CN102702110A - Preparation method of 4-amino-5, 6-dichloropyrimidine - Google Patents
Preparation method of 4-amino-5, 6-dichloropyrimidine Download PDFInfo
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- CN102702110A CN102702110A CN2012101624249A CN201210162424A CN102702110A CN 102702110 A CN102702110 A CN 102702110A CN 2012101624249 A CN2012101624249 A CN 2012101624249A CN 201210162424 A CN201210162424 A CN 201210162424A CN 102702110 A CN102702110 A CN 102702110A
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Abstract
The invention discloses a preparation method of 4-amino-5, 6-dichloropyrimidine, which is the method comprising the steps of chloridizing dimethyl malonate, closing loop with formamidine acetate, converting hydroxyl into chlorine, and then ammonifying 4-chlorine, and finally obtaining the target compound.
Description
Technical field
The present invention relates to a kind of 4-amino-5, the synthesis technology of 6-dichloro pyrimidine improves, and belongs to the medicine bioengineering chemical technology field.Also relate to some midbody that obtains through this method.
Background technology
4-amino-5, the 6-dichloro pyrimidine is a kind of pale solid, is a kind of important medicine bioengineering chemical intermediate.
4-amino-5, the preparation of 6-dichloro pyrimidine by methyl-malonate and SULPHURYL CHLORIDE reaction, obtains the chloromalonic acid dimethyl ester, closes ring with the acetate carbonamidine, and hydroxyl is converted into chlorine, and 4-position chlorine is through ammonification acquisition target compound.
Summary of the invention
The present invention mainly improves former operational path, makes per step operation controlled easy to operate, is beneficial to amplify to produce, and improves yield.
The present invention provides formula (1) compound
.
The present invention also provides by formula (5) compound
Ammonification prepares the method for formula (1) compound
This method is in autoclave, to add compound 4; 5; The ammonification of 6-trichloropyrimidine, solvent for use include but not limited to the methanol solution of ammoniacal liquor, ammonia, the ethanolic soln of ammonia, tetrahydrofuran solution, ammoniacal liquor and the THF mixing solutions of ammonia, preferred ammoniacal liquor and THF mixing solutions; Temperature of reaction 20 ~ 120 degree, preferred 40 ~ 60 degree; 2 ~ 16 hours reaction times, preferred 2 ~ 3 hours.
The present invention provides by formula (4) compound
The method for preparing formula (5) compound
Compound 4, two hydroxyls on 6-dihydroxyl-5-chloropyrimide are converted into chlorine, and used chlorination reagent includes but not limited to sulfur oxychloride, SULPHURYL CHLORIDE, methylsulfonyl chloride, Phosphorus Oxychloride and chlorine, preferred oxygen phosphorus chloride; Used alkali includes but not limited to diethylamine, triethylamine, Diisopropylamine, diisopropylethylamine, pyridine and 4-Dimethylamino pyridine, preferred triethylamine; Temperature of reaction 20 ~ 105 degree, preferred 100 ~ 105 degree; 6 ~ 24 hours reaction times, preferred 12 ~ 16 hours.
The present invention provides by formula (3) compound
The method for preparing formula (4) compound
Compound chloromalonic acid dimethyl ester and acetate carbonamidine close ring, and solvent for use is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol and terepthaloyl moietie, preferred alcohol; Temperature of reaction-10 ~ 80 degree, preferred 20 ~ 30 degree; 10 ~ 12 hours reaction times; Used acid includes but not limited to hydrochloric acid, nitric acid, sulfuric acid, formic acid, trifluoroacetic acid, Glacial acetic acid min. 99.5 and oxalic acid, preferred hydrochloric acid.
The present invention provides by formula (2) compound
The method for preparing formula (3) compound
This method drips SULPHURYL CHLORIDE by methyl-malonate, and solvent for use includes but not limited to benzene, toluene, methylene dichloride, chloroform, EGME, glycol dimethyl ether and DMSO 99.8MIN., preferred methylene dichloride and chloroform; Temperature of reaction-10 ~ 40 degree, preferred 20 ~ 30 degree; 8 ~ 72 hours reaction times, preferred 60 ~ 72 hours; Used alkali includes but not limited to yellow soda ash, sodium hydrogencarbonate, salt of wormwood, sodium hydroxide and Pottasium Hydroxide, preferred yellow soda ash and sodium hydrogencarbonate.
