Method for producing nicotinic acid derivatives

Abstract

The present disclosure relates to methods for preparing nicotinic acid derivatives, which are useful in the chemical field, for example, in the manufacture of pharmaceuticals or agricultural chemicals. In particular, the present disclosure relates to novel methods for preparing certain nicotinic acid derivatives.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Patent Application No. 63 / 104,954, filed on 23 October 2020, the entire disclosure of which is incorporated herein by reference.

[0002] This disclosure relates to a method for preparing nicotinic acid derivatives that are useful in the chemical field, for example, in the manufacture of pharmaceutical products or agrochemicals. In particular, this disclosure relates to a novel method for preparing a specific nicotinic acid derivative. [Background technology]

[0003] The manufacture of pharmaceutical and agrochemical products is a complex and highly regulated industry. Among the many considerations in the manufacture of pharmaceutical and agrochemical products are aspects such as the cost of raw materials, processing costs of intermediates and products, efficiency of chemical synthesis, and ease of purification and handling. Due to the many forces influencing the manufacture of pharmaceutical and agrochemical products, manufacturers expend considerable resources to optimize chemical synthesis methods and intermediates.

[0004] For example, 2-trifluoromethylnicotinic acid and its carboxylic acid derivatives, such as esters, nitriles, and amides, are used as intermediates in both pharmaceutical and agrochemical products. For example, 2-trifluoromethylnicotinic acid is used as an intermediate in the preparation of fungicides (see Shigehara, I.; Nakajima, T.; Nishide, H.; Tanimura, T., JP03081263A (April 5, 1991)); heterocyclic carboxamides produced from 2-trifluoromethylnicotinic acid are also used as fungicides (see Mansfield, DJ; Rieck, H.; Geul, JN et al., EP1449841A1 (August 25, 2004)); heteroaryl carboxamides produced using 2-trifluoromethylnicotinic acid and aniline derivatives are also used as fungicides (see Gewehr, M.; Dietz, J.; Grote, See T. et al., WO2006097490A1 (September 21, 2006); 2-trifluoromethylnicotinic acid is used in the pharmaceutical industry as an intermediate for synthetic COMT (catechol-O-methyltransferase) inhibitors used in the treatment of neurological disorders, such as Parkinson's disease (see Learmonth, D.; Kiss, L.; Leal Palma, P. et al., WO2007013830A1 (2007)); 2-trifluoromethylnicotinamide derivatives are used in the synthesis of pesticide products used against nematodes (see Loiseleur, O.; Jeanguenat, A.; Mondleve, RJG, WO2015004091A1 (January 15, 2015)); 2-trifluoromethylnicotinic acid is used in the pesticide industry in the synthesis of pyridopyridine and pyrimidinopyridine for use as herbicides (Carter, See NB, etc., WO2017162522A1 (September 28, 2017); WO2017162521A1 (September 28, 2017); WO2017162524A1 (September 28, 2017).

[0005] The use of amides derived from 2-trifluoromethylnicotinic acid as herbicides has been reported (see Xu, l., CN108623518A (October 9, 2018)). The use of 2-trifluoromethylnicotinic acid in the synthesis of final pesticide products used as insecticides has also been reported. The active compounds have other heterocycles at the nitrogen substituent of the amide derivatives of 2-trifluoromethylnicotinic acid (see Decor, A.; Lishchynskyi, A. et al., WO2018108791A (June 21, 2018); Decor, A.; Fischer, R. et al., WO2019105875A1 (June 6, 2019)). The use of N-substituted amides of 2-trifluoromethylnicotinic acid as nematicides or fungicides has also been reported. The N-substituent also has a four-membered ring with a 2,4-dichlorophenyl group. (Hone, I.; Jones, I.K., WO2019158476A1 (August 22, 2019)).

[0006] Various methods have been used to prepare nicotinic acid derivatives. For example, the preparation of 2-trifluoromethylnicotinic acid has been achieved using both cyclic synthesis and chemical transformation of the pyridine ring. One problem associated with the chemical transformation of the pyridine ring was the introduction of the CF3 group. For this purpose, various reagents have been used, usually involving halogen substitution. Illustrative options for this transformation are shown in the retrosynthetic wheel diagram below.

[0007] [ka]

[0008] A method starting with 2-chloronicotinic acid and replacing the chlorine atom with a CF3 anion has been used to synthesize 2-trifluoromethylnicotinic acid. The trifluoromethyl anion is produced using iodotrifluoromethane and copper (see Shigehara, I.; Nakajima, T.; Nishide, H.; Tanimura, T., JP03081263A (April 5, 1991)).

[0009] An alternative method for preparing 2-trifluoromethylnicotinic acid has also been used, which involves starting with 2-trifluoromethylpyridine prepared using lithium 2,2,6,6-tetramethylpiperidine as the base, CF3Cu, and 2-chloropyridine, followed by deactivation with carbon dioxide. In this method, the formation of the 4-isomer, 2-trifluoromethylisonicotinic acid, has been observed as a byproduct (Taylor, RT, Reagents for Organic Synthesis, 2001).

[0010] 2-Trifluoromethylnicotinic acid has also been synthesized using 2-chloro-3-trimethylsilylpyridine as a starting material and the reagent CF3SiMe3 as a transfer agent (Cottet, F. et al., European Journal of Organic Chemistry, 1559, 2003).

[0011] Alternatively, the formation of a Grignard reagent from 2-trifluoromethyl-3-bromopyridine by contact with magnesium followed by inactivation with carbon dioxide has been used for the synthesis of 2-trifluoromethylnicotinic acid (Didiuk, MT et al., Bioorganic & Medicinal Chemistry Letters, 19, 4555, 2009).

[0012] The product, 2-trifluoromethylnicotinic acid, has also been synthesized starting from either 2,3-dibromopyridine or 2-iodo-3-bromopyridine and the reagent CF3SiMe3 (Li, B. et al., Synlett, 2133, 2010).

