CN103351348A - Synthetic method for 2-methylamino pyrimidine hydrochloride - Google Patents
Synthetic method for 2-methylamino pyrimidine hydrochloride Download PDFInfo
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- CN103351348A CN103351348A CN201310301588XA CN201310301588A CN103351348A CN 103351348 A CN103351348 A CN 103351348A CN 201310301588X A CN201310301588X A CN 201310301588XA CN 201310301588 A CN201310301588 A CN 201310301588A CN 103351348 A CN103351348 A CN 103351348A
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Abstract
The invention belongs to the technical field of organic synthesis, relates to a synthetic method for 2-substitued pyrimidine hydrochloride, particularly to a synthetic method for 2-methylamino pyrimidine hydrochloride. The method firstly adopts 2-chloromethyl pyrimidine as starting raw material, and the 2-methylamino pyrimidine hydrochloride can be obtained after amination and alcoholysis reaction. The method has the advantages that the reaction period is short, the conversion rate is high, the product quality is superior, the content of prepared 2-methylamino pyrimidine hydrochloride is higher than 99%, the operation steps are simple, the required equipment is simple, and the energy consumption is low.
Description
Technical field
The invention belongs to technical field of organic synthesis, relate to a kind of synthetic method of 2-substituted pyrimidines hydrochloride, particularly a kind of synthetic method of 2-methylamino pyrimidine hydrochloride.
Technical background
Pyrimidine and derivative thereof are the heterogeneous ring compounds that a class has the good biological activity, being widely used in microbiotic, sedative hypnotic and new pyrimidine is the synthetic of ultra-high efficiency weedicide, because it has simple in structure and multiple biological activity (such as sterilization, weeding) characteristics and in agricultural chemicals and medicine, occupy very important status such as, and widely people's research.Studies show that simultaneously some heterocycle intermediate is introduced pyrimidine ring by certain mode of connection, can improve its activity, will obtain the new bioactive compound that has.2-methylamino pyrimidine hydrochloride is a kind of important medicine intermediate, be mainly used in the synthetic of antiseptic-germicide, sterilant, enzyme inhibitors, metal corrosion inhibitor, mechanical stain control agent and oxidation inhibitor, also can be used as simultaneously the preparation that part is widely used in metal complexes.
At present, the method for preparing 2-methylamino pyrimidine hydrochloride is mainly: take the 2-cyanopyrimidine as raw material, under the condition of catalyzer Raney's nickel and hydrogen, make 2-methylamino pyrimidine with the ammoniacal liquor reaction, because 2-methylamino pyrimidine is unstable, obtain 2-methylamino pyrimidine hydrochloride so can add hydrochloric acid.Reaction equation is:
The method reaction requires harsh, carry out in autoclave, will make catalyzer with Raney's nickel simultaneously, and dangerous inflammable, cost is higher, and by product is more, and yield is very low.
Summary of the invention
, the deficiencies such as product yield low, synthetic difficulty long for reaction time in the prior art, the invention provides the synthetic method of the 2-methylamino pyrimidine hydrochloride that a kind of technique is simple, with short production cycle, yield is high, product purity is high, the 2-chloromethyl pyrimidine that employing is easy to get is starting raw material, through amination, alcoholysis reaction makes 2-methylamino pyrimidine hydrochloride.Concrete synthetic route is as follows:
Its concrete steps are:
(1) adding 2-chloromethyl pyrimidine in reactor adds solvent I under the room temperature, stirs the lower amination reagent that drips, and finishes for 0.5-1 hour, and in 15-20 ℃ of stirring reaction 5-8 hour, suction filtration got solid;
(2) solid is added in the solvent II, in 20-30 ℃ of stirring reaction 10-16 hour, suction filtration got 2-methylamino pyrimidine hydrochloride crude product, and crude product gets white powder-like product with solvent III recrystallization;
Wherein said solvent I is methylene dichloride or ethylene dichloride;
Described solvent II is that massfraction is the ethanol solution of hydrogen chloride of 20-30%;
Described solvent III is methyl alcohol or ethanol;
Amination reagent is the dichloromethane solution of vulkacit H or the dichloroethane solution of vulkacit H in the described step (1);
The mass ratio of 2-chloromethyl pyrimidine and solvent I is 1:4-8 in the step (1), with the molar ratio computing of pure substance, and 2-chloromethyl pyrimidine: vulkacit H=1:1.05-1.1 in the described step (1);
The solid of step (1) gained and the mass ratio of solvent II are 1:2-5 in the step (2).