Embodiment
Embodiment 1
In 2 liters there-necked flask, drop into 500 gram ethyl malonates, 2 liters of methylene dichloride, stirring at room, 00 milliliter of SULPHURYL CHLORIDE of Dropwise 5, stirring at room 3 days, raw material reaction is complete.Add less water at reaction solution, transfer PH7 ~ 8 with saturated sodium carbonate solution, tell organic layer, water layer is used dichloromethane extraction, merges organic layer, and anhydrous sodium sulfate drying, concentrating under reduced pressure get 450 gram chloromalonic acid dimethyl esters.
Embodiment 2
In 3 liters there-necked flask, add 2 liters of absolute ethyl alcohols, add 120 gram sodium Metal 99.5s in batches, treat that sodium dissolves entirely after, be cooled to 0 degree, add 196 gram acetate carbonamidines, stirred 0.5 hour, be warming up to room temperature, add 300 and restrain the chloromalonic acid dimethyl esters. stirred overnight at room temperature.Filter, filter cake dissolves with less water, transfers pH2 ~ 3 with hydrochloric acid, separates out solid, filters, dry 130 grams 4,6-dihydroxyl-5-chloropyrimide.
Embodiment 3
In 2 liters there-necked flask, add 130 grams 4,6-dihydroxyl-5-chloropyrimide, 1.2 liters of Phosphorus Oxychlorides slowly drip 100 milliliters of triethylamines, and backflow is spent the night.Boil off Phosphorus Oxychloride,, get 115 grams 4,5, the 6-trichloropyrimidine through column chromatography purification.
Embodiment 4
In 5 liters of autoclaves, add compound 90 grams 4,5 respectively, 6-trichloropyrimidine, 1.5 liters of ammoniacal liquor and 1.5 liters of THFs; Drip to be heated to 60 degree and stirred 2 ~ 3 hours, take out the THF layer, boil off most of THF; Be cooled to room temperature, get compound 70 gram 4-amino-5, the 6-dichloro pyrimidine.
Claims (5)
1. 4-amino-5, the preparation method of 6-dichloro pyrimidine, methyl-malonate adds methylene dichloride, drips SULPHURYL CHLORIDE under the stirring at room, and reaction finishes, and adds entry; Transfer PH=7-8 with saturated sodium carbonate solution, merge organic layer, anhydrous sodium sulfate drying, concentrate compound chloromalonic acid dimethyl ester, sodium Metal 99.5 is dissolved in absolute ethyl alcohol, cooling; Add the acetate carbonamidine, be warmed up to room temperature, add compound chloromalonic acid dimethyl ester, stirred overnight at room temperature reacts completely, and filters; Filter cake dissolves with less water, transfers pH2-3 with hydrochloric acid, has solid to separate out, and filters, dry compound 4; 6-dihydroxyl-5-chloropyrimide, compound 4,6-dihydroxyl-5-chloropyrimide adds POCl3, slowly drips triethylamine, and backflow is spent the night; Raw material reaction is complete, boils off most of POCl3, and column chromatography purification gets compound 4,5; The 6-trichloropyrimidine adds compound 4,5,6-trichloropyrimidine, ammoniacal liquor and THF, 60 in the autoclave
oC stirred 2 hours, told the THF layer, boiled off most of THF, was cooled to room temperature, crossed and filtered bullion, washed twice with sherwood oil, got target compound 4-amino-5, the 6-dichloro pyrimidine.
2. 4-amino-5 according to claim 1; The preparation method of 6-dichloro pyrimidine; It is characterized in that: methyl-malonate drips SULPHURYL CHLORIDE, and solvent for use includes but not limited to benzene, toluene, methylene dichloride, chloroform, EGME, glycol dimethyl ether and DMSO 99.8MIN.; Temperature of reaction-10 ~ 40 degree; 8 ~ 72 hours reaction times; Used alkali includes but not limited to yellow soda ash, sodium hydrogencarbonate, salt of wormwood, sodium hydroxide and Pottasium Hydroxide.
