Preparation method of clethodim intermediate

Abstract

The invention relates to a preparation method of a clethodim intermediate, which comprises the following steps: carrying out addition reaction on dimethyl malonate and 6-ethylthio-3-heptene-2-ketone in the presence of a catalytic amount of dimethyl malonate sodium salt to generate an intermediate compound shown as a formula (3), # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a preparation method of clethodim intermediates. Background Art

[0002] The following compound of formula (1) is an important intermediate for preparing clethodim:

[0003]

[0004] In the prior art, it has been reported that the compound of formula (1) is prepared by a cyclization reaction using dimethyl malonate, sodium methoxide, and 6-ethylthio-3-hepten-2-one as raw materials.

[0005]

[0006] In the formula, SEt represents ethylthio.

[0007] The mechanism of the above cyclization reaction is as follows: Sodium methoxide first reacts with dimethyl malonate to form sodium dimethyl malonate, and this sodium salt further reacts with 6-ethylthio-3-hepten-2-one to form the compound of formula (1).

[0008]

[0009] The applicant has disclosed in Chinese Patent Application CN111362850A that in the above reaction, the methanol introduced by the raw material sodium methoxide and the methanol generated by the reaction will undergo the following addition side reaction with 6-ethylthio-3-hepten-2-one under the action of sodium methoxide:

[0010]

[0011] In order to reduce this side reaction, it is necessary to reduce the presence of free sodium methoxide in the reaction system. In Chinese Patent Application CN111362850A, by adjusting the feeding mode of the three raw materials of dimethyl malonate, sodium methoxide, and 6-ethylthio-3-hepten-2-one in this reaction, sodium methoxide and dimethyl malonate are first mixed and reacted to form sodium dimethyl malonate, and then this sodium salt reacts with 6-ethylthio-3-hepten-2-one, thereby reducing the contact between sodium methoxide and 6-ethylthio-3-hepten-2-one, and further reducing the above side reaction and the by-product impurity of formula (2).

[0012] At the same time, CN111362850A uses a specific feeding device of a large tube sleeving a small tube to not only ensure that sodium methoxide and dimethyl malonate can be first mixed and reacted, but also realize the continuous feeding of the three materials of dimethyl malonate, sodium methoxide, and 6-ethylthio-3-hepten-2-one, so as to enable continuous production. Summary of the Invention

[0013] However, when the inventors of the present application scaled up the method in CN111362850A to an industrial scale, it was found that the mass transfer effect in the reaction decreased due to the large amount of materials, affecting the full reaction of sodium methoxide and dimethyl malonate, and further resulting in the presence of free sodium methoxide in the system. Sodium methoxide is the substance that mediates the above side reactions. Therefore, the control effect of the side reactions in the method of CN111362850A under industrial scale-up is not as good as that under small scale.

[0014] The inventors of the present application have studied and found that the reaction between sodium methoxide and dimethyl malonate is actually a reversible reaction as follows:

[0015]

[0016] In order to reduce the presence of free sodium methoxide in the reaction system, it is necessary to make the reaction equilibrium proceed as far as possible in the forward direction. To achieve this goal, the inventors of the present application tried to first evaporate the methanol carried in the sodium methoxide solution to dryness, and then dropwise add dimethyl malonate to react to form the sodium salt of dimethyl malonate. However, this sodium salt is a solid, resulting in the reaction system after the formation of the sodium salt becoming a viscous solid-liquid two-phase, making it difficult to carry out continuous synthesis.

[0017] In view of the above problems, the present application aims to provide a new method for preparing the clethodim intermediate, which can stably control the above side reactions and reduce the generation amount of the impurity of formula (2) in large-scale industrial production, and can also carry out continuous production.

[0018] The method for preparing the clethodim intermediate of the present invention is achieved through the following route. Specifically, the present invention relates to:

[0019] (1) A method for preparing a clethodim intermediate, which comprises the following steps:

[0020] Dimethyl malonate and 6-ethylthio-3-hepten-2-one undergo an addition reaction in the presence of a catalytic amount of sodium salt of dimethyl malonate to form an intermediate compound of formula (3).