At first, add 2-chloromethyl pyrimidine in reactor, adding solvent I under the room temperature stirs the lower amination reagent that drips, and drips complete in 0.5-1 hour.Because whole reaction process temperature of reaction is very low, and solvent I need to have preferably solubleness to 2-chloromethyl pyrimidine and vulkacit H, be beneficial to reaction, also needing has less solubleness to product, lower boiling non-polar solvent methylene dichloride or ethylene dichloride during so solvent I selects, the low volatile methylene dichloride of preferred boiling point.In this process, if the add-on of solvent I too much can cause waste, and can reduce reactant concn and cause speed of reaction to descend; If the add-on of solvent I is very few, then reaction is carried out not exclusively, affect the yield of product, determine through contriver's test of many times, the mass ratio of the ethylene dichloride in the methylene dichloride in the dichloromethane solution of 2-chloromethyl pyrimidine and vulkacit H or the dichloroethane solution of vulkacit H is 1:2-6, and the mass ratio of 2-chloromethyl pyrimidine and solvent I is 1:4-8.
Amination reagent is the dichloromethane solution of vulkacit H or the dichloroethane solution of vulkacit H, if amination reagent directly adds with the vulkacit H solid form, vigorous reaction can occur, cause the punching material, affect yield, therefore form solution state after vulkacit H being dissolved in solvent, add in the dropping mode, can control level of response, guarantee carrying out smoothly of reaction, the solvent and the solvent I that wherein dissolve vulkacit H are consistent to bring into play best effect, the contriver gropes to find through test of long duration, with the molar ratio computing of pure substance, 2-chloromethyl pyrimidine: during vulkacit H=1:1.05-1.1, obtain preferably reaction result, if mol ratio is lower than 1.05, then can cause 2-chloromethyl pyrimidine excessive, cause the reaction of 2-chloromethyl pyrimidine not exclusively, reduce productive rate; If mol ratio is higher than 1.1, can not play obvious promoter action to reaction, if time for adding can cause reaction process too violent less than 0.5 hour, if time for adding can cause waste of time greater than 1 hour, so time for adding is controlled at 0.5-1 hour.
15-20 ℃ stirring reaction 5-8 hour, colourless reaction solution becomes muddy in the reaction process, along with the carrying out of reaction, separates out a large amount of white solids, reacts complete, suction filtration gets solid.In this reaction process, temperature of reaction is 15-20 ℃, if temperature of reaction is lower than 15 ℃, then can cause reacting insufficient, affects yield; If temperature of reaction is higher than 20 ℃ of wastes that can cause on the energy, determine through contriver's test of many times, select 20 ℃ to be optimal reaction temperature.
In this reaction process, the reaction times is 5-8 hour, if the reaction times is shorter than 5 hours, then can cause reaction not exclusively, affects yield; Can cause temporal waste in 8 hours if the reaction times is longer than, determine through contriver's test of many times, select to be optimum reacting time in 8 hours.
The solid that step (1) is made adds solvent II, in 20-30 ℃ of stirring 10-16 hour, separates out a large amount of solids, and suction filtration gets 2-methylamino pyrimidine hydrochloride crude product.The solid of step (1) gained and the mass ratio of solvent II are 1:2-5.If the mass ratio of solvent II is lower than 2, then alcoholysis reaction is incomplete, affects the yield of product; If the mass ratio of solvent II is higher than 5, can cause last handling process very complicated.Determine that through contriver's test of many times when its mass ratio was 1:2, reaction effect was best.Solvent II is that massfraction is the 20-30% ethanol solution of hydrogen chloride, alcoholic solvent has preferably solubleness to by-product ammonium chloride, ethanol solution of hydrogen chloride to reaction temperature and, environmentally friendly, if the ethanol solution of hydrogen chloride massfraction is lower than 20%, then can reduce speed of reaction, if its massfraction is higher than 30%, then can cause reacting wayward.
