CN103396395A - Method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and intermediate thereof - Google Patents
Method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and intermediate thereof Download PDFInfo
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Abstract
The invention relates to a method for synthesizing N-(5-nitryl-2-methyl pyridyl-3-)-4-(3-pyridyl)-2-pyrilamine and an intermediate thereof. The method comprises the following steps: adding a compound IV and a compound V with the molar ratio of 1:(1-2) into a reactor; adding an organic solvent, wherein the volume weight ratio of the organic solvent to the compound IV is 5 to 10; stirring and dissolving; cooling to -20 to 0 DEG C; maintaining the temperature range and adding sodium hydride in batches, wherein the molar ratio of the sodium hydride to the compound IV is (2-6):1; and after adding the sodium hydride, maintaining the temperature to be 20 to 50 DEG C until the reaction is complete and a compound I is obtained.
Description
Technical field:
The present invention relates to a kind of preparation method of pyrimidine derivatives.
Background technology:
A kind of N-(5-nitro-2-picolyl-3-)-4-(3-pyridyl is disclosed in Chinese patent CN1972917B specification sheets embodiment 1)-synthetic method of 2-PYRIMITHAMINE, namely adopt 2-methyl-3-amino-5-nitropyridine and 2-methylsulfonyl-4-(3-pyridyl) the pyrimidine reaction prepares.
And Chinese patent application CN201110323144.7 also discloses a kind of 2-methylsulfonyl-4-(3-pyridyl) synthetic method of pyrimidine is as follows:
When R is methyl; when X is iodine; in this application, disclosed synthetic method is actually a kind of employing methyl iodide and prepares 2-methylsulfonyl-4-(3-pyridyl as methylating reagent) method of pyrimidine; 2-methylsulfonyl-4-(3-pyridyl is disclosed in this application specification sheets embodiment 1) synthetic method of pyrimidine; wherein adopt methyl iodide to methylate and prepare 2-sulfydryl-4-(3-pyridyl) pyrimidine; and then with hydrogen peroxide oxidation, obtain target compound; yet because methyl iodide toxicity is larger; expensive; and in the disclosed situation of this application, yield also only has 65%.
methylcarbonate (dimethylcarbonate, DMC) as a kind of methylating reagent commonly used, also be used to methylating of sulfydryl, " focused microwave promotes 2-mercaptopyridine that lower Study of Dimethyl Carbonate as Methylating Reagent synthesizing methyl replaces also [2 to China's document, 3-d] pyrimidone " (Wang Xicun etc., Northwest Normal University's journal (natural science edition), the 5th phase in 2012, 61-66) also disclose a kind of methylcarbonate that utilizes the sulfydryl of 2-mercaptopyrimidine has been carried out methylated method, add DMSO or DMF, the phase-transfer catalyst Tetrabutyl amonium bromide also reacts under alkali exists, and employing focused microwave and two kinds of type of heating of direct heating are disclosed, temperature of reaction is in the situation that 180 ℃ of methylation reaction yields reach 80-95%, the document is pointed out simultaneously, utilize methylcarbonate to improve along with the raising of temperature the transformation efficiency of the methylation reaction of sulfydryl.When we make in this way to 2-sulfydryl-4-(3-pyridyl) when carrying out methylation reaction, pyrimidine finds, the equipment that needs while utilizing microwave heating is complicated, invests large and is difficult to carry out the amplification of industrially scalable.Although and the high transformation efficiency that improved of temperature of reaction, also improved the impurity output of side reaction.In addition, the phase-transfer catalysts such as Tetrabutyl amonium bromide, although can catalyzed reaction, toxicity own is larger, can pollute environment, and operator's health is had certain infringement.
Chinese patent application CN200910048833.4 discloses a kind of ionic liquid-catalyzed lower method for preparing the heterogeneous ring compound of methylthio group, a kind of method that adopts ionic liquid such as chlorination 1-butyl-catalysis previous reaction such as 3-Methylimidazole is disclosed, although reduced the temperature of reaction to the highest 130 ℃, but the product content that reaction obtains is 95-97%, and foreign matter content is higher.
N-(5-nitro-2-picolyl-3-)-4-(3-pyridyl)-2-PYRIMITHAMINE medicine intermediate, its foreign matter content directly affects the quality of subsequent reactions step and even final product.Therefore improve the transformation efficiency of each step reaction, reduce simultaneously foreign matter content and become problem to be solved in prior art.
