CN102127022A - Method for synthesizing 2-amino-4,6-dichloro-5-formamido pyrimidine - Google Patents
Method for synthesizing 2-amino-4,6-dichloro-5-formamido pyrimidine Download PDFInfo
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- CN102127022A CN102127022A CN2010106166695A CN201010616669A CN102127022A CN 102127022 A CN102127022 A CN 102127022A CN 2010106166695 A CN2010106166695 A CN 2010106166695A CN 201010616669 A CN201010616669 A CN 201010616669A CN 102127022 A CN102127022 A CN 102127022A
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Abstract
The invention provides a method for synthesizing 2-amino-4,6-dichloro-5-formamido pyrimidine. The method comprises the following steps of: undergoing a Vilsmeier reaction on 2,5-diamino-4,6-dihydroxy pyrimidine hydrochloride serving as a raw material, DMF (Dimethyl Formamide) and a chlorinating agent to generate 2,5-dimethylamine methyleneamino-4,6-dichloropyrimidine; and hydrolyzing stepwise under the action of alkali to obtain a product. The total yield is up to 58 percent, and the purity of the product is up to 98.7 percent. In the Vilsmeier reaction, halogenated hydrocarbon or aromatic hydrocarbon is not taken as a solvent, and a solvent-free method is adopted, so that raw materials are reduced, the reaction time is greatly shortened, and the production cost is remarkably lowered.
Description
Technical field
The present invention relates to a kind of 2-amino-4, the synthetic method of 6-two chloro-5-formamidopyrimidines belongs to technical field of pharmaceutical chemistry.
Background technology
Abacavir (abacavir, 1592U89, trade(brand)name Ziagen) the plain Weicon company of Ge Lan (GlaxoWellcomeInc) by Britain produces, what on December 18th, 1998 obtained U.S. FDA passes through, and go on the market in July, 1999, chemical being called (1S, 4R)-cis-4-(2-amino-6-cyclopropyl amino-9-H-purine-9-yl)-2-cyclopentenes-1-methyl alcohol.Belong to efabirenz, the inhibition that HI-1 is duplicated is to stop duplicating of viral DNA two strands by simulation nucleic acid, for virus, make their lack necessary chemical structure and can not connect the nucleic acid of back, clinical confirmation is duplicated HIV has very strong restraining effect.Abacavir is mainly synthetic by 2 key intermediates, and the one, 2-amino-4,6-two chloro-5-formamido group pyrimidines, the 2nd, (1S, 4R)-cis-4-acetylaminohydroxyphenylarsonic acid 2-cyclopentenes-1-methyl alcohol.
2-amino-4, the synthetic method of 6-two chloro-5-formamido group pyrimidines is with 2,5-diamino-4, the 6-dihydroxy-pyrimidine is that the synthetic report of raw material mainly contains as follows: patent EP1013647 has introduced elder generation and has reacted generation 2 with DMF, phosphorus oxychloride, trichloropropane under the catalysis of tetramethyl ammonium chloride, 5-diamino-4, the 6-dichloro pyrimidine carries out formamide with the formic acid selectivity again and obtains product.This method need be used the higher catalyzer of price, and can't recycle, and the selectivity of formamide is not high yet.Other report is earlier to carry out chlorination reaction in the presence of the solvent of halocarbon or aromatic hydrocarbon substantially, hydrolysis and getting under acidity or alkaline condition again.As Nucleosedes, Nucleotides﹠amp; Nucleic Acids 19 (1﹠amp; 2), 297-327,2000, JP2004300101, WO2004103979, CN101003511 etc.These method reaction times are all longer, and aftertreatment is all more loaded down with trivial details, used multiple solvent, and the needs that have are isolated intermediates, and the selectivity of hydrolysis is not high, and cost is all than higher.
Summary of the invention
The objective of the invention is to overcome the deficiency that prior art exists, a kind of 2-amino-4 is provided, the synthetic method of 6-two chloro-5-formamidopyrimidines is intended to simplify the operation, and reduces cost, and improves the yield of reaction, adapts to industrialization production more.