[0013] Regarding the synthesis of 2-trifluoromethylnicotinic acid, hydrolysis of 2-trifluoromethylnicotinic acid ester has also been reported (Sharma, S.; Dhaka, P.; Jangid, D.; Kumar, K.; Anand, R., Indian Patent Application No. 201611032457 (March 28, 2018); WO2018055640 (March 29, 2018)).

[0014] We compare two methods, one corresponding to ring transformation and the other to ring synthesis, and show them below.

[0015] [ka]

[0016] For example, the reported ring transformation method starts with the expensive starting material 2-chloronicotinic acid and involves nucleophilic substitution of a chlorine atom using a trifluoromethyl anion. The trifluoromethyl anion is generated from fluoroform using stoichiometric amounts of the base potassium t-butoxide and copper chloride (Lishchynskyi, A.; Novikov, MA; Martin, E.; Escudero-Adan, EC; Novak, P.; Grushin, VV, Journal of Organic Chemistry 78, 11126, 2013).

[0017] In cyclic synthesis, trifluoroacetic acid derivatives are used to introduce a CF3 group into the pyridine ring. In one reported cyclic synthesis method, the Vilsmeyer reaction is carried out on vinyl butyl ether to produce a 1,3-diformylpropane equivalent compound, which is then reacted with a trifluoroacetoacetate compound to form a five-carbon chain intermediate. This five-carbon intermediate is cyclized in the presence of ammonia to form the final product, 2-trifluoromethylnicotinate (Kiss, LE; Ferreira, HS; Learmonth, DA, Organic Letters 10, 1835, 2008). [Prior art documents] [Patent Documents]

[0018] [Patent Document 1] JP03081263A [Patent Document 2] EP1449841A1 [Patent Document 3] WO2006097490A1 [Patent Document 4] WO2007013830A1 [Patent Document 5] WO2015004091A1 [Patent Document 6] WO2017162522A1 [Patent Document 7] WO2017162521A1 [Patent Document 8] WO2017162524A1 [Patent Document 9] CN108623518A [Patent Document 10] WO2018108791A [Patent Document 11] WO2019105875A1 [Patent Document 12] WO2019158476A1 [Patent Document 13] JP03081263A

Patent Document 14

Patent Document 15

Non-Patent Documents

[0019]

Non-Patent Document 1

Non-Patent Document 2

[0021] In one embodiment, the present disclosure relates to a useful intermediate in the preparation of chemical products, such as pharmaceuticals and agrochemicals, of formula V:

[0022] [ka]

[0023] (In the formula, R 1 , R 3 and R 4 (Each is defined herein.) This invention provides a method for preparing nicotinic acid derivatives.

[0024] In another aspect, this disclosure relates to Formula III:

[0025] [ka]

[0026] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2is C1-C8 alkyl; R 3 and R 4 are each independently selected from the group consisting of H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 aryl may be optionally substituted independently with deuterium, fluoro, chloro, bromo, -OC1-C8 alkyl, -N(C1-C8 alkyl)2 or -SC1-C8 alkyl) to provide a compound of.

[0027] In another aspect, the present disclosure provides a compound of formula III:

[0028]

Chemical formula

[0029] (wherein, R 1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 aryl may be optionally substituted independently with deuterium, fluoro, chloro, bromo, -OC1-C8 alkyl, -N(C1-C8 alkyl)2 or -SC1-C8 alkyl; R 2 is C1-C8 alkyl; R 3 and R 4 are each independently selected from the group consisting of H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. A method for preparing the compound, Formula I:

[0030] [ka]

[0031] (In the formula, R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound of formula II:

[0032] [ka]

[0033] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 (These are C1-C8 alkyl groups.) The present invention provides a method comprising contacting a compound with a base in the presence of the compound.

[0034] In another aspect, this disclosure relates to formula V:

[0035] [ka]

[0036] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. A method for preparing a nicotinic acid derivative, i. Formula I:

[0037] [ka]

[0038] (In the formula, R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound of formula II:

[0039] [ka]

[0040] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 (These are C1-C8 alkyl groups.) When the compound is brought into contact with a base, formula III:

[0041] [ka]

[0042] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The process of obtaining the compound; and / or ii.Formula III:

[0043] [ka]

[0044] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound is brought into contact with an oxidizing agent and an additive, and formula IV:

[0045] [ka]

[0046] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The process includes obtaining the compound; optionally iii.Formula IV:

[0047] [ka]

[0048] (In the formula, R1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. When the compound is brought into contact with a base, formula V:

[0049] [ka]

[0050] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 3 and R 4These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The present invention provides a method which may further include the step of obtaining the compound. [Modes for carrying out the invention]

[0051] Additional embodiments, features, and advantages of the disclosure will become apparent from the following detailed description and implementation of the disclosure. The compounds of this disclosure may be described as embodiments in any of the following enumerated clauses. It will be understood that any embodiment described herein can be used in conjunction with any other embodiment described herein, provided that the embodiments do not conflict with each other.

[0052] 1.Formula:

[0053] [ka]

[0054] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4Each is independently selected from the group consisting of H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 [[ID=]](aryl may be optionally substituted independently by deuterium, fluoro, chloro, bromo, -OC1-C8 alkyl, -N(C1-C8 alkyl)2 or -SC1-C8 alkyl). Compound of

[0055] 2. R 1 is methyl, trifluoromethyl or difluoromethyl, the compound according to clause 1.

[0056] 3. R 4 is H, methyl, ethyl, n-propyl, i-propyl or allyl, the compound according to clause 1 or 2.

[0057] 4. R 3 is H, methyl, ethyl, n-propyl, i-propyl or allyl, the compound according to any one of the preceding clauses.

[0058] 5. R 2 is methyl, ethyl, n-propyl or i-propyl, the compound according to any one of the preceding clauses.

[0059] 6.

[0060]

Chemical formula

[0061] selected from the group consisting of, the compound according to any one of the preceding clauses.

