CN104496910A - Process for synthesizing 2-chloro-pyrimidine - Google Patents
Process for synthesizing 2-chloro-pyrimidine Download PDFInfo
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- CN104496910A CN104496910A CN201410708397.XA CN201410708397A CN104496910A CN 104496910 A CN104496910 A CN 104496910A CN 201410708397 A CN201410708397 A CN 201410708397A CN 104496910 A CN104496910 A CN 104496910A
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention discloses a process for synthesizing 2-chloro-pyrimidine. The process disclosed by the invention comprises the following steps: firstly, dissolving dicyandiamide into sulfuric acid at 2-6 DEG C, heating at 50-60 DEG C, and carrying out hydrolysis reaction for 4-6 hours, so as to obtain guanidine sulfate; reacting with propargyl ethyl alcohol at 50-55 DEG C for 8-12 hours, so as to obtain 2-aminopyrimidine; and finally restoring the 2-aminopyrimidine at -10 DEG C to 5 DEG C by taking NaNO2, HCl and ZnCl2 as catalysts, so as to obtain the product. Through the synthesis route, the 2-chloro-pyrimidine with relatively high purity and relatively high yield is obtained.
Description
Technical field
The present invention relates to technical field prepared by 2-chloropyrimide, particularly relate to a kind of technique of synthesizing 2-chloropyrimide.
Background technology
2-chloropyrimide has another name called 2-chloropyridine quinoline, and molecular formula is C
4h
3clN
2, its molecular weight is 114.53, No. CAS is 1722-12-9, and it is a kind of white or pale yellow powder, and fusing point is 63 ~ 66 DEG C, and boiling point is 75 ~ 76 DEG C, and flash-point is 98 DEG C.The technological deficiency that yield is lower and product purity is lower of the technique existence of prior art synthesis 2-chloropyrimide.
Summary of the invention
In view of this, the invention provides a kind of technique of synthesizing 2-chloropyrimide, the purity of the product of this synthesis technique is higher, yield is higher.
Synthesize a technique for 2-chloropyrimide, comprise the following steps:
(1) by Dyhard RU 100 (formula A) be dissolved in sulfuric acid at 2 ~ 6 DEG C, then 50 ~ 60 DEG C heating under make it hydrolysis reaction 4 ~ 6h, obtain guanidine sulfate (formula B), reaction formula is as follows,
(2) guanidine sulfate and propargyl alcohol (formula E) are reacted 8 ~ 12h at 50 ~ 55 DEG C, obtain 2-aminopyrimidine (formula C), reaction formula is as follows,
(3) by 2-aminopyrimidine with NaNO
2, HCl and ZnCl
2for catalyzer, be reduced at-10 ~ 5 DEG C, obtain 2-chloropyrimide (formula D), reaction formula is as follows,
In the step (1) of above-mentioned synthesis technique, the mass concentration of sulfuric acid is preferably 94 ~ 96wt%, is 95wt% better.The mol ratio of Dyhard RU 100 and sulfuric acid is preferably 1:1.5 ~ 6, is 1:3 better.The feed way that Dyhard RU 100 is dissolved in sulfuric acid can be, is slowly added by Dyhard RU 100 while stirring in sulfuric acid.
In the step (2) of above-mentioned synthesis technique, hydrolysate without the need to therefrom isolating guanidine sulfate, only can need be cooled to room temperature by the first step hydrolysate, just carries out the reaction of this step.The mol ratio of guanidine sulfate and propargyl alcohol is preferably 1 ~ 3:1, is 2.4:1 better.Isolate from product 2-aminopyrimidine mode be preferably by the product of reaction after filtration, washing and extract in the basic conditions.The alkalescence of extraction can select pH to be 8 ~ 9.
In the step (3) of above-mentioned synthesis technique, 2-aminopyrimidine, NaNO
2, HCl and ZnCl
2mol ratio be preferably 1:2.4 ~ 2.8:2.5 ~ 3.5:3.2 ~ 4.Reduction reaction is carried out in the solvent of methylene dichloride.After completion of the reaction, conventional means can be adopted to carry out separating-purifying to the 2-chloropyrimide in reaction product, such as, can first-selected reaction product cold water be made it to form aqueous phase and organic phase, by methylene dichloride repeatedly aqueous phase extracted and the organic phase retained in aqueous phase, mix whole organic phases, add siccative carry out drying and filtration to it, filtrate evaporate to dryness can obtain product 2-chloropyrimide.
