CN102952083A - Preparation method of 2-amino pyrimidine - Google Patents
Preparation method of 2-amino pyrimidine Download PDFInfo
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- CN102952083A CN102952083A CN2011102497068A CN201110249706A CN102952083A CN 102952083 A CN102952083 A CN 102952083A CN 2011102497068 A CN2011102497068 A CN 2011102497068A CN 201110249706 A CN201110249706 A CN 201110249706A CN 102952083 A CN102952083 A CN 102952083A
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Abstract
The invention discloses a preparation method of 2-amino pyrimidine, which comprises the following steps: performing addition on low-cost industrial N,N-dimethylformamide used as an initial raw material, phosphorus trichloride and acetal to prepare addition aldehyde oil; and under the catalytic effect of sodium methoxide, performing pressurized reaction on the addition aldehyde oil and guanidine nitrate to prepare the 2-amino pyrimidine. Compared with the existing synthesis process, the method has the advantages of accessible and low-cost raw material, simple synthesis operation, mild reaction conditions, easiness in control, good reaction selectivity and high yield, and is suitable for industrial big production.
Description
Technical field
The present invention relates to the synthetic method of medicine and chemical field intermediate, be specifically related to the preparation technology of 2-aminopyrimidine.
Background technology
2-aminopyrimidine (2-Aminopyrimidine, structural formula is as shown in the formula shown in the I) is important medicine, chemical intermediate, is the important intermediate of the products such as synthetic many disinfectant use in agriculture, sulfonamide herbicides or anxiolytic Travin simultaneously.
The synthetic method of relevant 2-aminopyrimidine is also few, prior art mainly is such as 4 from various substituted-amino pyrimidines, 6-dichloro pyrimidine and 4-chloropyrimide obtain through dechlorinations such as zinc powder reductions, or from 2-substituted pyrimidines such as synthetic this product of 2-hydroxy pyrimidine, and in polar solvent, carry out ring-closure reaction take strong acid ion exchange resin as catalyzer with four alkoxyl group contracting mdas and guanidinesalt and synthesize this product etc.The main synthetic method of having reported is as follows:
1, United States Patent (USP) 2242079,2344707,2391822,2425248, English Patent 564315, the patents such as 592166 have all been introduced the method for preparing the 2-aminopyrimidine with 2-amino-4-chloropyrimide with the zinc powder reduction dechlorination.
2, mucochloric acid and Guanidinium hydrochloride cyclization under the effect of sodium methylate, again decarboxylation under high temperature, the zinc powder dechlorination makes the 2-aminopyrimidine.
3, English Patent 750676 has been introduced the method that is prepared the 2-aminopyrimidine by propynal (ketone, alcohol) and guanidine condensation under acidic conditions.
4, the open text CN1876637A of Chinese patent discloses a kind of production method of 2-aminopyrimidine, namely comprise following processing step: four alkoxyl group contracting mdas and guanidinesalt carry out ring-closure reaction take strong acid ion exchange resin as catalyzer in polar solvent, after above-mentioned reaction finishes, to reaction mixture neutralize, underpressure distillation makes the 2-aminopyrimidine.
5, West Germany BASF has introduced in the English Patent 860423 that obtains with the dimethyl formamide photoreactive gas and has mixed in benzene, chloroform, methylene dichloride and add in the ethyl vinyl ether, after the cooling of this solution and sodium methylate, Guanidinium hydrochloride back flow reaction, obtain the 2-aminopyrimidine after removing solvent, its yield is 40～80%.
Aforesaid method all can make the 2-aminopyrimidine, and method 1,2 all will be used the zinc powder reduction dechlorination, and this operation is not easy control and raw material is not easy to obtain, and production cost is high; Method 3 will operate and be not easy control simultaneously with chlorsulfonic acid and some heavy metal catalysts of severe corrosive, and yield is low, and production cost is high; Method 4 catalyzer strong-acid ion exchange resins are not easy to obtain, and production cost is high, is not suitable for suitability for industrialized production; Method 5 will be used the severe poisonous chemicals phosgene, this chemical not only is difficult to produce and store, in case and leak then cause people's difficult to the appraisal life, property damage, cause larger environmental pollution accident and social influence, use simultaneously the solvent benzol of high poison, can cause than major injury operator and environment.