[0062] 7. Formula:

[0063]

Chemical formula

[0064] (wherein R 1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 aryl may be optionally substituted independently with deuterium, fluoro, chloro, bromo, -OC1-C8 alkyl, -N(C1-C8 alkyl)2 or -SC1-C8 alkyl; R 3 and R 4 are each independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 aryl may be optionally substituted independently with deuterium, fluoro, chloro, bromo, -OC1-C8 alkyl, -N(C1-C8 alkyl)2 or -SC1-C8 alkyl) A method for preparing a compound of i. Formula:

[0065]

Chemical formula

[0066] (wherein R 3 and R 4 are each independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 aryl may be optionally substituted independently with deuterium, fluoro, chloro, bromo, -OC1-C8 alkyl, -N(C1-C8 alkyl)2 or -SC1-C8 alkyl) A compound of is reacted with a compound of the formula:

[0067] [ka]

[0068] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 (These are C1-C8 alkyl groups.) When the compound is brought into contact with a base, formula:

[0069] [ka]

[0070] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. A method comprising the step of obtaining a compound.

[0071] 8.Formula:

[0072] [ka]

[0073] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. A method for preparing the compound, ii.Formula:

[0074] [ka]

[0075] (In the formula, R 1These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound is brought into contact with an oxidizing agent and an additive, and the formula is:

[0076] [ka]

[0077] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. A method comprising the step of obtaining a compound.

[0078] 9.Formula:

[0079] [ka]

[0080] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. A method for preparing the compound, i. Formula:

[0081] [ka]

[0082] (In the formula, R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound is given by the formula:

[0083] [ka]

[0084] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 (These are C1-C8 alkyl groups.) When the compound is brought into contact with a base, formula:

[0085] [ka]

[0086] (In the formula, R 1is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 selected from the group consisting of aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 aryl may be optionally substituted independently with deuterium, fluoro, chloro, bromo, -OC1-C8 alkyl, -N(C1-C8 alkyl)2 or -SC1-C8 alkyl; R 2 is C1-C8 alkyl; R 3 and R 4 are each independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 selected from the group consisting of aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 aryl may be optionally substituted independently with deuterium, fluoro, chloro, bromo, -OC1-C8 alkyl, -N(C1-C8 alkyl)2 or -SC1-C8 alkyl) to obtain a compound of; and ii. The compound of the formula prepared in step (i):

[0087]

Chemical formula

[0088] is contacted with an oxidizing agent and an additive to give a compound of the formula:

[0089]

Chemical formula

[0090] (wherein, R 1 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 selected from the group consisting of aryl, and each hydrogen atom of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. A method comprising the step of obtaining a compound.

[0091] 10.iii.Formula:

[0092] [ka]

[0093] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. When the compound is brought into contact with a base, formula:

[0094] [ka]

[0095] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The method according to any one of the provisions of provisions 7 to 9, further comprising the step of obtaining the compound.

[0096] 11. The method according to any one of the provisions 7 to 10, wherein the base in step (i) is an organic base.

[0097] 12. The method according to any one of the provisions of provisions 7 to 11, wherein the base in step (i) is an amine base.

[0098] 13. The method according to any one of the claims 7 to 12, wherein the base of step (i) is selected from the group consisting of triethylamine (TEA), tributylamine, N,N-diisopropylethylamine (DIPEA), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), and 2,6-di-tert-butylpyridine.

[0099] 14. The method according to any one of the provisions 7 to 13, wherein step (i) is carried out in the presence of an alcohol solvent.

[0100] 15. The method according to Clause 14, wherein the organic solvent in step (i) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol.

[0101] 16. The method according to any one of the provisions 7 to 15, wherein step (i) is carried out by adding acrolein to ethyl trifluoroacetoethyl at a temperature of approximately 0°C to approximately 25°C.

[0102] 17. The method according to any one of the provisions of provisions 7 to 16, wherein the oxidizing agent in step (ii) is O2 in the presence of a metal catalyst.

[0103] 18. The method according to Clause 17, wherein the metal catalyst is selected from the group consisting of copper(I) acetate, copper(I) chloride, copper(I) oxide, manganese(II) acetate, copper(II) acetate, copper(II) chloride, copper(II) oxide, and iron(III) acetate.

[0104] 19. The method according to any one of clauses 7 to 18, wherein the additive in step (ii) is selected from the group consisting of ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium nitrate.

[0105] 20. The method according to any one of clauses 7 to 19, wherein step (ii) is carried out in an alcohol solvent.

[0106] 21. The method according to clause 20, wherein the organic solvent in step (ii) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutyl carbinol, and propylene glycol.

[0107] 22. The method according to any one of clauses 7 to 21, wherein step (ii) is carried out at about 60 °C to about 280 °C.

[0108] 23. The method according to any one of clauses 7 to 22, wherein the base in step (iii) is an inorganic base.

[0109] 24. The method according to clause 23, wherein the base in step (iii) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, ammonium hydroxide, and magnesium hydroxide.

[0110] 25.R 1 is methyl, trifluoromethyl, or difluoromethyl, the method according to any one of clauses 7 to 24.

[0111] 26.R 4 is H, methyl, ethyl, n-propyl, i-propyl, or allyl, the method according to any one of clauses 7 to 25.

[0112] 27.R 3The method according to any one of the provisions of provisions 7 to 26, wherein is H, methyl, ethyl, n-propyl, i-propyl, or allyl.

[0113] 28.R 2 The method according to any one of the provisions of provisions 7 to 27, wherein is methyl, ethyl, n-propyl, or i-propyl.

[0114] 29. A method for preparing 29, 2-trifluoromethylnicotinic acid, i. Contact one or more 4,4,4-trifluoro-3-oxobutanoates in the presence of acrolein and a base to produce the formula:

[0115] [ka]

[0116] (In the formula, R 2 (These are C1-C8 alkyl groups.) A method comprising the step of obtaining a compound.