[0021]

[0022] (2) The preparation method described in (1) above, which comprises the following steps:

[0023] Step 1: Add a catalytic amount of sodium methoxide solution and all of the dimethyl malonate to carry out the following reaction to form a catalytic amount of sodium salt of dimethyl malonate.

[0024]

[0025] Step 2: Subject the dimethyl malonate and 6-ethylthio-3-hepten-2-one that have not reacted completely in Step 1 to an addition reaction in the presence of a catalytic amount of sodium dimethyl malonate to form an intermediate compound of formula (3).

[0026]

[0027] Step 3: Subject the compound of formula (3) to a cyclization reaction with the remaining sodium methoxide solution to form the compound of formula (1).

[0028]

[0029] (3) The preparation method according to (2) above, wherein the molar ratio of sodium methoxide to dimethyl malonate in Step 1 is (0.1 - 0.3):1, preferably (0.15 - 0.25):1.

[0030] (4) The preparation method according to (2) or (3) above, wherein the total amount of sodium methoxide used in Step 1 and Step 3 and dimethyl malonate has a molar ratio of (1.0 - 1.2):1, preferably (1.0 - 1.1):1.

[0031] (5) The preparation method according to any one of (1) to (4) above, wherein the reaction temperature of the addition reaction is 30 - 40°C, preferably 30 - 35°C.

[0032] (6) The preparation method according to any one of (2) to (5) above, wherein the reaction temperature of the cyclization reaction in Step 3 is 30 - 40°C, preferably 30 - 35°C.

[0033] (7) The preparation method according to any one of (1) to (6) above, wherein the sodium methoxide solution is a methanol solution of sodium methoxide. Detailed implementation mode

[0034] In Chinese Patent CN111362850A, in the reaction step of sodium methoxide and dimethyl malonate, sodium methoxide and dimethyl malonate are added simultaneously in substantially equal molar ratios. After the two react to form sodium dimethyl malonate, an addition reaction is further carried out with 6-ethylthio-3-hepten-2-one.

[0035] The inventors of the present application have found through research that the sodium dimethyl malonate formed in Step 1 can replace sodium methoxide as a catalyst to catalyze the addition reaction of dimethyl malonate and 6-ethylthio-3-hepten-2-one. Based on this discovery, the inventors of the present application only add a catalytic amount of sodium methoxide in Step 1, and the catalytic amount of sodium methoxide reacts with dimethyl malonate to form a catalytic amount of sodium dimethyl malonate.

[0036] In the new method of the present application, Step 1 is the following reversible reaction:

[0037]

[0038] In Step 1, a catalytic amount of sodium methoxide solution and all of the dimethyl malonate are added, such that the dimethyl malonate is in a large excess relative to the sodium methoxide, and a catalytic amount of sodium dimethyl malonate salt is formed. Since only a catalytic amount of the sodium methoxide solution is used, the amount of free methanol introduced by it is small, so there is no need to perform the evaporation operation to remove methanol; on the other hand, since the dimethyl malonate is in a large excess relative to the sodium methoxide, the reversible reaction can basically proceed in the forward direction until all of the sodium methoxide added in this step is consumed, thereby reducing the above-mentioned side reactions mediated by the sodium methoxide; further, only a small amount of solid sodium dimethyl malonate salt is formed in the reaction, and the reaction system is not viscous, so that a continuous reaction can be implemented.

[0039] In a preferred embodiment, the catalytic amount in Step 1 refers to an amount where the molar ratio of sodium methoxide to dimethyl malonate is (0.1 to 0.3):1, preferably (0.15 to 0.25):1.

[0040] In Step 2, the unreacted excess dimethyl malonate and 6-ethylthio-3-hepten-2-one in Step 1 are catalyzed by the catalytic amount of sodium dimethyl malonate salt obtained in Step 1 to undergo an addition reaction to form an intermediate compound of formula (3).

