CN102731412A - Synthetic method of 2,4-dichloro-5-pyrimidine formaldehyde - Google Patents
Synthetic method of 2,4-dichloro-5-pyrimidine formaldehyde Download PDFInfo
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- CN102731412A CN102731412A CN2012101938674A CN201210193867A CN102731412A CN 102731412 A CN102731412 A CN 102731412A CN 2012101938674 A CN2012101938674 A CN 2012101938674A CN 201210193867 A CN201210193867 A CN 201210193867A CN 102731412 A CN102731412 A CN 102731412A
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Abstract
The invention discloses a synthetic method of 2,4-dichloro-5-pyrimidine formaldehyde, characterized by using uracil as an initial raw material based on existing technology, processing uracil by using barium hydroxide and formaldehyde to obtain 5-hydroxymethyl uracil, oxidizing 5-hydroxymethyl uracil with manganese dioxide in a chloroform solvent to obtain 2,4-dihydroxy-5-pyrimidine formaldehyde, and letting 2,4-dihydroxy-5-pyrimidine formaldehyde reflux in phosphorous oxychloride to obtain 2,4-dichloro-5-pyrimidine formaldehyde. According to the invention, the rigorous conditions of waterless, nitrogen protection, etc. of the reaction are reduced, and the yield of 2,4-dichloro-5-pyrimidine formaldehyde is raised.
Description
Technical field
The present invention relates to a kind ofly 2, the synthesis technology of 4-two chloro-5-pyrimidine formaldehyde improves, and belongs to medicine, chemical technology field.
Background technology
2,4-two chloro-5-pyrimidine formaldehyde are a kind of white solid liquid, are a kind of important medicinal intermediates.
Have 2 now, the synthesis technique of 4-two chloro-5-pyrimidine formaldehyde is to adopt with 5-bromo-2, and the 4-dichloro pyrimidine is a raw material, handles through isopropylmagnesium chloride, and then with N, the dinethylformamide reaction is resulting.Yet there are following 2 deficiencies in above-mentioned technology, and first reaction yield is very low to be had only about 0.5%, scarcely ever to 2,4-two chloro-5-pyrimidine formaldehyde, its two be the reaction require anhydrous, the exacting terms of nitrogen protection.Given this, be necessary prior art is improved, to overcome the deficiency that it exists.
Summary of the invention
Not enough to prior art; The present invention is that the new starting raw material of employing is a raw material, and raw material obtains 5-hydroxylmethyluracil through the processing of hydrated barta and formaldehyde, and 5-hydroxylmethyluracil obtains 2 through peroxo-in chloroform solvent; 4-dihydroxyl-5-pyrimidine formaldehyde; 2,4-dihydroxyl-5-pyrimidine formaldehyde refluxes in POCl3 and obtains 2,4-two chloro-5-pyrimidine formaldehyde.Adopt this technology, not only reduced the anhydrous of reaction, severe condition such as nitrogen protection, and improved 2, the yield of 4-two chloro-5-pyrimidine formaldehyde.
According to the invention 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde is that to adopt uridylic be starting raw material, uridylic is joined in the water that contains hydrated barta, adds 37% formaldehyde solution; Reflux and make the uridylic dissolving half a hour, stirred overnight at room temperature, the feeding dioxide gas makes hydrated barta change into barium carbonate sediment and comes out filtration, water evaporate to dryness; Obtain viscous material, 70% alcohol reflux two hours is placed in the refrigerator the purified of 4 hours adularescents, and 5-hydroxylmethyluracil is separated out; With what obtain, 5-hydroxylmethyluracil joins in the chloroform that contains oxygenant and refluxed 10 hours, filtered while hot, and Manganse Dioxide boils with chloroform; Filtered while hot, organic phase merge to revolve and driedly obtain 2,4-dihydroxyl-5-pyrimidine formaldehyde, 2; 4-dihydroxyl-5-pyrimidine formaldehyde refluxed in POCl3 5 hours, spun off the POCl3 about half, residue was poured in the frozen water into ethyl acetate extraction; Revolve driedly, cross post, obtain 2 of purified white, 4-two chloro-5-pyrimidine formaldehyde.
Above-mentioned 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde is characterized in that: described starting raw material is to be starting raw material with the uridylic.
