CN106187914B - A kind of preparation method of 2,4- dichloro-5-methoxy pyrimidine - Google Patents
A kind of preparation method of 2,4- dichloro-5-methoxy pyrimidine Download PDFInfo
- Publication number
- CN106187914B CN106187914B CN201610546756.5A CN201610546756A CN106187914B CN 106187914 B CN106187914 B CN 106187914B CN 201610546756 A CN201610546756 A CN 201610546756A CN 106187914 B CN106187914 B CN 106187914B
- Authority
- CN
- China
- Prior art keywords
- added
- dichloro
- reaction
- pyrimidine
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
Abstract
The present invention relates to the preparation methods of one kind 2,4- dichloro-5-methoxy pyrimidine, belong to the preparation technical field of pesticide intermediate.Then this method successively carries out chlorination with chlorine and phosphorus oxychloride respectively, obtains 2,4- dichloro-5-methoxy pyrimidine so that first using Ethyl formate and methoxy menthyl acetate as raw material, through being condensed, 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine is made in cyclization.All raw materials of the present invention are easy to get, and synthetic route is novel, and cyclization step high income, chloro agent dosage is low, is suitable for industrialized production.
Description
Technical field
The invention belongs to the preparation technical fields of pesticide intermediate, and in particular to one kind 2,4- dichloro-5-methoxy pyrimidine
Preparation method.
Technical background
2,4- dichloro-5-methoxy pyrimidine is to synthesize a kind of novel, efficient, low toxicity herbicide important intermediate 2- ammonia
The important source material of base -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine.Chinese invention patent publication number
The synthetic method of one kind 2,4- dichloro-5-methoxy pyrimidine is described in CN101486684A, with Ethyl formate, methoxyacetic acid
Methyl esters is starting material, obtains target product by ester condensation, cyclization, chloro, chlorinating agent dosage is big, and total recovery is in 57%-
Between 67%, yield is relatively low.Applicant from cost angle is reduced, explore a kind of raw material be easy to get, be low in cost, synthesis letter
Just and the method that is able to satisfy industrialization production requirements.
Summary of the invention
The present invention is intended to provide a kind of raw material is easy to get, is low in cost, is convieniently synthesized and be able to satisfy industrialization production requirements
Method.
The preparation method of one kind 2,4- dichloro-5-methoxy pyrimidine, it is characterised in that: its specific reaction route are as follows:
The specific steps are that:
A) Ethyl formate is added into device preparation 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine, is added with stirring methanol
Methoxy menthyl acetate is added dropwise into system and carries out ester condensation reaction, obtains compound I for sodium solid after cooling, and backward system
Middle addition methanol heating stirring is uniformly dispersed to compound I, adds thiocarbamide, back flow reaction, concentrated after reaction plus water
Acid, filtering are adjusted in dissolution, are dried to obtain compound II；
B) dichloroethanes is added in preparation 2,4- dichloro-5-methoxy pyrimidine in compound II, is passed through chlorine under stirring and obtains
To intermediate III, and addition chlorinating agent and acid binding agent, temperature reaction are concentrated after reaction in backward system, cooling, dilute
It releases, filters, obtain 2,4- dichloro-5-methoxy pyrimidine.
Wherein, during prepare compound I, methoxy menthyl acetate uses dropwise addition mode, because methoxyl group is added
Methyl acetate process is exothermic process, and dropwise addition can make danger caused by reacting uncontrollable to avoid very exothermic, and can be to avoid
Methoxy menthyl acetate self-condensation.
In the present invention, compound I, which react with thiocarbamide, generates compound II.Step A) described in methoxyacetic acid first
The mass ratio of the material of ester and thiocarbamide is 1:1-3.
In order to guarantee reaction sufficiently and the abundant precipitation of compound II, step A) described in the return time of reflux be
100-600min, the acid for adjusting acid to adopt are hydrochloric acid, sulfuric acid, acetic acid, and pH value control is 2-6.
After obtaining compound II, since chlorinating agent phosphorus oxychloride can not make sulfydryl chloro, it is therefore desirable to which substep carries out.
Chloro is carried out with chlorine to the sulfydryl on compound II first, remaining hydroxyl uses phosphorus oxychloride chloro again, using such mode,
Both the dosage of chloro agent phosphorus oxychloride can have been reduced, and this two step is divided to carry out chloro, had been further ensured in high yield.
