CN101318935B - Method for preparing hydrochloric 1-(2-pyrimidine) diethylenediamine compound - Google Patents
Method for preparing hydrochloric 1-(2-pyrimidine) diethylenediamine compound Download PDFInfo
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- CN101318935B CN101318935B CN2008101169473A CN200810116947A CN101318935B CN 101318935 B CN101318935 B CN 101318935B CN 2008101169473 A CN2008101169473 A CN 2008101169473A CN 200810116947 A CN200810116947 A CN 200810116947A CN 101318935 B CN101318935 B CN 101318935B
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Abstract
The invention provides a method for preparing hydrochloric acid 1-(2-pyrimidinyl) piperazine. The method comprises the following steps that: bis(2-halogenoethyl) amine reacts with 2-amino-pyrimidin at a temperature of between 80 and 150 DEG C for 6 to 10 hours to produce a crude product of 1-(2-pyrimidnyl) piperazine, and then the crude product of 1-(2-pyrimidnyl) piperazine is subjected to post-treatment to produce the hydrochloric acid 1-(2-pyrimidinyl) piperazine. The preparation method has the advantages of low cost of raw materials, short reaction time, simple equipment, and suitability for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of compound, specifically, relate to the preparation method of a kind of hydrochloric acid 1-(2-pyrimidine) diethylenediamine compound.
Background technology
Compound hydrochloric acid 1-(2-pyrimidine) piperazine is an intermediate commonly used in some medication preparation processes, and this compound mostly is and is used to prepare the anxiolytic Travin at present, and is the key intermediate in this medication preparation process.
In existing documents and materials, preparation method about hydrochloric acid 1-(2-pyrimidine) piperazine is rare, representative is that people such as Xu Yan are at Chinese Journal of Pharmaceuticals, 1993,24 (2): the elder generation of introducing among the 49-51 is converted into the 2-chloropyrimide with the 2-aminopyrimidine, again 2-chloropyrimide and Piperazine anhydrous are reacted the method that obtains 1-(2-pyrimidine) piperazine, formula as follows:
In aforesaid method, utilized carcinogenic Sodium Nitrite as reactant, and consumption is big, the one-step reaction total mass number surpasses main raw material 2-aminopyrimidine 20%, has brought inconvenience for production safety and liquid waste disposal.Because this two step of method yield is all not high, cause 1-(2-pyrimidine) piperazine ultimate yield to have only about 40% simultaneously, industrial application value is not obvious.
What need to replenish is, hydrochloric acid 1-(2-pyrimidine) piperazine is to combine the salt that forms by a part 1-(2-pyrimidine) piperazine with some molecule HCl, and both can transform under acid or alkali environment mutually, as the last no essential distinction of intermediate application.Be shown below:
The present invention tries to explore to prepare the novel method of hydrochloric acid 1-(2-pyrimidine) piperazine in order to overcome the shortcoming that prior art exists, and makes its high efficiency, low cost, meets industrial production requirement.
Summary of the invention
The purpose of this invention is to provide the preparation method of a kind of hydrochloric acid 1-(2-pyrimidine) diethylenediamine compound, this method steps is simple, yield is high, is applicable to suitability for industrialized production.
The preparation method of hydrochloric acid 1-provided by the invention (2-pyrimidine) diethylenediamine compound comprises the steps:
1) earlier two (2-halogenated ethyl) amine and 2-aminopyrimidine are reacted 6～10h down at 80～150 ℃, get 1-(2-pyrimidine) piperazine crude product;
2) then 1-(2-pyrimidine) piperazine crude product is carried out aftertreatment and get hydrochloric acid 1-(2-pyrimidine) piperazine, yield is greater than 80%.
Wherein, described two (2-halogenated ethyl) amine is one or more in two (2-chloro ethyl) amine, two (2-bromoethyl) amine and two (the 2-iodo ethyl) amine.
The mol ratio of two (2-halogenated ethyl) amine and 2-aminopyrimidine is 1: 1～1.5: 1.
In the step 1) two (2-halogenated ethyl) amine is dissolved in earlier in the solvent, solvent for use is propyl carbinol, DMF or acetonitrile etc.
Hydrochloride solid and the alkali reaction of using stable two (2-halogenated ethyl) amine in actual building-up reactions always obtain two (2-halogenated ethyl) amine.Be that described two (2-halogenated ethyl) amine is obtained by two (2-halogenated ethyl) amine hydrochlorates and alkali substance reaction.
Alkaline matter is anhydrous sodium carbonate, Anhydrous potassium carbonate, sodium hydroxide, potassium hydroxide etc.Role is an acid-acceptor, eliminates the acid that generates in the reaction, and chemical reaction equilibrium is moved to favourable direction.
Preferable reaction temperature is 110～120 ℃.The preferred reaction time is 8～10h.
Described aftertreatment is: in dehydrated alcohol, the ethanolic soln that feeds HCl or adding HCl is again separated out filtering drying until the adularescent crystal with 1-(2-pyrimidine) piperazine dissolving crude product.
The inventive method is as shown in the formula expression:
X＝Cl，Br，I
The present invention adopt two (2-halogenated ethyl) amine directly and the 2-aminopyrimidine react and obtain target product, compare with existing technology, step is more simple, yield is doubled.And, environmentally friendly without Sodium Nitrite as reactant, meet the trend of modern Green Chemistry.Thereby the inventive method is suitable for suitability for industrialized production.
