A method for synthesizing a dimethenamid intermediate

Abstract

The present invention relates to a method for synthesizing a dimethenamid intermediate, and belongs to the technical field of organic synthesis. The present invention uses (2S) 1-methoxypropyl 2-amine as raw material, first reacts with dichloropyrazine compounds, and then adds 2,4-dimethylthiophene 3-alcohol to continue the reaction; Finally, acid and metal are used to carry out quenching treatment to obtain the target product. The preparation method provided by the present invention has mild reaction conditions, does not use special equipment such as autoclaves, and simultaneously reduces the temperature of the reaction. Product yield is high, and multiple batches of verifications are all above 96%, and purity and ee can reach more than 98%, which is very suitable for industrial preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a dimethenamid intermediate. Background Art

[0002] Dimethazone belongs to the chloroacetamide class of herbicides, and is classified as an amide herbicide. Its primary mechanism of action is to inhibit cell division to achieve weed control. It was developed by Syngenta and developed by BASF in Germany. Many amide herbicides have optical isomers, but only one configuration is actually effective. Dimethazone is one such example with optical isomers. Its active chiral isomer, pure dimethazone (the optical S configuration of dimethazone), was patented in 1992 and further developed, with commercialization in 2000. Its dosage requires only 50% of the racemic isomer. The synthesis of these chiral isomers is a significant challenge for amide herbicides, and their research and development represents a promising area of ​​research. Pure dimethazone has shown promising market prospects in recent years. Therefore, research into the synthesis of its optically distinct intermediates is particularly important. The first step in the preparation of dimethenamid is to react the intermediate (2,4-dimethylthiophen-3-yl)-(2-methoxy-1-methylethyl)amine with chloroacetyl chloride (the compound of the following formula I) as follows:

[0003] ;

[0004] The difficulty in synthesizing the compound of formula I lies in the process of forming the CN bond. The existing method for synthesizing the compound of formula I is as follows:

[0005] ;

[0006] U.S. Patent No. 5,457,085A reports a method for synthesizing the compound of Formula I, using the compound of Formula II and the compound of Formula III. The reaction conditions are harsh, requiring the use of an acidic catalyst (such as hydrochloric acid, acetic acid, or trifluoroacetic acid), high temperature (greater than 100°C), and high pressure (greater than 3 MPa). This route places high demands on equipment, making it unsuitable for large-scale industrial production.

[0007] Patent CN113024505B discloses a similar reaction, using 2,4-dimethyl-2,3-dihydrothiophen-3-one as the starting material. Under the catalysis of an acid (toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, or hydrogen chloride), it reacts with L-alaninol ((2S)-1-hydroxypropyl-2-amine) at 120-180°C for 6-24 hours to produce a hydroxy intermediate, which is then reacted with dimethyl sulfate to obtain a chiral secondary amine. The route is as follows:

[0008] ;

[0009] This route requires high temperatures and constant water removal. Post-processing also requires removing excess L-alaninol at high temperatures (180°C) and negative pressure, which is significantly unfavorable and places high demands on equipment. Furthermore, this route offers relatively low yields, with the two-step yield being only 65%. Summary of the Invention

[0010] Aiming at the problem that the existing synthesis of the intermediate compound of formula I of dimethenamid P is subject to harsh reaction conditions and is not conducive to industrial production, the present invention provides a method for synthesizing the intermediate of dimethenamid P to solve the above problems.

[0011] The technical solutions of the present invention are as follows:

[0012] A method for synthesizing a dimethenamid intermediate comprises using a compound of formula III as a raw material, first reacting it with a dichloropyrazine compound, then adding a compound of formula II to continue the reaction, and finally quenching it with an acid and a metal to obtain a compound of formula I. The reaction formula is as follows:

[0013] .

[0014] Furthermore, the dichloropyrazine compound is 5,6-dichloro-2,3-dicyanopyrazine.

[0015] Furthermore, the molar ratio of the compound of formula II, the compound of formula III and the dichloropyrazine compound is 1:1-1.5:1-1.3; preferably 1:1.3:1.2.

[0016] Furthermore, the acid is at least one of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid; preferably acetic acid.

[0017] Furthermore, the amount of the acid used is 1.0-1.5 ml / mol, preferably 1.2 ml / mol, based on the compound of formula II.

[0018] Furthermore, the metal is one of iron, zinc, tin or aluminum, preferably zinc.

[0019] Furthermore, the amount of the metal used is 5 to 15 mol / mol, preferably 10 mol / mol, based on the compound of formula II.

[0020] Further, the specific steps are:

[0021] (1) Mixing a dichloropyrazine compound and a compound of formula III (2S)-1-methoxypropyl-2-amine in solvent one, and reacting at temperature one under the action of a base; then adding a compound of formula II and solvent two and continuing the reaction at temperature two;

[0022] (2) After the reaction in step (1) is completed, acid and metal are added at temperature 3 to quench the reaction, and the reaction is stirred while maintaining the temperature;

[0023] (3) After the reaction in step (2) is completed, solvent tris is added for dilution, filtered, washed with water, and separated to obtain an organic phase; the organic phase is concentrated to obtain the compound of formula I.

