CN115873019A - Preparation method of pinoxaden and intermediate thereof - Google Patents
Preparation method of pinoxaden and intermediate thereof Download PDFInfo
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- CN115873019A CN115873019A CN202211478172.0A CN202211478172A CN115873019A CN 115873019 A CN115873019 A CN 115873019A CN 202211478172 A CN202211478172 A CN 202211478172A CN 115873019 A CN115873019 A CN 115873019A
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- 239000005597 Pinoxaden Substances 0.000 title claims abstract description 28
- MGOHCFMYLBAPRN-UHFFFAOYSA-N pinoxaden Chemical compound CCC1=CC(C)=CC(CC)=C1C(C1=O)=C(OC(=O)C(C)(C)C)N2N1CCOCC2 MGOHCFMYLBAPRN-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- 229940125782 compound 2 Drugs 0.000 claims abstract description 62
- 229940126214 compound 3 Drugs 0.000 claims abstract description 44
- 229940125904 compound 1 Drugs 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000010438 heat treatment Methods 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- 238000010923 batch production Methods 0.000 claims description 5
- 229940117389 dichlorobenzene Drugs 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000012805 post-processing Methods 0.000 claims description 4
- 239000003849 aromatic solvent Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 27
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 25
- 150000001412 amines Chemical class 0.000 abstract description 21
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000012467 final product Substances 0.000 abstract description 3
- 150000007530 organic bases Chemical class 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 244000025254 Cannabis sativa Species 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- KLDXJTOLSGUMSJ-BXKVDMCESA-N (3s,3as,6s,6as)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-diol Chemical compound O[C@H]1CO[C@H]2[C@@H](O)CO[C@H]21 KLDXJTOLSGUMSJ-BXKVDMCESA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- 235000007320 Avena fatua Nutrition 0.000 description 2
- 244000075850 Avena orientalis Species 0.000 description 2
- 244000067456 Chrysanthemum coronarium Species 0.000 description 2
- 235000007871 Chrysanthemum coronarium Nutrition 0.000 description 2
- 241000209082 Lolium Species 0.000 description 2
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 235000005373 Uvularia sessilifolia Nutrition 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 241000743985 Alopecurus Species 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000010086 Setaria viridis var. viridis Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- 244000230342 green foxtail Species 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of pinoxaden and an intermediate (compound 3) thereof. The preparation method of the compound 3 comprises the following steps: placing the compound 1 and an organic solvent which is not mutually soluble with water under the condition that the pressure is 0.06-0.09MPa, heating to 100-140 ℃, adding the compound 2 in batches, and reacting to obtain a compound 3. The method can control the content of the isomeric amine impurities and the decarboxylation impurities at a lower level, ensures the quality of the pinoxaden serving as a final product, avoids a complex impurity removal process, improves the conversion rate of the compound 2 and the atom utilization rate of the compound 1, does not use organic bases such as triethylamine and the like, and is suitable for industrial scale-up production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of pinoxaden and an intermediate thereof.
Background
Pinoxaden is a post-emergence gramineous weed herbicide with selectivity and systemic conductivity, can effectively prevent and remove annual gramineous weeds in wheat and barley fields, and is very suitable for spring cereals. The weeding composition has a good control effect on grassy weeds such as wild oats, ryegrass, green bristlegrass, stiff grass, crowndaisy grass, japanese alopecurus, club grass and the like, and particularly has a control effect on malignant grassy weeds such as wild oats, ryegrass, stiff grass and crowndaisy grass close to 100%. The composition has the characteristics of high efficiency, broad spectrum, high safety, wide application period, rain wash resistance and the like, is quickly degraded in animals, plants, soil and environment, does not stay or accumulate, and does not leach into underground water. Compared with other wheat field herbicides, pinoxaden has huge development potential and market competitiveness.
The pinoxaden is generally synthesized by the reaction of a compound 2 and a compound 1 to synthesize a compound 3, and in order to save process steps, the compound 3 is directly reacted with pivaloyl chloride without purification treatment to synthesize a compound 4, pinoxaden. Therefore, the compound 3 is a very important intermediate in the synthesis process of pinoxaden.