When carrying out chloro with chlorine to the sulfydryl on compound II, step B) described in the speed for being passed through chlorine be with 1-
3g/min, reaction temperature are 0-40 DEG C, reaction time 200-600min.The too small reaction of chlorine speed is slowly, excessive to be more than
The saturation adsorptive value of solvent, causes to waste；It is more slow that reaction temperature crosses low reaction, and excessively high reaction is too fast, is likely to result in anti-
Should be acutely uncontrollable, and then generate dangerous；Cross that low reaction is incomplete the reaction time, the reaction time is excessively high, and to cause energy consumption to waste same
When, it is also possible to increase side reaction.
Further, step B) described in compound ii and chlorinating agent the mass ratio of the material be 1:0.5-3；Compound ii
The mass ratio of the material with acid binding agent is 1:0.5-3.
Chlorinating agent of the present invention is phosphorus oxychloride, and the acid binding agent is triethylamine, pyridine or N, N- dimethyl benzene
One or more of amine.
Step B) described in temperature reaction temperature be 50-90 DEG C, reaction time 120-480min.
Step B) described in diluent be water, the temperature of water is 0-30 DEG C.
The advantages of technical solution provided by the invention is: all raw materials are easy to get, and synthetic route is novel, cyclization step yield
Height, chloro agent dosage is low, and total recovery 80%-89%, purity is suitable for industrialized production up to 99% or more.
Specific embodiment:
Embodiment 1
A 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine) is prepared, Ethyl formate 185g (2.5mol) is added in device, stirring
Lower addition sodium methoxide solid 91.8g (1.7mol), 20 DEG C or less are added dropwise methoxy menthyl acetate 104g (1mol) to system, are added dropwise
20 DEG C of insulation reaction 300min are finished, chemical compounds I is obtained；And 340ml methanol is added in backward chemical compounds I and is heated to 65 DEG C of stirrings
It is uniformly dispersed, is added thiocarbamide 114g (1.5mol), back flow reaction 260min to chemical compounds I, be concentrated into 1/4 volume, 330ml is added
Water dissolution is cooled to 10 DEG C, and hydrochloric acid tune pH value to 2, filtering is washed filter cake with 100ml moisture twice, obtained in 100 DEG C of dry 8h
145.3g compound ii, yield 92%, HPLC purity are 99.7%；
B 2,4- dichloro-5-methoxy pyrimidine) is prepared, is stirred equipped with thermometer, reflux condensing tube, air-breather and machinery
In the 500ml four-hole boiling flask mixed, to 250ml dichloroethanes is added in compound ii 79g (0.5mol), being passed through chlorine speed is
2g/min reacts 480min at 10 DEG C, obtains compound III.And n,N-Dimethylaniline is successively put into backward system
45.4g (0.375mol) and phosphorus oxychloride 57.5g (0.375mol) is warming up to 80 DEG C of reaction 180min, is concentrated into 1/4 volume,
It is cooled to room temperature, is slowly dropped in 8 DEG C of the mixture of ice and water of 300ml, control temperature is no more than 20 DEG C, a large amount of solid analysis
Out, it filters, filter cake is washed with water to neutrality and obtains 2,4- dichloro-5-methoxy pyrimidine, is dried in vacuo to obtain 80.55g, yield is
90%, purity 99.2%.
Embodiment 2
A 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine) is prepared, chemical compounds I is obtained using the same method of embodiment 1；And
It 340ml methanol is added in backward chemical compounds I is heated to 65 DEG C of stirring to chemical compounds Is and be uniformly dispersed, be added thiocarbamide 152g (2mol),
Back flow reaction 240min is concentrated into 1/4 volume, and the dissolution of 330ml water is added, and is cooled to 10 DEG C, and acetic acid tune pH value to 3 filters, and uses
100ml moisture washs filter cake twice, obtains 150.1g compound ii, yield 95% in 100 DEG C of dry 8h, HPLC purity is
99.6%；
B 2,4- dichloro-5-methoxy pyrimidine) is prepared, is stirred equipped with thermometer, reflux condensing tube, air-breather and machinery
In the 500ml four-hole boiling flask mixed, to 250ml dichloroethanes is added in compound ii 79g (0.5mol), being passed through chlorine speed is
3g/min reacts 400min at 20 DEG C, obtains compound III.And triethylamine 101g (0.5mol) is successively put into backward system
And phosphorus oxychloride 84.4g (0.55mol), 70 DEG C of reaction 240min are warming up to, 1/4 volume is concentrated into, is cooled to room temperature, are slowly dripped
It is added in 5 DEG C of the mixture of ice and water of 300ml, control temperature is no more than 20 DEG C, and a large amount of solids are precipitated, and filtering, filter cake is washed with water
2,4- dichloro-5-methoxy pyrimidine is obtained to neutrality, is dried in vacuo to obtain 83.24g, yield 93%, purity 99.4%.