[0024] Furthermore, the solvent is selected from one or more of tetrahydrofuran, dioxane, acetone or acetonitrile, preferably dioxane.

[0025] Furthermore, the second solvent is selected from one of dioxane, DMF, DMSO or acetonitrile; preferably DMSO.

[0026] Furthermore, the base is selected from at least one of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate or potassium phosphate, preferably potassium phosphate.

[0027] Furthermore, the temperature is 20-100°C, preferably 50°C.

[0028] Furthermore, the second temperature is 80-120°C, preferably 100°C.

[0029] Furthermore, in step (1), the reaction time of the dichloropyrazine compound and the compound of formula III is 1.5 to 6 hours, preferably 2 hours; and the reaction time after adding the compound of formula II is 0.5 to 2 hours, preferably 0.5 hour.

[0030] Furthermore, the temperature three is 0-50°C, preferably 25°C.

[0031] Furthermore, in the step (2), the reaction is kept warm for 0.5 to 2 hours after quenching, preferably 0.5 hours.

[0032] The beneficial effects of the present invention are:

[0033] The preparation method provided by the present invention has mild reaction conditions, eliminates the need for specialized equipment such as autoclaves, and reduces the reaction temperature. The product yield is high, with multiple batches consistently exceeding 96%, and both purity and EE can reach over 98%, making it very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0035] Figure 1 This is the HNMR spectrum of the product prepared in Example 1.

[0036] Figure 2 This is the MS spectrum of the product prepared in Example 1. DETAILED DESCRIPTION

[0037] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0038] Example 1

[0039] A method for synthesizing a dimethenamid intermediate is as follows:

[0040] (1) Compound III (8.9 g, 0.1 mol, 1 eq, ee greater than 99%), 120 mL of dry 1,4-dioxane, 5,6-dichloro-2,3-dicyanopyrazine (19.9 g, 0.1 mol, 1 eq) and anhydrous potassium phosphate (5 eq) were added to the reaction flask in sequence, and the system was heated to 50 °C and reacted for 2 h. Subsequently, a DMSO solution of compound II 2,4-dimethyl-3-hydroxythiophene (12.8 g, 0.1 mol, 1 eq) was added to the system, and the system was continued to be heated and reacted at 100 °C for 0.5 h.

[0041] (2) Detect the residual amount of compound II. If about 17% remains, continue to keep warm. After 0.5 h, detect that about 17% of compound II still remains. The reaction will no longer proceed. Lower the system temperature to room temperature, add acetic acid and zinc powder, raise the temperature to 80°C, and continue stirring for 0.5 h. After the conversion of the intermediate is complete, cool the system to room temperature.

[0042] (3) Ethyl acetate was added to the system, filtered, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by vacuum distillation to obtain 15.9 g of a yellow oil with a yield of 80.0%, HPLC (area normalized): 98.0%, and ee greater than 99%.

[0043] 1H-NMR (400 MHz, Chloroform-d): δ6.61 (d, J = 1.2 Hz, 1H), 3.36 (s,3H), 3.33-3.30 (m, 2H), 3.28 - 3.22 (m, 1H), 2.29 (s, 3H), 2.10 (d, J = 1.1Hz, 3H), 1.14 (d, J = 6.5 Hz, 3H).

[0044] MS: 200 (M+H) + .

[0045] Example 2

[0046] Using the preparation method of Example 1 as a standard, the feed ratio of compound I, compound III and dichloropyrazine compound was adjusted, and the yield, purity and ee of the obtained product were shown in Table 1 below.

[0047] Table 1 - Product yield, purity and ee value of different feed ratios

[0048]

[0049] From the experimental data in Table 1, it can be determined that the optimal molar ratio of the compound of formula II: the compound of formula III: 5,6-dichloro-2,3-dicyanopyrazine is 1:1.3:1.2.

[0050] Example 3

[0051] (1) Compound III (11.6 g, 0.13 mol, 1.3 eq, ee value greater than 99%), 120 mL of dioxane, 5,6-dichloro-2,3-dicyanopyrazine (23.9 g, 0.12 mol, 1.2 eq), and anhydrous potassium phosphate (5 eq) were added to a reaction flask in sequence. The mixture was heated to 50 °C and reacted for 2 h. Subsequently, a DMSO solution of compound II (12.8 g, 0.1 mol, 1 eq) was added to the system, the system was heated to 100 °C, and the reaction was carried out for 0.5 h.

[0052] (2) Detect the residual situation of the compound of formula II. The system temperature was lowered to room temperature, hydrochloric acid and zinc powder were added thereto, the temperature was raised to 80°C, and stirring was continued for 0.5 h. The conversion of the intermediate was detected. The intermediate remained 8%. The reaction was continued for 0.5 h. The conversion of the intermediate was detected. The intermediate still remained 8%. The reaction was no longer carried out. The system was lowered to room temperature. Ethyl acetate was added to the system, filtered, and the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by vacuum distillation to obtain a yellow oil (18.3 g, 92.0% yield, HPLC (area normalized): 98.2%, ee value greater than 99%).

