CN109293507B - Synthetic method and application of dimethyl 4-methoxymethylene-2-eneglutarate - Google Patents

Abstract

The invention discloses a method for synthesizing dimethyl 4-methoxymethenyl-2-glutaconate. The method uses methyl 3-methoxyacrylate as a raw material, and under appropriate alkaline conditions, the A condensation reaction is performed to synthesize the target product; the invention also discloses an application of the corresponding product. The synthesis method provided by the invention is simple to operate, and the process is easy to control, the yield of the obtained dimethyl 4-methoxymethyl-2-glutamate is 65.5%, and the prepared 4-methoxymethyl Two applications of dimethyl alkenyl-2-glutamate, one is as a standard to detect and monitor the synthesis of flonicamid and its intermediates, and the other is for the synthesis of N,N- Bis(4-methoxycarbonyl-2,4-methylpentadienoate-5-)azane.

Description

Synthetic method and application of dimethyl 4-methoxymethylene-2-eneglutarate

technical field

The invention belongs to the field of pharmacy, and relates to a method for synthesizing a pharmaceutical intermediate, in particular to a method for synthesizing dimethyl 4-methoxymethyl-2-pentenedioate and its application.

Background technique

Dimethyl 4-methoxymethylene-2-pentenedioate is an important pharmaceutical intermediate for the synthesis of pyridone derivatives such as nicotinic acetylcholine receptor agonists, calcimimetic agents and new Insecticides, etc., have also been found to be impurities in the synthesis of the pesticide flonicamid.

According to the literature (Synthetic Communications, 1987, Vol.17, No.7, 761-771), dimethyl 4-methoxymethylene-2-pentenedioate can be prepared using coumaric acid and methanol under acidic conditions. The method preparation of ring-opening reaction occurs below, and the reaction formula is as follows:

Coumaric acid first undergoes an esterification reaction, and then undergoes 12h of reflux to open the ring to obtain dimethyl 4-methoxymethylene-2-pentenedioate, with a yield of 48% and still 12% of the fragrance. Methyl stearate remains; when using 1:3 times the amount of methanol: trimethyl orthoformate to open the ring of coumaric acid, 89% of 4-methoxymethylene-2-pentenedi can be obtained after 48h dimethyl orthoformate and the addition impurity c in the above formula is generated. The use of a large proportion of trimethyl orthoformate not only brings difficulties to the separation, but also causes great pollution to the environment. Although more researchers have made improvements later (US8791147; US8952165; Bull.Korean Chem.Soc. 2001, Vol. 22, No. 2, 234-236; Phosphorus, Sulfur, and Silicon, 2008, Vol.183, 3145 –3155), also based on the ring-opening reaction of coumaric acid and methanol, the reaction formula is as follows:

Although an equal proportion of acetyl chloride is used to catalyze the ring-opening synthesis of dimethyl 4-methoxymethylene-2-pentenedioate with coumaric acid, the reaction time is still very long (≥10h), and the addition impurities are removed, but 12% of new isomer impurities were formed (a:b=7.3:1) and the product was a mixture. Moreover, the above method uses coumaric acid extracted from plants as a raw material, which is expensive and has a long reaction time (10-48h).

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a synthetic method of dimethyl 4-methoxymethylene-2-glutamate, aiming at using a more readily available industrial raw material, methyl 3-methoxyacrylate Ester as raw material, under appropriate conditions, through condensation reaction, 4-methoxymethylene-2-pentenedioic acid dimethyl ester is synthesized within 3h, and the synthesis method is simple, easy to control, and has high yield;

Another object of the present invention is to provide a kind of application of dimethyl 4-methoxymethylene-2-pentenedioate, the compound can be used for monitoring and controlling in addition to being used as an intermediate for pharmaceutical synthesis During the synthesis of flonicamid and its intermediates;

The third object of the present invention is to provide the second application of dimethyl 4-methoxymethylene-2-pentenedioate, namely for the synthesis of N,N-bis(4-methoxycarbonyl -2,4-Methyl pentadienoate-5-)azane.

For realizing the above-mentioned purpose of the invention, the technical scheme adopted in the present invention is:

A method for synthesizing dimethyl 4-methoxymethyl-2-glutarate, which uses methyl 3-methoxyacrylate as a raw material, and generates 4-methoxyl through self-condensation reaction under alkali catalysis Dimethyl methylenyl-2-pentenedioate.

