METHODS OF MAKING NICOTINIC ACID DERIVATIVES

Abstract

This disclosure relates to processes for preparing nicotinic acid derivatives that are useful in the chemical arts, such as in the manufacture of pharmaceutical products or agrochemicals. In particular, the present disclosure pertains to novel processes for preparing certain nicotinic acid derivatives.

Claims

1. A compound of the formula. ##STR00052## wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC-C.sub.3 alkyl; R.sup.2 is a C.sub.1-C.sub.8 alkyl; and each of R.sup.3 and R.sup.4 is independently selected from the group consisting of deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.7-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.5-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl.

2. The compound of claim 1, wherein R.sup.1 is methyl, trifluoromethyl, or difluoromethyl.

3. The compound of claim 1, wherein R.sup.4 is H, methyl, ethyl, n-propyl, i-propyl, or allyl.

4. The compound of claim 3, wherein R.sup.3 is H, methyl, ethyl, n-propyl, i-propyl, or allyl.

5. The compound of claim 3, wherein R.sup.2 is methyl, ethyl, n-propyl, or i-propyl.

6. The compound of claim 1, selected from the group consisting of ##STR00053##

7. A process for preparing a compound of the formula ##STR00054## wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bronco, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; and each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; comprising i. contacting a compound of the formula ##STR00055## wherein each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10; aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bronco, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; with a compound of the formula ##STR00056## wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl), or SC.sub.1-C.sub.8 alkyl; and R.sup.2 is a C.sub.1-C.sub.8 alkyl; in the presence of a base to provide a compound of the formula ##STR00057## wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bronco, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; R.sup.2 is a C.sub.1-C.sub.3 alkyl; and each of R.sup.3 and R.sup.4 is independently selected front the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, promo, OC.sub.1 -C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl.

8. A process for preparing a compound of the formula ##STR00058## wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; and each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; comprising ii. contacting a compound of the formula ##STR00059## wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 an is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; R.sup.2 is a C.sub.1-C.sub.3 alkyl; and each of R.sup.3 and R.sup.4 is independently selected front the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; with an oxidizing agent and an additive to provide a compound of the formula ##STR00060## wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl), or SC.sub.1-C.sub.8 alkyl; R.sup.2 is a C.sub.1-C.sub.8 alkyl; and each of R.sup.3 and R.sup.4 is independently selected from the group consisting of deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl.

9. (canceled)

10. The process of claim 7, further comprising iii. contacting the compound of the formula ##STR00061## wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, promo, alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; R.sup.2 is a C.sub.1-C.sub.8 alkyl and each of R.sup.3 and R.sup.4 is independently selected from the group consisting of deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; with a base to provide a compound of the formula ##STR00062## wherein R.sup.1 is selected from the group consisting of C.sub.1-Cs alkyl, alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10- aryl is independently optionally substituted with deuterium, fluoro, chloro, bronco, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; and each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl.

11. The process of claim 10, wherein the base in step (i) is an organic base.

12. The process of claim 11, wherein the base in step (i) is an amine base.

13. The process of any one of claim 12, wherein the base in step (i) is selected from the group consisting of triethyl amine (TEA), tributyl amine, N,N-diisopropyl ethyl amine (DIPEA), N,N,N,N-Tetramethyl-1,8-naphthalenediamine, 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo0.3.0)non-5-ene (DBN), and 2,6-di-tert-butylpyridine.

14. The process of claim 10, wherein step (i) is carried out in the presence of an alcohol solvent.

15. The process of claim 14, wherein the organic solvent step (i) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tent-butanol, n-pentanol, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutyl carbinol, and propylene glycol.

16. The process of claim 10, wherein step (i) is carried out by that addition of acrolein to ethyl trifluoro-acetoacetate at a temperature of about 0 C. to about 25 C.

17. The process of claim 10, wherein the oxidizing agent in step (ii) is O.sub.2 in the presence of a metal catalyst.

18. The process of claim 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 process of claim 10, wherein the additive in step (ii) is selected from the group consisting of ammoniurn acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium nitrate.

20. The process of claim 10, wherein step (ii) is carried out in an alcohol solvent.

21. The process of claim 20, wherein the organic solvent step (ii) is selected from the group consisting of methanol, ethanol, iso-propanol, n-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanoi, sec-pentanol, iso-pentanol, ethylene glycol, methyl isobutyl carbinol, and propylene glycol.