CN108794505A and CN108264492A both disclose a method for preparing compound 3, both compound 2 and compound 1 are added to a reaction vessel at one time, heated under reflux, and reacted, with yields of 84% and 90%, respectively. The yields of the two methods are to be improved, and a large amount of triethylamine is used in CN108264492A, so that the toxicity of the triethylamine is high, the post-treatment is complicated, and the process cost is increased.
CN106928253A also discloses a preparation method of compound 3: the compound 2, the hydrobromide of the compound 1 and triethylamine are added into a reaction vessel at one time, and the reaction is heated, so that the yield is lower and is only 76%. The 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.
Disclosure of Invention
Problems to be solved by the invention
The inventor finds that the synthesis process of the compound 3 often generates isomeric amine impurities and decarboxylation impurities, the isomeric amine impurities and the decarboxylation impurities respectively generate new impurities in the reaction process of the compound 3 and the pivaloyl chloride, and the two new impurities are difficult to remove in the post-treatment process, so that the yield and the purity of the pinoxaden are influenced. Therefore, it is necessary to control the relative amounts of the isomeric amine impurities and decarboxylation impurities during the reaction of compound 2 with compound 1.
However, the prior art has not investigated the effect of the process for the preparation of compound 3 on the levels of isomeric amine impurities and decarboxylation impurities. Therefore, it is highly desirable to develop a process for preparing pinoxaden and intermediates thereof, which has high reaction conversion and yield, low impurity content (especially isomeric amine impurities and decarboxylation impurities), high atom utilization of raw materials, low toxicity, and simple post-treatment (for example, without using reagents such as triethylamine).
The invention aims to provide a preparation method of pinoxaden and an intermediate (namely a compound 3) thereof, which can reduce the content of isomeric amine impurities and decarboxylation impurities, and has the advantages of high reaction conversion rate and yield, high atom utilization rate and no use of organic bases such as triethylamine and the like.
Means for solving the problems
In order to solve the above problems, the present invention provides a method for preparing pinoxaden intermediate, which comprises the following steps:
mixing the compound 1 with an organic solvent immiscible with water, heating to 100-140 ℃, adding the compound 2, and reacting to obtain a compound 3; the reaction further comprises at least one of the following conditions:
(1) The reaction pressure is 0.06-0.09MPa;
(2) The compound 2 was added as a batch.
Preferably, in the fed-batch process, the molar ratio of the fed-batch amount of the compound 2 to the total fed-batch amount of the compound 1 is 0.1-0.5:1, more preferably 0.2 to 0.4:1, further preferably 0.25:1.
preferably, the molar ratio of the total charge of compound 1 to the total charge of compound 2 is from 1 to 5:1, more preferably 1 to 1.2:1, further preferably 1.05:1.
further, in the fed-batch process, the interval time between each batch of feeding is 10 to 90 minutes, preferably 30 to 75 minutes, more preferably 60 minutes.
Preferably, the reaction pressure is from 0.065 to 0.085MPa, more preferably from 0.067 to 0.082MPa.
Preferably, the water-immiscible organic solvent is an aromatic solvent, preferably chlorobenzene, xylene or dichlorobenzene, more preferably chlorobenzene.
Preferably, the molar ratio of the water-immiscible organic solvent to the total charge of compound 2 is 2.
Preferably, the temperature of the heating is 110 to 130 ℃, more preferably 118 to 125 ℃.
Preferably, the preparation method further comprises a step of post-treatment.
Preferably, the post-processing step comprises: cooling after the reaction is finished, adding a hydrochloric acid aqueous solution, carrying out phase splitting, and taking an organic phase to obtain a compound 3; or
The post-processing step comprises: after the reaction is finished, cooling, adding hydrochloric acid, and filtering to obtain a compound 3; further, the temperature of the temperature reduction is below 20 ℃, and the molar ratio of the hydrochloric acid to the total feeding amount of the compound 2 is 1.
