Process for the preparation and isolation of certain mesoionic pesticide intermediates

Abstract

A process for producing sodium 2-(3-(trifluoromethyl)phenyl)malonate from dimethyl 2-(3-(trifluoromethyl)phenyl)malonate is disclosed.

Description

[Background technology]

[0001] Mesoionic pesticides and methods for their preparation have been previously disclosed, for example, in WO 2009 / 099929 A1, WO 2011 / 017334 A1, WO 2011 / 017342 A1, WO 2011 / 017347 A1, WO 2012 / 092115 A1, WO 2013 / 090547 A1, WO 2017 / 189339 A1, and WO 2019 / 173173 A1. Triflumezopyrim is a mesoionic pesticide used against rice planthoppers as well as other pests. Ammonium, potassium, sodium, other metal, and organic amine salts of 2-[3-(trifluoromethyl)phenyl]propanedioate can be used as intermediates in the synthesis of triflumezopyrim. However, certain previously disclosed synthetic steps have one or more drawbacks for large-scale production of triflumezopyrim. For example, Example 2, located on page 38 of WO 2013 / 090547, discloses a process for producing sodium 2-(3-(trifluoromethyl)phenyl)malonate, which generally involves a saponification reaction followed by azeotropic removal of excess water in the presence of toluene. This process requires more operating units and longer cycle times, generates a lot of waste, and thus limits production capacity. Therefore, there remains a need for alternative methods for preparing triflumezopyrim in high yield and high quality. DETAILED DESCRIPTION OF THE INVENTION

[0002] Triflumezopyrim has the following structure: [ka]

[0003] It is also known as 2,4-dioxo-1-(pyrimidin-5-ylmethyl)-3-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-1-ium-3-ide.

[0004] Sodium 2-[3-(trifluoromethyl)phenyl]propanedioate has the following structure (hereinafter also known as "STPP"): It is also known as sodium 2-(3-(trifluoromethyl)phenyl)malonate (hereinafter also known as "STPM"). [ka]

[0005] Scheme 1 below: [ka] In the present application, sodium 2-(3-(trifluoromethyl)phenyl)malonate is prepared from dimethyl 2-(3-(trifluoromethyl)phenyl)malonate (hereinafter also known as "DTPM"). STPM is generally prepared by a saponification reaction followed by crystallization to provide STPM in higher yield and higher purity than the prior art. If desired, other alkyl substituents, such as diethyl 2-(3-(trifluoromethyl)phenyl)malonate or dipropyl 2-(3-(trifluoromethyl)phenyl)malonate, as well as mixtures of alkyl substituents with or without DTPM, can be used.

[0006] In Scheme 1, DTPM and sodium hydroxide (NaOH) are mixed under conditions to produce STPM. Generally, about 2 to about 8 moles of NaOH can be used per mole of DTPM, preferably about 2 to about 4 moles of NaOH per mole of DTPM, and more preferably about 2 to about 3 moles of NaOH per mole of DTPM. The NaOH is preferably a 5 to 50 weight percent (wt%) aqueous sodium hydroxide solution, and even more preferably a 10 to 40 wt% aqueous sodium hydroxide solution.

[0007] In Scheme 1, temperatures of about 0° C. to about 50° C. may currently be used, with temperatures of about 5° C. to about 25° C. being preferred. Pressures of about 10 kilopascals (kPa) to about 1000 kPa may currently be used, with pressures of about 50 kPa to about 150 kPa being preferred, although ambient pressure is generally preferred.

[0008] The DTPM and NaOH are mixed in the presence of a solvent. While various solvents, such as nonpolar hydrocarbon solvents, polar aprotic solvents, and polar protic solvents, can be used, it has been discovered that using isopropyl alcohol (also known as propan-2-ol) as the solvent provides an unexpected and significant benefit. The amount of solvent used is about 1 mole to about 32 moles of solvent per mole of DTPM, preferably about 1 mole to about 16 moles of solvent per mole of DTPM, and more preferably about 1 mole to about 4 moles of solvent per mole of DTPM.

[0009] After mixing DTPM and NaOH in the presence of a solvent, preferably isopropyl alcohol, the resulting mixture containing STPM is further mixed with an additional solvent, preferably isopropyl alcohol, at a temperature of about 5° C. to about 20° C., preferably about 10° C. to about 15° C., and under the pressures suggested above. These conditions promote better crystallization of STPM, resulting in higher yields and higher purity of STPM.

[0010] The amount of additional solvent used is about 1 mole to about 50 moles of solvent per mole of STPM, preferably about 1 mole to about 30 moles of solvent per mole of STPM, and more preferably about 1 mole to about 4 moles of solvent per mole of STPM. It should be noted that mixtures of different solvents can be used, such as a mixture of isopropyl alcohol with water or another alcohol such as ethanol.

[0011] In light of the above and the examples below, further details (D) below are provided.