Embodiment 3
A 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine) is prepared, chemical compounds I is obtained using the same method of embodiment 1；And
It 340ml methanol is added in backward chemical compounds I is heated to 65 DEG C of stirring to chemical compounds Is and be uniformly dispersed, be added thiocarbamide 152g (3mol),
Back flow reaction 180min is concentrated into 1/4 volume, and the dissolution of 330ml water is added, and is cooled to 10 DEG C, and sulfuric acid tune pH value to 5 filters, and uses
100ml moisture washs filter cake twice, obtains 144.25g compound ii, yield 91.3% in 100 DEG C of dry 8h, HPLC purity is
99.2%；
B 2,4- dichloro-5-methoxy pyrimidine) is prepared, is stirred equipped with thermometer, reflux condensing tube, air-breather and machinery
In the 500ml four-hole boiling flask mixed, to 250ml dichloroethanes is added in compound ii 79g (0.5mol), being passed through chlorine speed is
1g/min reacts 420min at 30 DEG C, obtains compound III.And pyridine 79g (1mol) and three is successively put into backward system
Chlorethoxyfos 115.15g (0.75mol) is warming up to 85 DEG C of reaction 150min, is concentrated into 1/4 volume, is cooled to room temperature, be slowly added dropwise
Into 10 DEG C of 300ml of mixture of ice and water, control temperature is no more than 20 DEG C, and a large amount of solids are precipitated, filtering, filter cake be washed with water to
Neutrality obtains 2,4- dichloro-5-methoxy pyrimidine, is dried in vacuo to obtain 81g, yield 90.5%, purity 99.1%.
Embodiment 4
A 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine) is prepared, chemical compounds I is obtained using the same method of embodiment 1；And
It 340ml methanol is added in backward chemical compounds I is heated to 65 DEG C of stirring to chemical compounds Is and be uniformly dispersed, be added thiocarbamide 76g (1mol),
Back flow reaction 350min is concentrated into 1/4 volume, and the dissolution of 330ml water is added, and is cooled to 10 DEG C, and acetic acid tune pH value to 2 filters, and uses
100ml moisture washs filter cake twice, obtains 145.2g compound ii, yield 91.9% in 100 DEG C of dry 8h, HPLC purity is
99.6%；
B 2,4- dichloro-5-methoxy pyrimidine) is prepared, is stirred equipped with thermometer, reflux condensing tube, air-breather and machinery
In the 500ml four-hole boiling flask mixed, to 250ml dichloroethanes is added in compound ii 79g (0.5mol), being passed through chlorine speed is
3g/min reacts 300min at 10 DEG C, obtains compound III.And triethylamine 151.5g is successively put into backward system
(1.5mol) and phosphorus oxychloride 230.25g (1.5mol) is warming up to 50 DEG C of reaction 230min, is concentrated into 1/4 volume, is cooled to room
Temperature is slowly dropped in 5 DEG C of the mixture of ice and water of 300ml, and control temperature is no more than 20 DEG C, and a large amount of solids are precipitated, and is filtered, filter
Cake is washed with water to neutrality and obtains 2,4- dichloro-5-methoxy pyrimidine, is dried in vacuo to obtain 81.53g, yield 91.1%, and purity is
99.2%.
Embodiment 5
A 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine) is prepared, chemical compounds I is obtained using the same method of embodiment 1；And
It 340ml methanol is added in backward chemical compounds I is heated to 65 DEG C of stirring to chemical compounds Is and be uniformly dispersed, be added thiocarbamide 76g (1mol),
Back flow reaction 600min is concentrated into 1/4 volume, and the dissolution of 330ml water is added, and is cooled to 10 DEG C, and acetic acid tune pH value to 6 filters, and uses
100ml moisture washs filter cake twice, obtains 145.0g compound ii, yield 91.8% in 100 DEG C of dry 8h, HPLC purity is
99.3%；
B 2,4- dichloro-5-methoxy pyrimidine) is prepared, is stirred equipped with thermometer, reflux condensing tube, air-breather and machinery
In the 500ml four-hole boiling flask mixed, to 250ml dichloroethanes is added in compound ii 79g (0.5mol), being passed through chlorine speed is
2.5g/min reacts 600min at 10 DEG C, obtains compound III.And triethylamine 126.5g is successively put into backward system
(1.25mol) and phosphorus oxychloride 191.66g (1.25mol) is warming up to 60 DEG C of reaction 480min, is concentrated into 1/4 volume, is cooled to
Room temperature is slowly dropped in 5 DEG C of the mixture of ice and water of 300ml, and control temperature is no more than 20 DEG C, and a large amount of solids are precipitated, filtering,
Filter cake is washed with water to neutrality and obtains 2,4- dichloro-5-methoxy pyrimidine, is dried in vacuo to obtain 83.14g, yield 92.9%, purity
It is 99.1%.