22.-46. (canceled)

Description

DETAILED DESCRIPTION

[0181] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0182] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0183] As used herein and in the appended claims, the singular forms a, an, and the include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as solely, only and the like in connection with the recitation of claim elements, or use of a negative limitation.

REPRESENTATIVE EMBODIMENTS

[0184] Described herein is a carbon efficient approach to synthesize nicotinic acid derivatives, such as 2-trifluoromethylnicotinic acid, starting from trifluoro-acetoacetate derivatives, such as ethyl trifluoro-acetoacetate and vinylaldehyde derivatives, such as acrolein. The processes described herein provide novel dihydropyran derivatives that are useful in the preparation of nicotinic acid derivatives by further transformation. According to the processes of the disclosure, the dihydropyran derivative is readily converted in a second step to a pyridine ester derivative by reacting with a nitrogen source additive, such as ammonium acetate in presence of an oxidizing agent. Finally in a third step, ester hydrolysis of the pyridine ester derivative is accomplished using a base under mild conditions to generate the target product nicotinic acid derivative. The processes of the disclosure can be described according to Scheme 1.

##STR00037##

[0185] It will be appreciated that the present disclosure provides processes for preparing a compound of the formula V described in the paragraphs above and below, comprising step (i) and one or more than one of the recited steps (ii) and (iii). Accordingly, the present disclosure provides a process for preparing a compound of the formula V, comprising step (i). Alternatively, the present disclosure provides a process for preparing a compound of the formula V, comprising steps (i) and (ii). Alternatively, the present disclosure provides a process for preparing a compound of the formula V, comprising steps (i), (ii), and (iii). Alternatively, the present disclosure provides a process for preparing a compound of the formula III, comprising step (ii). Alternatively, the present disclosure provides a process for preparing a compound of the formula IV, comprising steps (i) and (ii).

[0186] In step (i), a compound of the formula I

##STR00038## [0187] wherein [0188] wherein each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; is contacted with a compound of the formula II

##STR00039## [0189] wherein [0190] R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; and [0191] R.sup.2 is a C.sub.1-C.sub.8 alkyl; in the presence of a base to provide a compound of the formula III

##STR00040## [0192] wherein [0193] R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; [0194] R.sup.2 is a C.sub.1-C.sub.8 alkyl; and [0195] each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl.

[0196] In step (i), the base can be any suitable base, such as an organic base or an inorganic base. In some embodiments, the base in step (i) can be an organic base, such as an amine base. Suitable amine bases include, but are not limited to, triethyl amine (TEA), tributyl amine, N,N-diisopropyl ethyl amine (DIPEA), N,N,N,N-Tetramethyl-1,8-naphthalenediamine, 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), and 2,6-di-tert-butylpyridine. Step (i) can be carried out in the presence of an optional solvent. The solvent can be any suitable solvent, such as an organic solvent. In some embodiments, the solvent in step (i) can be an alcohol based solvent. Suitable alcohol based 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 isobutyl carbinol, and propylene glycol. It will be appreciated that step (i) can be conducted at any temperature commonly used in connection with ring-formation using Michael addition chemistry processes, such as room temperature, under cooling, or under warming conditions. In some embodiments, step (i) can be carried out at a temperature of about 0 C. to about 25 C. In some embodiments, step (i) can be carried out by the addition of the compound of the formula Ito the compound of the formula II at a temperature of about 0 C. to about 25 C. In some embodiments, after addition of a compound of the formula Ito the compound of the formula II, the reaction can be heated to a temperature above room temperature, such as at the reflux temperature of a solvent used in connection with step (i). In some embodiments, step (i) can be carried out at a temperature of about 60 C. to about 280 C.

