CN113200865A - Synthetic method of diafenthiuron impurity A, B - Google Patents
Synthetic method of diafenthiuron impurity A, B Download PDFInfo
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- CN113200865A CN113200865A CN202110333940.2A CN202110333940A CN113200865A CN 113200865 A CN113200865 A CN 113200865A CN 202110333940 A CN202110333940 A CN 202110333940A CN 113200865 A CN113200865 A CN 113200865A
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
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- C07C263/00—Preparation of derivatives of isocyanic acid
- C07C263/10—Preparation of derivatives of isocyanic acid by reaction of amines with carbonyl halides, e.g. with phosgene
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- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
- C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
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Abstract
The invention provides a preparation method of diafenthiuron impurity A, B, which takes 2, 6-isopropyl aniline, phenol, triphosgene, tert-butylamine and tert-butyl formamidine hydrochloride as raw materials, provides a material basis for the research of impurities in a standard way, can also be used for qualitative and quantitative analysis of impurities in the production of diafenthiuron, and controls the impurities within a safe and reasonable limit range, thereby improving the quality standard of diafenthiuron and providing important guiding significance for the safe medication of the masses.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a synthetic method of a diafenthiuron impurity A and a diafenthiuron impurity B.
Background
Diafenthiuron (aka diafenthiuron, compound I with the structure shown in the specification) is a novel thiourea insecticide and acaricide developed by Ciba-Jia K.K. company in the 80 s. The pesticide is a selective pesticide, and has systemic and fumigating effects.
Diafenthiuron impurities a, B are two by-products of the production process of diafenthiuron and are difficult to enrich by purification because of their low content. No literature reports a synthetic method. This brings a lot of inconvenience to the production and reporting of pesticides.
In order to research impurities in a standard way and control the impurities within a safe and reasonable limit range, improve the quality and safety of the diafenthiuron, the synthesis method of diafenthiuron impurities A and B is of great significance.
Disclosure of Invention
The invention provides the preparation method of the diafenthiuron impurity, which is used for qualitative and quantitative analysis of the impurity in the production of the diafenthiuron, so that the quality standard of the diafenthiuron can be improved, and important guiding significance is provided for safe medication of people.
In a first aspect of the present invention, there is provided a process for the preparation of diafenthiuron impurity a comprising the steps of:
step S1, dissolving 2, 6-isopropyl aniline in DMF to obtain a first reaction solution, dropwise adding a DMF solution of NBS, reacting for a period of time, adding water and ethyl acetate, uniformly mixing, separating to obtain a first organic phase, washing, drying and concentrating the first organic phase to obtain a compound 2;
step S2, dissolving the compound 2, potassium carbonate, phenol, cuprous chloride and 1-methylimidazole in an organic solvent to obtain a second reaction solution, heating and refluxing until the reaction is finished, adding water and ethyl acetate, uniformly mixing, separating to obtain a second organic phase, and performing alkali washing, drying, concentrating and column chromatography on the second organic phase to obtain a compound 3;
step S3, sequentially adding the compound 3 and DIPEA into THF, cooling to obtain a third reaction solution, dripping a triphosgene THF solution into the third reaction solution, stirring until the reaction is complete, separating liquid to obtain a third organic phase, drying the third organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 4;
and step S4, dissolving the compound 4 in THF, cooling to obtain a fourth reaction solution, dripping a THF solution of tert-butylamine into the fourth reaction solution, stirring until the reaction is completed, adding ethyl acetate and water, separating to obtain a fourth organic phase, drying the fourth organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 5, namely diafenthiuron impurity A.