[0041]

[0042] In the addition reaction of Step 2, a small amount of sodium dimethyl malonate salt formed in Step 1 is used as a catalyst, and the presence of sodium methoxide is not required, thereby avoiding the direct contact between sodium methoxide and 6-ethylthio-3-hepten-2-one and mediating the above-mentioned side reactions.

[0043] In some specific embodiments, the reaction temperature in Step 2 is 30 to 40 °C, preferably 30 to 35 °C.

[0044] In Step 3, the compound of formula (3) is subjected to a cyclization reaction with the remaining part of the sodium methoxide solution to form the compound of formula (1). The temperature of the cyclization reaction is preferably 30 to 40 °C, more preferably 30 to 35 °C

[0045]

[0046] The total amount of sodium methoxide used in the above Steps 1 and 3 and the molar ratio of dimethyl malonate is (1.0 to 1.2):1, preferably (1.0 to 1.1):1.

[0047] Examples

[0048] The present invention will be described in more detail through specific embodiments below. However, the present application is not limited to these specific embodiments, and any modifications or changes within the scope of the gist of the present application fall within the scope of the present application.

[0049] The conditions for high-performance liquid chromatography analysis are as follows: The instrument is an Agilent 1100LC liquid chromatograph with a UV detector. The chromatographic column is Kromasil 100 - 5 - C18, 4.6×250mm. The mobile phase is acetonitrile: water = 80:20, the column temperature is 30°C, the flow rate is 1.0 mL / min, and the wavelength is 280 nm.

[0050] In the examples, the impurity compound of formula (2) used as a reference standard was prepared according to the method described in CN111362850A.

[0051] Example 1 on a small scale

[0052] Dimethyl malonate with a feeding rate of 66 g / h (0.5 mol / h) and a methanol solution of 30% sodium methoxide with a feeding rate of 13.5 g / h (0.075 mol / h) were simultaneously added into a 100 mL four-necked flask with an overflow. The temperature was controlled at 30 - 40°C, and a small amount of sodium salt of dimethyl malonate was formed by reaction, and the system did not become viscous. Then it overflowed into the next 1000 mL four-necked flask with an overflow. The stirring speed was set at 60 r / min. At the same time, a toluene solution of 6-ethylthio-3-hepten-2-one with a content of 35.8% and a feeding rate of 240 g / h (0.5 mol / h) was continuously added. The temperature was controlled at 30 - 40°C, and then it overflowed into the next 1000 mL four-necked flask with an overflow. The temperature was controlled at 30 - 40°C to complete the addition reaction. Then it continued to overflow into the last 1000 mL four-necked flask with an overflow. At the same time, a methanol solution of 30% sodium methoxide with a feeding rate of 81 g / h (0.45 mol / h) was continuously added. The temperature was controlled at 30 - 40°C to carry out the cyclization reaction. Sampling and testing showed that the content of the impurity compound of formula (2) was 0.23% by weight. The compound of formula (1) in the reaction solution was quantified, and the measured content was 35.8% (0.486 mol), and the calculated yield was 97.2%.

[0053] Example 2 on an industrial scale-up

[0054] In a 1000 L primary reaction kettle, 660 kg / h of dimethyl malonate and 135 kg / h of a methanol solution of 30% sodium methoxide were continuously added simultaneously. The temperature was controlled at 30 - 40°C, and then it entered a 10 m 3 secondary reaction kettle through an overflow port. 2400 kg / h of a toluene solution of 6-ethylthio-3-hepten-2-one with a content of 35.8% was continuously added simultaneously. The temperature was controlled at 30 - 40°C, and then it overflowed into a 10 m3 In the three-stage reactor, the temperature is controlled at 30 - 40 °C to ensure that the addition reaction is complete. Then it continues to overflow into a 10 m 3 In the four-stage reactor, while continuously adding a methanol solution of 30% sodium methoxide at a rate of 810 kg / h, the temperature is controlled at 30 - 40 °C for the cyclization reaction. Sampling and testing show that the content of the impurity compound of formula (2) is 0.25 wt%. The compound of formula (1) in the reaction solution is quantified, and the measured content is 35.8%, and the calculated yield is 97.2%.