In addition, the invention also provides a preparation method of pinoxaden, which comprises the following steps:
wherein the compound 3 is obtained by the preparation method of the pinoxaden intermediate.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention improves the preparation process of pinoxaden intermediate (namely compound 3), and obviously shortens the reaction time and effectively avoids the mass production of decarboxylation impurities by heating the reaction solution firstly and then adding the compound 2 in batches; through a micro negative pressure mode, the reaction temperature is reduced, and the retention time of ammonia in the reaction is reduced, so that the generation of isomeric amine impurities is reduced. Finally, the process method can effectively control the content of the isomeric amine impurities and the decarboxylation impurities to a lower level, ensure the quality of the pinoxaden in the final product, avoid a complex impurity removal process and greatly reduce the process cost; the conversion rate of the compound 2 and the atom utilization rate of the compound 1 are improved, the reaction yield is improved, and the reaction time is shortened; meanwhile, organic alkali such as triethylamine is not used in the reaction process, the toxicity is low, the complex post-treatment and recovery steps are avoided, and the method is suitable for industrial large-scale production.
Detailed Description
In the present invention, "pinoxaden intermediate" refers to compound 3 (or its keto-enol tautomer). In the preparation process of the compound 3, the inventor finds that the content of two impurities, namely the isomeric amine impurity and the decarboxylation impurity, can directly influence the reaction for synthesizing pinoxaden in the next step and influence the quality of the pinoxaden in the final product. In the prior art, the two impurities are basically not researched, the synthesis conversion rate and yield of the prior art are not high, the toxicity of the used triethylamine is high, and the post-treatment and recovery process is complicated.
The preparation process of the compound 3 is improved, the reaction time is obviously shortened by heating the reaction solution firstly and then adding the compound 2 in batches, and a large amount of decarboxylation impurities are effectively avoided; by means of micro negative pressure, the reaction temperature is reduced, the retention time of ammonia in the reaction is reduced, and therefore the generation of isomeric amine impurities is reduced.
Specifically, the preparation method of the compound 3 provided by the invention comprises the following steps: mixing the compound 1 with an organic solvent immiscible with water, heating to 100-140 ℃, adding the compound 2, and reacting to obtain a compound 3; wherein the reaction further comprises at least one of the following conditions:
(1) The reaction pressure is 0.06-0.09MPa;
(2) The compound 2 was added as a batch.
In some embodiments, during said feeding in portions, the molar ratio of the amount of said compound 2 fed per portion to the total amount of said compound 1 fed is from 0.1 to 0.5:1; in some preferred embodiments, the molar ratio is from 0.2 to 0.4:1; in some more preferred embodiments, the molar ratio is 0.25:1.
in some embodiments, the molar ratio of the total charge of compound 1 to the total charge of compound 2 is from 1 to 5:1; in some preferred embodiments, the molar ratio is 1 to 1.2:1; in some more preferred embodiments, the molar ratio is 1.05:1.
in some embodiments, during the fed-batch process, the time interval between each batch of feeding is 10 to 90 minutes; in some preferred embodiments, the interval is 30 to 75 minutes; in some more preferred embodiments, the interval time is 60 minutes.
In some embodiments, the reaction pressure is from 0.065 to 0.085MPa; in some preferred embodiments, the decarboxylation impurity and the isomeric amine impurity are each present in an amount of less than 0.5% at a reaction pressure of 0.067 to 0.082MPa.
In some embodiments, the water-immiscible organic solvent is an aromatic solvent, such as chlorobenzene, xylene, or dichlorobenzene. Under the non-negative pressure condition, the reaction effect of the high boiling point solvents such as chlorobenzene, dimethylbenzene or dichlorobenzene is better; under the condition of negative pressure, the chlorobenzene and the dichlorobenzene have better reaction effect.
In the present invention, the amount of solvent used has less influence on the effect of the reaction, and in some embodiments, the molar ratio of the water-immiscible organic solvent to the total charge of compound 2 is 2.
In some embodiments, the temperature of the heating is 110-130 ℃; in some preferred embodiments, the temperature of the heating is 118 to 125 ℃.
In some embodiments, where the reaction pressure is atmospheric and the compound 2 is fed in a batch mode, the reaction temperature is set at 130 ℃, and the molar ratio of the total feed of compound 1 to the total feed of compound 2 is 1.2:1, the content of decarboxylation impurities and isomannide impurities can be controlled to be below 0.5 percent, and the conversion rate and the yield of the reaction are high.