[0012] 1D. Process for producing sodium 2-(3-(trifluoromethyl)phenyl)malonate from dimethyl 2-(3-(trifluoromethyl)phenyl)malonate [ka] The process comprises: (1) combining dimethyl 2-(3-(trifluoromethyl)phenyl)malonate and NaOH in a solvent, the solvent comprising isopropyl alcohol, the combining being at a temperature and pressure to produce a mixture comprising sodium 2-(3-(trifluoromethyl)phenyl)malonate; and (2) crystallizing the mixture comprising sodium 2-(3-(trifluoromethyl)phenyl)malonate in the presence of an additional solvent, wherein the solvent comprises isopropyl alcohol, and the crystallizing is at a temperature and pressure to crystallize the sodium 2-(3-(trifluoromethyl)phenyl)malonate; Includes:

[0013] 2D. The process as described in detail 1D wherein about 2 moles to about 8 moles of NaOH are used per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

[0014] 3D. The process as described in detail 1D wherein about 2 moles to about 4 moles of NaOH are used per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

[0015] 4D. The process as described in detail 1D wherein about 2 moles to about 3 moles of NaOH are used per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

[0016] 5D. The process of Detail 1D, 2D, 3D, or 4D, wherein the temperature is from about 0°C to about 50°C.

[0017] 6D. The process of detail 5D, wherein the temperature is from about 5°C to about 25°C.

[0018] 7D. The process of Detail 1D, 2D, 3D, 4D, 5D, or 6D, wherein the pressure is from about 10 kilopascals (kPa) to about 1000 kPa.

[0019] 8D. The process of detail 7D, wherein the pressure is from about 50 kilopascals (kPa) to about 150 kPa.

[0020] 9D. The process of detail 7D, wherein the pressure is about ambient pressure.

[0021] 10D. The process of Details 1D, 2D, 3D, 4D, 5D, 6D, 7D, 8D, or 9D, wherein the amount of solvent used when mixed with NaOH is from about 1 mole to about 32 moles of solvent per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

[0022] 11D. The process of detail 10D, wherein the amount of solvent used, when mixed with NaOH, is from about 1 mole to about 16 moles of solvent per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

[0023] 12D. The process as described in detail in detail 10D, wherein the amount of solvent used when mixed with NaOH is from about 1 mole to about 4 moles of solvent per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

[0024] 13D. The process of detail 1D, 2D, 3D, 4D, 5D, 6D, 7D, 8D, 9D, 10D, 11D, or 12D, wherein the mixture containing sodium 2-(3-(trifluoromethyl)phenyl)malonate is in the presence of additional isopropyl alcohol, and the crystallizing is carried out at a temperature of about 5°C to about 20°C.

[0025] 14D. The process of detail 13D, wherein the additional solvent is from about 1 mole to about 50 moles of solvent per mole of sodium 2-(3-(trifluoromethyl)phenyl)malonate.

[0026] 15D. The process of detail 13D, wherein the additional solvent is from about 1 mole to about 25 moles of solvent per mole of sodium 2-(3-(trifluoromethyl)phenyl)malonate.

[0027] 16D. The process of detail 13D, wherein the additional solvent is from about 1 mole to about 4 moles of solvent per mole of sodium 2-(3-(trifluoromethyl)phenyl)malonate. [Example]

[0028] The following examples are for illustrative purposes and should not be construed as limiting. Starting materials, reagents, and solvents obtained from commercial sources were used without further purification. Anhydrous solvents were purchased from Aldrich as Sure / Seal™ and used as received. Molecules were given their known names, which were named according to the naming program within ChemDraw (version 17.1.0.105(19)). When such a program is unable to name a molecule, it is named using conventional naming conventions. Unless otherwise specified, 1H NMR spectral data are in ppm (δ) and were recorded at 400 MHz. 13 C NMR spectral data are in ppm (δ) and were recorded at 101 MHz.

[0029] Prior art example: Preparation of sodium 2-[3-(trifluoromethyl)phenyl]propanedioate from 1,3-dimethyl 2-[3-(trifluoromethyl)phenyl]propanedioate [ka] The procedure of Example 2, located on page 38 of WO 2013 / 090547 A1, was reproduced to determine the purity of the product sodium 2-[3-(trifluoromethyl)phenyl]propanedioate produced by this two-step procedure. This was done because the purity was not specifically shown in the example. This procedure gave a yield of 80% and a purity of 87.3%.

[0030] Example 1: Preparation of sodium 2-(3-(trifluoromethyl)phenyl)malonate (hereinafter "STPM") from dimethyl 2-(3-(trifluoromethyl)phenyl)malonate (hereinafter "DTPM") [ka] A 250 mL jacketed reactor was charged with 25% sodium hydroxide (17.51 g, 109 mmol) and propan-2-ol (7.5 mL, 98 mmol). The reaction mixture was cooled to 10-15°C. A mixture of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate (15 g, 49.7 mmol, hereafter "DTPM") and propan-2-ol (7.5 mL, 98 mmol) at 10-15°C was slowly added (approximately 30 minutes) while maintaining the temperature of the reaction mixture at 10-15°C. After this addition, the reaction mixture was stirred at 15°C for 30 minutes. The reaction mixture was then warmed to 21-23°C and stirred for 1 hour, until analysis by HPLC indicated the reaction was complete.