Summary of the invention
The objective of the invention is for the above-mentioned problems in the prior art, provide a kind of raw material to be easy to get, technique is simple, easy and simple to handle, production cost is low and be more suitable for the preparation method of the 2-aminopyrimidine of suitability for industrialized production.
The present invention is take industrial DMF (DMF) as starting raw material, makes addition aldehyde oil with phosphorus trichloride, acetal addition; Then addition aldehyde oil and Guanidinium nitrate compressive reaction under sodium methylate catalysis use chloroform extraction, and crystallization obtains the 2-aminopyrimidine.Its synthetic route is as follows:
Reactions steps is:
1) DMF (DMF) (Compound I I) reacts with phosphorus trichloride first, then adds immediately acetal and carries out addition, makes addition aldehyde oil (compound IV);
2) addition aldehyde oil (compound IV) and Guanidinium nitrate are under the catalysis of sodium methylate, and compressive reaction makes target product 2-aminopyrimidine (Compound I).
Concrete, in step 1) make solvent with kerosene, drop into DMF (DMF), the control temperature of charge is no more than 50.0 ℃; Then control temperature and drip phosphorus trichloride at 30.0～40.0 ℃; Control again temperature and drip acetal at 30.0～40.0 ℃.Dropwise, continue to stir for some time (common 20～30 minutes), then be warming up to 45.0～55.0 ℃, leave standstill for some time (such as 15～20 minutes), material layering, upper strata kerosene can be recycled, and takes off layer solution and adds methyl alcohol and control temperature at 0～20.0 ℃, gets the methanol solution that addition aldehyde oil-methanol solution namely gets compound IV.
Step 2) sodium methylate, Guanidinium nitrate, addition aldehyde oil-methanol solution are dropped in the retort, the tank internal pressure is controlled at 0.20～0.25MPa, and temperature of reaction is controlled at 80～90 ℃, reacts (usually needing reaction 2.5～3.0 hours).After having reacted, reclaim under reduced pressure methyl alcohol also adds water, is cooled to normal temperature, and the gained reaction solution adds chloroform and extracts, extraction liquid distillation remove portion chloroform, and cooling, crystallization, filtration, dried crystals obtains the 2-aminopyrimidine.
The feed ratio (weight ratio) of each step reaction of the present invention is preferably:
Step 1) in, DMF: phosphorus trichloride: acetal: kerosene: methyl alcohol=1: (1～1.2): (1.8～1.9): (7～8): (3～4);
Step 2) in, addition aldehyde oil-methanol solution: Guanidinium nitrate: sodium methylate=1: (0.2～0.3): (1～2).
In above-mentioned feed ratio scope, the reaction yield of each step is higher.
The synthesis technique of 2-aminopyrimidine provided by the present invention makes the 2-aminopyrimidine take the industrial goods DMF (DMF) of cheapness as starting raw material by addition, condensation, extractive distillation.Compare with existing synthesis technique, raw material of the present invention is easy to get and is cheap, and synthetic operation is simple, and reaction conditions is gentle, is easy to control, good reaction selectivity, and yield is higher, is fit to suitability for industrialized production.
Embodiment
Now in conjunction with the embodiments, the present invention is further elaborated.
Embodiment 1
1) preparation of addition aldehyde oil (compound IV):
Add kerosene 145g in reaction vessel, drop into industrial DMF (DMF) 19.5g, launch process control temperature of charge is no more than 50.0 ℃.The control temperature 30.0～50.0 ℃ drip industrial DMF (DMF) after, the control temperature drips industrial phosphorus trichloride 20.6g at 30.0～40.0 ℃, then controls temperature and drips acetal 36g at 30.0～40.0 ℃.Dropwise, continue to stir 20～30 minutes, when treating that temperature of charge no longer rises (generally can be warming up to 35.0～45.0 ℃), system is warming up to 45.0～55.0 ℃, left standstill material layering 15～20 minutes, upper strata kerosene is for applying mechanically, lower floor's solution adds industrial methanol 60g and controls temperature at 0～20.0 ℃, gets the about 110g～120g of addition aldehyde oil-methanol solution, namely obtains the methanol solution of compound IV.