[0117] 30. A method for preparing 2-trifluoromethylnicotinic acid, ii.Formula:

[0118] [ka]

[0119] (In the formula, R 2 (These are C1-C8 alkyl groups.) A method comprising the step of contacting a compound with an oxidizing agent and optionally an additive to obtain one or more 2-trifluoromethylnicotinic acid esters.

[0120] 31. A method for preparing 2-trifluoromethylnicotinic acid, i. Contact one or more 4,4,4-trifluoro-3-oxobutanoates in the presence of acrolein and a base, and prepare the following: [ka] (In the formula, R 2 (These are C1-C8 alkyl groups.) The process of obtaining the compound; and ii.Formula:

[0121] [ka]

[0122] (In the formula, R 2 (These are C1-C8 alkyl groups.) A method comprising the step of contacting a compound with an oxidizing agent and optionally an additive to obtain one or more 2-trifluoromethylnicotinic acid esters.

[0123] 32.iii. The method according to any one of the provisions of 29 to 31, further comprising the step of contacting one or more 2-trifluoromethylnicotinic acid esters with a base to obtain 2-trifluoromethylnicotinic acid.

[0124] 33. The method according to any one of the provisions 29 to 32, wherein the base in step (i) is an organic base.

[0125] 34. The method according to any one of the provisions 29 to 33, wherein the base in step (i) is an amine base.

[0126] 35. The method according to any one of the claims 29 to 34, wherein the base of step (i) is selected from the group consisting of triethylamine (TEA), tributylamine, N,N-diisopropylethylamine (DIPEA), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), and 2,6-di-tert-butylpyridine.

[0127] 36. The method according to any one of the provisions 29 to 35, wherein step (i) is carried out in the presence of an alcohol solvent.

[0128] 37. The method according to Clause 36, wherein the organic solvent in step (i) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol.

[0129] 38. The method according to any one of the claims 29 to 37, wherein step (i) is carried out by adding acrolein to ethyl trifluoroacetoethyl at a temperature of approximately 0°C to approximately 25°C.

[0130] 39. The method according to any one of the provisions of provisions 29 to 38, wherein the oxidizing agent in step (ii) is O2 in the presence of a metal catalyst.

[0131] 40. The method according to clause 39, wherein the metal catalyst is selected from the group consisting of copper(I) acetate, copper(I) chloride, copper(I) oxide, manganese(II) acetate, copper(II) acetate, copper(II) chloride, copper(II) oxide, and iron(III) acetate.

[0132] 41. The method according to any one of the provisions 29 to 40, wherein the additive in step (ii) is selected from the group consisting of ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium nitrate.

[0133] 42. The method according to any one of the provisions 29 to 41, wherein step (ii) is carried out in an alcohol solvent.

[0134] 43. The method according to Clause 42, wherein the organic solvent in step (ii) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol.

[0135] 44. The method according to any one of the provisions 29 to 43, wherein step (ii) is performed at a temperature of approximately 60°C to approximately 280°C.

[0136] 45. The method according to any one of the provisions of 29 to 44, wherein the base in step (iii) is an inorganic base.

[0137] 46. ​​The method according to Clause 45, wherein the base in step (iii) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, ammonium hydroxide, and magnesium hydroxide.

[0138] definition As used herein, the term “alkyl” includes a chain of carbon atoms containing 1 to 20 carbon atoms, or alternative ranges such as 1 to 8 carbon atoms or 1 to 6 carbon atoms, which may optionally be branched. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. It is understood that alkyl groups may or may not be substituted as described herein. Alkyl groups may be substituted with any of the substituents of the various embodiments described herein, including one or more such substituents.

[0139] As used herein, the term “alkenyl” includes a carbon chain containing 2 to 20 carbon atoms, or alternative ranges such as 2 to 8 carbon atoms or 2 to 6 carbon atoms, and one or more carbon-carbon double bonds (also known as π bonds), which may be optionally branched. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, and 2-pentenyl. It is understood that the alkenyl group may or may not be substituted as described herein. The alkenyl group may be substituted with any of the substituents of the various embodiments described herein, including one or more such substituents.

[0140] As used herein, the term "alkynyl" includes a chain of carbon atoms containing 2 to 20 carbon atoms, or alternative ranges such as 2 to 8 carbon atoms or 2 to 6 carbon atoms, and one or more carbon-carbon triple bonds, which may optionally be branched. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and 2-pentynyl. It is understood that the alkynyl group may be substituted or not substituted as described herein. The alkynyl group may be substituted with any of the substituents of the various embodiments described herein, which may include one or more such substituents.

[0141] As used herein, the term "aryl" refers to a group of 6 to 14 carbon atoms (C6 to C6). 14 Aryl, or alternatively, 6 to 10 carbon atoms (C6 to C6) 10 This refers to a monovalent, all-carbon monocyclic or fused polycyclic group having an aryl (aryl) and a fully conjugated π-electron system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. It is understood that the aryl group may be substituted or not substituted as described herein. The aryl group may be substituted with any of the substituents of the various embodiments described herein, including one or more such substituents.

[0142] Detailed explanation Before further description of this disclosure, it should be understood that the embodiments described are not limited to and may naturally differ from those described. Since the scope of this disclosure is limited only by the appended claims, it should also be understood that the terminology used herein is intended to describe, and not to limit, specific embodiments.

[0143] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains. All patents, applications, published applications and other publications referenced herein are incorporated herein by reference in their entirety. If any definition set forth in this section conflicts with or does not coincide with any definition set forth in any patent, application or other publication incorporated herein by reference, the definition set forth in this section shall prevail over the definition incorporated herein by reference.

[0144] Where used herein and in the appended claims, unless otherwise clearly indicated in the context, the singular forms “a, an” and “the” refer to multiple objects. It should be further noted that the claims may be drafted to exclude any optional element. In this manner, this statement is intended to function as an antecedent to the use of exclusive terms such as “solely,” “only,” or “negative” limitation in connection with the enumeration of elements of the claims.

