A process for preparing N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide

Abstract

The present invention provides a method of preparing a compound of formula 1, comprising the steps of: a) dissolving a compound represented by formula 2 in an organic solvent; b) adding thionyl chloride to the solution of step a); and c) adding a compound of formula 3 to the solution of step b) and allowing them to react.

Description

TECHNICAL FIELD

[0001] This application claims priority based on Korean Patent Application No. 10-2020-0177706, filed on December 17, 2020, the entire contents of which are incorporated herein as part of the present specification.

[0002] The present application relates to a method for preparing N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide using thionyl chloride. BACKGROUND

[0003] N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide is a novel compound that can be used as a wheat selective herbicide in the HPPD series, similar to sulcotrione in crop protection agents.

[0004] As a general method for synthesizing N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide, as shown in the following reaction scheme, a method of reacting 2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinic acid with 1-methyl-1H-tetrazol-5-amine in the presence of an organic or inorganic base and a dialkylcarboimide can be mentioned.

[0005]

[0006] However, the method has a disadvantage in that the yield of the target compound is low and expensive raw materials are used, and thus is not suitable for industrial production.

[0007] Therefore, in order to industrially produce N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide and supply it as a herbicide, there is a need to develop a preparation method capable of synthesizing the compound in a high yield using low-cost raw materials.

[0008] [Related Art Document]

[0009] [Patent Document]

[0010] Korean Patent Laid-Open Publication No. 10-2018-0095901 SUMMARY

[0011] TECHNICAL PROBLEM

[0012] An object of the present application is to provide a production method of N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide, which can produce the same in a high yield in a short time using a low-cost raw material.

[0013] In addition, an object of the present application is to provide a production method of N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide, which can produce the same industrially under mild conditions.

[0014] Technical Solution

[0015] To achieve the above object, the present application provides a production method of a compound of the following formula 1, which comprises the following steps:

[0016] a) dissolving a compound represented by the following formula 2 in an organic solvent;

[0017] b) adding thionyl chloride to the solution of step a); and

[0018] c) adding a compound of the following formula 3 to the solution of step b) and allowing them to react:

[0019] [Formula 1]

[0020]

[0021] [Formula 2]

[0022]

[0023] [Formula 3]

[0024]

[0025] wherein,

[0026] R1may be a (C1-C6)alkyl group, a (C1-C6)haloalkyl group, a (C2-C6)alkenyl group, a (C2-C6)haloalkenyl group, a (C2-C6)alkynyl group, a (C2-C6)haloalkynyl group, a (C3-C6)cycloalkyl group, a (C3-C6)halocycloalkyl group, a (C1-C3)alkyl-O-(C1-C3)alkyl group, or a (C1-C3)alkyl-S-(C1-C3)alkyl group, and

[0027] R2may be a (C1-C6)alkyl group, a (C1-C6)haloalkyl group, a (C2-C6)alkenyl group, a (C2-C6)haloalkenyl group, a (C2-C6)alkynyl group, a (C2-C6)haloalkynyl group, a (C3-C6)cycloalkyl group, or a (C3-C6)halocycloalkyl group.

[0028] Advantageous effects

[0029] The preparation method of the present application provides the effect of preparing the compound of Formula 1 in a short time with a high yield using low-cost raw materials.

[0030] In addition, the present application provides the effect of industrially preparing the compound of Formula 1 under mild conditions. DETAILED DESCRIPTION

[0031] Hereinafter, the present application will be described in detail.

[0032] The present application relates to a preparation method of a compound of the following Formula 1, comprising the steps of:

[0033] a) dissolving a compound represented by Formula 2 in an organic solvent;

[0034] b) adding thionyl chloride to the solution of step a); and

[0035] c) adding a compound of Formula 3 to the solution of step b) and allowing them to react:

[0036] [Formula 1]

[0037]

[0038] [Formula 2]

[0039]

[0040] [Formula 3]

[0041]

[0042] wherein,

[0043] R1may be a (C1-C6)alkyl group, a (C1-C6)haloalkyl group, a (C2-C6)alkenyl group, a (C2-C6)haloalkenyl group, a (C2-C6)alkynyl group, a (C2-C6)haloalkynyl group, a (C3-C6)cycloalkyl group, a (C3-C6)halocycloalkyl group, a (C1-C3)alkyl-O-(C1-C3)alkyl group, or a (C1-C3)alkyl-S-(C1-C3)alkyl group, and

[0044] R2may be a (C1-C6)alkyl group, a (C1-C6)haloalkyl group, a (C2-C6)alkenyl group, a (C2-C6)haloalkenyl group, a (C2-C6)alkynyl group, a (C2-C6)haloalkynyl group, a (C3-C6)cycloalkyl group, or a (C3-C6)halocycloalkyl group.