In some embodiments, the reaction pressure is 0.065 to 0.085MPa (e.g., 0.067 MPa), and compound 2 is fed without a fed-batch mode (e.g., with a one-shot feed), the reaction temperature is set at 118 ℃, and the molar ratio of the total feed of compound 1 to the total feed of compound 2 is 1.05:1, the content of decarboxylation impurities and isomannide impurities can be controlled below 0.5 percent, and the conversion rate and yield of the reaction are also high.
In some embodiments, the method of preparation may further comprise a step of post-treatment.
In some embodiments, after the reaction is completed, the temperature is reduced, hydrochloric acid solution is added, phase separation is performed, and the organic phase is taken to obtain a solution of compound 3, such as chlorobenzene solution of compound 3. The solution of the compound 3 can directly participate in the subsequent reaction for preparing pinoxaden.
In some embodiments, when the solvent is chlorobenzene, after the reaction is finished, the temperature is reduced, hydrochloric acid is added, and the solid obtained by filtering is the compound 3. In some embodiments, the temperature of the temperature reduction can be 20 ℃ or lower, and the molar amount of the hydrochloric acid is the same as the molar amount of the total charge of the compound 2. In the examples of the present invention, the HPLC relative content of compound 3 in the reaction solution was monitored after the completion of the reaction, and the absolute yield of compound 3 obtained by this post-treatment method was reduced by approximately 2 to 3% from the relative content.
In addition, the preparation method of the pinoxaden intermediate can also be applied to the synthesis of pinoxaden, and specifically, the invention also provides a preparation method of pinoxaden, which comprises the following steps:
wherein the compound 3 is obtained by the preparation method of the pinoxaden intermediate.
In the present invention, compound 1 can be obtained by the following reaction:
hydrolyzing the compound 4 by using potassium hydroxide with a certain concentration under the condition of using chlorobenzene as a solvent, after the reaction is finished, carrying out phase separation, collecting a chlorobenzene solution of the compound 1, wherein the chlorobenzene solution of the compound 1 can be directly used for the next reaction, namely the synthesis of the compound 3.
Examples
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
Compound 2 (HPLC purity 98%,5.96g, 0.0235mol) and the chlorobenzene solution of compound 1 (mass concentration 5%,57.5g, 0.0282mol) were weighed into a 100mL three-necked flask, heated, the reaction temperature was kept at 130 ℃, after 5h of reaction, the reaction was stopped, and the relative contents were measured by HPLC: 96% of compound 3, 0.8% of decarboxylation impurities, 0.6% of isomeric amine impurities and less than 0.1% of compound 2.
Examples 2 to 5
The reaction temperature was varied in the same manner as in example 1, and the results are shown in Table 1 below.
TABLE 1
As can be seen from Table 1: the reaction raw materials are added at one time and react under normal pressure, so that the content of decarboxylation impurities and isomeric amine impurities is still high even if the reaction temperature is changed, and the conversion rate of the raw materials is obviously reduced.
Example 6
A chlorobenzene solution of compound 1 (mass concentration 5%,28.5g, 0.0282mol) was charged into a 100mL three-necked flask, the reaction pressure condition of the reaction system was maintained at normal pressure, heating was started, and after the reaction temperature was maintained at 130 ℃, compound 2 (HPLC purity 98%,5.96g, 0.0235mol) was added in four portions using a solid batch feeder, and the amount of compound 2 added per portion was 1.49g. The specific mode of adding the materials in batches is as follows: adding a first batch of compound 2, and reacting for 1h; adding a second batch of compound 2, and reacting for 1h; adding a third batch of compound 2, and reacting for 1h; finally, the fourth batch of compound 2 was added and the reaction was stopped after 1 h. The reaction was carried out for a total of 4h, and relative contents were determined by HPLC, wherein: 98% of compound 3, 0.3% of decarboxylation impurity, 0.5% of isomeric amine impurity and less than 0.1% of compound 2.
Example 7
The procedure of example 6 was followed, with the reaction temperature set to 110 ℃. HPLC to detect relative content, wherein: 85% of compound 3, 0.3% of decarboxylation impurities, 0.3% of isomeric amine impurities and 11% of compound 2.