Embodiment 6
A 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine) is prepared, chemical compounds I is obtained using the same method of embodiment 1；And
It 340ml methanol is added in backward chemical compounds I is heated to 65 DEG C of stirring to chemical compounds Is and be uniformly dispersed, be added thiocarbamide 76g (1mol),
Back flow reaction 100min is concentrated into 1/4 volume, and the dissolution of 330ml water is added, and is cooled to 10 DEG C, and acetic acid tune pH value to 4 filters, and uses
100ml moisture washs filter cake twice, obtains 144.9g compound ii, yield 91.7% in 100 DEG C of dry 8h, HPLC purity is
99.2%；
B 2,4- dichloro-5-methoxy pyrimidine) is prepared, is stirred equipped with thermometer, reflux condensing tube, air-breather and machinery
In the 500ml four-hole boiling flask mixed, to 250ml dichloroethanes is added in compound ii 79g (0.5mol), being passed through chlorine speed is
1.5g/min reacts 200min at 40 DEG C, obtains compound III.And triethylamine 25.3g is successively put into backward system
(0.25mol) and phosphorus oxychloride 38.33g (0.25mol) is warming up to 90 DEG C of reaction 120min, is concentrated into 1/4 volume, is cooled to
Room temperature is slowly dropped in 5 DEG C of the mixture of ice and water of 300ml, and control temperature is no more than 20 DEG C, and a large amount of solids are precipitated, filtering,
Filter cake is washed with water to neutrality and obtains 2,4- dichloro-5-methoxy pyrimidine, is dried in vacuo to obtain 81.59g, yield 91.2%, purity
It is 99.4%.
Claims (1)
1. one kind 2, the preparation method of 4- dichloro-5-methoxy pyrimidine, it is characterised in that: its specific reaction route are as follows:
The specific steps are that:
A 2- sulfydryl -4- hydroxy-5-methyl oxygroup pyrimidine) is prepared, Ethyl formate 185g is added in device, is added with stirring sodium methoxide
Solid 91.8g, 20 DEG C or less are added dropwise methoxy menthyl acetate 104g to system, and 20 DEG C of insulation reaction 300min are added dropwise, obtain
To chemical compounds I；And 340ml methanol is added in backward chemical compounds I is heated to 65 DEG C of stirring to chemical compounds Is and be uniformly dispersed, sulphur is added
Urea 152g, back flow reaction 240min, are concentrated into 1/4 volume, and the dissolution of 330ml water is added, and are cooled to 10 DEG C, acetic acid tune pH value to 3,
Filtering, washs filter cake with 100ml moisture twice, obtains 150.1g compound ii in 100 DEG C of dry 8h, yield 95%, HPLC is pure
Degree is 99.6%；
B 2,4- dichloro-5-methoxy pyrimidine) is prepared, equipped with thermometer, reflux condensing tube, air-breather and churned mechanically
In 500ml four-hole boiling flask, 250ml dichloroethanes is added into compound ii 79g, being passed through chlorine speed is 3g/min, at 20 DEG C
Lower reaction 400min, obtains compound III；And triethylamine 101g and phosphorus oxychloride 84.4g is successively put into backward system, it heats up
To 70 DEG C of reaction 240min, it is concentrated into 1/4 volume, is cooled to room temperature, is slowly dropped in 5 DEG C of the mixture of ice and water of 300ml,
It controls temperature and is no more than 20 DEG C, a large amount of solids are precipitated, filtering, and filter cake is washed with water to neutrality that obtain 2,4-, bis- chloro-5-methoxyl phonetic
Pyridine is dried in vacuo to obtain 83.24g, yield 93%, purity 99.4%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610546756.5A CN106187914B (en) | 2016-07-12 | 2016-07-12 | A kind of preparation method of 2,4- dichloro-5-methoxy pyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610546756.5A CN106187914B (en) | 2016-07-12 | 2016-07-12 | A kind of preparation method of 2,4- dichloro-5-methoxy pyrimidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106187914A CN106187914A (en) | 2016-12-07 |
