CN109851565A - A kind of preparation method of the chloro- 2- methylthiopyrimidine of 4,6- bis- - Google Patents
A kind of preparation method of the chloro- 2- methylthiopyrimidine of 4,6- bis- Download PDFInfo
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- CN109851565A CN109851565A CN201910079206.0A CN201910079206A CN109851565A CN 109851565 A CN109851565 A CN 109851565A CN 201910079206 A CN201910079206 A CN 201910079206A CN 109851565 A CN109851565 A CN 109851565A
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- methylthiopyrimidine
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Abstract
The present invention provides the preparation methods of the chloro- 2- methylthiopyrimidine of 4,6- of one kind bis-, with 4,6- dihydroxy -2- methylthiopyrimidine for raw material, use oxalyl chloride as chlorination reagent chlorination, react the chloro- 2- methylthiopyrimidine of 4,6- bis- is made in a solvent.That the beneficial effects of the present invention are embodied in: integrated artistic processes is simple, without containing phosphorus waste liquid and generations of useless solid, high income, can stability contorting product quality, suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field technical fields, and in particular to the system of the chloro- 2- methylthiopyrimidine of 4,6- of one kind bis-
Preparation Method.
Background technique
4,6- bis- chloro- 2- methylthiopyrimidines are the important intermediate of synthesizing new, efficient, low-toxin farm chemicals and medicine, master
Wanting synthetic method is to pass through phosphorous chlorination reagent, such as POCl with 4,6- dihydroxy -2- methylthiopyrimidine for raw material3, PCl3Deng
Chlorination obtains.
Synthetic method involved in United States Patent (USP) (US5149357) and Chinese patent (CN1396158) is as follows:
Above-mentioned synthetic method after the completion of reaction, is all that reaction solution is down to low temperature, a large amount of water is then added thereto
It is quenched, obtains product finally by the method for filtering or organic solvent extraction.The good product purity of the method acquisition is received
Rate is high；But the water phase containing a large amount of phosphoric acid and hydrochloric acid is also produced simultaneously.Phosphoric acid and hydrochloric acid in water phase need to be further converted into
Phosphate and hydrochloride are filtered, and after collecting filter cake, could be discharged or be applied, and a large amount of solid waste is be easy to cause to generate, and are needed
Much room is wanted to stack a large amount of solid waste, to generate great pressure to large-scale production and environmental protection.
Summary of the invention
In order to solve the deficiencies in the prior art, the present invention provides the preparation sides of the chloro- 2- methylthiopyrimidine of 4,6- of one kind bis-
Method.
The purpose of the present invention is achieved through the following technical solutions:
The preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind bis-, with 4,6- dihydroxy -2- methylthiopyrimidine for raw material,
It uses oxalyl chloride as chlorination reagent chlorination, reacts the chloro- 2- methylthiopyrimidine of 4,6- bis-, the following institute of reaction equation is made in a solvent
Show:
Preferably, specifically comprise the following steps,
S1, with 4,6- dihydroxy -2- methylthiopyrimidine be raw material, use oxalyl chloride as chlorination reagent, in catalyst action
Under, it is heated to flowing back in reaction dissolvent, insulation reaction 1-48 hours；
S2, the reaction solution in S1 is cooled down, is evaporated under reduced pressure simultaneously recycling design；
S3, solvent dissolution is added in crude product after distilling in S2, achievees the purpose that isolate and purify through diatomite filtering；
S4, solution purified in S3 is concentrated to the chloro- 2- methylthiopyrimidine of 4,6- bis- for obtaining purity and being greater than 96%.
Preferably, catalyst is n,N-Dimethylformamide in the S1.
Preferably, reaction dissolvent includes toluene in the S1, dimethylbenzene, 1,2- dichloroethanes, n,N-Dimethylformamide,
N,N-dimethylacetamide, N-Methyl pyrrolidone, tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol diformazan
Ether.
Preferably, reaction temperature is 70~150 DEG C in the S1.
Preferably, the reactant feed: chlorination reagent: the reaction molar ratio of catalyst is 1:2~4:0~1.0.