[0045] More preferably, R1may be a (C1-C4)alkyl group, and R2may be a (C1-C4)alkyl group.

[0046] The compound of Formula 1 is a novel compound, which can be used as a wheat selective herbicide in the HPPD series, similar to sulcotrione in crop protection, which can be a compound of the formula C 13 H 13 F3N 10 O2and has a molecular weight of 398.31.

[0047] The preparation method of the present application can be represented by the following Reaction Scheme 1.

[0048] [Reaction Scheme 1]

[0049]

[0050] The present application is characterized by using thionyl chloride (SOCl2) as a coupling source. Compared to other coupling sources, SOCl2is capable of realizing an inexpensive and efficient amide coupling reaction, and thus it can be preferably used in the preparation method of the present application.

[0051] In the field, in addition to thionyl chloride, oxalyl chloride ((COCl)2), CDI (1'-carbonyldiimidazole), DCC (dicyclohexylcarbodiimide), PPAA (poly(phosphazene-arylamide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), and HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), etc. are used as a coupling source. However, when these coupling sources are applied to the present application, they are not preferable in terms of yield, reaction time, and manufacturing cost, etc.

[0052] In one embodiment of the present application, as the organic solvent in step a), at least one selected from the group consisting of pyridine, acetonitrile, THF (tetrahydrofuran), toluene, xylene, dichloromethane, NMP (N-methyl-2-pyrrolidone), and ODCB (1,2-dichlorobenzene), etc. can be used. In particular, pyridine among them can be preferably used. Pyridine simultaneously functions as a base and a solvent.

[0053] In one embodiment of the present application, when pyridine is used as the organic solvent in step a), the amount of pyridine used can be 3 to 20 times by weight, more preferably 3.5 to 15 times, with respect to the compound of formula 2. If the amount of pyridine used is less than 3 times, the reaction does not proceed efficiently, resulting in a decrease in yield, while if the amount of pyridine used exceeds 20 times, the reaction proceeds inefficiently due to a decrease in the concentration of the reactants in the reaction solution, resulting in a decrease in yield and an increase in the amount of washing in the extraction step, which is undesirable.

[0054] In this field, dichloroethane, TEA (triethylamine), DMF (dimethylformamide), DMAC (dimethylacetamide), or DMSO (dimethyl sulfoxide), etc. are used as solvents similar to organic solvents. However, when these solvents are applied to the present application, poor results are obtained in terms of yield, reaction time, and manufacturing cost, etc., and thus are not preferred.

[0055] In one embodiment of the present application, step a) can further include a step of cooling the solution to 0 to 15°C, preferably 0 to 10°C, more preferably 0 to 5°C. In the case of cooling the solution as described above, since the temperature increase due to the exothermic reaction upon the addition of thionyl chloride is controlled, effects such as suppression of by-product generation, increase in yield, and increase in reaction rate, etc. can be expected, and thus is preferred.

[0056] In one embodiment of the present application, in step b), the amount of thionyl chloride added can be 1 to 2 equivalents, preferably 1.2 to 1.8 equivalents, more preferably 1.4 to 1.6 equivalents, with respect to the compound of formula 2. If thionyl chloride is added within the above range, suppression of by-product generation, increase in reaction rate, increase in yield, etc. can be expected, and if excess thionyl chloride is added, increased by-product generation and decreased yield can occur.

[0057] In one embodiment of the present application, the amount of the compound of formula 3 added in step c) can be 0.5 to 10 equivalents, preferably 1 to 5 equivalents, more preferably 1.5 to 2.5 equivalents, with respect to the compound of formula 2. If the compound of formula 3 is added within the above range with respect to the compound of formula 2, desired effects such as suppression of by-product generation, increase in reaction rate, and increase in yield can be obtained.