In a second aspect of the present invention, there is provided a process for the preparation of diafenthiuron impurity B, comprising the steps of: step S1, dissolving 2, 6-isopropyl aniline in DMF to obtain a first reaction solution, dropwise adding a DMF solution of NBS, reacting for a period of time, adding water and ethyl acetate, uniformly mixing, separating to obtain a first organic phase, washing, drying and concentrating the first organic phase to obtain a compound 2;
step S2, dissolving the compound 2, potassium carbonate, phenol, cuprous chloride and 1-methylimidazole in an organic solvent to obtain a second reaction solution, heating and refluxing until the reaction is finished, adding water and ethyl acetate, uniformly mixing, separating to obtain a second organic phase, and performing alkali washing, drying, concentrating and column chromatography on the second organic phase to obtain a compound 3;
step S3, sequentially adding the compound 3 and DIPEA into THF, cooling to obtain a third reaction solution, dripping a triphosgene THF solution into the third reaction solution, stirring until the reaction is complete, separating liquid to obtain a third organic phase, drying the third organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 4;
and step S5, uniformly mixing tert-butyl formamidine hydrochloride, potassium carbonate and acetonitrile, dripping the compound 4 to obtain a fifth reaction solution, filtering after complete reaction to obtain a filtrate, adding ethyl acetate water into the filtrate, separating the solution to obtain a fifth organic phase, and drying the fifth organic phase by sodium sulfate and carrying out column chromatography to obtain a compound 6, namely the diafenthiuron impurity B.
Preferably, in step S1, the first reaction solution is cooled to 0-5 ℃ before adding the DMF solution of NBS dropwise.
Preferably, in step S1, the first reaction solution is added dropwise with a DMF solution of NBS, and then reacted at 0-5 ℃ for 0.5-2 hours.
Preferably, in step S1, the mass-to-volume ratio of 2, 6-isopropylaniline to DMF in the first reaction solution is 1: 8-12 g/ml.
Preferably, in step S2, the molar ratio of the compound 2 to the phenol is 1: 1-1.5.
Preferably, in step S2, the molar ratio of the compound 2, potassium carbonate and cuprous chloride is 1: 2-2.5: 5 to 6.
Preferably, in step S3, the molar volume ratio of the compound 3, DIPEA, and THF in the third reaction solution is 1: 100-120: 200 to 300.
Preferably, the molar ratio of compound 4 to tert-butylamine in step S4 is 1: 1.3 to 1.5.
Preferably, in step S5, the molar ratio of compound 4 to tert-butylformamidine hydrochloride is 1:1 to 1.5.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
the invention provides a preparation method of diafenthiuron impurities A and B, which takes 2, 6-isopropyl aniline, phenol, triphosgene, tert-butylamine and tert-butyl formamidine hydrochloride as raw materials, provides a material basis for the research of impurities in a standard way, can also be used for qualitative and quantitative analysis of impurities in the production of diafenthiuron, and controls the impurities within a safe and reasonable limit range, thereby improving the quality standard of diafenthiuron and providing important guiding significance for the safe medication of the masses.
Drawings
FIG. 1 is a flow diagram of a process for making diafenthiuron impurity A, B in accordance with the present invention.
Detailed Description
The invention provides a preparation method of diafenthiuron impurity A, as shown in figure 1, comprising the following steps:
step S1, dissolving 2, 6-isopropyl aniline in DMF to obtain a first reaction solution, dropwise adding a DMF solution of NBS, reacting for a period of time, adding water and ethyl acetate, uniformly mixing, separating to obtain a first organic phase, washing, drying and concentrating the first organic phase to obtain a compound 2;
step S2, dissolving the compound 2, potassium carbonate, phenol, cuprous chloride and 1-methylimidazole in an organic solvent to obtain a second reaction solution, heating and refluxing until the reaction is finished, adding water and ethyl acetate, uniformly mixing, separating to obtain a second organic phase, and performing alkali washing, drying, concentrating and column chromatography on the second organic phase to obtain a compound 3;
step S3, sequentially adding the compound 3 and DIPEA into THF, cooling to obtain a third reaction solution, dripping a triphosgene THF solution into the third reaction solution, stirring until the reaction is complete, separating liquid to obtain a third organic phase, drying the third organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 4;
and step S4, dissolving the compound 4 in THF, cooling to obtain a fourth reaction solution, dripping a THF solution of tert-butylamine into the fourth reaction solution, stirring until the reaction is completed, adding ethyl acetate and water, separating to obtain a fourth organic phase, drying the fourth organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 5, namely diafenthiuron impurity A.