Summary of the invention
For overcoming defect of the prior art; the invention provides a kind of Compound I (N-(5-nitro-2-picolyl-3-)-4-(3-pyridyl)-2-PYRIMITHAMINE) and midbody compound IV(2-methylsulfonyl-4-(3-pyridyl) pyrimidine) the preparation method; adopt the one kettle way preparation that methylcarbonate is methylated and merges with the oxidation two-step reaction; improve yield, shortened reaction process.
The invention provides a kind of preparation method of compound IV, route is as follows
Step (1) is for adopting Compound I I and dimethyl carbonate to obtain compound III;
Step (2) is for to obtain compound IV with the compound III oxidation; It is characterized in that described step (1) and the preparation of (2) employing one kettle way, technique is as follows:
The Compound I I of mol ratio 1:2-3:1.5-2, HMPA (HMPA), methylcarbonate are mixed and be placed in reactor, be heated to 60-80 ℃, after reacting completely, be evaporated to 80 ℃.Be cooled to-10 ℃ ~ 10 ℃, with acid for adjusting pH to the H that adds after 4-5 with the 3-10 of Compound I I mol ratio
2O
2, reaction is to fully, with adding the excessive H of reductive agent consumption under 20-50 ℃
2O
2, regulate pH to 7.5-8, add the water with HMPA volume ratio 20-50, filter and obtain compound IV.
Described Compound I I and H
2O
2The preferred 4-6 of mol ratio.Described H
2O
2Preferably be mixed with 30% the aqueous solution, namely adopt commercially available hydrogen peroxide.
The preferred sodium bisulfite of described reductive agent, one or more in S-WAT, Sodium Pyrosulfite.
The present invention also provides a kind of preparation method of Compound I, it is characterized in that carrying out step (3) after arbitrary described method prepares compound IV: compound V and compound IV and alkalimetal hydride reaction are obtained Compound I.Reaction formula is as follows
The preferred sodium hydride of alkalimetal hydride in described step (3), potassium hydride KH, temperature of reaction are-20 ℃ ~ 50 ℃.
Described step (3) selection process is as follows, the compound IV of mol ratio 1:1-2 and compound V are added in reactor, add the organic solvent with compound IV envelope-bulk to weight ratio 5-10, be cooled to-20 ℃ ~ 0 ℃ after stirring and dissolving, remain in this temperature range and add sodium hydride in batches, the sodium hydride that adds and the mol ratio of compound IV are 2 ~ 6:1, maintain the temperature at 20-50 ℃ after sodium hydride finishes and obtain Compound I until react completely.
The preferred DMF of organic solvent of described step (3).
The preparation method of Compound I provided by the invention and midbody compound IV thereof, improved technique of the prior art, use methylcarbonate as methylating reagent, adopted simultaneously one kettle way preparation technology, compare with adopting methyl iodide in CN201110323144.7 and be divided into the techniques (Comparative Examples 1-4) that two steps made, both improved the yield of reaction, total recovery from Compound I I to compound IV has been brought up to 80-90% from 58-64%, and the IV content of the compound that obtains also can reach more than 98%.Adopt methylcarbonate to avoid pollution and the murder by poisoning problem of bringing due to methyl iodide high volatile volatile and toxicity, and employing HMPA is as the solvent of methylation reaction, it is unexpected that discovery can carry out at lesser temps the methylation reaction of methylcarbonate, and with existing reacting phase ratio, yield and the purity of product all increase, and have also avoided the use of the larger phase-transfer catalyst of toxicity.
Embodiment
Hydrogen peroxide, density 1.11g/mL, contain H
2O
230%, amount to and contain H
2O
20.333g/mL
Compound I I, commercially available, content 98.2%
The preparation of embodiment 1-embodiment 4 compound IV, fill a prescription as follows
Reaction process:
(1) will drop in reactor as the Compound I I of raw material and HMPA, methylcarbonate solution, stirring and dissolving, be heated to 60-80 ℃, and the 1.5h afterreaction is complete.Be evaporated to 80 ℃.The reaction solution that takes a morsel obtains compound III sample and detection level with rear filtration of large water gaging dilution
(2) reaction solution of step (1) directly is cooled to-10 ℃ ~ 10 ℃, with 0.1M salt acid for adjusting pH, adds hydrogen peroxide to 4-5, reaction, to fully, adds S-WAT consumption to cross excessive H under 20-50 ℃
2O
2, regulate pH to 7.5-8, add the water with HMPA volume ratio 20-50, stir while adding, after solidifying to precipitation, to filter and obtain filter cake, after the filter cake washing, drying obtains compound IV.Product is weighed and is used the content of HPLC detection compound IV.