Preferably, the mass ratio of the reactant feed and solvent is 1:2~15.
Preferably, it is toluene that agent is isolated and purified in the S3.
Preferably, the reactant feed: chlorination reagent: the reaction molar ratio of catalyst is 1:3:0.1.
Preferably, the mass ratio of the reactant feed and solvent is 1:10.
Preferably, the reaction temperature is 80 DEG C.
The beneficial effects of the present invention are embodied in: integrated artistic process is simple, nothing contains phosphorus waste liquid and useless solid generates, yield
Height, is suitable for industrialized production at energy stability contorting product quality.
Specific embodiment
Present invention discloses the preparation methods of the chloro- 2- methylthiopyrimidine of 4,6- of one kind bis-, with 4,6- dihydroxy -2- methyl mercapto
Pyrimidine is raw material, uses oxalyl chloride as chlorination reagent, and n,N-Dimethylformamide is catalyst, is heated to reflux in a solvent, i.e.,
It is converted into chlorization product, reaction solution shows that conversion ratio can reach 96% by HPLC.Wherein, reaction dissolvent includes toluene, diformazan
Benzene, 1,2- dichloroethanes, n,N-Dimethylformamide, n,N-dimethylacetamide, N-Methyl pyrrolidone, tetrahydrofuran, two
Six ring of oxygen, glycol dimethyl ether, diethylene glycol dimethyl ether.4,6- dihydroxy -2- the methylthiopyrimidine: oxalyl chloride: N, N- bis-
It is 1:2~4:0~1.0 that methylformamide, which reacts molar ratio, and optimal is 1:3:0.1.4, the 6- dihydroxy -2- methylthiopyrimidine
With the mass ratio of solvent are as follows: 1:2~15, preferably 1:10.The reaction temperature is 70~150 DEG C, preferably 80 DEG C.
The reaction equation is as follows:
The by-product of the above chlorination reaction is mainly carbon monoxide, carbon dioxide and hydrogen chloride gas, after reaction will
The distillation of reaction solution solvent is clean, and in order to preferably isolate and purify, residue is dissolved with toluene, and first is distilled off in diatomite filtering
Benzene is to get the chlorization product for being greater than 96% to purity.Specifically, the polarity due to toluene is small, boiling point good to the solubility of product
Height is easily recycled in plant produced using more, can achieve the purpose that separation, save the cost in the case where dosage is few.
Embodiment one:
Take the four-hole bottle of a 2L, configure mechanical stirring, reflux condensing tube, device for absorbing tail gas, constant pressure funnel with
And thermometer, 4,6- dihydroxy -2- methylthiopyrimidine (100g), toluene (1000mL), N, N- dimethyl formyl are added thereto
Oxalyl chloride (241g) is added dropwise under room temperature in amine (4.61g).It is added dropwise, is heated to flowing back and keeping the temperature 6 hours, end of reaction, react
Liquid is cooled to 45~55 DEG C, and vacuum distillation recovered solvent is steamed until substantially solvent-free, toluene is added, and be down to room temperature, product
Toluene solution, filtered by diatomite, filtrate concentration, obtain the chloro- 2- methylthiopyrimidine product 115g of 4,6- bis-, yield
93%, purity 98.5%.
Embodiment two:
Take the four-hole bottle of a 1L, configure mechanical stirring, reflux condensing tube, device for absorbing tail gas, constant pressure funnel with
And thermometer, 4,6- dihydroxy -2- methylthiopyrimidine (50g), 1,2- dichloroethanes (500mL), N, N- diformazan are added thereto
Base formamide (2.31g).It is added dropwise under room temperature under room temperature and oxalyl chloride (100.3g) is added dropwise.It is added dropwise, is heated to flowing back and keeps the temperature 6
Hour, end of reaction, reaction solution is cooled to 45~55 DEG C, and vacuum distillation recovered solvent is steamed until substantially solvent-free, and first is added
Benzene, and it is down to room temperature, the toluene solution of product is filtered by diatomite, and it is phonetic to obtain the chloro- 2- methyl mercapto of 4,6- bis- for filtrate concentration
Pyridine product 55.5g, yield 90%, purity 98.0%.