[0145] Typical Embodiments This specification describes a highly carbon-efficient method for synthesizing nicotinic acid derivatives, such as 2-trifluoromethylnicotinic acid, starting from trifluoroacetoacetate derivatives, such as trifluoroacetoethyl, and vinylaldehyde derivatives, such as acrolein. The method described herein provides novel dihydropyran derivatives useful for the preparation of nicotinic acid derivatives by further conversion. According to the method of this disclosure, the dihydropyran derivative is readily converted to a pyridine ester derivative in a second step by reacting it with a nitrogen source additive, such as ammonium acetate, in the presence of an oxidizing agent. Finally, in a third step, ester hydrolysis of the pyridine ester derivative is carried out using a base under mild conditions to produce the target product, the nicotinic acid derivative. The method of this disclosure can be described according to Scheme I.

[0146] [ka]

[0147] It is understood that this disclosure provides a method for preparing the compounds of formula V described in the preceding and following sections, comprising step (i) and one or more of the enumerated steps (ii) and (iii). Accordingly, this disclosure provides a method for preparing the compounds of formula V, comprising step (i). Alternatively, this disclosure provides a method for preparing the compounds of formula V, comprising steps (i) and (ii). Alternatively, this disclosure provides a method for preparing the compounds of formula V, comprising steps (i), (ii), and (iii). Alternatively, this disclosure provides a method for preparing the compounds of formula III, comprising step (ii). Alternatively, this disclosure provides a method for preparing the compounds of formula IV, comprising steps (i) and (ii).

[0148] In process (i), Equation I:

[0149] [ka]

[0150] (In the formula, R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound of formula II:

[0151] [ka]

[0152] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 (These are C1-C8 alkyl groups.) When the compound is brought into contact with a base, formula III:

[0153] [ka]

[0154] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound is obtained.

[0155] In step (i), the base may be any suitable base, such as an organic base or an inorganic base. In some embodiments, the base in step (i) may be an organic base, such as an amine base. Suitable amine bases include, but are not limited to, triethylamine (TEA), tributylamine, N,N-diisopropylethylamine (DIPEA), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), and 2,6-di-tert-butylpyridine. Step (i) may be carried out in the presence of an optional solvent. The solvent may be any suitable solvent, such as an organic solvent. In some embodiments, the solvent in step (i) may be an alcoholic solvent. Suitable alcoholic solvents include, but are not limited to, methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol. It is understood that step (i) may be carried out at any temperature commonly used in connection with ring formation using the Michael addition method, for example, at room temperature, under cooling or heat retention conditions. In some embodiments, step (i) may be carried out at a temperature of about 0°C to about 25°C. In some embodiments, step (i) may be carried out by adding the compound of formula I to the compound of formula II at a temperature of about 0°C to about 25°C. In some embodiments, after adding the compound of formula I to the compound of formula II, the reaction may be heated to a temperature above room temperature, for example, at the reflux temperature of the solvent used in connection with step (i). In some embodiments, step (i) may be carried out at a temperature of about 60°C to about 280°C.

[0156] In some embodiments of step (i), the compound of formula I may be acrolein (also known as propenal), and the compound of formula II may be one or more 4,4,4-trifluoro-3-oxobutanoates. One or more 4,4,4-trifluoro-3-oxobutanoates may be of the following formula:

[0157] [ka]

[0158] (In the formula, R 2 (These are C1-C8 alkyl groups.) It is understood that the product of step (i) may be a mixture of C1-C8 alkyl esters of 4,4,4-trifluoro-3-oxobutanoic acid represented by:

[0159] [ka]

[0160] (In the formula, R 2 (These are C1-C8 alkyl groups.) This can be shown by:

[0161] In process (ii), Equation III:

[0162] [ka]

[0163] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound is brought into contact with an oxidizing agent and an additive, such as a nitrogen source additive, to form formula IV:

[0164] [ka]

[0165] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. This allows us to obtain the compound.

[0166] In step (ii), the oxidizing agent may be any suitable oxidizing agent in the presence of an optional catalyst, such as oxygen (O2). The optional catalyst may be any suitable catalyst, such as a metal catalyst. Suitable metal catalysts include, but are not limited to, copper(I) acetate, copper(I) chloride, copper(I) oxide, manganese(II) acetate, copper(II) acetate, copper(II) chloride, copper(II) oxide, and iron(III) acetate. The additive in step (ii) may be a nitrogen source additive, such as ammonia, ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium nitrate. It may be advantageous to use the nitrogen source in equimolar amounts or in molar excess relative to the compound of formula III. In some embodiments, the nitrogen source, such as ammonium acetate, may be used in molar excess relative to the compound of formula III. Step (ii) may be carried out in the presence of an optional solvent. The solvent may be any suitable solvent, such as an organic solvent. In some embodiments, the solvent in step (ii) may be an alcoholic solvent. Suitable alcoholic solvents include, but are not limited to, methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol. It is understood that step (ii) may be carried out at any temperature commonly used in relation to oxidation chemical processes, for example, at room temperature, under cooling or heat retention conditions. In some embodiments, step (ii) may be heated to a temperature above room temperature, for example, at the reflux temperature of the solvent used in relation to step (ii). In some embodiments, step (ii) may be carried out at a temperature of about 60°C to about 280°C. The compound of formula IV may be purified, for example, by steam distillation, or the compound of formula IV may be further synthesized without purification.

[0167] In some embodiments of step (ii), the compound of formula III is:

[0168] [ka]

[0169] (In the formula, R 2 (These are C1-C8 alkyl groups.) The compound produced by formula IV is

[0170] [ka]

[0171] (In the formula, R 2 (These are C1-C8 alkyl groups.) That's fine.

[0172] In process (iii), Equation IV:

[0173] [ka]

[0174] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. When the compound is brought into contact with a base, formula V:

[0175] [ka]

[0176] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. This allows us to obtain the compound.