[0058] In one embodiment of the present application, the reaction of step c) can be performed at a temperature of 20 to 30°C. In the previous step, since there is a process of cooling the reaction solution to 0 to 15°C, in order for the reaction to proceed efficiently, it is preferred to increase the temperature to the above range in step c). However, if the reaction temperature is higher than the desired temperature, a decrease in yield can occur due to increased by-product generation.

[0059] The reaction temperature can be adjusted by adding the compound of Formula 3, then the fume disappears from the reaction solution, and then increasing the temperature. If the temperature is increased while the fume is generated, problems such as a decrease in yield and a decrease in reaction rate can occur due to an increase in the generation of by-products, and thus are not preferred.

[0060] In one embodiment of the present application, the reaction in step c) can be performed for 2 to 4 hours. Thus, the present application is characterized by a very short reaction time. If the reaction is performed for less than 2 hours, the yield can decrease due to insufficient reaction. If the reaction is performed for more than 4 hours, the yield can decrease due to an increase in the generation of by-products.

[0061] In one embodiment of the present application, the addition of thionyl chloride in step b) and the addition of the compound of Formula 3 in step c) can be performed continuously. That is, since the preparation method of the present application is characterized in that the activation of the carboxylic acid of the compound of Formula 2 and the amidation of the compound of Formula 2 with the compound of Formula 3 are performed in one step, the preparation method of the present application can provide higher efficiency compared to a method in which the process is performed in two steps.

[0062] In one embodiment of the present application, the preparation method of the present application can further include the steps of, after the reaction in step c) is completed, removing the reaction solvent and adding an acid to prepare an acidic solution having a pH of 2 to 5, preferably a pH of 3 to 4, and then extracting with an organic solvent 1 to 5 times, preferably 1 to 3 times, and then removing the organic solvent to obtain the compound of Formula 1 in a crystalline state.

[0063] As the acid, at least one selected from the group consisting of HCI, NH4CI, CH3COOH (acetic acid), and H2SO4, and the like can be used. In particular, among them, the use of HCI can be preferred.

[0064] As the organic solvent used for extraction, at least one selected from the group consisting of ethyl acetate, dichloromethane, dichloroethane, toluene, xylene, chloroform, diethyl ether, and butanone, and the like can be used. In particular, among them, the use of ethyl acetate can be preferred.

[0065] In one embodiment of the present application, the preparation method of the present application can further include the step of purifying the compound of Formula 1 in a crystalline state by recrystallization.

[0066] The recrystallization can be performed using various solvents known in the art such as methanol and water.

[0067] In the preparation method of the present application, the reaction can be performed under mild conditions at 5 to 30°C, more preferably 5 to 25°C. In addition, the yield of the compound of Formula 1 can be 80% or more, 85% or more, 88% or more, or 90% or more.

[0068] In the following, preferred embodiments are given to help understand the present application. However, the following embodiments are merely illustrative of the present application and it will be obvious to those skilled in the art that various changes and modifications can be made within the scope and spirit of the present application, and such changes and modifications naturally fall within the scope of the appended claims.

[0069] Example 1: Preparation of compound of Formula 1 (N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide)

[0070]

[0071] The compound of Formula 2 (2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6- (trifluoromethyl)nicotinic acid, 10 g, 31.5 mmol) was dissolved in 150 ml of pyridine, cooled to 5 to 10 °C, then thionyl chloride (4.5 g, 37.8 mmol) was slowly added, then the compound of Formula 3 (1-methyl-1H-tetrazol-5-amine (AMTT), 6.25 g, 63.0 mmol) was continuously added. After the smoke from the reaction solution disappeared, the temperature was raised to room temperature and stirred for 12 hours. After confirming the completion of the reaction by HPLC, the reaction solvent (pyridine) was removed by evaporation under reduced pressure. Then, 2N-HCl was added to make an acidic solution of about pH 3 to 4, extracted with ethyl acetate (100 ml) three times, washed with water, and then the solvent of the extracted organic layer was removed by distillation under reduced pressure. It was purified by recrystallization with methanol and water to obtain 10.1 g (81% yield) of the target compound (Formula 1) as a white solid.