And continuously prolonging the reaction time to 15h at the reaction temperature of 110 ℃, and detecting the relative content by HPLC, wherein: 93% for compound 3, 0.6% for decarboxylation impurities, 0.7% for isomeric amine impurities, and 2% for compound 2.
Example 8
A toluene solution of Compound 1 (5% by mass, 28.5g, 0.0282mol) was charged into a 100mL three-necked flask, heating was started, and after the reaction temperature was maintained at 110 ℃ (toluene reflux), compound 2 (HPLC purity 98%,7.00g, 0.0282mol) was added in four portions using a solid batch feeder, and the amount of Compound 2 added per portion was 1.75g. The specific mode of adding the materials in batches is as follows: adding a first batch of compound 2, and reacting for 1h; adding a second batch of compound 2, and reacting for 1h; adding a third batch of compound 2, and reacting for 1h; finally, a fourth batch of compound 2 was added and reacted for 1h before HPLC to determine relative content, where: 73.6% for compound 3, 0.44% for decarboxylation impurities, 0.2% for isomeric amine impurities, and 25% for compound 2.
And (3) continuing to prolong the reaction time to 12h at the reflux temperature, finishing the reaction, and detecting the relative content by HPLC (high performance liquid chromatography), wherein: 96% of compound 3, 0.6% of decarboxylation impurity, 0.8% of isomeric amine impurity and less than 0.1% of compound 2.
Examples 9 to 11
Examples 9 and 10 were carried out as in example 6, with different molar ratios of compound 1 to compound 2 being set.
Example 11 was carried out as in example 7, setting the reaction temperature at 120 ℃.
The reaction results are shown in table 2.
TABLE 2
As can be seen from Table 2: in the fed-batch mode, decarboxylated impurities are significantly reduced. The higher the molar ratio of the compound 1 to the compound 2 is, the higher the content of the compound 3 after the reaction is finished is, the content of decarboxylation impurities and isomer impurities is slightly reduced, but the higher the molar ratio of the compound 1 to the compound 2 is, the lower the atom utilization rate of the compound 1 is, and the waste of materials is caused.
Example 12
A chlorobenzene solution (mass concentration: 5%,28.5g, 0.0282mol) of Compound 1 was charged into a 100mL three-necked flask, the reaction system was maintained at a reaction pressure of 0.082MPa, heating was started, and after the reaction temperature was maintained at 125 ℃, compound 2 (HPLC purity: 98%,6.8g, 0.0268mol) was added in four portions using a solid portion feeder, and the amount of Compound 2 added per portion was 1.7g. The specific mode of batch feeding is as follows: adding a first batch of compound 2, and reacting for 1h; adding a second batch of compound 2, and reacting for 1h; adding a third batch of compound 2, and reacting for 1h; finally, the fourth batch of compound 2 was added and the reaction was stopped after 1 h. The reaction was carried out for a total of 4h, and relative contents were determined by HPLC, wherein: 98.5 percent of compound 3, 0.3 percent of decarboxylation impurity, 0.2 percent of isomeric amine impurity and less than 0.1 percent of compound 2.
Example 13
Weighing a chlorobenzene solution (mass concentration is 5 percent, 28.5g, 0.0282mol) of a compound 2 (HPLC purity is 98 percent, 6.8g, 0.0268mol) and a compound 1 into a 100mL three-necked bottle, keeping a reaction system at a reaction pressure condition of 0.067MPa, starting heating, keeping a reaction temperature at 118 ℃, stopping the reaction after 4 hours of reaction, and detecting relative content by HPLC, wherein: 97.2% of compound 3, 0.5% of decarboxylation impurity, 0.3% of isomeric amine impurity and less than 0.1% of compound 2.
Examples 14 to 15
The results are shown in Table 3, with different negative pressure conditions and reaction temperatures set as in example 12.
TABLE 3
As can be seen from Table 3: the reaction pressure is controlled between 0.067MPa and 0.082MPa, the temperature is controlled at about 120 ℃, the reaction condition is the optimal condition, the decarboxylation impurities and the isomannide impurities can be effectively controlled below 0.5 percent at the same time, the conversion rate of the compound 2 is higher, and the content of the compound 3 is above 97 percent.