[0177] In step (iii), the base may be any suitable base, such as an organic base or an inorganic base. In some embodiments, the base in step (iii) may be an inorganic base, such as a hydroxide base. Suitable hydroxide bases include, but are not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, ammonium hydroxide, and magnesium hydroxide. In some embodiments, the base may be sodium hydroxide. In some embodiments, the base may be a 25% sodium hydroxide solution. Step (iii) may be carried out in the presence of an optional solvent. The solvent may be any suitable solvent, such as an organic solvent. In some embodiments, the solvent in step (iii) may be an alcoholic solvent. Suitable alcoholic solvents include, but are not limited to, methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol. It is understood that step (iii) may be carried out at any temperature commonly used in relation to oxidation chemical processes, e.g., room temperature, under cooling or heating conditions. In some embodiments, step (iii) may be carried out at low temperatures by using a base hydroxide solution with a concentration range of about 10% to about 40% of the base hydroxide. In some embodiments, step (i) may be carried out at a temperature of about 0°C to about 25°C. In some embodiments, the reaction is cooled to below room temperature at a temperature of about 0°C to about 25°C, the base is added to the cooled reaction, and after the addition is complete, the temperature is raised to room temperature. It is understood that the base hydrolysis reaction may be stopped, and the product is isolated by acidifying the reaction with, for example, an inorganic acid (e.g., sulfuric acid) solution, followed by filtration of the final product.

[0178] In some embodiments of step (iii), the compound of formula IV is:

[0179] [ka]

[0180] (In the formula, R 2 (These are C1-C8 alkyl groups.) It can be anything.

[0181] In some embodiments, this disclosure relates to Formula III:

[0182] [ka]

[0183] (In the formula, R 1 These are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl; R 2 It is a C1-C8 alkyl group; R 3 and R 4 These are independently H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C 10 Selected from the group consisting of aryls, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C6-C 10 Each hydrogen atom of the aryl group may be independently substituted with deuterium, fluoro, chloro, bromo, -OC1~C8 alkyl, -N(C1~C8 alkyl)2, or -SC1~C8 alkyl. The compound is obtained.

[0184] In some embodiments, R 1 R is methyl, trifluoromethyl, or difluoromethyl. In some embodiments, 4is H, methyl, ethyl, n-propyl, i-propyl, or allyl. In some embodiments, R 3 is H, methyl, ethyl, n-propyl, i-propyl, or allyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or i-propyl. In some embodiments, the compound of formula III is

[0185] [ka]

[0186] It is selected from the group consisting of the following. [Examples]

[0187] The examples and preparations provided below further illustrate and demonstrate specific aspects of the embodiments of the present disclosure. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples.

[0188] (Example 1) Step 1: 2-Hydroxy-6-(trifluoromethyl)-3,4-dihydro-2H-pyran-5carboxylate ethyl: Methanol (200 mL) and ethyl trifluoroacetoethyl acetate (37.0 g, 0.199 mol) were packed into a pot, stirred, and kept at a temperature of 5-10°C. Triethylamine (2.1 g, 0.021 mol) was added, followed by the addition of acrolein (11.6 g, 0.201 mol) solution in methanol (50 mL) over 1 hour, and the entire mixture was stirred at 23°C for 35 minutes. The reaction mixture was used directly in step 2. After stripping the solvent, the product was obtained as an amber liquid. Characterization was performed using GCMS Mw240 and fluorine NMR (-85.8 ppm).

[0189] Step 2: Ethyl 2-(trifluoromethyl)nicotinate: Ammonium acetate (30.8 g, 0.400 mol) and copper acetate monohydrate (4.1 g, 0.021 mol) were packed into the above reaction mixture and heated under reflux (67°C) with oxygen (50%) introduced below the surface. Water (100 mL) was added to raise the reflux temperature to 73°C. The progress of the reaction was tracked by NMR. The product was isolated by steam distillation, with all methanol being eliminated first, followed by the product and water. A yield of 41% of the final product was observed. The product could also be isolated by distillation. The product was characterized using GC-MS Mw219 and fluorine NMR (-75.5 ppm).

[0190] Step 3: 2-(trifluoromethyl)nicotinic acid: Ethyl 2-(trifluoromethyl)nicotinate (14.6 g, 0.063 mol) and methanol (10 mL) were packed into a pot and cooled to 10-15°C. Sodium hydroxide (25%, 11.4 g, 0.071 mol) was added to this reaction mixture over 5 minutes. After the addition and stirring at 25°C for 1 hour, the reaction mixture was work-treated with water (17 g) and sulfuric acid (3.7 g) to pH 2. After stirring for 30 minutes, the product was isolated by filtration, washed with water (3 × 20 mL), and dried to obtain the final product, 2-(trifluoromethyl)nicotinic acid, in 85% yield. Proton NMR (acetone-d6) 8.9(d, 1H), 8.3(d, 1H), 7.8(dd, 1H); and fluorine NMR (-65.2 ppm).

[0191] (Example 2) 5-Propyl-2-trifluoromethylnicotinic acid: 5-Propyl-2-trifluoromethylnicotinic acid was prepared according to the method described in Example 1, except that 2-propyl acrolein was used instead of acrolein. The final product, 5-propyl-2-trifluoromethylnicotinic acid, was characterized by proton NMR (acetone-d6) 8.7(s, 1H), 8.1(s, 1H), 2.7(t, 2H), 1.6(m, 2H), 0.9(t, 3H) and fluorine NMR (-62.8 ppm).