Purpose of the present invention is achieved through the following technical solutions:
2-amino-4, the synthetic method of 6-two chloro-5-formamidopyrimidines, with 2,5-diamino-4,6-dihydroxy-pyrimidine hydrochloride (DADHP) is a raw material, obtains product through Vilsmeier reaction and hydrolysis reaction, may further comprise the steps:
1) in reactor, adds chlorizating agent and 2,5-diamino-4,6-dihydroxy-pyrimidine hydrochloride (DADHP), stir down and drip N, dinethylformamide (DMF) dropwises stirring reaction, after reaction finishes reactant is poured in the frozen water, obtain 2,5-two dimethylamine methylene amino-4,6-dichloro pyrimidine;
2) to step 1) obtain 2,5-two dimethylamine methylene amino-4 drip alkali in the 6-dichloro pyrimidine aqueous solution, are hydrolyzed, and when pH is 1～2, stop to drip, insulation reaction generates 2-amino-4,6-two chloro-5-dimethylamine methylene aminopyrimidines;
3) to step 2) the 2-amino-4 that obtains, continue in the 6-two chloro-5-dimethylamine methylene aminopyrimidine aqueous solution to drip alkali, when pH is 4～5, stop to drip, insulation reaction is reacted finish cooling, suction filtration, washing, drying, obtain 2-amino-4,6-two chloro-5-formamidopyrimidines (FADCP).
Further, above-mentioned 2-amino-4, the synthetic method of 6-two chloro-5-formamidopyrimidines, chlorizating agent described in the step 1) is phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or thionyl chloride.Drip N described in the step 1), the temperature of dinethylformamide is 20～80 ℃, and the stirring reaction temperature is 90～120 ℃, and the reaction times is 2～10 hours.
Further, above-mentioned 2-amino-4, the synthetic method of 6-two chloro-5-formamidopyrimidines, step 2) and step 3) described in alkali be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or ammoniacal liquor.The temperature of insulation reaction step 2) is 30～80 ℃, and the reaction times is: 0.5～5 hour.
Again further, above-mentioned 2-amino-4, the synthetic method of 6-two chloro-5-formamidopyrimidines, the temperature of insulation reaction described in the step 3) is 10～60 ℃, the reaction times is 0.5～6 hour.
Substantive distinguishing features and obvious improvement that technical solution of the present invention is outstanding are mainly reflected in:
The total recovery of the inventive method reaches 58%, and product purity reaches 98.7%.The Vilsmeier reaction does not use halohydrocarbon or aromatic hydrocarbons as solvent, adopts solventless method, has not only reduced raw material, and the time of reaction shortens greatly.Adopt the mode of fractional hydrolysis under the alkali environment to obtain product, the degree of the pH value monitoring hydrolysis during by control hydrolysis, the selectivity of raising hydrolysis reaction.Vilsmeier reaction and hydrolysis reaction have all been selected chlorination reagent and mineral alkali commonly used commonly used, have reduced production cost.The method of " treating different things alike " is adopted in this reaction, and intermediate product need not to separate, and has improved the convenience of operation, avoids material to contact with air.
Description of drawings
Below in conjunction with accompanying drawing technical solution of the present invention is described further:
Fig. 1: the synthetic synoptic diagram of intermediate product I;
Fig. 2: the synthetic synoptic diagram of intermediate product II;
The synthetic synoptic diagram of Fig. 3: FADCP.
Embodiment
2-amino-4 of the present invention, the synthetic method of 6-two chloro-5-formamidopyrimidines, with 2,5-diamino-4,6-dihydroxy-pyrimidine hydrochloride (DADHP) is a raw material, obtains product through Vilsmeier reaction and hydrolysis reaction, concrete processing step is:
1) in reactor, adds chlorizating agent and 2,5-diamino-4,6-dihydroxy-pyrimidine hydrochloride (DADHP), chlorizating agent is phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or thionyl chloride, stir and drip N down, dinethylformamide (DMF), the temperature that drips DMF is 20～80 ℃, dropwises stirring reaction, temperature of reaction is 90～120 ℃, reaction times is 2～10 hours, after reaction finishes reactant is poured in the frozen water, obtains 2,5-two dimethylamine methylene amino-4, the 6-dichloro pyrimidine, i.e. intermediate product I, as shown in Figure 1;
2) drip alkali in the intermediate product I that obtains to step 1) (2,5-two dimethylamine methylene amino-4, the 6-dichloro pyrimidine) aqueous solution, alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or ammoniacal liquor, is hydrolyzed, when pH is 1～2, stop to drip, insulation reaction, the temperature of insulation reaction are 30～80 ℃, and the reaction times is 0.5～5 hour, generate 2-amino-4,6-two chloro-5-dimethylamine methylene aminopyrimidines, i.e. intermediate product II, as shown in Figure 2;
3) to step 2) intermediate product II (the 2-amino-4 that obtains, 6-two chloro-5-dimethylamine methylene aminopyrimidines) continue in the aqueous solution to drip alkali, alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or ammoniacal liquor, when pH is 4～5, stop to drip, insulation reaction, the temperature of insulation reaction are 10～60 ℃, and the reaction times is 0.5～6 hour, react finish cooling, suction filtration, washing, drying, obtain 2-amino-4,6-two chloro-5-formamidopyrimidines (FADCP), as shown in Figure 3.