The present invention is by Dyhard RU 100 and be dissolved in sulfuric acid at 2 ~ 6 DEG C, then under 50 ~ 60 DEG C of heating, make it hydrolysis reaction 4 ~ 6h, obtain guanidine sulfate, then at 50 ~ 55 DEG C, react 8 ~ 12h with propargyl alcohol, obtain 2-aminopyrimidine, finally by 2-aminopyrimidine with NaNO
2, HCl and ZnCl
2for catalyzer, be reduced at-10 ~ 5 DEG C and namely obtain product.By above-mentioned synthetic route, obtain the 2-chloropyrimide that purity is higher, yield is higher.
Embodiment
Technical scheme of the present invention is further illustrated below in conjunction with embodiment.
Below implement involved industrial chemicals to be mode commercially available or well-known to those skilled in the art and to obtain.As space is limited, below eliminate the concrete available sources of these industrial chemicals, should not be considered as the query to the present invention program's embodiment to this.
Embodiment 1
Be 1.5mol by solute, mass concentration is add 250ml four-hole bottle in 96wt% sulfuric acid, its temperature is adjusted to 2 DEG C, while constantly stirring, in four-hole boiling flask, slowly adds 1mol Dyhard RU 100, be warming up to 50 DEG C and make it hydrolysis reaction 6h.Then be cooled to room temperature, 1/3mol propargyl alcohol is added in four-hole boiling flask, cyclization 12h at being warming up to 50 DEG C, by the product of cyclization after filtration, washing and regulate pH to 8 to carry out employing isopropylcarbinol and extract by sodium hydroxide, obtain product 2-aminopyrimidine.
In the reactor of 500mL, add 2.5mol hydrochloric acid and 80g methylene dichloride, then under agitation add 1mol 2-aminopyrimidine.3.2mol ZnCl is added at 10 ~ 15 DEG C
2, after reaction 30min, generate the suspended substance of deep yellow.Then be cooled to-10 DEG C, in 4h, slowly add 2.4mol Sodium Nitrite under nitrogen protection.After continuing to pass into nitrogen 1h, termination reaction.Reactant is poured in 150mL water and cool.Separatory, all organic phases, are finally filtered with after 6 ~ 10g drying over sodium sulfate to collect organic phase wherein with 40mL dichloromethane extraction 4 ~ 6 times by aqueous phase; At normal pressure, concentrated filtrate at 45 ~ 50 DEG C, reclaims methylene dichloride.Then reduce pressure (3.3kPa) concentrate, after filtration at 40 DEG C dry 1 ~ 2h.Finally obtain light yellow crystal, be product 2-chloropyrimide.
Embodiment 2
Be 6mol by solute, mass concentration is add 250ml four-hole bottle in 94wt% sulfuric acid, its temperature is adjusted to 6 DEG C, while constantly stirring, in four-hole boiling flask, slowly adds 1mol Dyhard RU 100, be warming up to 60 DEG C and make it hydrolysis reaction 4h.Then be cooled to room temperature, 1mol propargyl alcohol is added in four-hole boiling flask, cyclization 8h at being warming up to 55 DEG C, by the product of cyclization after filtration, washing and regulate pH to 9 to carry out employing isopropylcarbinol and extract by sodium hydroxide, obtain product 2-aminopyrimidine.
In the reactor of 500mL, add 3.5mol hydrochloric acid and 80g methylene dichloride, then under agitation add 1mol 2-aminopyrimidine.4mol ZnCl is added at 10 ~ 15 DEG C
2, after reaction 60min, generate the suspended substance of deep yellow.Then be cooled to 5 DEG C, in 3h, add 2.8mol Sodium Nitrite under nitrogen protection.After continuing to pass into nitrogen 0.5h, termination reaction.Reactant is poured in 150mL water and cool.Separatory, all organic phases, are finally filtered with after 6 ~ 10g drying over sodium sulfate to collect organic phase wherein with 40mL dichloromethane extraction 4 ~ 6 times by aqueous phase; At normal pressure, concentrated filtrate at 45 ~ 50 DEG C, reclaims methylene dichloride.Then reduce pressure (3.3kPa) concentrate, after filtration at 40 DEG C dry 1 ~ 2h.Finally obtain light yellow crystal, be product 2-chloropyrimide.