As limitation of the present invention, the reaction scheme of above-mentioned synthetic method is as follows:

As a further limitation of the present invention, the above-mentioned synthetic method is carried out in the following order of steps:

The catalyst base is added to the solvent, and then the methyl 3-methoxyacrylate is added, reacted at a suitable temperature, and the reaction solution A is obtained after the reaction is completed; the reaction solution A is filtered to obtain a filtrate B; the filtrate B is added to the ice water The reaction was quenched, the organic phase was extracted and concentrated, and separated by column chromatography to obtain dimethyl 4-methoxymethylene-2-pentenedioate as white solid particles.

As a further limitation of the present invention:

Described alkali can be sodium methoxide, sodium ethoxide, potassium methoxide or sodium hydroxide, preferably sodium methoxide or potassium methoxide;

The equivalent ratio of the amount of base used in the reaction to the amount of methyl 3-methoxyacrylate is 0.5 to 5:1, preferably 1.5 to 2.5:1;

The solvent can be THF, DMF, DMAC, methanol or acetonitrile, preferably DMF or DMAC;

The reaction temperature may be 20 to 80°C, preferably 35 to 40°C.

The present invention also provides 4-methoxymethenyl-

An application of dimethyl 2-pentenedioate, which can be used as a standard to detect and monitor the synthesis of flonicamid and its intermediates.

The present invention also provides another application of dimethyl 4-methoxymethylene-2-pentenedioate prepared by the aforementioned preparation method, which is used for synthesizing N,N-bis(4-methoxycarbonyl- Methyl 2,4-pentadienoate-5-)azane.

Because the present invention adopts the above-mentioned technical scheme, compared with the prior art, the technical progress achieved is:

The synthesis method provided by the invention can use the industrialized raw material 3-methoxyacrylate methyl ester as the raw material, and through a simple condensation reaction, 4-methoxymethylene-2-glutaconate dimethyl can be synthesized in a short time Esters, isomers and addition impurities are not detected, the operation process is simple and easy to control, and the product yield can be as high as 65.5%.

The preparation method of the invention is suitable for synthesizing dimethyl 4-methoxymethylene-2-pentenedioate, the prepared compound can be used for detecting and monitoring the synthesis of flonicamid and its intermediates, and also It can be used to synthesize N,N-two (4-methoxycarbonyl-2,4-pentadienoic acid methyl ester-5-) azane.

The present invention will be described in further detail below with reference to specific embodiments.

Description of drawings

Fig. 1 is the ¹ HNMR chart of dimethyl 4-methoxymethylene-2-pentenedioate;

Fig. 2 is the ¹³ CNMR chart of dimethyl 4-methoxymethylene-2-pentenedioate;

Figure 3 is a liquid phase diagram of dimethyl 4-methoxymethyl-2-pentenedioate (wavelength 288 nm);

Fig. 4 is the liquid phase diagram of flonicamid prepared by a factory;

Figure 5 is a liquid phase diagram of dimethyl 4-methoxymethylene-2-pentenedioate (wavelength 265 nm);

Figure 6 is a liquid phase diagram of the intermediate N-(2-methoxycarbonylvinyl)-4,4,4-trifluoro-3-one-1-butenamine synthesized in a factory.

Detailed ways

The reagents used in the following examples are all existing commercially available reagents unless otherwise specified, and the existing test methods are used for the test methods unless otherwise specified.

Embodiment 1 A kind of synthetic method of 4-methoxymethylene-2-pentenedioic acid dimethyl ester

Add 5.4 g of sodium methoxide (base, as a catalyst) to 80 mL of N,N-dimethylformamide (solvent) at room temperature, turn it on and stir to form a suspension, and add 11.6 g of methyl 3-methoxyacrylate at one time. g, slowly heat up to 35 °C, and control the temperature to 35 to 40 °C for 3 h. After the reaction was completed, filtered, the filtrate was added to 250 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated into a viscous liquid. A white solid was obtained by column chromatography, which was dimethyl 4-methoxymethylene-2-pentenedioate, and the relevant detection data were shown in Fig. 1 to Fig. 2 .