Embodiment 1
Drop into phosphorus trichloride 55g, DADHP18g in four-hole bottle, slowly drip 18gDMF, keep the dropping temperature about 40 ℃, dropwise, be warming up to 90 ℃, reaction is 4 hours under this temperature.Reaction finishes to reduce to room temperature.Slowly be poured in the reactor that frozen water is housed, the limit bevelling stirs.Topple over and finish, drip 10% aqueous sodium carbonate, when pH1～2, stop to drip, in 40 ℃ of insulations 2 hours, and then reduce to room temperature, Dropwise 5 % aqueous sodium carbonate when pH6～7, stops to drip, and insulation is 2 hours under room temperature.Filter, filter cake washes with water to neutrality.Dry product 7.9g, purity 97.3%.
Embodiment 2
Drop into phosphorus pentachloride 104g, DADHP18g in four-hole bottle, slowly drip 22gDMF, keep the dropping temperature about 30 ℃, dropwise, be warming up to 100 ℃, reaction is 6 hours under this temperature.Reaction finishes to reduce to room temperature.Slowly be poured in the reactor that frozen water is housed, the limit bevelling stirs.Topple over and finish, drip 10% aqueous sodium carbonate, when pH1～2, stop to drip, in 30 ℃ of insulations 5 hours down, Dropwise 5 % aqueous sodium carbonate then when pH6～7, stops to drip, in 50 ℃ of insulations 1 hour down.Filter, filter cake washes with water to neutrality.Dry product 8.9g, purity 98.2%.
Embodiment 3
Drop into phosphorus oxychloride 92g, DADHP18g in four-hole bottle, slowly drip 26gDMF, keep the dropping temperature about 50 ℃, dropwise, be warming up to 100 ℃, reaction is 6 hours under this temperature.Reaction finishes to reduce to room temperature.Slowly be poured in the reactor that frozen water is housed, the limit bevelling stirs.Topple over and finish, dropping ammonia when pH1～2, stops to drip, and in 30 ℃ of insulations 4 hours down, and then drips 10% ammonia soln, when pH6～7, stops to drip, in 50 ℃ of insulations 1 hour down.Filter, filter cake washes with water to neutrality.Dry product 10.7g, purity 98.5%.
Embodiment 4
Drop into phosphorus oxychloride 92g, DADHP18g in four-hole bottle, slowly drip 44gDMF, keep the dropping temperature about 30 ℃, dropwise, be warming up to 95 ℃, reaction is 8 hours under this temperature.Reaction finishes to reduce to room temperature.Slowly be poured in the reactor that frozen water is housed, the limit bevelling stirs.Topple over and finish, dropping ammonia when pH1～2, stops to drip, and in 60 ℃ of insulations 1 hour down, reduces to room temperature then, drips 10% ammonia soln again, when pH6～7, stops to drip, in 60 ℃ of insulations 1 hour down.Filter, filter cake washes with water to neutrality.Dry product 12g, purity 98.7%.
The total recovery of the inventive method reaches 58%, and product purity reaches 98.7%.The Vilsmeier reaction does not use halohydrocarbon or aromatic hydrocarbons as solvent, adopts solventless method, has not only reduced raw material, and the time of reaction shortens greatly.Adopt the mode of fractional hydrolysis under the alkali environment to obtain product, the degree of the pH value monitoring hydrolysis during by control hydrolysis, the selectivity of raising hydrolysis reaction.Vilsmeier reaction and hydrolysis reaction have all been selected chlorination reagent and mineral alkali commonly used commonly used, have reduced production cost.The method of " treating different things alike " is adopted in this reaction, and intermediate product need not to separate, and has improved the convenience of operation, avoids material to contact with air.