The HPLC condition:
Take octadecylsilane chemically bonded silica as stationary phase; With 0.05mol/L phosphate buffered saline buffer (get potassium primary phosphate 6.8g, after adding water approximately 900ml dissolving, then add the 10ml triethylamine, with phosphorus acid for adjusting pH value to 3.0, then add water to 1000ml)-acetonitrile (90:10) as moving phase; The detection wavelength is 242nm.Get testing sample during mensuration appropriate, accurately weighed rear with moving phase dissolve and quantitatively dilution make every 1ml and approximately contain the solution of 0.03mg, precision measures 20 μ l injection liquid chromatographies.
Embodiment 1-4 product output and compound IV purity see the following form
The yield calculation formula is: ((product weight * compound IV content)/235.3)/((raw material weight * content)/189.2).
Comparative Examples 1-Comparative Examples 4, according to the method in CN200910048833.4, I prepares compound III from Compound I, then adopts disclosed method in CN201110323144.7 to prepare compound IV from compound III, and reaction process is as follows:
The preparation of step (1) compound III
Take Compound I I(content 98.2% identical with embodiment 1-4 raw material) 18.9g, be dissolved in chlorination 1-butyl-3-Methylimidazole, add methylcarbonate, be warming up to 90-130 ℃ under stirring, reaction is to complete, go out product with ethyl acetate extraction after cooling, water is used ethyl acetate extraction three times again, the concentrated compound III that obtains after combined ethyl acetate.
The preparation of step (2) compound IV
Get the compound III that step (1) prepares, be dissolved in 100ML acetone, add hydrogen peroxide, under 40 ℃ of conditions, reaction is 2 hours, the reaction solution evaporate to dryness, be dissolved in methylene dichloride, adding saturated sodium sulfite solution, wash three times, distilled water wash, organic phase adds anhydrous sodium sulfate drying, solvent evaporated, obtain the product compound IV, calculate the compound IV yield.
Comparative example 1-4 fills a prescription and the results are shown in following table
Comparative Examples 5 is according to formula and the technique of Comparative Examples 1, and difference is to change the temperature of reaction of step (1) into 60-80 ℃, but stir over the 24h reaction, also can't carry out therefore can't calculating product yield fully.
Comparative Examples 6, according to CN200810202419.X, in the preparation of disclosed method, adopt 18.9g Compound I I(content 98.2%), the 18g methylcarbonate, salt of wormwood 1.6g, Tetrabutyl amonium bromide 3g, progressively be warmed up to 75 ~ 110 ℃ under mix and blend, reaction is to cooling washing layering after fully, and water merges to organic phase after with extracted with diethyl ether, obtains compound III 11.7g after the organic phase concentrating under reduced pressure, content 96.9%, yield are 57%
Comparative Examples 7, " focused microwave promotes 2-mercaptopyridine that lower Study of Dimethyl Carbonate as Methylating Reagent synthesizing methyl replaces also [2 to China's document, 3-d] pyrimidone " (Wang Xicun etc., Northwest Normal University's journal (natural science edition), the 5th phase in 2012, disclosed method 61-66), adopt 18.9g Compound I I(content 98.2%), the 18g methylcarbonate, MgO5.6 g, Tetrabutyl amonium bromide 30g, 10mlDMSO, adopt the mode of focused microwave heating, be heated to 170-180 ℃, continuing microwave heating keeps temperature to reacting completely, be cooled to room temperature, add the second alcohol and water, separate out a large amount of solids, the suction filtration washing, obtain compound III 13.6g after drying, content 95.7%, yield 65.4%,
Show by Comparative Examples, adopt the preparation technology of prior art, the compound IV yield of embodiment 1-4 is apparently higher than Comparative Examples 1-4, and step (1) reaction of prior art is adopted in Comparative Examples 5 explanations, and reaction is carried out fully.And Comparative Examples 6-7 also shows, adopts existing other schemes, even add the phase-transfer catalyst Tetrabutyl amonium bromide, and has improved temperature of reaction,, the content of the compound III that obtains and reaction yield are all lower.