Above-mentioned 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde, it is characterized in that: described oxygenant refers to Manganse Dioxide.
Above-mentioned 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde is characterized in that: said 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde makes: get uridylic 25 grams; Join in 400 ml waters that contain 15 gram barium hydroxides, the formaldehyde solution of 4 milliliter 37% of Dropwise 5 then, magnetic agitation refluxed half a hour is with the urine-soluble pyrimidine; Room temperature condition reaction down spends the night, and the feeding dioxide gas makes hydrated barta change into barium carbonate sediment and comes out filtration, water evaporate to dryness; Obtain viscous material, 250 milliliter 70% alcohol reflux two hours is placed in the refrigerator the purified of 4 hours adularescents, and 5-hydroxylmethyluracil is separated out; Filter, oven dry obtains 23 grams, and productive rate is 73%.23 gram 5-methylols urine are phonetic to join in 400 milliliters the chloroform, adds 100 gram Manganse Dioxide, reflux 10 hours; Filtered while hot, filter cake refluxes half a hour filtered while hot again with 200 milliliters of chloroforms; Again repetitive operation once, combined chloroform revolves dried; Obtain 2, bullion 14 grams of 4-dihydroxyl-5-pyrimidine formaldehyde.14 grams 2,4-dihydroxyl-5-pyrimidine formaldehyde joins in 100 milliliters of POCl3s, refluxes 5 hours, spins off the POCl3 about 50 milliliters; Resistates is poured in the 200 gram frozen water into 100 milliliters of ethyl acetate extractions 3 times, combined ethyl acetate; Anhydrous sodium sulfate drying filters, and revolves dried; Cross post, obtain 2 of purified white, 4-two chloro-5-pyrimidine formaldehyde 8.3 grams.
Above-mentioned is the raw material Synthetic 2 with the uridylic, and the chemical reaction and the reaction formula of 4-two chloro-5-pyrimidine formaldehyde are following:
(1) reaction equation of synthetic 5-hydroxylmethyluracil is:
(2) reaction is accomplished, and purifying reaction equation later and Manganse Dioxide is:
(3) reaction is accomplished, and the change reaction equation of bullion and POCl3 is:
(4) after reaction is accomplished, cross column purification obtain purified 2,4-two chloro-5-pyrimidine formaldehyde.
Embodiment
Embodiment:
Said 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde makes: get uridylic 25 grams, join in 400 ml waters that contain 15 gram barium hydroxides, then the formaldehyde solution of 4 milliliter 37% of Dropwise 5; Magnetic agitation refluxed half a hour, with the urine-soluble pyrimidine, room temperature condition reaction down spends the night, and feeds dioxide gas and makes hydrated barta change into barium carbonate sediment to come out; Filter, the water evaporate to dryness obtains viscous material; 250 milliliter 70% alcohol reflux two hours is placed in the refrigerator the purified of 4 hours adularescents, and 5-hydroxylmethyluracil is separated out; Filter, oven dry obtains 23 grams, and productive rate is 73%.23 gram 5-methylols urine are phonetic to join in 400 milliliters the chloroform, adds 100 gram Manganse Dioxide, reflux 10 hours; Filtered while hot, filter cake refluxes half a hour filtered while hot again with 200 milliliters of chloroforms; Again repetitive operation once, combined chloroform revolves dried; Obtain 2, bullion 14 grams of 4-dihydroxyl-5-pyrimidine formaldehyde.14 grams 2,4-dihydroxyl-5-pyrimidine formaldehyde joins in 100 milliliters of POCl3s, refluxes 5 hours, spins off the POCl3 about 50 milliliters; Resistates is poured in the 200 gram frozen water into 100 milliliters of ethyl acetate extractions 3 times, combined ethyl acetate; Anhydrous sodium sulfate drying filters, and revolves dried; Cross post, obtain 2 of purified white, 4-two chloro-5-pyrimidine formaldehyde 8.3 grams.
Claims (4)
1.2, the compound method of 4-two chloro-5-pyrimidine formaldehyde, the present invention adopts new starting raw material; Raw material obtains 5-hydroxylmethyluracil through the processing of hydrated barta and formaldehyde; 5-hydroxylmethyluracil obtains 2 through peroxo-in chloroform solvent, 4-dihydroxyl-5-pyrimidine formaldehyde, 2; 4-dihydroxyl-5-pyrimidine formaldehyde refluxes in POCl3 and obtains 2,4-two chloro-5-pyrimidine formaldehyde.