Description of drawings
Fig. 1 is the infared spectrum of 1-of the present invention (2-pyrimidine) piperazine.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Amine 21.5g (0.12mol) is dissolved in the 50ml propyl carbinol solvent with hydrochloric acid two (2-chloro ethyl), add Anhydrous potassium carbonate 16.62g (0.12mol), add 2-aminopyrimidine 11.5g (0.12mol) back flow reaction 8h in batches, temperature is 120 ℃, remove by filter the salt that reaction generates, steaming desolventizes propyl carbinol, obtain viscous liquid, it is dissolved in the 20ml dehydrated alcohol, feed HCl until there being a large amount of white solids to separate out, filtering drying gets hydrochloric acid 1-(2-pyrimidine) piperazine solid 23.7g, yield 82.8%.Hydrochloric acid 1-(2-pyrimidine) piperazine is converted into 1-(2-pyrimidine) piperazine detects its structure of matter, get 177 ℃ of fusing points, the IR collection of illustrative plates is seen Fig. 1, meets the material property of this compound fully.
Embodiment 2
Amine 17.0g (0.12mol) is dissolved in the 50ml acetonitrile solvent with two (2-chloro ethyl), add 2-aminopyrimidine 11.5g (0.12mol) back flow reaction 10h in batches, temperature is 80 ℃, solids removed by filtration impurity, and steaming desolventizes acetonitrile, obtain viscous liquid, it is dissolved in the 20ml dehydrated alcohol, and the ethanolic soln that adds HCl is until there being a large amount of white solids to separate out filtering drying, get solid 23.1g, yield 80.7%.
Embodiment 3
Amine 32.3g (0.18mol) is dissolved in the 50ml DMF solvent with hydrochloric acid two (2-chloro ethyl), add anhydrous sodium carbonate 19.08g (0.18mol), add 2-aminopyrimidine 11.5g (0.12mol) back flow reaction 6h in batches, temperature is 150 ℃, remove by filter the salt that reaction generates, steaming desolventizes DMF, obtains viscous liquid, and it is dissolved in the 25ml dehydrated alcohol, feed HCl until there being a large amount of white solids to separate out, filtering drying gets solid 24.2g, yield 84.5%.
Embodiment 4
Hydrochloric acid two (the 2-chloro ethyl) amine that adds among the embodiment 1 replaces with hydrochloric acid two (2-bromoethyl) amine, and its mole dosage and other steps are identical with embodiment 1.
Embodiment 5
Hydrochloric acid two (the 2-chloro ethyl) amine that adds among the embodiment 1 replaces with hydrochloric acid two (2-iodo ethyl) amine, and its mole dosage and other steps are identical with embodiment 1.
Embodiment 6
Two (the 2-chloro ethyl) amine that adds among the embodiment 2 replaces with two (2-bromoethyl) amine, and its mole dosage and other steps are identical with embodiment 2.
Embodiment 7
Two (the 2-chloro ethyl) amine that adds among the embodiment 2 replaces with two (2-iodo ethyl) amine, and its mole dosage and other steps are identical with embodiment 2.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. the preparation method of a 1-(2-pyrimidyl) piperazine hydrochloride compound is characterized in that, comprises the steps:
1) earlier two (2-halogenated ethyl) amine and 2-aminopyrimidine are reacted 6～10h down at 80～150 ℃, get 1-(2-pyrimidyl) piperazine crude product;
2) then 1-(2-pyrimidyl) piperazine crude product is carried out aftertreatment and get 1-(2-pyrimidyl) piperazine hydrochloride.
2. preparation method according to claim 1 is characterized in that, described two (2-halogenated ethyl) amine is one or more in two (2-chloro ethyl) amine, two (2-bromoethyl) amine and two (the 2-iodo ethyl) amine.
3. preparation method according to claim 1 and 2 is characterized in that, the mol ratio of described two (2-halogenated ethyl) amine and 2-aminopyrimidine is 1: 1～1.5: 1.
4. preparation method according to claim 1 and 2 is characterized in that, in the step 1) two (2-halogenated ethyl) amine is dissolved in earlier in the solvent, and solvent for use is propyl carbinol, DMF or acetonitrile.
5. preparation method according to claim 3 is characterized in that, in the step 1) two (2-halogenated ethyl) amine is dissolved in earlier in the solvent, and solvent for use is propyl carbinol, DMF or acetonitrile.
6. preparation method according to claim 1 and 2 is characterized in that, described two (2-halogenated ethyl) amine is obtained by two (2-halogenated ethyl) amine hydrochlorates and alkali substance reaction.
7. preparation method according to claim 6 is characterized in that, described alkaline matter is anhydrous sodium carbonate, Anhydrous potassium carbonate, sodium hydroxide or potassium hydroxide.
8. preparation method according to claim 1 is characterized in that, the temperature of reaction is 110～120 ℃.
9. preparation method according to claim 1 is characterized in that, the time of reaction is 8～10h.
10. preparation method according to claim 1 is characterized in that, described aftertreatment is: in dehydrated alcohol, the ethanolic soln that feeds HCl or adding HCl is again separated out filtering drying until the adularescent crystal with 1-(2-pyrimidyl) piperazine dissolving crude product.
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| CN103880750A (en) * | 2014-03-18 | 2014-06-25 | 上海皓元生物医药科技有限公司 | Method for preparing key intermediate of Tenelia |
| CN106543089A (en) * | 2016-11-04 | 2017-03-29 | 山东铂源药业有限公司 | A kind of synthetic method of Dasatinib intermediate |
| CN115557902A (en) * | 2022-11-09 | 2023-01-03 | 武汉海特生物创新医药研究有限公司 | Preparation method of N- (2-pyrimidine) piperazine hydrochloride |
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Non-Patent Citations (2)
| Title |
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| 李勇 等.哌嗪的合成工艺评述.《化学研究与应用》.1998,第10卷(第1期),15-20. |
| 李勇等.哌嗪的合成工艺评述.《化学研究与应用》.1998,第10卷(第1期),15-20. * |
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