The invention also provides a preparation method of diafenthiuron impurity B, which comprises the following steps: step S1, dissolving 2, 6-isopropyl aniline in DMF to obtain a first reaction solution, dropwise adding a DMF solution of NBS, reacting for a period of time, adding water and ethyl acetate, uniformly mixing, separating to obtain a first organic phase, washing, drying and concentrating the first organic phase to obtain a compound 2;
step S2, dissolving the compound 2, potassium carbonate, phenol, cuprous chloride and 1-methylimidazole in an organic solvent to obtain a second reaction solution, heating and refluxing until the reaction is finished, adding water and ethyl acetate, uniformly mixing, separating to obtain a second organic phase, and performing alkali washing, drying, concentrating and column chromatography on the second organic phase to obtain a compound 3;
step S3, sequentially adding the compound 3 and DIPEA into THF, cooling to obtain a third reaction solution, dripping a triphosgene THF solution into the third reaction solution, stirring until the reaction is complete, separating liquid to obtain a third organic phase, drying the third organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 4;
and step S5, uniformly mixing tert-butyl formamidine hydrochloride, potassium carbonate and acetonitrile, dripping the compound 4 to obtain a fifth reaction solution, filtering after complete reaction to obtain a filtrate, adding ethyl acetate water into the filtrate, separating the solution to obtain a fifth organic phase, and drying the fifth organic phase by sodium sulfate and carrying out column chromatography to obtain a compound 6, namely the diafenthiuron impurity B.
The present invention will be described in detail and specifically with reference to the following examples to facilitate better understanding of the present invention, but the following examples do not limit the scope of the present invention.
Example 1
This example provides a method for preparing compound 2 (i.e., step S1):
dissolving 2, 6-isopropyl aniline (compound 1, 53g, 0.3mol) in N, N-dimethylformamide (DMF, 500ml), cooling to 0-5 ℃ to obtain a first reaction solution, dropwise adding a DMF (200ml) solution of N-bromosuccinimide (NBS 63g, 0.36mol), reacting at 0-5 ℃ for 0.5 hour after dropwise adding is completed, confirming that the reaction is complete by TLC detection, adding water and ethyl acetate, stirring for 10 minutes, separating liquid, washing an organic phase twice, drying, and concentrating to obtain compound 2(70g, yield 98%);
performing nuclear magnetic hydrogen spectrum detection on the prepared compound 2:
1H NMR(300MHz,DMSO)δ6.93(s,2H),4.76(s,2H),2.93–3.04(m,2H)， 1.10(d,J＝6.9Hz,12H)
example 2
This example provides a method for preparing compound 3 (i.e., step S2):
dissolving compound 2(30g, 0.11mol), potassium carbonate (32.4g,0.23mol), phenol (13.2g, 0.14mol), cuprous chloride (0.58mol) and 1-methylimidazole (4.7ml) in xylene (300ml) to obtain a second reaction solution, heating and refluxing for 12 hours, cooling, adding water and ethyl acetate, stirring for 10 minutes, separating, carrying out alkali washing on an organic phase by using an aqueous potassium carbonate solution, drying by using sodium sulfate, concentrating, and carrying out column chromatography to obtain compound 3(23g, yield 72%)
Performing nuclear magnetic hydrogen spectrum detection on the prepared compound 3:
1H NMR(300MHz,DMSO)7.21-7.23(m,2H)，6.93-7.01(m,1H)，6.79-6.86(m, 2H)，6.60(s,2H),4.50(s,2H),2.98-3.09(m,2H)，1.11(d,J＝6.9Hz,12H)
example 3
This example provides a method for preparing compound 4 (i.e., step S3):
compound 3(8.9g, 0.33mol) and N, N-diisopropylethylamine (DIPEA, 11.2ml) were sequentially added in tetrahydrofuran (THF, 80ml), and cooled to 0 ℃ to give a third reaction solution, and a solution of triphosgene (32g) in THF (30ml) was added dropwise to the third reaction solution, followed by stirring for 10 minutes, liquid separation, drying over anhydrous sodium sulfate as an organic phase, and concentration under reduced pressure to give Compound 4(8.2g, yield 85%).