[0072] Example 2: Preparation of compound of Formula 1 (N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide)

[0073]

[0074] The compound of formula 2 (2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6- (trifluoromethyl)nicotinic acid, 10 g, 31.5 mmol) was dissolved in 150 ml of pyridine, cooled to 5 to 10 °C, then thionyl chloride (5.6 g, 47.3 mmol) was slowly added, then the compound of formula 3 (1-methyl-1H-tetrazol-5-amine (AMTT), 6.25 g, 63.0 mmol) was added. After the smoke from the reaction solution disappeared, the temperature was raised to room temperature and stirred for 3 hours. After confirming the completion of the reaction by HPLC, the reaction solvent (pyridine) was removed by evaporation under reduced pressure. Then, 2N-HCl was added to make an acidic solution of about pH 3 to 4, extracted with ethyl acetate (100 ml) three times, washed with water, and then the solvent of the extracted organic layer was removed by distillation under reduced pressure. This was purified by recrystallization with methanol and water to obtain 11 g (88% yield) of the target compound (compound of formula 1) as a white solid.

[0075] Example 3: Preparation of a compound of formula 1 (N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide)

[0076]

[0077] The compound of formula 2 (2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6- (trifluoromethyl)nicotinic acid, 10 g, 31.5 mmol) was dissolved in 150 ml of pyridine, cooled to 5 to 10 °C, then thionyl chloride (5.6 g, 47.3 mmol) was slowly added, then the compound of formula 3 (1-methyl-1H-tetrazol-5-amine (AMTT), 6.25 g, 63.0 mmol) was added. After the smoke from the reaction solution disappeared, the temperature was raised to room temperature and stirred for 3 hours. After confirming the completion of the reaction by HPLC, the reaction solvent (pyridine) was removed by evaporation under reduced pressure. Then, 2N-HCl was added to make an acidic solution of about pH 3 to 4, extracted with ethyl acetate (100 ml) three times, washed with water, and then the solvent of the extracted organic layer was removed by distillation under reduced pressure. This was purified by recrystallization with methanol and water to obtain 11 g (88% yield) of the target compound (compound of formula 1) as a white solid.

[0078] Comparative Example 1: Preparation of a compound of formula 1 (N-(1-methyl-1H-tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide)

[0079]

[0080] The compound of Formula 2 (2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6- (trifluoromethyl)nicotinic acid, 10 g, 31.5 mmol) was dissolved in 150 ml of pyridine, cooled to 5 to 10 °C, then oxalyl chloride (6.0 g, 47.3 mmol) was slowly added, and the compound of Formula 3 (1-methyl-1H-tetrazol-5-amine (AMTT), 6.25 g, 63.0 mmol) was continuously added. After the smoke from the reaction solution disappeared, the temperature was raised to room temperature and stirred for 3 hours. After confirming the completion of the reaction by HPLC, the reaction solvent (pyridine) was removed by evaporation under reduced pressure. Then, 2N-HCl was added to make an acidic solution of about pH 3 to 4, extracted with ethyl acetate (100 ml) three times, washed with water, and then the solvent of the extracted organic layer was removed by distillation under reduced pressure. It was purified by recrystallization with methanol and water to obtain 8.9 g (71% yield) of the target compound (the compound of Formula 1) as a white solid.

[0081] Comparative Example 2: Preparation of the compound of Formula 1 (N-(1-methyl-1H- tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide)

[0082]

[0083] The compound of Formula 2 (2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6- (trifluoromethyl)nicotinic acid, 10 g, 31.5 mmol) was dissolved in 150 ml of dichloromethane, oxalyl chloride (6.0 g, 47.3 mmol) was added, and stirred at room temperature for 1 hour. After stirring, the solvent (dichloromethane) was removed by distillation under reduced pressure, and then 150 ml of pyridine was added. Then, the compound of Formula 3 (1-methyl-1H-tetrazol-5-amine (AMTT), 6.25 g, 63.0 mmol) was added, and then stirred at room temperature for 3 hours. The subsequent processes were carried out in the same manner as in Example 1. In this comparative example, the reaction conversion rate of the compound of Formula 1 was 56%.