In this reaction process, temperature of reaction is 20-30 ℃, if temperature of reaction is lower than 20 ℃, then can cause reacting insufficient, affects yield; If temperature of reaction is higher than 30 ℃ of wastes that can cause on the energy, determine through contriver's test of many times, select 25 ℃ to be optimal reaction temperature.
In this reaction process, the reaction times is 10-16 hour, if the reaction times is shorter than 10 hours, then can cause reaction not exclusively, affects yield; Can cause temporal waste in 16 hours if the reaction times is longer than, determine through contriver's test of many times, select 16 hours optimum reacting times.
Crude product gets white powder-like product with solvent III recrystallization, and purity is more than 99%.Methyl alcohol or ethanol have preferably solubleness to impurity, and conveniently are easy to get, so the solvent III is selected methyl alcohol or ethanol.The temperature of crystallization is too low, can raise the cost; Temperature is too high, has portioned product and is dissolved in the solvent III, determines through test of many times, and is better at 5 ℃ of-10 ℃ of recrystallizations.
In sum, the invention provides a kind of synthetic method of 2-methylamino pyrimidine hydrochloride, the method is first take 2-chloromethyl pyrimidine as starting raw material, and through amination, alcoholysis reaction makes 2-methylamino pyrimidine hydrochloride.The method is short reaction time, and transformation efficiency is high, and product quality is excellent, and the 2-methylamino pyrimidine hydrochloride yield of producing is more than 70%, and content is more than 99%.Satisfying the market is to the technical requirements of 2-methylamino pyrimidine hydrochloride, and operation steps is simple, and required equipment is simple, and energy consumption is low.
Embodiment
Further specify the present invention below in conjunction with embodiment, can make those skilled in the art more fully understand the present invention, but not limit the present invention in any way.
Embodiment 1
(1) in reactor, adds 12.85g2-chloromethyl pyrimidine, add the 51.4g methylene dichloride under the room temperature, stir the dichloromethane solution of the lower 40.4g of dropping vulkacit H, vulkacit H 14.7g wherein, methylene dichloride 25.7g dripped and to finish in 0.5 hour, in 15 ℃ of stirring reactions 5 hours, suction filtration gets solid 21.37g, yield 79.62%;
(2) solid being added the 42.74g massfraction is in 20% the ethanol solution of hydrogen chloride, in 20 ℃ of stirring reactions 10 hours, and suction filtration, 2-methylamino pyrimidine hydrochloride crude product, crude product with recrystallizing methanol after 5 ℃ of crystallizations, get white powder-like product 10.49g, yield 89.96%, purity 99.6%.Collect rate as 71.62% take 2-chloromethyl pyrimidine.
Embodiment 2
(1) in reactor, adds 12.85g2-chloromethyl pyrimidine, add the 102.8g methylene dichloride under the room temperature, stir the dichloromethane solution of the lower 92.6g of dropping vulkacit H, vulkacit H 15.5g wherein, methylene dichloride 77.1g dripped and to finish in 1 hour, in 20 ℃ of stirring reactions 8 hours, suction filtration gets solid 22.17g, yield 82.60%;
(2) solid being added the 44.34g massfraction is in 30% the ethanol solution of hydrogen chloride, in 30 ℃ of stirring reactions 16 hours, and suction filtration, 2-methylamino pyrimidine hydrochloride crude product, crude product with recrystallizing methanol after 10 ℃ of crystallizations, get white powder-like product 10.75g, yield 88.91%, purity 99.7%.Collect rate as 73.43% take 2-chloromethyl pyrimidine.
Embodiment 3
(1) in reactor, adds 12.85g2-chloromethyl pyrimidine, add the 77.1g methylene dichloride under the room temperature, stir the dichloromethane solution of the lower 66.5g of dropping vulkacit H, vulkacit H 15.1g wherein, methylene dichloride 51.4g dripped and to finish in 0.8 hour, in 18 ℃ of stirring reactions 7 hours, suction filtration gets solid 21.88g, yield 81.49%;
(2) solid being added the 43.76g massfraction is in 25% the ethanol solution of hydrogen chloride, in 25 ℃ of stirring reactions 13 hours, and suction filtration, 2-methylamino pyrimidine hydrochloride crude product, crude product with recrystallizing methanol after 7 ℃ of crystallizations, get white powder-like product 10.69g, yield 89.51%, purity 99.8%.Collect rate as 72.94% take 2-chloromethyl pyrimidine.