Embodiment three:
Take the four-hole bottle of a 1L, configure mechanical stirring, reflux condensing tube, device for absorbing tail gas, constant pressure funnel with
And thermometer, 4,6- dihydroxy -2- methylthiopyrimidine (50g), 1,2- dichloroethanes (500mL), N, N- diformazan are added thereto
Base formamide (1.15g).It is added dropwise under room temperature under room temperature and oxalyl chloride (120.4g) is added dropwise.It is added dropwise, is heated to flowing back and keeps the temperature 6
Hour, end of reaction, reaction solution is cooled to 45~55 DEG C, and vacuum distillation recovered solvent is steamed until substantially solvent-free, and first is added
Benzene, and it is down to room temperature, the toluene solution of product is filtered by diatomite, and it is phonetic to obtain the chloro- 2- methyl mercapto of 4,6- bis- for filtrate concentration
Pyridine product 54g, yield 87.6%, purity 98.5%.
Example IV:
Take the four-hole bottle of a 1L, configure mechanical stirring, reflux condensing tube, device for absorbing tail gas, constant pressure funnel with
And thermometer, 4,6- dihydroxy -2- methylthiopyrimidine (50g), 1,2- dichloroethanes (250mL), N, N- diformazan are added thereto
Base formamide (2.31g).It is added dropwise under room temperature under room temperature and oxalyl chloride (120.4g) is added dropwise.It is added dropwise, is heated to flowing back and keeps the temperature 6
Hour, end of reaction, reaction solution is cooled to 45~55 DEG C, and vacuum distillation recovered solvent is steamed until substantially solvent-free, and first is added
Benzene, and it is down to room temperature, the toluene solution of product is filtered by diatomite, and it is phonetic to obtain the chloro- 2- methyl mercapto of 4,6- bis- for filtrate concentration
Pyridine product 45g, yield 73%, purity 98.0%.
Embodiment five:
The four-hole bottle of a 500mL is taken, mechanical stirring, reflux condensing tube, device for absorbing tail gas, constant pressure funnel are configured
And thermometer, 4,6- dihydroxy -2- methylthiopyrimidine (20g), toluene (200mL), N, N- dimethyl formyl are added thereto
Amine (0.92g).It is added dropwise under room temperature under room temperature and oxalyl chloride (48.1g) is added dropwise.It is added dropwise, is heated to 90 DEG C and keeps the temperature 6 hours, instead
It should finish, reaction solution is cooled to 45~55 DEG C, and vacuum distillation recovered solvent is steamed until substantially solvent-free, toluene is added, and drop
To room temperature, the toluene solution of product is filtered by diatomite, and filtrate concentration obtains the chloro- 2- methylthiopyrimidine product of 4,6- bis-
19.7g, yield 80%, purity 96%.
Embodiment six:
The four-hole bottle of a 500mL is taken, mechanical stirring, reflux condensing tube, device for absorbing tail gas, constant pressure funnel are configured
And thermometer, 4,6- dihydroxy -2- methylthiopyrimidine (20g), Isosorbide-5-Nitrae-dioxane (200mL), N, N- bis- are added thereto
Methylformamide (0.92g).It is added dropwise under room temperature under room temperature and oxalyl chloride (48.1g) is added dropwise.It is added dropwise, is heated to 90 DEG C and keeps the temperature
6 hours, end of reaction, reaction solution was cooled to 45~55 DEG C, and vacuum distillation recovered solvent is steamed until substantially solvent-free, was added
Toluene, and it is down to room temperature, the toluene solution of product is filtered by diatomite, and filtrate concentration obtains the chloro- 2- methyl mercapto of 4,6- bis-
Pyrimidine product 17.3g, yield 70%, purity 96%.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although
Present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that: it still may be used
To modify the technical solutions described in the foregoing embodiments or equivalent replacement of some of the technical features；
And these are modified or replaceed, technical solution of various embodiments of the present invention that it does not separate the essence of the corresponding technical solution spirit and
Range.