[0197] In some embodiments of step (i), the compound of the formula I can be acrolein (aka propenal) and the compound of the formula II can be one or more esters of 4,4,4-trifluoro-3-oxobutanoic acid. It will be appreciated that the one or more esters of 4,4,4-trifluoro-3-oxobutanoic acid can be a mixture of C.sub.1-C.sub.8 alkyl esters of 4,4,4-trifluoro-3-oxobutanoic acid as depicted by the following formula

##STR00041## [0198] wherein R.sup.2 is C.sub.1-C.sub.8 alkyl. In some embodiments, the product of step (i) when the compound of the formula I is acrolein (aka propenal) and the compound of the formula II is one or more esters of 4,4,4-trifluoro-3-oxobutanoic acid can be described by the formula

##STR00042## [0199] wherein R.sup.2 is C.sub.1-C.sub.8 alkyl.

[0200] In step (ii), a compound of the formula III

##STR00043## [0201] wherein [0202] R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; [0203] R.sup.2 is a C.sub.1-C.sub.8 alkyl; and [0204] each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; can be contacted with oxidizing agent and an additive, such as a nitrogen source additive, to provide a compound of the formula IV

##STR00044## [0205] wherein [0206] R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; [0207] R.sup.2 is a C.sub.1-C.sub.8 alkyl; and [0208] each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl.

[0209] In step (ii), the oxidizing agent can be any suitable oxidizing agent, such as oxygen (O.sub.2) in the presence of an optional catalyst. The optional catalyst can 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) can be a nitrogen source additive, such as ammonia, ammonium acetate, ammonium hydroxide, ammonium chloride, ammonium carbonate, and ammonium nitrate. It can be advantageous to use the nitrogen source in an equimolar amount relative to the compound of the formula III, or in a molar excess relative to the compound of the formula III. In some embodiments, the nitrogen source, such as ammonium acetate, can be used in a molar excess relative to the compound of the formula III. Step (ii) can be carried out in the presence of an optional solvent. The solvent can be any suitable solvent, such as an organic solvent. In some embodiments, the solvent in step (ii) can be an alcohol based solvent. Suitable alcohol based 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 isobutyl carbinol, and propylene glycol. It will be appreciated that step (ii) can be conducted at any temperature commonly used in connection with oxidation chemistry processes, such as room temperature, under cooling, or under warming conditions. In some embodiments, step (ii) can be heated to a temperature above room temperature, such as at the reflux temperature of a solvent used in connection with step (ii). In some embodiments, step (ii) can be carried out at a temperature of about 60 C. to about 280 C. The compound of the formula IV can be purified, for example by steam distillation, or the compound of the formula IV can be carried on in further synthesis without purification.

[0210] In some embodiments of step (ii), the compound of the formula III can be of the formula

##STR00045## [0211] wherein R.sup.2 is a C.sub.1-C.sub.8 alkyl, and the product compound of the formula IV can be

##STR00046## [0212] wherein R.sup.2 is a C.sub.1-C.sub.8 alkyl.

[0213] In step (iii), a compound of the formula IV

##STR00047## [0214] wherein [0215] R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; [0216] R.sup.2 is a C.sub.1-C.sub.8 alkyl; and [0217] each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; can be contacted with a base to provide a compound of the formula V

##STR00048## [0218] wherein [0219] R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; [0220] R.sup.2 is a C.sub.1-C.sub.8 alkyl; and [0221] each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl.

[0222] In step (iii), the base can be any suitable base, such as an organic base or an inorganic base. In some embodiments, the base in step (iii) can 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 mangnesium hydroxide. In some embodiments, the base can be sodium hydroxide. In some embodiments, the base can be a 25% solution of sodium hydroxide. Step (iii) can be carried out in the presence of an optional solvent. The solvent can be any suitable solvent, such as an organic solvent. In some embodiments, the solvent in step (iii) can be an alcohol based solvent. Suitable alcohol based 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 isobutyl carbinol, and propylene glycol. It will be appreciated that step (iii) can be conducted at any temperature commonly used in connection with oxidation chemistry processes, such as room temperature, under cooling, or under warming conditions. In some embodiments, step (iii) can be carried out at a lower temperature by using a hydroxide base solution that is in a concentration range of from about 10% hydroxide base to about 40% hydroxide base. In some embodiments, step (i) can 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. and the base is added to the cooled reaction, which is allowed to warm to room temperature after addition is complete. It will be appreciated that the base hydrolysis reaction can be stopped and the product isolated by acidifying the reaction with, for example a solution of an inorganic acid (e.g. sulfuric acid), followed by filtering the final product.