Embodiment 4
(1) in reactor, adds 12.85g2-chloromethyl pyrimidine, add the 65g methylene dichloride under the room temperature, stir the dichloromethane solution of the lower 53.55g of dropping vulkacit H, vulkacit H 15g wherein, methylene dichloride 38.55g dripped and to finish in 0.6 hour, in 17 ℃ of stirring reactions 6 hours, suction filtration gets solid 21.63g, yield 80.55%;
(2) solid being added the 43.26g massfraction is in 23% the ethanol solution of hydrogen chloride, in 23 ℃ of stirring reactions 12 hours, and suction filtration, 2-methylamino pyrimidine hydrochloride crude product, crude product with recrystallizing methanol after 6 ℃ of crystallizations, get white powder-like product 10.58g, yield 89.66%, purity 99.8%.Collect rate as 72.22% take 2-chloromethyl pyrimidine.
Embodiment 5
(1) in reactor, adds 12.85g2-chloromethyl pyrimidine, add the 90g methylene dichloride under the room temperature, stir the dichloromethane solution of the lower 79.65g of dropping vulkacit H, vulkacit H 15.4g wherein, methylene dichloride 64.25g dripped and to finish in 0.9 hour, in 18 ℃ of stirring reactions 7 hours, suction filtration gets solid 22.36g, yield 83.30%;
(2) solid being added the 44.72g massfraction is in 28% the ethanol solution of hydrogen chloride, in 28 ℃ of stirring reactions 14 hours, and suction filtration, 2-methylamino pyrimidine hydrochloride crude product, crude product with recrystallizing methanol after 9 ℃ of crystallizations, get white powder-like product 10.43g, yield 85.51%, purity 99.9%.Collect rate as 71.23% take 2-chloromethyl pyrimidine.
Embodiment 6
(1) in reactor, adds 12.85g2-chloromethyl pyrimidine, add the 90g methylene dichloride under the room temperature, stir the dichloromethane solution of the lower 40.4g of dropping vulkacit H, vulkacit H 14.7g wherein, methylene dichloride 25.7g dripped and to finish in 1 hour, in 15 ℃ of stirring reactions 8 hours, suction filtration gets solid 22.27g, yield 82.94%;
(2) solid being added the 44.54g massfraction is in 22% the ethanol solution of hydrogen chloride, in 22 ℃ of stirring reactions 15 hours, and suction filtration, 2-methylamino pyrimidine hydrochloride crude product, crude product with ethyl alcohol recrystallization after 9 ℃ of crystallizations, get white powder-like product 10.47g, yield 86.13%, purity 99.5%.Collect rate as 71.44% take 2-chloromethyl pyrimidine.
Embodiment 7
(1) in reactor, adds 12.85g2-chloromethyl pyrimidine, add the 90g methylene dichloride under the room temperature, stir the dichloroethane solution of the lower 41.6g of dropping vulkacit H, vulkacit H 14.7g wherein, ethylene dichloride 26.9g dripped and to finish in 1 hour, in 15 ℃ of stirring reactions 8 hours, suction filtration gets solid 21.36g, yield 79.58%;
(2) solid being added the 44.72g massfraction is in 25% the ethanol solution of hydrogen chloride, in 20 ℃ of stirring reactions 16 hours, and suction filtration, 2-methylamino pyrimidine hydrochloride crude product, crude product with recrystallizing methanol after 9 ℃ of crystallizations, get white powder-like product 10.03g, yield 82.22%, purity 99.6%.Collect rate as 65.43% take 2-chloromethyl pyrimidine.