What need understand is: the above only is a preferred implementation of the present invention; for those skilled in the art; under the prerequisite that does not break away from the principle of the invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1.2-amino-4, the synthetic method of 6-two chloro-5-formamidopyrimidines is characterized in that may further comprise the steps:
1) in reactor, add chlorizating agent and 2,5-diamino-4,6-dihydroxy-pyrimidine hydrochloride stirs and drips N down, dinethylformamide dropwises stirring reaction, after reaction finishes reactant is poured in the frozen water, obtain 2,5-two dimethylamine methylene amino-4,6-dichloro pyrimidine;
2) to step 1) obtain 2,5-two dimethylamine methylene amino-4 drip alkali in the 6-dichloro pyrimidine aqueous solution, are hydrolyzed, and when pH is 1～2, stop to drip, insulation reaction generates 2-amino-4,6-two chloro-5-dimethylamine methylene aminopyrimidines;
3) to step 2) the 2-amino-4 that obtains, continue in the 6-two chloro-5-dimethylamine methylene aminopyrimidine aqueous solution to drip alkali, when pH is 4～5, stop to drip, insulation reaction is reacted finish cooling, suction filtration, washing, drying, obtain 2-amino-4,6-two chloro-5-formamidopyrimidines.
2. 2-amino-4 according to claim 1, the synthetic method of 6-two chloro-5-formamidopyrimidines is characterized in that: chlorizating agent described in the step 1) is phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or thionyl chloride.
3. 2-amino-4 according to claim 1, the synthetic method of 6-two chloro-5-formamidopyrimidines is characterized in that: drip N described in the step 1), the temperature of dinethylformamide is 20～80 ℃, the stirring reaction temperature is 90～120 ℃, and the reaction times is 2～10 hours.
4. 2-amino-4 according to claim 1, the synthetic method of 6-two chloro-5-formamidopyrimidines is characterized in that: step 2) and step 3) described in alkali be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or ammoniacal liquor.
5. 2-amino-4 according to claim 1, the synthetic method of 6-two chloro-5-formamidopyrimidines is characterized in that: step 2) described in the temperature of insulation reaction be 30～80 ℃, the reaction times is 0.5～5 hour.
6. 2-amino-4 according to claim 1, the synthetic method of 6-two chloro-5-formamidopyrimidines is characterized in that: the temperature of insulation reaction described in the step 3) is 10～60 ℃, the reaction times is 0.5～6 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145768A (en) * | 2013-03-06 | 2013-06-12 | 陕西科技大学 | Method for preparing ferrocenecarboxaldehyde |
| CN115536595A (en) * | 2022-11-29 | 2022-12-30 | 苏州开元民生科技股份有限公司 | Synthesis method of 2-amino-4, 6-dichloro-5-formamido pyrimidine |
| CN117050024A (en) * | 2023-10-13 | 2023-11-14 | 苏州开元民生科技股份有限公司 | Synthesis method of 2-amino-4, 6-dichloro-5-formamidopyrimidine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1259517A (en) * | 1994-04-27 | 2000-07-12 | 隆萨股份公司 | Method for preparing 2,5-diamino-4,6-dichloropyrimidine |
| WO2004103979A1 (en) * | 2003-05-26 | 2004-12-02 | Sumitomo Chemical Company, Limited | Method for producing n-(2-amino-4,6-dichloropyrimidine-5-yl)formamide |
| CN1910160A (en) * | 2004-01-15 | 2007-02-07 | 德古萨股份公司 | Method for producing 2-amino-4,6-dichloro-5-formamidopyrimidine |
-
2010
- 2010-12-30 CN CN2010106166695A patent/CN102127022A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1259517A (en) * | 1994-04-27 | 2000-07-12 | 隆萨股份公司 | Method for preparing 2,5-diamino-4,6-dichloropyrimidine |
| WO2004103979A1 (en) * | 2003-05-26 | 2004-12-02 | Sumitomo Chemical Company, Limited | Method for producing n-(2-amino-4,6-dichloropyrimidine-5-yl)formamide |
| CN1910160A (en) * | 2004-01-15 | 2007-02-07 | 德古萨股份公司 | Method for producing 2-amino-4,6-dichloro-5-formamidopyrimidine |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145768A (en) * | 2013-03-06 | 2013-06-12 | 陕西科技大学 | Method for preparing ferrocenecarboxaldehyde |
| CN103145768B (en) * | 2013-03-06 | 2016-02-10 | 陕西科技大学 | A kind of method preparing ferrocene carboxaldehyde |
| CN115536595A (en) * | 2022-11-29 | 2022-12-30 | 苏州开元民生科技股份有限公司 | Synthesis method of 2-amino-4, 6-dichloro-5-formamido pyrimidine |
| CN117050024A (en) * | 2023-10-13 | 2023-11-14 | 苏州开元民生科技股份有限公司 | Synthesis method of 2-amino-4, 6-dichloro-5-formamidopyrimidine |
| CN117050024B (en) * | 2023-10-13 | 2024-01-05 | 苏州开元民生科技股份有限公司 | Synthesis method of 2-amino-4, 6-dichloro-5-formamidopyrimidine |
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Application publication date: 20110720 |