Claims (9)
1. A preparation method of pinoxaden intermediate shown as a formula 3 comprises the following steps:
mixing the compound 1 with an organic solvent immiscible with water, heating to 100-140 ℃, adding the compound 2, and reacting to obtain a compound 3; the reaction further comprises at least one of the following reaction conditions:
(1) The reaction pressure is 0.06-0.09MPa;
(2) The compound 2 is added in batches.
2. The method of claim 1, wherein: in the fed-batch process, the molar ratio of the fed-batch amount of the compound 2 to the total fed-batch amount of the compound 1 is 0.1-0.5:1, preferably 0.2 to 0.4:1, more preferably 0.25:1.
3. the production method according to claim 1 or 2, characterized in that: the molar ratio of the total feeding amount of the compound 1 to the total feeding amount of the compound 2 is 1-5:1, preferably 1 to 1.2:1, more preferably 1.05:1.
4. the production method according to any one of claims 1 to 3, characterized in that: in the fed-batch process, the time interval between each batch of feeding is 10 to 90 minutes, preferably 30 to 75 minutes, more preferably 60 minutes.
5. The production method according to any one of claims 1 to 4, characterized in that: the reaction pressure is 0.065-0.085MPa, preferably 0.067-0.082MPa.
6. The production method according to any one of claims 1 to 5, characterized in that: the organic solvent immiscible with water is an aromatic solvent, preferably chlorobenzene, xylene or dichlorobenzene, more preferably chlorobenzene.
7. The production method according to any one of claims 1 to 6, characterized in that: the heating temperature is 110-130 deg.C, preferably 118-125 deg.C.
8. The production method according to any one of claims 1 to 7, characterized in that: the preparation method also comprises the step of post-treatment;
preferably, the post-processing step comprises: cooling after the reaction is finished, adding a hydrochloric acid aqueous solution, carrying out phase splitting, and taking an organic phase to obtain a compound 3; or alternatively
The post-processing step comprises: after the reaction is finished, cooling, adding hydrochloric acid, and filtering to obtain a compound 3; more preferably, the temperature of the temperature reduction is below 20 ℃, and the molar ratio of the hydrochloric acid to the total charging amount of the compound 2 is 1.
9. A preparation method of pinoxaden comprises the following steps:
wherein compound 3 is obtained by the production method according to any one of claims 1 to 8.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355806A (en) * | 1999-06-16 | 2002-06-26 | 辛根塔参与股份公司 | Process for preparation of herbicidal derivatives |
| CN108264492A (en) * | 2016-12-30 | 2018-07-10 | 浙江省诸暨合力化学对外贸易有限公司 | A kind of preparation process of oxygen diazacyclo compound and application |
| WO2020201974A1 (en) * | 2019-04-01 | 2020-10-08 | Bhagiradha Chemicals & Industries Limited | Novel process for preparation of key intermediate of pinoxaden |
| CN113968798A (en) * | 2020-07-24 | 2022-01-25 | 沈阳中化农药化工研发有限公司 | Cyclohexyl ester compound, preparation method and application thereof |
| WO2022123541A1 (en) * | 2020-12-11 | 2022-06-16 | Gharda Chemicals Limited | A process for the preparation of pyrazole-oxadiazepine |
-
2022
- 2022-11-23 CN CN202211478172.0A patent/CN115873019A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355806A (en) * | 1999-06-16 | 2002-06-26 | 辛根塔参与股份公司 | Process for preparation of herbicidal derivatives |
| CN108264492A (en) * | 2016-12-30 | 2018-07-10 | 浙江省诸暨合力化学对外贸易有限公司 | A kind of preparation process of oxygen diazacyclo compound and application |
| WO2020201974A1 (en) * | 2019-04-01 | 2020-10-08 | Bhagiradha Chemicals & Industries Limited | Novel process for preparation of key intermediate of pinoxaden |
| CN113968798A (en) * | 2020-07-24 | 2022-01-25 | 沈阳中化农药化工研发有限公司 | Cyclohexyl ester compound, preparation method and application thereof |
| WO2022123541A1 (en) * | 2020-12-11 | 2022-06-16 | Gharda Chemicals Limited | A process for the preparation of pyrazole-oxadiazepine |
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