[0192] (Example 3) 5-(1-propenyl)-2-trifluoromethylnicotinic acid: 5-(1-propenyl)-2-trifluoromethylnicotinic acid was prepared according to the method described in Example 1, except that 2-(2-propenyl)acrolein was used instead of acrolein. During the third step of hydrolysis of the ester group with sodium hydroxide, the double bond of the propenyl group isomerized from position 2 (2-propenyl) to position 1 (1-propenyl). The final product, 5-(1-propenyl)-2-trifluoromethylnicotinic acid, was characterized by proton NMR (acetone-d6) 8.8(s, 1H), 8.2(s, 1H), 6.7-6.5(m, 2H), 1.9(d, 3H); and fluorine NMR (-62.8 ppm). Another aspect of the present invention may be as follows: 〔1〕 formula: [C1] JPEG0007883490000052.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 It is alkyl; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) A compound of [this]. 〔2〕 R 1 The compound described in [1] above, wherein the compound is methyl, trifluoromethyl, or difluoromethyl. 〔3〕 R 4 The compound according to [1] or [2] above, wherein H is methyl, ethyl, n-propyl, i-propyl, or allyl. 〔4〕 R 3 The compound described in [3] above, wherein H is methyl, ethyl, n-propyl, i-propyl, or allyl. 〔5〕 R 2 The compound described in [3] above, wherein the compound is methyl, ethyl, n-propyl, or i-propyl. 〔6〕 [C2] JPEG0007883490000053.jpg43150 A compound selected from the group consisting of the above [1]. 〔7〕 formula: [C3] JPEG0007883490000054.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) A method for preparing the compound, i. Formula: [C4] JPEG0007883490000055.jpg20150 (In the formula, R 3 and R4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) The compound of formula: [5] JPEG0007883490000056.jpg19150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 (It is alkyl.) When the compound is brought into contact with a base, formula: [6] JPEG0007883490000057.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 It is alkyl; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) Steps to obtain the compound A method that includes this. 〔8〕 formula: [7] JPEG0007883490000058.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) A method for preparing the compound, ii.Formula: [8] JPEG0007883490000059.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 It is alkyl; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1~C 8 (May be optionally substituted with alkyl groups) The compound is brought into contact with an oxidizing agent and an additive, and the formula is: [9] JPEG0007883490000060.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 It is alkyl; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) Steps to obtain the compound A method that includes this. 〔9〕 formula: [C10] JPEG0007883490000061.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) A method for preparing the compound, i. Formula: [C11] JPEG0007883490000062.jpg20150 (In the formula, R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) The compound of formula: [C12] JPEG0007883490000063.jpg19150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 (It is alkyl.) When the compound is brought into contact with a base, formula: [C13] JPEG0007883490000064.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 It is alkyl; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) The process of obtaining the compound; and ii. Formula prepared in step (i): [C14] JPEG0007883490000065.jpg20150 The compound is brought into contact with an oxidizing agent and an additive, and the formula is: [C15] JPEG0007883490000066.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 It is alkyl; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) Steps to obtain the compound A method that includes this. 〔10〕 iii.Formula: [C16] JPEG0007883490000067.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 2 is C 1 ~C 8 It is alkyl; R3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) When the compound is brought into contact with a base, formula: [C17] JPEG0007883490000068.jpg20150 (In the formula, R 1 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 It may be optionally substituted with alkyl groups; R 3 and R 4 These are H, deuterium, and C, respectively, independently. 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl and C 6 ~C 10 Selected from the group consisting of aryls, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenil, C 2 ~C 8 Alkinyl or C 6 ~C 10 Each hydrogen atom of the aryl group is independently deuterium, fluoro, chloro, bromo, -OC. 1 ~C 8 Alkyl, -N(C 1 ~C 8 Alkyl) 2 or -SC 1 ~C 8 (May be optionally substituted with alkyl groups) Steps to obtain the compound The method according to any one of the above [7] to [9], further comprising: 〔11〕 The method according to

[10] , wherein the base in step (i) is an organic base. 〔12〕 The method according to

[11] , wherein the base in step (i) is an amine base. 〔13〕 The method according to

[12] , wherein the base of step (i) is selected from the group consisting of triethylamine (TEA), tributylamine, N,N-diisopropylethylamine (DIPEA), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), and 2,6-di-tert-butylpyridine. 〔14〕 The method according to

[10] , wherein step (i) is carried out in the presence of an alcohol solvent. 〔15〕 The method according to

[14] , wherein the organic solvent in step (i) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol. 〔16〕 The method according to

[10] , wherein step (i) is carried out by adding acrolein to ethyl trifluoroacetoethyl at a temperature of approximately 0°C to approximately 25°C. 〔17〕 The oxidizing agent in step (ii) is O in the presence of a metal catalyst. 2 The method according to

[10] above. 〔18〕 The method according to

[17] , wherein the metal catalyst is selected from the group consisting of copper(I) acetate, copper(I) chloride, copper(I) oxide, manganese(II) acetate, copper(II) acetate, copper(II) chloride, copper(II) oxide, and iron(III) acetate. 〔19〕 The method according to

[10] , wherein the additive in step (ii) is selected from the group consisting of ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium nitrate. 〔20〕 The method according to

[10] , wherein step (ii) is carried out in an alcohol solvent. 〔21〕 The method according to

[20] , wherein the organic solvent in step (ii) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol. 〔22〕 The method according to

[10] , wherein step (ii) is performed at a temperature of approximately 60°C to approximately 280°C. 〔23〕 The method according to

[10] , wherein the base in step (iii) is an inorganic base. 〔24〕 The method according to

[23] , wherein the base in step (iii) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, ammonium hydroxide, and magnesium hydroxide. 〔25〕 R 1 The method according to

[10] , wherein the methyl, trifluoromethyl, or difluoromethyl 〔26〕 R 4 The method according to

[25] , wherein the compound is H, methyl, ethyl, n-propyl, i-propyl, or allyl. 〔27〕 R 3 The method according to

[26] , wherein the compound is H, methyl, ethyl, n-propyl, i-propyl, or allyl. 〔28〕 R 2 The method according to