[0084] Comparative Example 3: Preparation of the compound of Formula 1 (N-(1-methyl-1H- tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide)

[0085]

[0086] The compound of formula 2 (2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6- (trifluoromethyl)nicotinic acid, 10 g, 31.5 mmol) was dissolved in 150 ml of TEA (triethylamine), cooled to 5 to 10 °C, then thionyl chloride (5.6 g, 47.3 mmol) was slowly added, then the compound of formula 3 (1-methyl-1H-tetrazol-5-amine (AMTT), 6.25 g, 63.0 mmol) was added. After the disappearance of smoke from the reaction solution, the temperature was raised to room temperature and stirred for 3 hours. The subsequent processes were carried out in the same way as in Example 1. In this comparative example, the reaction conversion rate of the compound of formula 1 was 0%.

[0087] Comparative Example 4: Preparation of the compound of formula 1 (N-(1-methyl-1H- tetrazol-5-yl)-2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6-(trifluoromethyl)nicotinamide)

[0088]

[0089] The compound of formula 2 (2-(((2-methyl-2H-tetrazol-5-yl)methoxy)methyl)-6- (trifluoromethyl)nicotinic acid, 10 g, 31.5 mmol) was dissolved in 150 ml of DMF (dimethylformamide), cooled to 5 to 10 °C, then thionyl chloride (5.6 g, 47.3 mmol) was slowly added, then the compound of formula 3 (1-methyl-1H-tetrazol-5-amine (AMTT), 6.25 g, 63.0 mmol) was added. After the disappearance of smoke from the reaction solution, the temperature was raised to room temperature and stirred for 3 hours. The subsequent processes were carried out in the same way as in Example 1. In this comparative example, the reaction conversion rate of the compound of formula 1 was 11%.

Claims

1. A method for preparing a compound of formula 1, comprising the following steps: a) Dissolving the compound represented by Formula 2 in an organic solvent, wherein the organic solvent is at least one selected from the group consisting of pyridine and dichloromethane; b) Add thionyl chloride to the solution from step a); and c) Add the compound of formula 3 to the solution from step b) and allow them to react: [Formula 1] [Equation 2] [Formula 3] in, R1 is a (C1-C6) alkyl group, (C2-C6) alkenyl group, (C2-C6) alkynyl group, or (C3-C6) cycloalkyl group, and R2 is a (C1-C6) alkyl group, (C2-C6) alkenyl group, (C2-C6) alkynyl group, or (C3-C6) cycloalkyl group.

2. The method for preparing compound of formula 1 according to claim 1, wherein step a) further comprises cooling the solution to 0 to 15°C.

3. The method for preparing compound of formula 1 according to claim 2, wherein the reaction in step c) is carried out at a temperature of 20 to 30°C.

4. The method for preparing the compound of formula 1 according to claim 3, wherein the reaction temperature is controlled by the following process: after adding the compound of formula 3, the flue gas disappears in the reaction solution, and then the temperature is increased.

5. The method for preparing compound of formula 1 according to claim 1, wherein the addition of thionyl chloride in step b) and the addition of compound of formula 3 in step c) are carried out sequentially.

6. The method for preparing compound of formula 1 according to claim 1, wherein the thionyl chloride in step b) is added in an amount of 1 to 2 equivalents relative to compound of formula 2.

7. The method for preparing compound of formula 1 according to claim 1, wherein the compound of formula 3 in step c) is added in an amount of 0.5 to 10 equivalents relative to the compound of formula 2.

8. The method for preparing compound of formula 1 according to claim 1, wherein the reaction in step c) is carried out for 2 to 4 hours.

9. The method for preparing compound of formula 1 according to claim 1, further comprising the following steps: After the reaction in step c) is completed, the reaction solvent is removed and acid is added to prepare an acidic solution with a pH of 2 to 5. The solution is then extracted 1 to 5 times with an organic solvent, and the organic solvent is removed to obtain the compound of formula 1 in a crystalline state.

10. The method for preparing compound of formula 1 according to claim 9, wherein the acid is at least one selected from the group consisting of HCl, NH4Cl, CH3COOH and H2SO4.

11. The method for preparing compound of formula 1 according to claim 9, wherein the extraction is carried out with at least one organic solvent selected from the group consisting of ethyl acetate, dichloromethane, dichloroethane, toluene, xylene, chloroform, diethyl ether and butanone.

12. The method for preparing a compound of formula 1 according to claim 9, further comprising the step of purifying the crystalline compound of formula 1 by recrystallization.

13. The method for preparing compound of formula 1 according to claim 12, wherein the recrystallization is carried out with methanol and water.

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