Embodiment 3
Be 3mol by solute, mass concentration is add 250ml four-hole bottle in 95wt% sulfuric acid, its temperature is adjusted to 5 DEG C, while constantly stirring, in four-hole boiling flask, slowly adds 1mol Dyhard RU 100, be warming up to 55 DEG C and make it hydrolysis reaction 5h.Then be cooled to room temperature, 0.418mol propargyl alcohol is added in four-hole boiling flask, cyclization 10h at being warming up to 53 DEG C, by the product of cyclization after filtration, washing and regulate pH to 8.5 to carry out employing isopropylcarbinol and extract by sodium hydroxide, obtain product 2-aminopyrimidine.
In the reactor of 500mL, add 3mol hydrochloric acid and 80g methylene dichloride, then under agitation add 1mol 2-aminopyrimidine.3.5mol ZnCl is added at 10 ~ 15 DEG C
2, after reaction 45min, generate the suspended substance of deep yellow.Then be cooled to 0 DEG C, in 3.5h, add 2.5mol Sodium Nitrite under nitrogen protection.After continuing to pass into nitrogen 40min, reactant is poured in 150mL water and cool.Separatory, all organic phases, are finally filtered with after 6 ~ 10g drying over sodium sulfate to collect organic phase wherein with 40mL dichloromethane extraction 4 ~ 6 times by aqueous phase; At normal pressure, concentrated filtrate at 45 ~ 50 DEG C, reclaims methylene dichloride.Then reduce pressure (3.3kPa) concentrate, after filtration at 40 DEG C dry 1 ~ 2h.Finally obtain light yellow crystal, be product 2-chloropyrimide.
Embodiment 4
Be 3.5mol by solute, mass concentration is add 250ml four-hole bottle in 95wt% sulfuric acid, its temperature is adjusted to 4 DEG C, while constantly stirring, in four-hole boiling flask, slowly adds 1mol Dyhard RU 100, be warming up to 55 DEG C and make it hydrolysis reaction 5h.Then be cooled to room temperature, 0.5mol propargyl alcohol is added in four-hole boiling flask, cyclization 11h at being warming up to 52 DEG C, by the product of cyclization after filtration, washing and regulate pH to 9 to carry out employing isopropylcarbinol and extract by sodium hydroxide, obtain product 2-aminopyrimidine.
In the reactor of 500mL, add 2.8mol hydrochloric acid and 80g methylene dichloride, then under agitation add 1mol 2-aminopyrimidine.3.6mol ZnCl is added at 10 ~ 15 DEG C
2, after reaction 40min, generate the suspended substance of deep yellow.Then be cooled to-5 DEG C, in 3h, add 2.6mol Sodium Nitrite under nitrogen protection.After continuing to pass into nitrogen 50min, termination reaction.Reactant is poured in 150mL water and cool.Separatory, all organic phases, are finally filtered with after 6 ~ 10g drying over sodium sulfate to collect organic phase wherein with 40mL dichloromethane extraction 4 ~ 6 times by aqueous phase; At normal pressure, concentrated filtrate at 45 ~ 50 DEG C, reclaims methylene dichloride.Then reduce pressure (3.3kPa) concentrate, after filtration at 40 DEG C dry 1 ~ 2h.Finally obtain light yellow crystal, be product 2-chloropyrimide.
Embodiment 5
Be 4.5mol by solute, mass concentration is add 250ml four-hole bottle in 95wt% sulfuric acid, its temperature is adjusted to 5 DEG C, while constantly stirring, in four-hole boiling flask, slowly adds 1mol Dyhard RU 100, be warming up to 55 DEG C and make it hydrolysis reaction 5h.Then be cooled to room temperature, 0.6mol propargyl alcohol is added in four-hole boiling flask, cyclization 10h at being warming up to 53 DEG C, by the product of cyclization after filtration, washing and regulate pH to 8 ~ 9 to carry out employing isopropylcarbinol and extract by sodium hydroxide, obtain product 2-aminopyrimidine.