[0055] Comparative Example 1

[0056] Add 94.5 g of 30% sodium methoxide solution (0.525 mol) to a four-necked flask, heat up to 100 °C to distill out methanol, and then dropwise add 66 g of dimethyl malonate (0.5 mol) within 1 h at 30 - 40 °C. After the addition is complete, the material is in a very viscous solid-liquid state and cannot undergo continuous overflow reaction. Continue to dropwise add 240 g of a toluene solution of 6-ethylthio-3-hepten-2-one with a content of 35.8% (0.5 mol) to the four-necked flask within 1 h at 30 - 40 °C. After the addition is complete, continue the reaction for 2 h. Through the above high-performance liquid chromatography, the content of the impurity compound of formula (2) in the reaction solution is measured to be 0.34 wt%. The compound of formula (1) in the reaction solution is quantified, and the measured content is 35.5% (0.482 mol), and the yield is 96.4%.

[0057] Comparative Example 2

[0058] Simultaneously add dimethyl malonate with a feeding rate of 66 g / h (0.5 mol / h) and a methanol solution of 30% sodium methoxide with a feeding rate of 31.5 g / h (0.175 mol / h) to a 100 mL four-necked flask with overflow, control the temperature at 30 - 40 °C, and a certain amount of sodium salt of dimethyl malonate is formed in the reaction system, and the system does not become viscous. Then it overflows into the next 1000 mL four-necked flask with overflow, set the stirring speed to 60 r / min, and simultaneously continuously add a toluene solution of 6-ethylthio-3-hepten-2-one with a content of 35.8% and a feeding rate of 240 g / h (0.5 mol / h), control the temperature at 30 - 40 °C, and then overflow into the next 1000 mL four-necked flask with overflow, control the temperature at 30 - 40 °C to ensure that the addition reaction is complete. Then it continues to overflow into the last 1000 mL four-necked flask with overflow, and simultaneously continuously add a methanol solution of 30% sodium methoxide with a feeding rate of 63 g / h (0.35 mol / h), control the temperature at 30 - 40 °C for the cyclization reaction. Sampling and testing show that the content of the impurity compound of formula (2) is 0.63 wt%. The compound of formula (1) in the reaction solution is quantified, and the measured content is 35.5% (0.482 mol), and the calculated yield is 96.4%.

Claims

1. Preparation method of clethodim intermediate, which comprises the following steps: Dimethyl malonate and 6-ethylthio-3-hepten-2-one undergo an addition reaction in the presence of a catalytic amount of sodium salt of dimethyl malonate to form an intermediate compound of formula (3).

2. The preparation method according to claim 1, which comprises the following steps: Step 1: Add a catalytic amount of sodium methoxide solution and all of the dimethyl malonate to carry out the following reaction to form a catalytic amount of sodium salt of dimethyl malonate. Step 2: Let the unreacted dimethyl malonate in Step 1 and 6-ethylthio-3-hepten-2-one undergo an addition reaction in the presence of a catalytic amount of sodium salt of dimethyl malonate to form an intermediate compound of formula (3). Step 3: Let the compound of formula (3) undergo a cyclization reaction with the remaining part of the sodium methoxide solution to form a compound of formula (1).

3. The preparation method according to claim 2, wherein the molar ratio of sodium methoxide to dimethyl malonate in Step 1 is (0.1 - 0.3):1, preferably (0.15 - 0.25):

1.

4. The preparation method according to claim 2 or 3, wherein the molar ratio of the total amount of sodium methoxide used in Step 1 and Step 3 to dimethyl malonate is (1.0 - 1.2):1, preferably (1.0 - 1.1):

1.

5. The preparation method according to any one of claims 1 to 4, wherein the reaction temperature of the addition reaction is 30 - 40 °C, preferably 30 - 35 °C.

6. The preparation method according to any one of claims 2 to 5, wherein the reaction temperature of the cyclization reaction in Step 3 is 30 - 40 °C, preferably 30 - 35 °C.

7. The preparation method according to any one of claims 1 to 6, wherein the sodium methoxide solution is a sodium methoxide methanol solution.

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