Claims (10)
1. one kind 4, the preparation method of the chloro- 2- methylthiopyrimidine of 6- bis-, it is characterised in that: phonetic with 4,6- dihydroxy -2- methyl mercapto
Pyridine is raw material, uses oxalyl chloride as chlorination reagent chlorination, reacts the chloro- 2- methylthiopyrimidine of 4,6- bis- is made in a solvent, anti-
Answer formula as follows:
2. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as described in claim 1 bis-, it is characterised in that: including such as
Lower step,
S1, with 4,6- dihydroxy -2- methylthiopyrimidine be raw material, use oxalyl chloride as chlorination reagent, under the action of catalyst,
It is heated to flowing back in reaction dissolvent, insulation reaction 1-48 hours；
S2, the reaction solution in S1 is cooled down, is evaporated under reduced pressure simultaneously recycling design；
S3, solvent dissolution is added in crude product after distilling in S2, achievees the purpose that isolate and purify through diatomite filtering；
S4, solution purified in S3 is concentrated to the chloro- 2- methylthiopyrimidine of 4,6- bis- for obtaining purity and being greater than 96%.
3. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as claimed in claim 2 bis-, it is characterised in that: the S1
Middle catalyst is N,N-dimethylformamide.
4. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as claimed in claim 2 bis-, it is characterised in that: the S1
Middle reaction dissolvent includes toluene, dimethylbenzene, 1,2- dichloroethanes, n,N-Dimethylformamide, n,N-dimethylacetamide, N- first
Base pyrrolidones, tetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether.
5. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as claimed in claim 2 bis-, it is characterised in that: the S1
Middle reaction temperature is 70~150 DEG C.
6. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as claimed in claim 2 bis-, it is characterised in that: described anti-
Answer raw material: chlorination reagent: the reaction molar ratio of catalyst is 1:2~4:0~1.0.
7. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as claimed in claim 2 bis-, it is characterised in that: described anti-
Answering the mass ratio of raw material and solvent is 1:2~15.
8. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as claimed in claim 2 bis-, it is characterised in that: the S3
In isolate and purify agent be toluene.
9. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as claimed in claim 6 bis-, it is characterised in that: described anti-
Answer raw material: chlorination reagent: the reaction molar ratio of catalyst is 1:3:0.1.
10. the preparation method of the chloro- 2- methylthiopyrimidine of 4,6- of one kind as claimed in claim 7 bis-, it is characterised in that: described anti-
Answering the mass ratio of raw material and solvent is 1:10.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101519377A (en) * | 2009-04-10 | 2009-09-02 | 江苏常隆化工有限公司 | Method for producing substituted dichloropyrimidine |
| WO2010020432A2 (en) * | 2008-08-22 | 2010-02-25 | Summit Corporation Plc | Compounds for treatment of duchenne muscular dystrophy |
| CN105646368A (en) * | 2016-03-03 | 2016-06-08 | 深圳诺普信农化股份有限公司 | Preparation method of 2, 4-dichloro-5-methoxy pyrimidine |
| CN109053590A (en) * | 2018-08-31 | 2018-12-21 | 江苏富鼎化学有限公司 | A method of preparing the chloro- 2- aminopyrimidine of 4,6- bis- |
-
2019
- 2019-01-28 CN CN201910079206.0A patent/CN109851565A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010020432A2 (en) * | 2008-08-22 | 2010-02-25 | Summit Corporation Plc | Compounds for treatment of duchenne muscular dystrophy |
| CN101519377A (en) * | 2009-04-10 | 2009-09-02 | 江苏常隆化工有限公司 | Method for producing substituted dichloropyrimidine |
| CN105646368A (en) * | 2016-03-03 | 2016-06-08 | 深圳诺普信农化股份有限公司 | Preparation method of 2, 4-dichloro-5-methoxy pyrimidine |
| CN109053590A (en) * | 2018-08-31 | 2018-12-21 | 江苏富鼎化学有限公司 | A method of preparing the chloro- 2- aminopyrimidine of 4,6- bis- |
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Application publication date: 20190607 |