[0053] Example 4

[0054] (1) Compound III (11.6 g, 0.13 mol, 1.3 eq, ee value greater than 99%), 120 mL of acetonitrile, 5,6-dichloro-2,3-dicyanopyrazine (23.9 g, 0.12 mol, 1.2 eq), and anhydrous potassium phosphate (5 eq) were added to a reaction flask in sequence. The mixture was heated to 50 °C and reacted for 2 h. Subsequently, a DMSO solution of compound II (12.8 g, 0.1 mol, 1 eq) was added to the system, the system was heated to 100 °C, and the reaction was carried out for 0.5 h.

[0055] (2) Detect the residual situation of compound of formula II, and the residual situation is about 14%; continue to keep warm, and detect after 0.5h, the thiophene raw material still remains about 14%, and the reaction no longer proceeds. The temperature of the system is lowered to room temperature, acetic acid and zinc powder are added thereto, and the temperature is raised to 80℃, and stirring is continued for 0.5h; detect the conversion of intermediate, and the residual situation of intermediate is 8%. Continue to react for 0.5h, and detect the conversion of intermediate, and the residual situation of intermediate is still 8%, and the reaction no longer proceeds. Cool to room temperature, add ethyl acetate to the system, filter, wash the organic phase with water three times, dry over anhydrous sodium sulfate, and concentrate. The crude product is purified by vacuum distillation to obtain a yellow oil (17.7g, 89% yield, HPLC (area normalized): 98.0%, ee value greater than 99%).

[0056] The reason for the low yield of the product in Example 4 may be related to the low boiling point of the added solvent acetonitrile, which leads to a low reaction temperature and incomplete reaction.

[0057] Comparative Example 1

[0058] (1) Compound III (11.6 g, 0.13 mol, 1.3 eq, ee value greater than 99%), 120 mL of dioxane, 2,3-dichloropyrazine (17.9 g, 0.12 mol, 1.2 eq) and anhydrous potassium phosphate (5 eq) were added to the reaction flask in sequence. The reaction system was heated to 50 °C and reacted for 2 h. Subsequently, a DMSO solution of compound II (12.8 g, 0.1 mol, 1 eq) was added to the system. The reaction system was heated to 100 °C and reacted for 0.5 h.

[0059] The reaction solution was tested, but no intermediate product was detected. The reaction mixture was kept warm for 3 hours, but no intermediate was detected. The system was cooled to room temperature, acetic acid and zinc powder were added, and the temperature was raised to 80°C. Stirring was continued for 0.5 hours. The reaction system was tested, but no target product was detected.

[0060] The reason why the reaction did not proceed is presumably because the catalytic activity of 2,3-dichloropyrazine was low and the reaction did not proceed.

[0061] Although the present invention has been described in detail with reference to the accompanying drawings and in conjunction with preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, persons of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall be within the scope of the present invention. Any changes or substitutions that can be easily conceived by persons skilled in the art within the technical scope disclosed in the present invention shall be within the scope of protection of the present invention.

Claims

1. A method for synthesizing a dimethenamid intermediate, characterized in that: The compound of formula III is used as a raw material, first reacted with a dichloropyrazine compound, and then the compound of formula II is added to continue the reaction; finally, an acid and a metal are used for quenching to obtain the compound of formula I; the reaction formula is as follows: ； The dichloropyrazine compound is 5,6-dichloro-2,3-dicyanopyrazine.

2. The method according to claim 1, wherein The molar ratio of the compound of formula II, the compound of formula III and the dichloropyrazine compound is 1:1-1.5:1-1.

3.

3. The method according to claim 1, wherein The acid is at least one of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid.

4. The method according to claim 1, wherein The amount of the acid used is 1.0-1.5 ml / mol based on the compound of formula II.

5. The method according to claim 1, wherein The amount of the metal used is 5 to 15 mol / mol based on the compound of formula II.

6. The method according to claim 1, wherein The metal is one of iron, zinc, tin or aluminum.

7. The method according to claim 1, wherein The specific steps are: (1) Mixing a dichloropyrazine compound and a compound of formula III in solvent one, reacting at temperature one under the action of a base; then adding a compound of formula II and solvent two and continuing the reaction at temperature two; (2) After the reaction in step (1) is completed, acid and metal are added at temperature 3 to quench the reaction, and the reaction is stirred while maintaining the temperature; (3) After the reaction in step (2) is completed, solvent tris is added for dilution, filtered, washed with water, and separated to obtain an organic phase; the organic phase is concentrated to obtain the compound of formula I.

8. The method according to claim 7, wherein The second solvent is selected from one of dioxane, DMF, DMSO or acetonitrile.

9. The method according to claim 7, wherein The second temperature is 80-120°C.

Images