2. as claimed in claim 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde is characterized in that: said new initial feed is meant with the uridylic to be raw material.
3. as claimed in claim 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde, it is characterized in that: described oxygenant refers to Manganse Dioxide.
4. as claimed in claim 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde is characterized in that: said 2, the compound method of 4-two chloro-5-pyrimidine formaldehyde makes: get uridylic 25 grams, join in 400 ml waters that contain 15 gram barium hydroxides; The formaldehyde solution of 4 milliliter 37% of Dropwise 5 then, magnetic agitation refluxed half a hour, with the urine-soluble pyrimidine, room temperature condition reaction down spends the night, and feeds dioxide gas and makes hydrated barta change into barium carbonate sediment to come out; Filter, the water evaporate to dryness obtains viscous material, and 250 milliliter 70% alcohol reflux two hours is placed in the refrigerator the purified of 4 hours adularescents; 5-hydroxylmethyluracil is separated out, and filters, and oven dry obtains 23 grams, and productive rate is 73%; 23 gram 5-methylols urine are phonetic to join in 400 milliliters the chloroform, adds 100 gram Manganse Dioxide, reflux 10 hours, filtered while hot; Filter cake refluxes half a hour with 200 milliliters of chloroforms again, filtered while hot, again repetitive operation once, combined chloroform; Revolve driedly, obtain 2, bullion 14 grams of 4-dihydroxyl-5-pyrimidine formaldehyde, 14 grams 2; 4-dihydroxyl-5-pyrimidine formaldehyde joins in 100 milliliters of POCl3s, refluxes 5 hours, spins off the POCl3 about 50 milliliters, and resistates is poured in the 200 gram frozen water; 100 milliliters of ethyl acetate extractions 3 times, combined ethyl acetate, anhydrous sodium sulfate drying filters; Revolve driedly, cross post, obtain 2 of purified white, 4-two chloro-5-pyrimidine formaldehyde 8.3 grams.
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| CN2012101938674A CN102731412A (en) | 2012-06-13 | 2012-06-13 | Synthetic method of 2,4-dichloro-5-pyrimidine formaldehyde |
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| CN2012101938674A CN102731412A (en) | 2012-06-13 | 2012-06-13 | Synthetic method of 2,4-dichloro-5-pyrimidine formaldehyde |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731375A (en) * | 2012-06-20 | 2012-10-17 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesizing of 4,6-dichloro-5-pyrimidinecarbaldehyde |
| CN112176043A (en) * | 2019-07-04 | 2021-01-05 | 北京大学 | Sequencing, enrichment and detection method of modified nucleoside based on chemical marker |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102066340A (en) * | 2008-04-16 | 2011-05-18 | 波托拉医药品公司 | 2, 6-diamino-pyrimidin- 5-yl-carboxamides as SRK or JAK kinases inhibitors |
-
2012
- 2012-06-13 CN CN2012101938674A patent/CN102731412A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102066340A (en) * | 2008-04-16 | 2011-05-18 | 波托拉医药品公司 | 2, 6-diamino-pyrimidin- 5-yl-carboxamides as SRK or JAK kinases inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| CHIACCHIO, UGO ET AL: "Isoxazolidine analogs of pseudouridine: a new class of modified nucleosides", 《TETRAHEDRON》, vol. 59, no. 26, 31 December 2003 (2003-12-31), pages 4733 - 4738 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731375A (en) * | 2012-06-20 | 2012-10-17 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesizing of 4,6-dichloro-5-pyrimidinecarbaldehyde |
| CN112176043A (en) * | 2019-07-04 | 2021-01-05 | 北京大学 | Sequencing, enrichment and detection method of modified nucleoside based on chemical marker |
| WO2021000889A1 (en) * | 2019-07-04 | 2021-01-07 | 北京大学 | Chemical tagging-based method for modified nucleoside sequencing, enrichment, and measurement |
| CN112176043B (en) * | 2019-07-04 | 2022-07-12 | 北京大学 | Sequencing, enrichment and detection method of modified nucleoside based on chemical marker |
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Application publication date: 20121017 |