Embodiment 2 A kind of synthetic method of 4-methoxymethylene-2-pentenedioic acid dimethyl ester

Add 4.3 g of potassium methoxide (base, as a catalyst) to 50 mL of N,N-dimethylacetamide (solvent) at room temperature, turn on and stir to form a suspension, add 10 g of methyl 3-methoxyacrylate, room temperature The reaction was carried out for 3 hours. After the reaction is completed, filter, add the filtrate into 200 mL of ice water, extract with ethyl acetate, add anhydrous sodium sulfate, dry, and concentrate to a viscous liquid. A white solid was obtained by column chromatography, which was dimethyl 4-methoxymethylene-2-pentenedioate.

Embodiment 3～8 The synthetic method of 4-methoxymethylene-2-pentenedioic acid dimethyl ester

Embodiments 3 to 8 are respectively a kind of synthetic method of dimethyl 4-methoxymethylene-2-pentenedioate, and their operation steps are all similar to those of embodiment 1 and embodiment 2, and are only reactants The type and dosage of the product, as well as the control parameters in the process, the yield of the product, etc. are different, and the target product is separated by recrystallization using n-hexane/ethyl acetate. The relevant parameters of Examples 3 to 8 are shown in the following table:

Embodiment 9 A kind of application of dimethyl 4-methoxymethyl-2-pentenedioate

The synthetic route of flonicamid is shown below. The final synthesis of flonicamid is through trifluoroacetylation, aminolysis, condensation, cyclization, acid chlorination and amidation of vinyl ether.

During the synthesis of the intermediate N-(2-methoxycarbonylvinyl)-4,4,4-trifluoro-3-one-1-butenamine, the impurity 4-methoxymethenyl appeared Dimethyl-2-pentenedioate, because it is difficult to remove, the existence of this impurity will not only affect the quality of the intermediate, but also affect the quality of the final product flonicamid.

The present invention provides an application to the dimethyl 4-methoxymethylene-2-pentenedioate prepared in Examples 1 to 8, that is, it can be used as a standard reference substance to detect flonicamid and its intermediates Whether there is an impurity dimethyl 4-methoxymethyl-2-pentenedioate and its content. In addition, in the process of synthesizing flonicamid intermediate by the above method, it can be used as a standard to detect and monitor the generation of this impurity, which is of great significance to the improvement of reaction conditions.

HPLC conditions:

Mobile phase: methanol/water=60/40

Detection wavelength: 288 nm

Flow rate: 1.0 mL/min

The liquid phase diagram of dimethyl 4-methoxymethylene-2-pentenedioate under this liquid phase condition is shown in Fig. 3 .

Figure 4 is a liquid phase diagram of flonicamid prepared in a factory.

The HPLC method can be used to detect whether the product of flonicamid contains the impurity dimethyl 4-methoxymethyl-2-pentenedioate. It can be seen from the figure that the flonicamid sample does not contain this impurity after testing.

HPLC conditions:

Mobile phase: methanol/water=40/60

Detection wavelength: 265 nm

Flow rate: 1.0 mL/min

Figure 5 is a liquid phase diagram of dimethyl 4-methoxymethylene-2-pentenedioate under the liquid phase conditions.

The liquid phase diagram of the intermediate N-(2-methoxycarbonylvinyl)-4,4,4-trifluoro-3-keto-1-butenamine synthesized in a factory is shown in Figure 6.

It can be seen that the produced intermediate N-(2-methoxycarbonylvinyl)-4,4,4-trifluoro-3-keto-1-butenamine contains a certain amount of 4-methoxymethane Dimethyl-2-pentenedioate impurity.

Embodiment 10 A kind of application of dimethyl 4-methoxymethylene-2-pentenedioate

This example provides another application of dimethyl 4-methoxymethylene-2-pentenedioate, which is used for the amination reaction with ammonia gas to synthesize N,N-bis(4 -Methoxycarbonyl-2,4-pentadienoate methyl-5-)azane. Its synthetic route is as follows:

4-Methoxymethylene-2-pentenedioic acid dimethyl ester is introduced into ammonia gas under normal pressure or positive pressure, and the temperature is controlled to react for 3 to 4 hours at room temperature or slightly heated until the reaction is complete, and then add 4 ~5 times of the solvent capacity in ice water, stir under ice water bath for 28 ~ 35min, and precipitate small yellow-green solid particles, filter and dry to obtain N,N-bis(4-methoxycarbonyl-2,4-pentadiene) Methyl acid-5-)azane product.