3. 4-is amino-5 according to claim 1, and the preparation method of 6-dichloro pyrimidine is characterized in that: compound chloromalonic acid dimethyl ester closes with the acetate carbonamidine and encircles, and solvent for use is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol and terepthaloyl moietie; Temperature of reaction-10 ~ 80 degree; 5 ~ 24 hours reaction times; Used acid includes but not limited to hydrochloric acid, nitric acid, sulfuric acid, formic acid, trifluoroacetic acid, Glacial acetic acid min. 99.5 and oxalic acid.
4. 4-amino-5 according to claim 1; The preparation method of 6-dichloro pyrimidine; It is characterized in that: 4, the hydroxyl of 6-dihydroxyl-5-chloropyrimide is converted into chlorine, and used chlorination reagent includes but not limited to sulfur oxychloride, SULPHURYL CHLORIDE, methylsulfonyl chloride, Phosphorus Oxychloride and chlorine; Used alkali includes but not limited to diethylamine, triethylamine, Diisopropylamine, diisopropylethylamine, pyridine and 4-Dimethylamino pyridine; Temperature of reaction 20 ~ 105 degree; 6 ~ 24 hours reaction times.
5. 4-amino-5 according to claim 1; The preparation method of 6-dichloro pyrimidine; It is characterized in that: add compound 4 in the autoclave; 5, the ammonification of 6-trichloropyrimidine, solvent for use includes but not limited to the methanol solution of ammoniacal liquor, ammonia, the ethanolic soln of ammonia, tetrahydrofuran solution, ammoniacal liquor and the THF mixing solutions of ammonia; Temperature of reaction 20 ~ 120 degree; 2 ~ 16 hours reaction times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2012101624249A CN102702110A (en) | 2012-05-24 | 2012-05-24 | Preparation method of 4-amino-5, 6-dichloropyrimidine |
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| CN2012101624249A CN102702110A (en) | 2012-05-24 | 2012-05-24 | Preparation method of 4-amino-5, 6-dichloropyrimidine |
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| CN2012101624249A Pending CN102702110A (en) | 2012-05-24 | 2012-05-24 | Preparation method of 4-amino-5, 6-dichloropyrimidine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111440123A (en) * | 2020-05-27 | 2020-07-24 | 南京普锐达医药科技有限公司 | Synthetic method of 4,5, 6-trichloropyrimidine |
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| US3313816A (en) * | 1964-07-20 | 1967-04-11 | Kyowa Hakko Kogyo Kk | Processes of producing 4-amino-6-hydroxypyrimidine |
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| CN1113237A (en) * | 1994-04-27 | 1995-12-13 | 隆萨股份公司 | N-(2-amino-4,6-pyrimidine bichloride-5-) formamide and preparation of same |
| CN1126205A (en) * | 1994-05-13 | 1996-07-10 | 林茨化学有限公司 | Process for the preparation of 2-amino-4,6-dichloro-pyrimidine |
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| US3313816A (en) * | 1964-07-20 | 1967-04-11 | Kyowa Hakko Kogyo Kk | Processes of producing 4-amino-6-hydroxypyrimidine |
| CN1077193A (en) * | 1992-01-22 | 1993-10-13 | 瑞士隆萨股份公司 | N-5 position-protected 2,5-diamino-4,6-dichloro pyrimidine and production method thereof |
| CN1113237A (en) * | 1994-04-27 | 1995-12-13 | 隆萨股份公司 | N-(2-amino-4,6-pyrimidine bichloride-5-) formamide and preparation of same |
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| WO2005047280A1 (en) * | 2003-11-10 | 2005-05-26 | Merck Sharp & Dohme Limited | Substituted nitrogen-containing six-membered amino-heterocycles as vanilloid-1 receptor antagonists for treating pain |
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| WO2011029043A1 (en) * | 2009-09-04 | 2011-03-10 | Biogen Idec Ma Inc. | Heteroaryl btk inhibitors |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111440123A (en) * | 2020-05-27 | 2020-07-24 | 南京普锐达医药科技有限公司 | Synthetic method of 4,5, 6-trichloropyrimidine |
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Application publication date: 20121003 |