| CN106187914B true CN106187914B (en) | 2019-03-15 |
Family
ID=57476560
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610546756.5A Active CN106187914B (en) | 2016-07-12 | 2016-07-12 | A kind of preparation method of 2,4- dichloro-5-methoxy pyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106187914B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003087067A1 (en) * | 2002-04-03 | 2003-10-23 | Syngenta Participations Ag | Aryl-alkyne compounds as herbicides |
| WO2008092049A1 (en) * | 2007-01-26 | 2008-07-31 | Smithkline Beecham Corporation | Anthranilamide inhibitors of aurora kinase |
| CN101486684A (en) * | 2009-02-20 | 2009-07-22 | 常熟华益化工有限公司 | Preparation of 2,4-dichloro-5-methoxy pyrimidine |
-
2016
- 2016-07-12 CN CN201610546756.5A patent/CN106187914B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003087067A1 (en) * | 2002-04-03 | 2003-10-23 | Syngenta Participations Ag | Aryl-alkyne compounds as herbicides |
| WO2008092049A1 (en) * | 2007-01-26 | 2008-07-31 | Smithkline Beecham Corporation | Anthranilamide inhibitors of aurora kinase |
| CN101486684A (en) * | 2009-02-20 | 2009-07-22 | 常熟华益化工有限公司 | Preparation of 2,4-dichloro-5-methoxy pyrimidine |
Non-Patent Citations (1)
| Title |
|---|
| Pyrimidines. XI. Synthesis of 5-hydroxypyrimidine and related compounds;J. H. CHESTERFIELD;《Journal of the Chemical Society》;19601231;第4590-4594页 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106187914A (en) | 2016-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112552284B (en) | Preparation method of chlorantraniliprole | |
| CN111848446B (en) | Synthesis method of 2-bromo-5-cyano-4-fluorobenzoic acid methyl ester | |
| CN109456329B (en) | Preparation method of famciclovir | |
| CN106187914B (en) | A kind of preparation method of 2,4- dichloro-5-methoxy pyrimidine | |
| CN109824675A (en) | A kind of synthetic method of 4- chloropyrrolo [2,3-d | |
| CN104177321B (en) | A kind of copper ion fluorescence probe based on chromene diketone and preparation method thereof | |
| CN112250599A (en) | Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester | |
| CN106397358A (en) | Method for synthesizing 3-fluoro-4-(4-morpholinyl)aniline by using micro-channel reactor | |
| CN114805327A (en) | Intermediate for thiohydantoin medicine and preparation method and application thereof | |
| CN109384827A (en) | A kind of budesonide industrialized process for preparing | |
| CN104402728A (en) | Preparation method for 5-chlorine-2-hydroxyl-3-nitroacetophenone | |
| CN107089982A (en) | 4,5 two 1 hydrogen pyrroles of substitution (2,3 f) quinoline 2,7,9 tricarboxylic ester compounds and applications | |
| CN111848505A (en) | Preparation method of vatacostat intermediate | |
| CN107382877A (en) | A kind of synthetic method of 4 amino 2 methyl 5 (bromomethyl) pyrimidine hydrobromate | |
| CN104496885B (en) | A kind of preparation method of the Nitroisatoic of 4 amino of N methyl 5 | |
| CN112125790A (en) | Synthesis method of 7-chloro-1-naphthaldehyde | |
| CN108929217B (en) | Preparation method of 2-methyl-5-fluorobenzoic acid | |
| CN105541709A (en) | Method for preparing boscalid | |
| CN111087294A (en) | Preparation method of high-purity prohexadione calcium | |
| CN109438422A (en) | It is a kind of difficult to understand uncommon for Buddhist nun's impurity and preparation method thereof | |
| CN109535074A (en) | The preparation method of 2- cyano -5- bromopyridine | |
| CN108658999A (en) | The synthetic method of 2- phenyl heterocycles simultaneously [2,3-d] pyrimidine -4 (3H) -one class compound | |
| CN108840819A (en) | A kind of preparation method of felodipine | |
| CN106831585A (en) | A kind of preparation method of pyrazole compound | |
| CN106986834B (en) | The preparation method of 5- ethyl -5- (1- methyl butyl) barbiturates sodium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |