A method for preparing pinoxaden and its intermediates

Abstract

The present invention belongs to the field of chemical synthesis, and in particular to a method for preparing pinoxaden and its intermediate (compound 3). The method for preparing compound 3 comprises the following steps: compound 1 and an organic solvent immiscible with water are placed under a pressure of 0.06-0.09MPa, heated to 100-140°C, compound 2 is added in batches, reacted, and compound 3 is obtained. The method can control the content of isomeric amine impurities and decarboxylation impurities at a relatively low level, ensures the quality of the finished product pinoxaden, avoids complicated impurity removal processes, and improves the conversion rate of compound 2 and the atomic utilization rate of compound 1, without using organic bases such as triethylamine, and is suitable for industrialized amplification production.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing pinoxaden and an intermediate thereof. Background Art

[0002] Pinoxaden is a selective, systemic post-emergence grass weed herbicide that can effectively control annual grass weeds in wheat and barley fields and is very suitable for spring cereals. It has good control effects on grass weeds such as wild oats, ryegrass, foxtail grass, hard grass, chrysanthemum, Japanese foxtail grass, and clover, especially for some vicious grass weeds such as wild oats, ryegrass, hard grass, and chrysanthemum, with a control effect of nearly 100%. It has the characteristics of high efficiency, broad spectrum, high safety, wide application period, and resistance to rain erosion. It degrades quickly in animals, plants, soil and the environment, does not retain, accumulate, or leach into groundwater. Compared with other wheat field herbicides, pinoxaden has huge development potential and market competitiveness.

[0003] The synthesis method of pinoxaden is generally to react compound 2 with compound 1 to synthesize compound 3. In order to save process steps, compound 3 is usually not purified and directly reacted with pivaloyl chloride to synthesize compound 4 pinoxaden. Therefore, compound 3 is a very important intermediate in the synthesis process of pinoxaden.

[0004]

[0005] CN108794505A and CN108264492A both disclose methods for preparing compound 3, both of which involve adding compound 2 and compound 1 to a reaction vessel at one time, heating under reflux, and reacting, with yields of 84% and 90%, respectively. The yields of the above two methods need to be improved, and CN108264492A also uses a large amount of triethylamine, which has high toxicity, cumbersome post-processing, and also increases process costs.

[0006] CN106928253A also discloses a method for preparing compound 3: Compound 2, the hydrobromide of compound 1 and triethylamine are added to a reaction vessel at one time, and heated for reaction, with a lower yield of only 76%. This method also uses a large amount of triethylamine (4.2 eq), and also has the problems of high toxicity, complicated post-treatment and high process cost. Summary of the invention

[0007] Problem that the invention aims to solve

[0008]

[0009] The inventors found that isomeric amine impurities and decarboxylation impurities are often produced during the synthesis of compound 3. These two impurities will generate new impurities during the reaction of compound 3 and pivaloyl chloride. These two new impurities are difficult to remove during the post-treatment process, thereby affecting the product yield and purity of pinoxaden. Therefore, during the reaction of compound 2 and compound 1, it is necessary to control the relative content of isomeric amine impurities and decarboxylation impurities.

[0010] However, the prior art has not studied the effect of the preparation process of compound 3 on the content of isomeric amine impurities and decarboxylation impurities. Therefore, it is urgent to develop a process for preparing pinoxaden and its intermediates with high reaction conversion rate and yield, low impurity content (especially isomeric amine impurities and decarboxylation impurities), high atomic utilization of raw materials, low toxicity and simple post-treatment (for example, without using reagents such as triethylamine).

[0011] The present invention aims to provide a method for preparing pinoxaden and its intermediate (i.e., compound 3). The process method can reduce the content of isomeric amine impurities and decarboxylation impurities, has high reaction conversion rate and yield, high atom utilization rate, and does not use organic bases such as triethylamine.

[0012] Solutions for solving problems

[0013] In order to solve the above problems, the present invention provides a method for preparing a pinoxaden intermediate, which comprises the following steps:

[0014]

[0015] Compound 1 and an organic solvent immiscible with water are mixed, heated to 100-140° C., and compound 2 is added to react to obtain compound 3; the reaction further comprises at least one of the following conditions:

[0016] (1) The reaction pressure is 0.06-0.09 MPa;

[0017] (2) The compound 2 is added in batches.

[0018] Preferably, during the batch-wise addition process, the molar ratio of the amount of compound 2 added in each batch to the total amount of compound 1 added is 0.1-0.5:1, more preferably 0.2-0.4:1, and further preferably 0.25:1.

[0019] Preferably, the molar ratio of the total amount of the compound 1 added to the total amount of the compound 2 added is 1-5:1, more preferably 1-1.2:1, and further preferably 1.05:1.

[0020] Furthermore, in the process of adding materials in batches, the interval time of adding materials in each batch is 10-90 minutes, preferably 30-75 minutes, and more preferably 60 minutes.

[0021] Preferably, the reaction pressure is 0.065-0.085 MPa, more preferably 0.067-0.082 MPa.

[0022] Preferably, the water-immiscible organic solvent is an aromatic solvent, preferably chlorobenzene, xylene or dichlorobenzene, and more preferably chlorobenzene.

[0023] Preferably, the molar ratio of the water-immiscible organic solvent to the total added amount of the compound 2 is 2:1 or more.

[0024] Preferably, the heating temperature is 110-130°C, more preferably 118-125°C.

[0025] Preferably, the preparation method further comprises a post-processing step.

[0026] Preferably, the post-treatment step comprises: cooling after the reaction is completed, adding aqueous hydrochloric acid, separating the phases, and taking the organic phase to obtain compound 3; or

[0027] The post-treatment step includes: cooling after the reaction is completed, adding hydrochloric acid, and filtering to obtain compound 3; further, the cooling temperature is below 20°C, and the molar ratio of the total amount of hydrochloric acid added to the compound 2 is 1.

[0028] In addition, the present invention also provides a method for preparing pinoxaden, which comprises the following steps:

[0029]

[0030] Among them, compound 3 is obtained by the preparation method of the above-mentioned pinoxaden intermediate.

[0031] Effects of the Invention

[0032] The present invention improves the preparation process of the oxadiazine intermediate (i.e., compound 3), and significantly shortens the reaction time by first heating the reaction solution and then adding compound 2 in batches, effectively avoiding the large-scale generation of decarboxylation impurities; by means of a slight negative pressure, the temperature of the reaction is reduced, and the residence time of ammonia in the reaction is reduced, thereby reducing the generation of isomeric amine impurities. Finally, the process method of the present invention can effectively control the content of isomeric amine impurities and decarboxylation impurities to a relatively low level, ensures the quality of the final product oxadiazine, avoids a complicated impurity removal process, and greatly reduces the process cost; and improves the conversion rate of compound 2 and the atomic utilization rate of compound 1, improves the reaction yield, and shortens the reaction time; at the same time, organic bases such as triethylamine are not used in the reaction process, and the toxicity is low, and complicated post-processing and recovery steps are avoided, which is suitable for industrialized amplification production. DETAILED DESCRIPTION

[0033] In the present invention, "piroxaden intermediate" refers to compound 3 (or its keto-enol tautomer). In the preparation process of compound 3, the inventors found two impurities, isomeric amine impurities and decarboxylation impurities, whose content will directly affect the next step of the synthesis of pinoxaden and affect the quality of the final product pinoxaden. In the prior art, the above two impurities are basically not studied, and the synthesis conversion rate and yield of the existing process are not high, the triethylamine used is more toxic, and the post-processing and recovery process are cumbersome.

[0034]

[0035] The present invention improves the preparation process of compound 3. By heating the reaction solution first and then adding compound 2 in batches, the reaction time is significantly shortened, and the large-scale generation of decarboxylation impurities is effectively avoided. The reaction temperature is lowered by means of a slight negative pressure, and the residence time of ammonia in the reaction is reduced, thereby reducing the generation of isomeric amine impurities.

[0036] Specifically, the preparation method of compound 3 provided by the present invention comprises the following steps: mixing compound 1 and an organic solvent immiscible with water, heating to 100-140° C., adding compound 2, and reacting to obtain compound 3; wherein the reaction further comprises at least one of the following conditions:

[0037] (1) The reaction pressure is 0.06-0.09 MPa;

[0038] (2) The compound 2 is added in batches.

[0039] In some embodiments, during the batch addition process, the molar ratio of the amount of compound 2 added in each batch to the total amount of compound 1 added is 0.1-0.5:1; in some preferred embodiments, the molar ratio is 0.2-0.4:1; in some more preferred embodiments, the molar ratio is 0.25:1.

[0040] In some embodiments, the molar ratio of the total amount of compound 1 added to the total amount of compound 2 added is 1-5:1; in some preferred embodiments, the molar ratio is 1-1.2:1; in some more preferred embodiments, the molar ratio is 1.05:1.

[0041] In some embodiments, during the batch-wise addition process, the interval time between each batch of additions is 10-90 minutes; in some preferred embodiments, the interval time is 30-75 minutes; in some more preferred embodiments, the interval time is 60 minutes.

[0042] In some embodiments, the reaction pressure is 0.065-0.085 MPa; in some preferred embodiments, when the reaction pressure is 0.067-0.082 MPa, the contents of decarboxylation impurities and isomeric amine impurities are both less than 0.5%.

[0043] In some embodiments, the water-immiscible organic solvent is an aromatic solvent, such as chlorobenzene, xylene or dichlorobenzene. Under non-negative pressure conditions, high boiling point solvents such as chlorobenzene, xylene or dichlorobenzene have better reaction effects; under negative pressure conditions, chlorobenzene and dichlorobenzene have better reaction effects.

[0044] In the present invention, the amount of solvent used has little effect on the effect of the reaction. In some embodiments, the molar ratio of the water-immiscible organic solvent to the total amount of compound 2 added is 2:1 or more.

[0045] In some embodiments, the heating temperature is 110-130°C; in some preferred embodiments, the heating temperature is 118-125°C.

[0046] In some embodiments, the reaction pressure is normal pressure, and when the compound 2 is added in batches, the reaction temperature is set to 130°C, and the molar ratio of the total amount of compound 1 added to the total amount of compound 2 added is 1.2:1, the content of decarboxylation impurities and isomeric amine impurities can be controlled below 0.5%, and the conversion rate and yield of the reaction are also high.

[0047] In some embodiments, the reaction pressure is 0.065-0.085 MPa (such as 0.067 MPa), and the compound 2 is added in a batch manner rather than in a one-time manner, and the reaction temperature is set to 118°C. When the molar ratio of the total amount of compound 1 added to the total amount of compound 2 added is 1.05:1, the content of decarboxylation impurities and isomeric amine impurities can be controlled below 0.5%, and the conversion rate and yield of the reaction are also high.

[0048] In some embodiments, the preparation method may further include a post-processing step.

[0049] In some embodiments, after the above reaction is completed, the temperature is lowered, a hydrochloric acid solution is added, the phases are separated, and the organic phase is taken to obtain a solution of compound 3, such as a chlorobenzene solution of compound 3. The solution of compound 3 can directly participate in the subsequent reaction of preparing pinoxaden.

[0050] In some embodiments, when the solvent is chlorobenzene, after the above reaction is completed, the temperature is lowered, hydrochloric acid is added, and the solid is filtered, and the obtained solid is compound 3. In some embodiments, the temperature of the cooling can be below 20°C, and the molar amount of the hydrochloric acid is the same as the molar amount of the total added amount of compound 2. In an embodiment of the present invention, after the reaction is completed, the HPLC relative content of compound 3 in the reaction solution is monitored, and the absolute yield of compound 3 obtained by the post-treatment method is approximately 2-3% lower than the relative content.

[0051] In addition, the preparation method of the above-mentioned pinoxaden intermediate can also be applied to the synthesis of pinoxaden. Specifically, the present invention also provides a preparation method of pinoxaden, which comprises the following steps:

[0052]

[0053] Among them, compound 3 is obtained by the preparation method of the above-mentioned pinoxaden intermediate.

[0054] In the present invention, compound 1 can be obtained by the following reaction:

[0055]

[0056] Compound 4 is hydrolyzed by using potassium hydroxide of a certain concentration under the condition of chlorobenzene as solvent. After the reaction is completed, the phases are separated and the chlorobenzene solution of compound 1 is collected. The chlorobenzene solution of compound 1 can be directly used in the next reaction, i.e., the synthesis of compound 3.

[0057] Example

[0058] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0059] Example 1

[0060] Compound 2 (HPLC purity 98%, 5.96 g, 0.0235 mol) and a chlorobenzene solution of compound 1 (mass concentration 5%, 57.5 g, 0.0282 mol) were weighed and added into a 100 mL three-necked flask, and heating was started. The reaction temperature was maintained at 130° C. After reacting for 5 h, the reaction was stopped and the relative content was detected by HPLC, wherein: compound 3 was 96%, decarboxylation impurities were 0.8%, isomeric amine impurities were 0.6%, and compound 2 was <0.1%.

[0061] Embodiment 2-5

[0062] The reaction temperature was changed in the same manner as in Example 1. The results are shown in Table 1 below.

[0063] Table 1

[0064]

[0065] It can be seen from Table 1 that when the reaction raw materials are added at once and reacted at normal pressure, even if the reaction temperature is changed, the content of decarboxylation impurities and isomeric amine impurities is still high, and the conversion rate of the raw materials is significantly reduced.

[0066] Example 6

[0067] The chlorobenzene solution of compound 1 (mass concentration 5%, 28.5g, 0.0282mol) was added to a 100mL three-necked flask, the reaction system was kept under normal pressure, heating was started, the reaction temperature was kept at 130°C, and compound 2 (HPLC purity 98%, 5.96g, 0.0235mol) was added in four batches using a solid batch feeder, and the amount of compound 2 added in each batch was 1.49g. The specific method of batch addition is: add the first batch of compound 2, react for 1h; then add the second batch of compound 2, react for 1h; then add the third batch of compound 2, react for 1h; finally add the fourth batch of compound 2, react for 1h, and stop the reaction. The reaction lasted for 4h in total, and the relative content was detected by HPLC, wherein: compound 3 was 98%, decarboxylation impurities were 0.3%, isomeric amine impurities were 0.5%, and compound 2 was <0.1%.

[0068] Example 7

[0069] The reaction was carried out in the same manner as in Example 6, with the reaction temperature set at 110° C. The relative contents were detected by HPLC, where compound 3 accounted for 85%, decarboxylation impurities accounted for 0.3%, isomeric amine impurities accounted for 0.3%, and compound 2 accounted for 11%.

[0070] The reaction time was further extended to 15 h at a reaction temperature of 110° C., and the relative contents were detected by HPLC, where compound 3 accounted for 93%, decarboxylation impurities accounted for 0.6%, isomeric amine impurities accounted for 0.7%, and compound 2 accounted for 2%.

[0071] Example 8

[0072] The toluene solution of compound 1 (mass concentration 5%, 28.5g, 0.0282mol) was added to a 100mL three-necked flask, and heating was started. After the reaction temperature was maintained at 110°C (toluene reflux), compound 2 (HPLC purity 98%, 7.00g, 0.0282mol) was added in four batches using a solid batch feeder, and the amount of compound 2 added in each batch was 1.75g. The specific method of batch addition is: add the first batch of compound 2, react for 1h; then add the second batch of compound 2, react for 1h; then add the third batch of compound 2, react for 1h; finally add the fourth batch of compound 2, react for 1h, and then detect the relative content by HPLC, wherein: compound 3 is 73.6%, decarboxylation impurities are 0.44%, isomeric amine impurities are 0.2%, and compound 2 remains 25%.

[0073] The reaction time was extended to 12 h at the reflux temperature. After the reaction was completed, the relative contents were detected by HPLC, where compound 3 was 96%, decarboxylation impurities were 0.6%, isomeric amine impurities were 0.8%, and compound 2 was less than 0.1%.

[0074] Examples 9-11

[0075] Examples 9 and 10 were carried out in the same manner as Example 6, with different molar ratios of Compound 1 to Compound 2 being set.

[0076] Example 11 was carried out in the same manner as Example 7, with the reaction temperature set at 120°C.

[0077] The reaction results are shown in Table 2.

[0078] Table 2

[0079]

[0080] It can be seen from Table 2 that in the batch feeding mode, the decarboxylation impurities are significantly reduced. The higher the molar ratio of compound 1 to compound 2, the higher the content of compound 3 after the reaction is completed, and the content of decarboxylation impurities and isomer impurities decreases slightly. However, the higher the molar ratio of compound 1 to compound 2, the lower the atomic utilization rate of compound 1, resulting in waste of materials.

[0081] Example 12

[0082] The chlorobenzene solution of compound 1 (mass concentration 5%, 28.5g, 0.0282mol) was added to a 100mL three-necked flask, the reaction system was kept at a reaction pressure of 0.082MPa, heating was started, the reaction temperature was kept at 125°C, and compound 2 (HPLC purity 98%, 6.8g, 0.0268mol) was added in four batches using a solid batch feeder, and the amount of compound 2 added in each batch was 1.7g. The specific method of batch feeding is: add the first batch of compound 2, react for 1h; then add the second batch of compound 2, react for 1h; then add the third batch of compound 2, react for 1h; finally add the fourth batch of compound 2, react for 1h, and stop the reaction. The reaction lasted for a total of 4h, and the relative content was detected by HPLC, wherein: compound 3 was 98.5%, decarboxylation impurities were 0.3%, isomeric amine impurities were 0.2%, and compound 2 was <0.1%.