Performing nuclear magnetic hydrogen spectrum detection on the prepared compound 4:
1H NMR(300MHz,DMSO)7.33-7.43(m,2H)，7.08-7.16(m,1H)，6.94-7.02(m, 2H)，6.80(s,2H),3.07-3.19(m,2H)，1.15(d,J＝7.0Hz,12H)
example 4
This example provides a method for the preparation of compound 5 (i.e., step S4):
dissolving compound 4(4g, 13.5mmol) in THF (40ml), cooling to 0 deg.C to obtain a fourth reaction solution, adding tert-butylamine (1.4g, 20.2mmol) in THF (10ml) dropwise into the fourth reaction solution, stirring for 1 hr, adding ethyl acetate and water, separating, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain compound 5(4.0g, yield 80%);
performing nuclear magnetic hydrogen spectrum detection on the prepared compound 5:
1H NMR(300MHz,DMSO)7.33-7.43(m,2H)，7.05-7.16(m,1H)，6.94-7.00(m, 2H)，6.72(s,2H),5.94(s,1H),3.05-3.18(m,2H)，1.26(s,9H)，1.07(d,J＝6.9Hz, 12H)。
example 5
This example provides a method for the preparation of compound 6 (i.e., step S4):
tert-butylformamidine hydrochloride (5.4g, 39.8mmol), potassium carbonate (11g, 80mmol) and acetonitrile (200ml) were sequentially charged into a three-necked flask, and after stirring for 10 minutes, compound 4(11.8g, 39.8mmol) was added dropwise to the above solution to obtain a fifth reaction solution, which was reacted at room temperature for 2 hours, filtered to remove insoluble matter, and ethyl acetate water was added to the filtrate to separate an organic phase, dried over sodium sulfate and subjected to column chromatography to obtain compound 6(10g, yield 63%).
Performing nuclear magnetic hydrogen spectrum detection on the prepared compound 5 (the nitrogen atom belongs to active hydrogen, and the nuclear magnetic hydrogen spectrum can not be obtained):
NMR(300MHz,DMSO)7.33-7.43(m,2H)，7.07-7.18(m,1H)，6.96-7.02(m, 2H)，6.75(s,2H),3.06-3.17(m,2H)，1.56(s,9H)，1.12(d,J＝6.9Hz,12H)
the embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (10)
1. The preparation method of the diafenthiuron impurity A is characterized by comprising the following steps:
step S1, dissolving 2, 6-isopropyl aniline in DMF to obtain a first reaction solution, dropwise adding a DMF solution of NBS, reacting for a period of time, adding water and ethyl acetate, uniformly mixing, separating to obtain a first organic phase, washing, drying and concentrating the first organic phase to obtain a compound 2;
step S2, dissolving the compound 2, potassium carbonate, phenol, cuprous chloride and 1-methylimidazole in an organic solvent to obtain a second reaction solution, heating and refluxing until the reaction is finished, adding water and ethyl acetate, uniformly mixing, separating to obtain a second organic phase, and performing alkali washing, drying, concentrating and column chromatography on the second organic phase to obtain a compound 3;
step S3, sequentially adding the compound 3 and DIPEA into THF, cooling to obtain a third reaction solution, dripping a triphosgene THF solution into the third reaction solution, stirring until the reaction is complete, separating liquid to obtain a third organic phase, drying the third organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 4;
and step S4, dissolving the compound 4 in THF, cooling to obtain a fourth reaction solution, dripping a THF solution of tert-butylamine into the fourth reaction solution, stirring until the reaction is completed, adding ethyl acetate and water, separating to obtain a fourth organic phase, drying the fourth organic phase by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 5, namely diafenthiuron impurity A.