2) preparation of 2-aminopyrimidine (Compound I):
Successively sodium methylate 160g, Guanidinium nitrate 25g, addition aldehyde oil-methanol solution 110g are dropped in the dry retort.The tank internal pressure rises to 0.20～0.25MPa, and keeps the tank internal pressure between 0.20～0.25MPa, and temperature of reaction is controlled at 80～90 ℃, reacts 2.5～3.0 hours.After having reacted, reclaim under reduced pressure methyl alcohol, and in the retort with tap water, be cooled to normal temperature, reaction solution changes in the layering narrow-necked earthen jar, add chloroform extraction, combining extraction liquid, distillation extraction liquid is removed most of chloroform, then cooling, crystallization, filtration, vacuum-drying (50 ℃) crystal 1h, get 2-aminopyrimidine 15.8g, yield 81.1%.
Embodiment 2
1) preparation of addition aldehyde oil (compound IV):
Add kerosene 145kg in retort, drop into industrial DMF (DMF) 19.5kg, launch process control temperature of charge is no more than 50.0 ℃.The control temperature continues to drip industrial DMF (DMF) at 30.0～50.0 ℃, then controls temperature and drips industrial phosphorus trichloride 21kg at 30.0～40.0 ℃; Control again temperature and drip acetal 36kg at 30.0～40.0 ℃.Dropwise, continue to stir 20～30 minutes, when treating that temperature of charge no longer rises (usually being warming up to 35.0～45.0 ℃), system is warming up to 45.0～55.0 ℃, left standstill material layering 15～20 minutes, upper strata kerosene is for applying mechanically, lower floor's solution adds industrial methanol 60kg and controls temperature at 0～20.0 ℃, gets the about 115kg of addition aldehyde oil-methanol solution, namely obtains the methanol solution of compound IV.
2) preparation of 2-aminopyrimidine (Compound I):
Successively sodium methylate 160kg, Guanidinium nitrate 25kg, addition aldehyde oil-methanol solution 115kg are dropped in the dry retort.The tank internal pressure rises to 0.20～0.25MPa, and keeps the tank internal pressure between 0.20～0.25MPa, and temperature of reaction is controlled at 80～90 ℃, reacts 2.5～3.0 hours.After having reacted, reclaim under reduced pressure methyl alcohol, and in the retort with tap water 100kg, be cooled to normal temperature, reaction solution changes in the layering narrow-necked earthen jar, add chloroform 50kg * 3 extractions, combining extraction liquid, distillation extraction liquid is removed most of chloroform, then cooling, crystallization, filtration, vacuum-drying (50 ℃) crystal 1.5h, get 2-aminopyrimidine 15.9kg, yield 81.6%.
Claims (7)
1. the preparation method of a 2-aminopyrimidine may further comprise the steps:
1) DMF reacts with phosphorus trichloride first, then adds acetal CH
3CH (OC
2H
5)
2Carry out addition, make the addition aldehyde oil shown in the formula IV;
2) oil of the addition aldehyde shown in the formula IV and Guanidinium nitrate are under the catalysis of sodium methylate, and compressive reaction makes the 2-aminopyrimidine.
2. preparation method as claimed in claim 1 is characterized in that step 1) make solvent with kerosene, drop into DMF, the control temperature of charge is no more than 50.0 ℃; Then control temperature and drip phosphorus trichloride at 30.0～40.0 ℃; Control again temperature and drip acetal at 30.0～40.0 ℃; Dropwise, continue to stir for some time, then be warming up to 45.0～55.0 ℃, leave standstill for some time, material layering takes off layer solution and adds methyl alcohol and control temperature at 0～20.0 ℃, gets addition aldehyde oil-methanol solution for step 2).