Embodiment 11 A kind of application of dimethyl 4-methoxymethylene-2-pentenedioate

The present embodiment provides a third application of dimethyl 4-methoxymethylene-2-pentenedioate, which is used for the ammoniation reaction with a compound that generates ammonia in situ to synthesize N, N-bis(4-methoxycarbonyl-2,4-pentadienoate methyl ester-5-)azane. Its synthetic route is as follows:

Compounds that can generate ammonia gas in situ (such as (E)-4-amino-1,1,1-trifluorobut-3-en-2-one) are dissolved in the solvent and added dropwise into the solvent In the dimethyl 4-methoxymethylene-2-pentenedioate in , the temperature is controlled, and the reaction is performed for 3 to 4 h until the reaction is complete, then add ice water with 4 to 5 times the solvent capacity, and stir in an ice water bath. After 28 to 35 minutes, small yellow-green solid particles were precipitated, filtered and dried to obtain N,N-bis(4-methoxycarbonyl-2,4-pentadienoic acid methyl ester-5-)azane product.

Claims (9)

1. A method for synthesizing 4-methoxy methyl alkenyl-2-glutaconic acid dimethyl ester is characterized in that: the synthesis method takes 3-methoxy methyl acrylate as a raw material, and the 4-methoxy methyl alkenyl-2-pentenedioic acid dimethyl ester is synthesized through the self-condensation reaction under the catalysis of alkali.

2. The method for synthesizing 4-methoxy methyl alkenyl-2-glutaconic acid dimethyl ester according to claim 1, wherein the synthetic route of the method is as follows:

。

3. the method of synthesizing 4-methoxymethyllene-2-pentenedioic acid dimethyl ester according to claim 1 or 2, wherein: the synthesis method comprises the following steps in sequence:

adding alkali into a solvent, adding 3-methoxy methyl acrylate for reaction, and obtaining a reaction solution A after the reaction is finished;

filtering the reaction solution A to obtain a filtrate B;

adding the filtrate B into ice water to quench the reaction, extracting and concentrating an organic phase, and separating by column chromatography to obtain the 4-methoxy methyl alkenyl-2-pentenedioic acid dimethyl ester.

4. The method of synthesizing 4-methoxymethyllene-2-pentenedioic acid dimethyl ester according to claim 3, wherein: the alkali is sodium methoxide, sodium ethoxide, potassium methoxide or sodium hydroxide.

5. The method of claim 3, wherein the synthesis of dimethyl 4-methoxymethyllene-2-pentenedioate comprises: the equivalent ratio of the amount of the alkali used in the reaction to the amount of the methyl 3-methoxyacrylate is 0.5-5: 1.

6. The method of claim 3, wherein the synthesis of dimethyl 4-methoxymethyllene-2-pentenedioate comprises: the solvent is THF, DMF, DMAC, methanol or acetonitrile.

7. The method of claim 3, wherein the synthesis of dimethyl 4-methoxymethyllene-2-pentenedioate comprises: the reaction temperature is 20-80 ℃.

8. An application of the dimethyl 4-methoxymethyl ene-2-pentenedioate prepared by the method for synthesizing dimethyl 4-methoxymethyl ene-2-pentenedioate according to any one of claims 1 to 7, wherein the method comprises the following steps: the 4-methoxy methyl alkenyl-2-glutaconic acid dimethyl ester is used as a standard substance, and whether the impurity 4-methoxy methyl alkenyl-2-glutaconic acid dimethyl ester exists or not and the content of the impurity is detected by an HPLC method; and detecting and monitoring the generation condition of the impurities in the final synthesis process of flonicamid by the steps of trifluoroacetylation, ammonolysis, condensation, cyclization, acyl chlorination and amidation of vinyl ethyl ether.

9. An application of the dimethyl 4-methoxymethyl ene-2-pentenedioate prepared by the method for synthesizing dimethyl 4-methoxymethyl ene-2-pentenedioate according to any one of claims 1 to 7, wherein the method comprises the following steps: the 4-methoxy methyl alkenyl-2-pentenedioic acid dimethyl ester is used for synthesizing N, N-di (4-methoxycarbonyl-2, 4-pentadienoic acid methyl ester-5-) azane.

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