[0223] In some embodiments of step (iii), the compound of the formula IV can be of the formula

##STR00049## [0224] wherein R.sup.2 is a C.sub.1-C.sub.8 alkyl.

[0225] In some embodiments, the disclosure provides a compound of the formula III

##STR00050## [0226] wherein [0227] R.sup.1 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl; [0228] R.sup.2 is a C.sub.1-C.sub.8 alkyl; and [0229] each of R.sup.3 and R.sup.4 is independently selected from the group consisting of H, deuterium, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, and C.sub.6-C.sub.10 aryl, wherein each hydrogen atom in C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, or C.sub.6-C.sub.10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC.sub.1-C.sub.8 alkyl, N(C.sub.1-C.sub.8 alkyl).sub.2, or SC.sub.1-C.sub.8 alkyl.

[0230] In some embodiments, R.sup.1 is methyl, trifluoromethyl, or difluoromethyl. In some embodiments, R.sup.4 is H, methyl, ethyl, n-propyl, i-propyl, or allyl. In some embodiments, R.sup.3 is H, methyl, ethyl, n-propyl, i-propyl, or allyl. In some embodiments, R.sup.2 is methyl, ethyl, n-propyl, or i-propyl. In some embodiments, the compound of the formula III is selected from the group consisting of

##STR00051##

EXAMPLES

[0231] The examples and preparations provided below further illustrate and exemplify particular aspects of embodiments of the disclosure. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples.

Example 1

Step 1Ethyl 2-hydroxy-6-(trifluoromethyl)-3,4-dihydro-2H-pyran-5-carboxylate

[0232] Methanol (200 mL) and ethyl trifluoro-acetoacetate (37.0 g, 0.199 mol) charged to a pot and stirred and kept below 5-10 C. Triethylamine (2.1 g, 0.021 mol) was added followed by a solution of acrolein (11.6 g, 0.201 mol) in methanol (50 mL) was added over 1 h and the whole mixture stirred for 35 min at 23 C. The reaction mixture is directly used in step 2. On stripping the solvent the product is obtained as a liquid with amber color. The characterization has been done using GCMS Mw 240 and Fluorine NMR (-85.8 ppm).

Step 2 Ethyl 2-(trifluoromethyl)nicotinate

[0233] Ammonium acetate (30.8 g, 0.400 mol) and copper acetate monohydrate (4.1 g, 0.021 mol) were charged to the above reaction mixture and heated reflux (67 C.) while introducing oxygen (50%) subsurface. Water (100 mL) added to increase reflux temperature to 73 C. Progress of the reaction was followed by NMR. The product was isolated by steam distillation with all the methanol coming off first followed by the product and water. A 41% yield of the final product was observed. The product could also be isolated using distillation. The product was characterized using GCMS Mw 219 and Fluorine NMR (-75.5 ppm).

Step 32-(Trifluoromethyl)nicotinic Acid

[0234] Ethyl 2-(trifluoromethyl)nicotinate (14.6 g, 0.063 mol) and methanol (10 mL) were charged to a pot and cooled to 10-15 C. To this reaction mixture was added sodium hydroxide (25%, 11.4 g, 0.071 mol) over five min. After addition and then stirring at 25 C. for 1 h. The reaction mixture was worked up with addition of water (17 g) and sulfuric acid (3.7 g) to pH 2. After stirring for 30 min the product was isolated by filtration and washed with water (320 mL), dried and gave 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).

Example 2

5-Propyl-2-trifluoromethyl-nicotinic Acid

[0235] 5-Propyl-2-trifluoromethyl-nicotinic acid was prepared according to the methods described in Example 1, except that 2-propyl-acrolein was used in place of acrolein. The final product 5-propyl-2-trifluoromethyl-nicotinic 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).

Example 3

5-(1-Propenyl)-2-trifluoromethyl-nicotinic Acid

[0236] 5-(1-Propenyl)-2-trifluoromethyl-nicotinic acid was prepared according to the methods described in Example 1, except that 2-(2-propenyl)-acrolein in place of acrolein. During the third step of the hydrolysis of the ester group using sodium hydroxide the double bond in the propenyl group isomerizes from 2-position (2-propenyl) to 1-position (1-propenyl). The final product 5-(1-propenyl)-2-trifluoromethyl-nicotinic 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).