[0083] Example 13

[0084] Weigh compound 2 (HPLC purity 98%, 6.8 g, 0.0268 mol) and a chlorobenzene solution of compound 1 (mass concentration 5%, 28.5 g, 0.0282 mol) and add them into a 100 mL three-necked flask, keep the reaction system at a reaction pressure condition of 0.067 MPa, start heating, keep the reaction temperature at 118°C, react for 4 hours, stop the reaction, and detect the relative content by HPLC, wherein: compound 3 is 97.2%, decarboxylation impurities are 0.5%, isomeric amine impurities are 0.3%, and compound 2 is <0.1%.

[0085] Examples 14-15

[0086] In the same manner as in Example 12, different negative pressure conditions and reaction temperatures were set, and the results are shown in Table 3.

[0087] Table 3

[0088]

[0089] It can be seen from Table 3 that the reaction pressure is controlled between 0.067MPa and 0.082MPa, and the temperature is controlled at about 120°C. The reaction conditions are optimal, and the decarboxylation impurities and isomeric amine impurities can be effectively controlled to be below 0.5%. At the same time, the conversion rate of compound 2 is also high, and the content of compound 3 is also above 97%.

Claims

1. A method for preparing a pinoxaden intermediate as shown in Formula 3, comprising the following steps: Compound 1 and an organic solvent immiscible with water are mixed, heated to 100-140° C., and compound 2 is added to react to obtain compound 3; the reaction comprises the following reaction conditions: (1) The reaction pressure is 0.06-0.09 MPa; (2) Compound 2 is added in batches; The water-immiscible organic solvent is an aromatic solvent; During the batch addition process, the molar ratio of the amount of compound 2 added in each batch to the total amount of compound 1 added is 0.1-0.5:1; During the batch-wise feeding process, the interval between each batch of feeding is 10-90 minutes.

2. The preparation method according to claim 1, characterized in that: During the batch addition process, the molar ratio of the amount of compound 2 added in each batch to the total amount of compound 1 added is 0.2-0.4:

1.

3. The preparation method according to claim 2, characterized in that: During the batch addition process, the molar ratio of the amount of compound 2 added in each batch to the total amount of compound 1 added is 0.25:

1.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the total amount of the compound 1 added to the total amount of the compound 2 added is 1-5:

1.

5. The preparation method according to claim 4, characterized in that: The molar ratio of the total amount of the compound 1 added to the total amount of the compound 2 added is 1-1.2:

1.

6. The preparation method according to claim 5, characterized in that: The molar ratio of the total amount of the compound 1 added to the total amount of the compound 2 added is 1.05:

1.

7. The preparation method according to claim 1, characterized in that: During the batch-wise feeding process, the interval between each batch of feeding is 30-75 minutes.

8. The preparation method according to claim 7, characterized in that: During the batch-wise feeding process, the interval between each batch of feeding is 60 minutes.

9. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction pressure is 0.065-0.085 MPa.

10. The preparation method according to claim 9, characterized in that: The reaction pressure is 0.067-0.082 MPa.

11. The preparation method according to any one of claims 1 to 3, characterized in that: The water-immiscible organic solvent is chlorobenzene, xylene or dichlorobenzene.

12. The preparation method according to claim 11, characterized in that: The water-immiscible organic solvent is chlorobenzene.

13. The preparation method according to any one of claims 1 to 3, characterized in that: The heating temperature is 110-130°C.

14. The preparation method according to claim 13, characterized in that: The heating temperature is 118-125°C.

15. The preparation method according to any one of claims 1 to 3, characterized in that: The preparation method also includes a post-processing step.

16. The preparation method according to claim 15, characterized in that: The post-treatment step comprises: cooling after the reaction is completed, adding a hydrochloric acid aqueous solution, separating the phases, and taking the organic phase to obtain compound 3; or The post-treatment step includes: cooling after the reaction is completed, adding hydrochloric acid, and filtering to obtain compound 3.

17. The preparation method according to claim 16, characterized in that: The cooling temperature is below 20° C., and the molar ratio of the total amount of the hydrochloric acid to the compound 2 added is 1.

18. A method for preparing pinoxaden, comprising the following steps: The method for preparing the pinoxaden intermediate shown in Formula 3 is as described in any one of claims 1 to 17.

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