[0031] The reaction mixture was then cooled to 15° C. and propan-2-ol (45 mL, 589 mmol) was added slowly over 30 minutes with stirring at 15° C. The resulting slurry was stirred for an additional hour at 15° C. After that, propan-2-ol (60 mL, 785 mmol) was added slowly over 20 minutes at 15° C. o The mixture was stirred at 40°C for 3 hours. The slurry was cooled to 5°C and stirred for 1 hour. The reaction slurry was filtered. The resulting solid was washed with propan-2-ol, and the white filter cake was dried under nitrogen (N2) / vacuum for 30 minutes, then dried at 40°C for 48 hours. The product, sodium 2-(3-trifluoromethyl)phenyl)malonate (14.3 g, 46.9 mmol, 94% yield) was obtained as a white solid (95.78 wt% purity).

[0032] The procedure was otherwise the same as in Example 1 carried out four more times using different solvents selected from methanol, ethanol, 1-propanol, and n-butanol instead of using propan-2-ol.

[0033] A summary of the results of the prior art examples, the results of Example 1, and the results of using the procedure of Example 1 with different solvents is disclosed in Table 1.

[0034] [Table 1]

[0035] As can be seen from Table 1, propan-2-ol is significantly better than the prior art example of a two-step process using toluene as the solvent. In fact, the yield is 14% better and the purity is almost 10% better. Furthermore, propan-2-ol provides significantly better yield and purity than any of the other solvents (methanol, ethanol, 1-propanol, or n-butanol).

Claims

1. Method for producing sodium 2-(3-(trifluoromethyl)phenyl) malonate from dimethyl 2-(3-(trifluoromethyl)phenyl) malonate 【Chemistry 1】 The method is as follows: (1) Mixing dimethyl 2-(3-(trifluoromethyl)phenyl)malonate and NaOH in a solvent, wherein the solvent contains isopropyl alcohol under a temperature and pressure that produces a mixture containing sodium 2-(3-(trifluoromethyl)phenyl)malonate, and (2) Crystallizing the mixture containing sodium 2-(3-(trifluoromethyl)phenyl)malonate in the presence of a solvent, wherein the solvent contains isopropyl alcohol at the temperature and pressure required for crystallization of the sodium 2-(3-(trifluoromethyl)phenyl)malonate. Methods that include...

2. The method according to claim 1, wherein about 2 to 8 moles of NaOH are used per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

3. The method according to claim 1, wherein about 2 to 4 moles of NaOH are used per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

4. The method according to claim 1, wherein about 2 to 3 moles of NaOH are used per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate.

5. The method according to claim 1, wherein the temperature is approximately 0°C to approximately 50°C.

6. The method according to claim 5, wherein the temperature is approximately 5°C to approximately 25°C.

7. The method according to claim 1, wherein the pressure is approximately 10 kilopascals (kPa) to approximately 1000 kPa.

8. The method according to claim 7, wherein the pressure is approximately 50 kilopascals (kPa) to approximately 150 kPa.

9. The method according to claim 7, wherein the pressure is approximately ambient pressure.

10. The method according to claim 1, wherein the amount of solvent used is about 1 mole to about 32 moles of solvent per mole of dimethyl 2-(3-(trifluoromethyl)phenyl)malonate when mixed with NaOH.

11. The method according to claim 10, wherein the amount of solvent used is about 1 mole to about 16 moles of solvent per mole of dimethyl 2-(3-(trifluoromethyl)phenyl) malonate when mixed with NaOH.

12. The method according to claim 10, wherein the amount of solvent used is about 1 mole to about 4 moles of solvent per mole of dimethyl 2-(3-(trifluoromethyl)phenyl) malonate when mixed with NaOH.

13. The method according to claim 1, wherein the mixture comprising sodium 2-(3-(trifluoromethyl)phenyl)malonate is in the presence of additional isopropyl alcohol, and the crystallization is carried out at a temperature of about 5°C to about 20°C.

14. The method according to claim 13, wherein the additional solvent is a solvent in an amount of about 1 mole to about 50 moles per mole of sodium 2-(3-(trifluoromethyl)phenyl)malonate.

15. The method according to claim 13, wherein the additional solvent is a solvent in an amount of about 1 mole to about 25 moles per mole of sodium 2-(3-(trifluoromethyl)phenyl)malonate.

16. The method according to claim 13, wherein the additional solvent is about 1 mole to about 4 moles of solvent per mole of sodium 2-(3-(trifluoromethyl)phenyl)malonate.

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