[27] , wherein the compound is methyl, ethyl, n-propyl, or i-propyl. 〔29〕 A method for preparing 2-trifluoromethylnicotinic acid, i. One or more 4,4,4-trifluoro-3-oxobutanoates are brought into contact with acrolein in the presence of a base, and the formula is: [C18] JPEG0007883490000069.jpg20150 (In the formula, R 2 is C 1 ~C 8 (It is alkyl.) Steps to obtain the compound A method that includes this. 〔30〕 A method for preparing 2-trifluoromethylnicotinic acid, ii.Formula: [C19] JPEG0007883490000070.jpg20150 (In the formula, R 2 is C 1 ~C 8 (It is alkyl.) The process of contacting the compound with an oxidizing agent and optionally an additive to obtain one or more 2-trifluoromethylnicotinic acid esters. A method that includes this. 〔31〕 A method for preparing 2-trifluoromethylnicotinic acid, i. One or more 4,4,4-trifluoro-3-oxobutanoates are brought into contact with acrolein in the presence of a base, and the formula is:

[20] JPEG0007883490000071.jpg20150 (In the formula, R 2 is C 1 ~C 8 (It is alkyl.) The process of obtaining the compound; and ii.Formula:

[21] JPEG0007883490000072.jpg20150 (In the formula, R 2 is C 1 ~C 8 (It is alkyl.) The process of contacting the compound with an oxidizing agent and optionally an additive to obtain one or more 2-trifluoromethylnicotinic acid esters. A method that includes this. 〔32〕 iii. A step of contacting one or more 2-trifluoromethylnicotinic acid esters with a base to obtain 2-trifluoromethylnicotinic acid. The method according to any one of the preceding items

[29] to

[31] , further comprising: 〔33〕 The method according to

[32] , wherein the base in step (i) is an organic base. 〔34〕 The method according to

[33] , wherein the base in step (i) is an amine base. 〔35〕 The method according to

[34] , wherein the base of step (i) is selected from the group consisting of triethylamine (TEA), tributylamine, N,N-diisopropylethylamine (DIPEA), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), and 2,6-di-tert-butylpyridine. 〔36〕 The method according to

[32] , wherein step (i) is carried out in the presence of an alcohol solvent. 〔37〕 The method according to

[36] , wherein the organic solvent in step (i) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol. 〔38〕 The method according to

[32] , wherein step (i) is carried out by adding acrolein to ethyl trifluoroacetoethyl at a temperature of approximately 0°C to approximately 25°C. 〔39〕 The oxidizing agent in step (ii) is O in the presence of a metal catalyst. 2 The method described in

[32] above. 〔40〕 The method according to

[39] , wherein the metal catalyst is selected from the group consisting of copper(I) acetate, copper(I) chloride, copper(I) oxide, manganese(II) acetate, copper(II) acetate, copper(II) chloride, copper(II) oxide, and iron(III) acetate. 〔41〕 The method according to

[32] , wherein the additive in step (ii) is selected from the group consisting of ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium nitrate. 〔42〕 The method according to

[32] , wherein step (ii) is carried out in an alcohol solvent. 〔43〕 The method according to

[42] , wherein the organic solvent in step (ii) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol. 〔44〕 The method according to

[32] , wherein step (ii) is performed at a temperature of approximately 60°C to approximately 280°C. 〔45〕 The method according to

[32] , wherein the base in step (iii) is an inorganic base. 〔46〕 The method according to

[45] , wherein the base in step (iii) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, ammonium hydroxide, and magnesium hydroxide.

Claims

1. A method for preparing 2-trifluoromethylnicotinic acid, i. Contact one or more 4,4,4-trifluoro-3-oxobutanoates in the presence of acrolein and a base, and prepare the following: 【Chemistry 20】 (In the formula, R 2 is C 1 ~C 8 (It is alkyl.) The process of obtaining the compound; and ii.Formula: 【Chemistry 21】 (In the formula, R 2 is C 1 ~C 8 (It is alkyl.) A step of contacting the aforementioned compound with an oxidizing agent and an additive to obtain one or more 2-trifluoromethylnicotinic acid esters. A method comprising, wherein the additive in step (ii) is selected from the group consisting of ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium nitrate.

2. iii. A step of contacting one or more 2-trifluoromethylnicotinic acid esters with a base to obtain 2-trifluoromethylnicotinic acid. The method according to claim 1, further comprising:

3. The method according to claim 1, wherein the base in step (i) is selected from the group consisting of triethylamine (TEA), tributylamine, N,N-diisopropylethylamine (DIPEA), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, 1,8-diazabicycloundeca-7-ene (DBU), 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), and 2,6-di-tert-butylpyridine.

4. The method according to claim 1, wherein step (i) is carried out in the presence of an alcohol solvent selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol.

5. The method according to claim 1, wherein step (i) is carried out by adding acrolein to ethyl trifluoroacetoethyl at a temperature of 0°C to 25°C.

6. The oxidizing agent in step (ii) is O in the presence of a metal catalyst. 2 The method according to claim 1, wherein the metal catalyst is selected from the group consisting of copper(I) acetate, copper(I) chloride, copper(I) oxide, manganese(II) acetate, copper(II) acetate, copper(II) chloride, copper(II) oxide, and iron(III) acetate.

7. The method according to claim 1, wherein step (ii) is carried out in an alcohol solvent selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutylcarbinol, and propylene glycol.

8. The method according to claim 1, wherein step (ii) is performed at a temperature of 60°C to 280°C.

9. The method according to claim 1, wherein the base in step (iii) is an inorganic base selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, ammonium hydroxide, and magnesium hydroxide.

10. R 2 The method according to any one of claims 1 to 9, wherein is methyl, ethyl, n-propyl, or i-propyl.

11. formula: (In the formula, R 1 is trifluoromethyl; R 2 is C 1 ~C 8 It is alkyl; R 3 and R 4 (Each of these is H) A compound of [this].

12. R 2 The compound according to claim 11, wherein the compound is methyl, ethyl, n-propyl, or i-propyl.

13. R 2 The compound according to claim 12, wherein the compound is ethyl.

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