2. The preparation method of the diafenthiuron impurity B is characterized by comprising the following steps:
step S1, dissolving 2, 6-isopropyl aniline in DMF to obtain a first reaction solution, dropwise adding a DMF solution of NBS, reacting for a period of time, adding water and ethyl acetate, uniformly mixing, separating to obtain a first organic phase, washing, drying and concentrating the first organic phase to obtain a compound 2;
step S2, dissolving the compound 2, potassium carbonate, phenol, cuprous chloride and 1-methylimidazole in an organic solvent to obtain a second reaction solution, heating and refluxing until the reaction is finished, adding water and ethyl acetate, uniformly mixing, separating to obtain a second organic phase, and performing alkali washing, drying, concentrating and column chromatography on the second organic phase to obtain a compound 3;
step S3, sequentially adding the compound 3 and DIPEA into THF, cooling to obtain a third reaction solution, dripping a triphosgene THF solution into the third reaction solution, stirring until the reaction is complete, separating liquid to obtain a third organic phase, drying the third organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound 4;
and step S5, uniformly mixing tert-butyl formamidine hydrochloride, potassium carbonate and acetonitrile, dripping the compound 4 to obtain a fifth reaction solution, filtering after complete reaction to obtain a filtrate, adding ethyl acetate water into the filtrate, separating the solution to obtain a fifth organic phase, and drying the fifth organic phase by sodium sulfate and carrying out column chromatography to obtain a compound 6, namely the diafenthiuron impurity B.
3. The method according to any one of claims 1 to 2, wherein in step S1, the first reaction solution is cooled to 0 to 5 ℃ before adding the DMF solution of NBS dropwise.
4. The method according to any one of claims 1 to 2, wherein in step S1, the first reaction solution is reacted at 0 to 5 ℃ for 0.5 to 2 hours after the dropwise addition of a DMF solution of NBS.
5. The preparation method according to any one of claims 1 to 2, wherein in step S1, the mass-to-volume ratio of 2, 6-isopropylaniline to DMF in the first reaction solution is 1:8 to 12 g/ml.
6. The method according to any one of claims 1 to 2, wherein in step S2, the molar ratio of the compound 2 to the phenol is 1:1 to 1.5.
7. The preparation method according to any one of claims 1 to 2, wherein in the step S2, the molar ratio of the compound 2 to the potassium carbonate to the cuprous chloride is 1: 2-2.5: 5 to 6.
8. The method according to any one of claims 1 to 2, wherein in step S3, the molar volume ratio of the compound 3, DIPEA, THF in the third reaction solution is 1: 100-120: 200 to 300.
9. The process according to claim 1, wherein the molar ratio of compound 4 to tert-butylamine in step S4 is 1: 1.3 to 1.5.
10. The method according to claim 2, wherein in step S5, the molar ratio of compound 4 to t-butylformamidine hydrochloride is 1:1 to 1.5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060264622A1 (en) * | 2003-09-11 | 2006-11-23 | Spirogen Limited | Synthesis of protected pyrrolobenzodiazepines |
| CN102993075A (en) * | 2012-11-29 | 2013-03-27 | 江苏长青农化股份有限公司 | Synthesis process for diafenthiuron as thiourea insecticide and acaricide |
| WO2017202357A1 (en) * | 2016-05-25 | 2017-11-30 | 四川海思科制药有限公司 | Method for preparing trifluoromethyl-substituted pyran derivative |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060264622A1 (en) * | 2003-09-11 | 2006-11-23 | Spirogen Limited | Synthesis of protected pyrrolobenzodiazepines |
| CN102993075A (en) * | 2012-11-29 | 2013-03-27 | 江苏长青农化股份有限公司 | Synthesis process for diafenthiuron as thiourea insecticide and acaricide |
| WO2017202357A1 (en) * | 2016-05-25 | 2017-11-30 | 四川海思科制药有限公司 | Method for preparing trifluoromethyl-substituted pyran derivative |
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| Title |
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| 钱梦飞等: "丁醚脲的合成", 《精细化工》 * |
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