The preparation of embodiment 5 Compound I
Get the compound IV for preparing by embodiment 1 method as raw material, adopting sodium hydride is commercially available 60% product, while calculating charging capacity in sodium hydride
Described step (3) selection process is as follows, the compound IV of mol ratio 1:1.5 and compound V are added in reactor, adding with the compound IV envelope-bulk to weight ratio is 8 DMF, be cooled to-10 ℃ after stirring and dissolving, remain in this temperature and add sodium hydride () in batches, the sodium hydride that adds and the mol ratio of compound IV are 2:1, maintain the temperature at 20-30 ℃ after sodium hydride finishes and obtain Compound I until react completely.
Claims (7)
1. the preparation method of a compound IV, route is as follows
Step (1) is for adopting Compound I I and dimethyl carbonate to obtain compound III;
Step (2) is for to obtain compound IV with the compound III oxidation; It is characterized in that described step (1) and the preparation of (2) employing one kettle way, technique is as follows:
The Compound I I of mol ratio 1:2-3:1.5-2, HMPA (HMPA), methylcarbonate are mixed and be placed in reactor, be heated to 60-80 ℃, after reacting completely, be evaporated to 80 ℃.Be cooled to-10 ℃ ~ 10 ℃, with acid for adjusting pH to the H that adds after 4-5 with the 3-10 of Compound I I mol ratio
2O
2, reaction is to fully, with adding the excessive H of reductive agent consumption under 20-50 ℃
2O
2, regulate pH to 7.5-8, add the water with HMPA volume ratio 20-50, filter and obtain compound IV.
2. preparation method as claimed in claim 1, is characterized in that described H
2O
2Be preferably 4-6 with the mol ratio of Compound I I.
3. preparation method as claimed in claim 1, is characterized in that the preferred sodium bisulfite of described reductive agent, one or more in S-WAT, Sodium Pyrosulfite.
4. the preparation method of a Compound I, after it is characterized in that method prepares compound IV as described in as arbitrary in claim 1-3, carry out step (3): compound V and compound IV and alkalimetal hydride reaction are obtained Compound I, and reaction formula is as follows:
。
5. preparation method as claimed in claim 4, is characterized in that the preferred sodium hydride of alkalimetal hydride, potassium hydride KH in described step (3), and temperature of reaction is-20 ℃ ~ 50 ℃.
6. preparation method as claimed in claim 4, it is characterized in that described step (3) selection process is as follows, the compound IV of mol ratio 1:1-2 and compound V are added in reactor, add the organic solvent with compound IV envelope-bulk to weight ratio 5-10, be cooled to-20 ℃ ~ 0 ℃ after stirring and dissolving, remain in this temperature range and add sodium hydride in batches, the sodium hydride that adds and the mol ratio of compound IV are 2 ~ 6:1, maintain the temperature at 20-50 ℃ after sodium hydride finishes and obtain Compound I until react completely.
7. preparation method as claimed in claim 6, the organic solvent that it is characterized in that described step (3) is DMF.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939910A (en) * | 2004-12-31 | 2007-04-04 | 孙飘扬 | Amino-metadiazine compound and its salt, its preparation and pharmaceutical use |
| CN101391984A (en) * | 2008-11-07 | 2009-03-25 | 东华大学 | Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate |
| CN102603710A (en) * | 2011-10-22 | 2012-07-25 | 成都格蓝洋生物医药科技有限公司 | Preparation method of imatinib intermediate |
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2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939910A (en) * | 2004-12-31 | 2007-04-04 | 孙飘扬 | Amino-metadiazine compound and its salt, its preparation and pharmaceutical use |
| CN101391984A (en) * | 2008-11-07 | 2009-03-25 | 东华大学 | Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate |
| CN102603710A (en) * | 2011-10-22 | 2012-07-25 | 成都格蓝洋生物医药科技有限公司 | Preparation method of imatinib intermediate |
Non-Patent Citations (1)
| Title |
|---|
| EUGENIO QUARANTA ET AL.，: "The reaction of pyrrole with dimethyl carbonate under phosphazene catalysis: N-methoxycarbonylation vs N-methylation", 《APPLIED CATALYSIS B: ENVIRONMENTAL》 * |
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