hydrochloric acid salt is 1: 1～2, mol/mol.
Beneficial effect: of the present invention 4, the compound method of 6-dihydroxyl-2-methylpyrimidine adopts TRIPHOSGENE 99.5 to replace environmental pollutions such as POCl3, phosgene serious, the reagent that toxicity is big, and safety is easy to operate, and synthesis technique is simple, is fit to suitability for industrialized production.
Embodiment
Embodiment 1
In the 500ml there-necked flask, add methyl alcohol 150ml, under condition of ice bath, add sodium methylate 18.4g (0.34mol) while stirring; Treat to add methyl-malonate 13.2g (0.1mol) and B amidine hydrochloric acid salt 9.45g (0.1mol) after its dissolving finishes, remove ice bath then and be warming up to 18～25 ℃ of reaction 4h, solution is creamy white; Methyl alcohol (30～35 ℃) was removed in underpressure distillation after reaction finished, and added the 50mL water dissolution then, regulated pH to 1～2 with the Hydrogen chloride of 4mol/L; This moment, the adularescent solid was separated out stirring and crystallizing 4h under 0 ℃ of condition, suction filtration; Pass through frozen water, 0～5 ℃ ice methanol wash successively, drying obtains white solid 4; 6-dihydroxyl-2-methylpyrimidine 10.8g, yield is 86%.
Embodiment 2
In the 3L there-necked flask, add methyl alcohol 1060ml, under condition of ice bath, add sodium methylate 108.2g (2mol) while stirring; Treat to add methyl-malonate 105.6g (0.8mol) and B amidine hydrochloric acid salt 113.4g (1.2mol) after its dissolving finishes, remove ice bath then and be warming up to 18～25 ℃ of reaction 5h, solution is creamy white; Methyl alcohol (30～35 ℃) was removed in underpressure distillation after reaction finished, and added the 400mL water dissolution then, regulated pH to 1～2 with the Hydrogen chloride of 4mol/L; This moment, the adularescent solid was separated out stirring and crystallizing 4h under 0 ℃ of condition, suction filtration; Pass through frozen water, 0～5 ℃ ice methanol wash successively, drying obtains white solid 4; 6-dihydroxyl-2-methylpyrimidine 86g, yield is 87%.
Embodiment 3
In the 10L there-necked flask, add methyl alcohol 3960ml, under condition of ice bath, add sodium methylate 608.8g (11.25mol) while stirring; Treat to add methyl-malonate 330g (2.5mol) and B amidine hydrochloric acid salt 472.5g (5mol) after its dissolving finishes, remove ice bath then and be warming up to 18～25 ℃ of reaction 5h, solution is creamy white; Methyl alcohol (30～35 ℃) was removed in underpressure distillation after reaction finished, and added the 50mL water dissolution then, regulated pH to 1～2 with the Hydrogen chloride of 4mol/L; This moment, the adularescent solid was separated out stirring and crystallizing 5h under 0 ℃ of condition, suction filtration; Pass through frozen water, 0～5 ℃ ice methanol wash successively, drying obtains white solid 4; 6-dihydroxyl-2-methylpyrimidine 250g, yield is 86%.
The foregoing description does not limit the present invention in any way, and every employing is equal to the technical scheme that replacement or the mode of equivalent transformation obtain and all drops in protection scope of the present invention.
Claims (5)
1. one kind 4, the compound method of 6-dihydroxyl-2-methylpyrimidine is characterized in that it comprises the steps:
In reactor drum, add methyl alcohol, under condition of ice bath, add sodium methylate while stirring; Treat to add methyl-malonate and B amidine hydrochloric acid salt after its dissolving finishes, remove ice bath then and be warming up to 18～25 ℃ of reaction 3～5h, methyl alcohol is removed in underpressure distillation; Add water dissolution, regulate pH value to 1～2, stirring and crystallizing 3～5h under 0 ℃ of condition; Suction filtration, washing, drying obtain white solid 4,6-dihydroxyl-2-methylpyrimidine;
Reaction formula is as follows:
2. according to claim 1 a kind of 4, the compound method of 6-dihydroxyl-2-methylpyrimidine is characterized in that: described washing methods, washs under 0～5 ℃ of condition through ice methyl alcohol through the mixture of ice and water washing for earlier then.
3. according to claim 1 a kind of 4, the compound method of 6-dihydroxyl-2-methylpyrimidine is characterized in that: the volume of said methyl alcohol and the mass ratio of methyl-malonate are: 10～12: 1, and ml/g.
4. according to claim 1 a kind of 4, the compound method of 6-dihydroxyl-2-methylpyrimidine is characterized in that: the mol ratio of said sodium methylate and methyl-malonate is: 2.5～4.5: 1, and mol/mol.
5. according to claim 1 a kind of 4, the compound method of 6-dihydroxyl-2-methylpyrimidine is characterized in that: the mol ratio of said methyl-malonate and B amidine hydrochloric acid salt is 1: 1～2, mol/mol.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011103715144A CN102399196A (en) | 2011-11-22 | 2011-11-22 | Synthesizing method of 4,6-dihydroxy-2-methylpyrimidine |
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| CN2011103715144A CN102399196A (en) | 2011-11-22 | 2011-11-22 | Synthesizing method of 4,6-dihydroxy-2-methylpyrimidine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675215A (en) * | 2012-05-17 | 2012-09-19 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis method of ethyl 2-methylpyrimidyl-4-carboxylate |
| CN110642788A (en) * | 2019-10-24 | 2020-01-03 | 广州大学 | Preparation method of 5-bromo-2-substituted pyrimidine compound |
-
2011
- 2011-11-22 CN CN2011103715144A patent/CN102399196A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| JULIEN FARARD ET AL.: "A convenient synthesis of 5-arylamino-4H-pyran-4-ones using palladium-catalyzed amination", 《TETRAHEDRON LETTERS》 * |
| R.S.PATIL ET AL.: "Process chemistry of 4,6-dihydroxy-2-methylpyrimidine-A potential precursor in pharmaceutical and explosive industries", 《ORGANIC CHEMSTRY:AN INDIAN JOURNAL》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675215A (en) * | 2012-05-17 | 2012-09-19 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis method of ethyl 2-methylpyrimidyl-4-carboxylate |
| CN110642788A (en) * | 2019-10-24 | 2020-01-03 | 广州大学 | Preparation method of 5-bromo-2-substituted pyrimidine compound |
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Application publication date: 20120404 |