3. preparation method as claimed in claim 2, it is characterized in that, step 1) DMF in: phosphorus trichloride: acetal: kerosene: the weight ratio of methyl alcohol is 1: (1～1.2): (1.8～1.9): (7～8): (3～4).
4. preparation method as claimed in claim 2 is characterized in that step 1) acetal dropwises rear stirring reaction 20～30 minutes, and then be warming up to 45.0～55.0 ℃ and left standstill material layering 15～20 minutes.
5. preparation method as claimed in claim 2, it is characterized in that, step 2) with sodium methylate, Guanidinium nitrate and step 1) the addition aldehyde oil-methanol solution of preparation drops in the retort, and control tank internal pressure is at 0.20～0.25MPa, and temperature of reaction is reacted at 80～90 ℃, reclaim under reduced pressure methyl alcohol and add water after reaction is finished, be cooled to normal temperature, the gained reaction solution adds chloroform and extracts, extraction liquid distillation remove portion chloroform, cooling, crystallization, filtration, dried crystals obtain the 2-aminopyrimidine.
6. preparation method as claimed in claim 5 is characterized in that step 2) reaction times is 2.5～3.0 hours.
7. preparation method as claimed in claim 5 is characterized in that step 2) middle addition aldehyde oil-methanol solution: Guanidinium nitrate: the weight ratio of sodium methylate is 1: (0.2～0.3): (1～2).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103319419A (en) * | 2013-06-18 | 2013-09-25 | 复旦大学 | Preparation method of 4-parafluorophenyl6-isopropyl-2-(N-methylmethanesulfamine)pyrimidine-5-carboxylic acid |
| CN107602412A (en) * | 2017-09-04 | 2018-01-19 | 吉林北沙制药有限公司 | A kind of preparation of aldehyde oil methanol solution and method of purification |
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| GB577119A (en) * | 1944-04-05 | 1946-05-06 | Manchester Oxide Co Ltd | Improvements in the production of 2-amino pyrimidine |
| CN1876637A (en) * | 2006-05-17 | 2006-12-13 | 杭州江南化工有限公司 | 2-amido pyrimidine production method |
| CN101602757A (en) * | 2009-07-14 | 2009-12-16 | 丹东恒悦新材料有限公司 | 4-substituent-2-amido pyrimidine compound and preparation method thereof |
| CN101851229A (en) * | 2010-06-11 | 2010-10-06 | 浙江工业大学 | N-substituted pyridine acyl-N-substituted pyrimidyl thiourea derivant as well as preparation and application thereof |
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2011
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB577119A (en) * | 1944-04-05 | 1946-05-06 | Manchester Oxide Co Ltd | Improvements in the production of 2-amino pyrimidine |
| CN1876637A (en) * | 2006-05-17 | 2006-12-13 | 杭州江南化工有限公司 | 2-amido pyrimidine production method |
| CN101602757A (en) * | 2009-07-14 | 2009-12-16 | 丹东恒悦新材料有限公司 | 4-substituent-2-amido pyrimidine compound and preparation method thereof |
| CN101851229A (en) * | 2010-06-11 | 2010-10-06 | 浙江工业大学 | N-substituted pyridine acyl-N-substituted pyrimidyl thiourea derivant as well as preparation and application thereof |
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| MARTIN, GERARD等: "Research on the Vilsmeier-Haack reaction. I. Study of the structure of the intermediary complexes by nuclear magnetic resonance", 《BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319419A (en) * | 2013-06-18 | 2013-09-25 | 复旦大学 | Preparation method of 4-parafluorophenyl6-isopropyl-2-(N-methylmethanesulfamine)pyrimidine-5-carboxylic acid |
| CN107602412A (en) * | 2017-09-04 | 2018-01-19 | 吉林北沙制药有限公司 | A kind of preparation of aldehyde oil methanol solution and method of purification |
| CN107602412B (en) * | 2017-09-04 | 2020-04-03 | 吉林北沙制药有限公司 | Preparation and purification method of aldehyde oil methanol solution |
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