In the reactor of 500mL, add 3.2mol hydrochloric acid and 80g methylene dichloride, then under agitation add 1mol 2-aminopyrimidine.3.7mol ZnCl is added at 10 ~ 15 DEG C
2, after reaction 30min, generate the suspended substance of deep yellow.Then be cooled to 0 DEG C, in 3h, add 2.65mol Sodium Nitrite under nitrogen protection.After continuing to pass into nitrogen 0.5h, reactant is poured in 150mL water and cool.Separatory, all organic phases, are finally filtered with after 6 ~ 10g drying over sodium sulfate to collect organic phase wherein with 40mL dichloromethane extraction 4 ~ 6 times by aqueous phase; At normal pressure, concentrated filtrate at 45 ~ 50 DEG C, reclaims methylene dichloride.Then reduce pressure (3.3kPa) concentrate, after filtration at 40 DEG C dry 1 ~ 2h.Finally obtain light yellow crystal, be product 2-chloropyrimide.
2-chloropyrimide embodiment 1 ~ 5 obtained carries out transformation efficiency and yield is tested, and what deserves to be explained is, these tests the means of testing be familiar with by those skilled in the art, concrete test technology does not repeat at this.Its test result is as following table:
Table 1
Applicant states, the present invention illustrates detailed process equipment and process flow process of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned detailed process equipment and process flow process, namely do not mean that the present invention must rely on above-mentioned detailed process equipment and process flow process and could implement.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of ancillary component, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (8)
1. synthesize a technique for 2-chloropyrimide, it is characterized in that, comprise the following steps:
(1) by Dyhard RU 100 (formula A) be dissolved in sulfuric acid at 2 ~ 6 DEG C, then 50 ~ 60 DEG C heating under make it hydrolysis reaction 4 ~ 6h, obtain guanidine sulfate (formula B), reaction formula is as follows,
(2) guanidine sulfate and propargyl alcohol (formula E) are reacted 8 ~ 12h at 50 ~ 55 DEG C, obtain 2-aminopyrimidine (formula C), reaction formula is as follows,
(3) by 2-aminopyrimidine with NaNO
2, HCl and ZnCl
2for catalyzer, be reduced at-10 ~ 5 DEG C, obtain 2-chloropyrimide (formula D), reaction formula is as follows,
2. technique according to claim 1, is characterized in that, described in step (1), the mass concentration of sulfuric acid is 94 ~ 96wt%.
3. technique according to claim 1, is characterized in that, described in step (1), the mol ratio of Dyhard RU 100 and sulfuric acid is 1:1.5 ~ 6.
4. technique according to claim 1, is characterized in that, described in step (2), the mol ratio of guanidine sulfate and propargyl alcohol is 1 ~ 3:1.
5. technique according to claim 1, is characterized in that, reacts after 8 ~ 12h described in step (2), by the product of reaction after filtration, washing and extracting in the basic conditions, obtain 2-aminopyrimidine.
6. technique according to claim 5, is characterized in that, described in step (2), the pH of extraction is 8 ~ 9.
7. technique according to claim 1, is characterized in that, 2-aminopyrimidine, NaNO described in step (3)
2, HCl and ZnCl
2mol ratio be 1:2.4 ~ 2.8:2.5 ~ 3.5:3.2 ~ 4.
8. technique according to claim 1, is characterized in that, described in step (3), reduction reaction is carried out in the solvent of methylene dichloride.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1583418A1 (en) * | 1988-10-14 | 1990-08-07 | Всесоюзный научно-исследовательский институт химических средств защиты растений | Method of producing 2-amino-4,6-dimethylpyrimidine |
| CN1876637A (en) * | 2006-05-17 | 2006-12-13 | 杭州江南化工有限公司 | 2-amido pyrimidine production method |
| CN102079725A (en) * | 2011-01-27 | 2011-06-01 | 台州市尔康药业有限公司 | Method for preparing 2-chloropyrimidine |
-
2014
- 2014-11-27 CN CN201410708397.XA patent/CN104496910A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1583418A1 (en) * | 1988-10-14 | 1990-08-07 | Всесоюзный научно-исследовательский институт химических средств защиты растений | Method of producing 2-amino-4,6-dimethylpyrimidine |
| CN1876637A (en) * | 2006-05-17 | 2006-12-13 | 杭州江南化工有限公司 | 2-amido pyrimidine production method |
| CN102079725A (en) * | 2011-01-27 | 2011-06-01 | 台州市尔康药业有限公司 | Method for preparing 2-chloropyrimidine |
Non-Patent Citations (2)
| Title |
|---|
| 张进等: "2-氯嘧啶的合成工艺研究", 《化工时刊》 * |
| 战佩英: "2-氨基嘧啶的合成方法及应用", 《通化师范学院学报》 * |
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Application publication date: 20150408 |