Embodiment 8
(1) in reactor, adds 12.85g2-chloromethyl pyrimidine, add the 90g methylene dichloride under the room temperature, stir the dichloromethane solution of the lower 42.97g of dropping vulkacit H, vulkacit H 14.7g wherein, methylene dichloride 28.27g dripped and to finish in 1 hour, in 20 ℃ of stirring reactions 8 hours, suction filtration gets solid 22.36g, yield 83.30%;
(2) solid being added the 44.72g massfraction is in 25% the ethanol solution of hydrogen chloride, in 25 ℃ of stirring reactions 16 hours, and suction filtration, 2-methylamino pyrimidine hydrochloride crude product, crude product with recrystallizing methanol after 8 ℃ of crystallizations, get white powder-like product 10.98g, yield 90.01%, purity 99.9%.Collect rate as 74.98% take 2-chloromethyl pyrimidine.
Can find out by embodiment 1-8, the invention provides a kind of synthetic method of synthetic 2-substituted pyrimidines hydrochloride newly, synthesize 2-methylamino pyrimidine hydrochloride take 2-chloromethyl pyrimidine as starting raw material, raw material is easy to get; The employing medium-boiling solvent is reaction solvent, and solvent is recyclable, has improved simultaneously product yield, and product yield is more than 70%, and content is more than 99%.
Claims (7)
1. the synthetic method of a 2-methylamino pyrimidine hydrochloride, it is characterized in that: take 2-chloromethyl pyrimidine as starting raw material, concrete steps are:
(1) adding 2-chloromethyl pyrimidine in reactor adds solvent I under the room temperature, stirs the lower amination reagent that drips, and finishes for 0.5-1 hour, and in 15-20 ℃ of stirring reaction 5-8 hour, suction filtration got solid;
(2) solid is added in the solvent II, in 20-30 ℃ of stirring reaction 10-16 hour, suction filtration got 2-methylamino pyrimidine hydrochloride crude product, and crude product gets white powder-like product with solvent III recrystallization;
Wherein said solvent I is methylene dichloride or ethylene dichloride;
Described solvent II is that massfraction is the ethanol solution of hydrogen chloride of 20-30%;
Described solvent III is methyl alcohol or ethanol;
Amination reagent is the dichloromethane solution of vulkacit H or the dichloroethane solution of vulkacit H in the described step (1);
The mass ratio of 2-chloromethyl pyrimidine and solvent I is 1:4-8 in the step (1), with the molar ratio computing of pure substance, and 2-chloromethyl pyrimidine: vulkacit H=1:1.05-1.1 in the described step (1);
The solid of step (1) gained and the mass ratio of solvent II are 1:2-5 in the step (2).
2. the synthetic method of 2-methylamino pyrimidine hydrochloride according to claim 1 is characterized in that: the mass ratio of the ethylene dichloride in the methylene dichloride in the step (1) in the dichloromethane solution of 2-chloromethyl pyrimidine and vulkacit H or the dichloroethane solution of vulkacit H is 1:2-6.
3. the synthetic method of 2-methylamino pyrimidine hydrochloride according to claim 1 is characterized in that: solvent I is methylene dichloride in the step (1).
4. the synthetic method of 2-methylamino pyrimidine hydrochloride according to claim 1 is characterized in that: amination reagent is the dichloromethane solution of vulkacit H in the step (1).
5. the synthetic method of 2-methylamino pyrimidine hydrochloride according to claim 1 is characterized in that: the stirring reaction temperature is 20 ℃ in the step (1), and the reaction times is 8 hours.
6. the synthetic method of 2-methylamino pyrimidine hydrochloride according to claim 1 is characterized in that: the solid of step (1) gained and the mass ratio of solvent II are 1:2 in the step (2).
7. the synthetic method of 2-methylamino pyrimidine hydrochloride according to claim 1 is characterized in that: the stirring reaction temperature is 25 ℃ in the step (2), and the reaction times is 16 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104447757A (en) * | 2014-11-17 | 2015-03-25 | 合肥华方医药科技有限公司 | Method for synthesizing epinastine |
| CN114890953A (en) * | 2022-07-15 | 2022-08-12 | 济南宣正药业有限公司 | Preparation method of 2-aminomethyl pyrimidine hydrochloride |
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Application publication date: 20131016 |