Synthesis of 2-(trifluoromethyl)pyridin-4-amine

Abstract

A process for the preparation of a 2-trifluoromethyl-4-aminopyridine compound of formula (IV) or a salt thereof is provided.

Description

[0001] SYNTHESIS OF 2-(TRIFLUOROMETHYL)PYRIDIN-4-AMINE

[0002] The present invention relates to a process for preparing 2-(trifluoromethyl)pyridin-4-amine or a salt thereof. 2-(trifluoromethyl)pyridin-4-amine is a widely used building block for preparation of active ingredients in both pharmaceutical (for example as described in W02020123674 and WO2022262855) as well as agrochemical (for example as described in WO2021177410) industry. Therefore, an efficient, high yielding and environmentally friendly method of preparation of this building block is highly desired.

[0003] The first synthesis of 2-(trifluoromethyl)pyridin-4-amine (1) was reported 30 years ago (J. Med. Chem. 1993, 36, 733-746 and W09320055) and proceeds via a nitration of 2-trifluromethyl pyridine N-oxide followed by reduction (Scheme 1).

[0004] Scheme 1

[0005] Unfortunately, both oxidation and nitration steps are low yielding and the latter has to be run in harsh conditions using an excess of a mixture of neat nitric and sulfuric acid.

[0006] A shorter synthesis of 2-trifluoromethyl-4-aminopyridine via cyclization of the enamino derivative (Scheme 2) has also been reported (Tetrahedron Letters 42, 2001 , 1847-1849). However, the reported yields are low (30%) and the synthesis of the starting material for the cyclization requires the use of nBuLi which is expensive and difficult to use on larger scales. Q.

[0007] Scheme 2

[0008] The most attractive approach reported so far (WO2011161612), particularly for large scale preparation, proceeds by first condensing 4,4-dimethoxybutan-2-one with ethyl trifluoroacetate (Scheme 3). The resulting product is not isolated, but instead treated with HCI to yield intermediate pyrane type intermediate which is directly treated with aqueous ammonia to yield 2-(trifluoromethyl) pyridin-4-ol in an excellent yield. This hydroxy compound was then converted to chloro derivative using thionyl chloride. The final step has been reported to proceed either via:

[0009] (1) A copper catalyzed amination (WO2018099812) or (2) via a photochemical C-N coupling (ACS Catalysis, 2022, 12, 15590-15599).

[0010] Scheme 3

[0011] 82% (3 steps)

[0012] While this works better than methods described earlier the synthesis is still plagued by many synthetic steps as well as the need for a metal catalyzed coupling as the last step inevitably leading to production of potentially harmful waste.

[0013] Therefore, in accordance with the present invention, a new more efficient route to 2-trifluoromethyl-4- aminopyridine alleviating the issues described above is provided (Scheme 4).

[0014] As further described below, a process for preparing 2-(trifluoromethyl)pyridin-4-amine or a salt thereof is provided wherein a compound of formula (I) is reacted with ammonia yielding a compound of formula (II). The compound of formula (II) is then reacted with an appropriate acid to yield a compound of formula (III). Finally, the compound of formula (III) is treated with an appropriate ammonia source to yield the compound of formula (IV). In the case of R being methyl compounds of formula (I) and (II) have been prepared previously (WO2018099812) Scheme 4

[0015] IV

[0016] Accordingly, the present invention provides a process for the preparation of a 2-trifluoromethyl-4- aminopyridine compound of formula (IV) or a salt thereof. Suitable salts consist of but are not limited to chloride, bromide, sulfate, acetate, trifluoroacetate and methanesulfonate. by A) reaction of compound of formula (I)

[0017] Wherein R is C1-C4 alkoxy or both R groups together form a five or six membered carbocycle;

[0018] With ammonia in an appropriate solvent to produce a compound of formula (II)

[0019] D

[0020] O NH O'

[0021] F3C M AoJ'

[0022] Wherein R is as defined for a compound of formula (I) And B) reacting a compound of formula (II)

[0023] Wherein R is as defined for a compound of formula (I);

[0024] With an appropriate acid in an appropriate solvent to produce a compound of formula (III)

[0025] Wherein X is halogen, HSO4, acetate, trifluoroacetate, methanesulfonyl or p-toluenesulfonyl

[0026] And C) reacting a compound of formula (III) With an appropriate ammonia source in an appropriate solvent to produce a compound of formula (IV)

[0027] IV

[0028] Optionally a compound of formula (IV) could be prepared in a one pot procedure without isolation of compound of formula (III) In one embodiment of the invention step (A) comprises

[0029] Reacting of compound of formula (I) with ammonia source in an appropriate solvent to produce a compound of formula (II). Example of suitable and preferred ammonia sources are selected from ammonia, such as gaseous ammonia, aqueous ammonia solution, ammonium halides such as ammonium chloride or ammonium bromide, ammonium carboxylates such as ammonium acetate, ammonium formate, and ammonium sulfate.

[0030] Preferably the ammonia source is gaseous ammonia, aqueous ammonia, ammonium acetate, or ammonium chloride. Most preferably the ammonia source is gaseous ammonia.

[0031] Preferably the reaction is conducted under a positive pressure of ammonia. The preferred pressure is between 1.5 and 10 bar, more preferably between 2 and 5 bar.

[0032] Examples of suitable and preferred solvents (or diluents) for step A are esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons.

[0033] Examples include but are not limited to: tetra hydrofuran, 2-methyl tetra hydrofuran, acetonitrile, butyronitrile, dichloromethane, 1 ,2-dichloroethane, chlorobenzene, ethyl acetate, toluene, xylenes, dioxane, cyclopentylmethyl ether, t-butylmethyl ether, diethyl ether, anisole, fluorobenzene

[0034] Preferably the solvent is an ether, nitrile or a halogenated hydrocarbon, for example: tetrahydrofuran, 2- methyl tetrahydrofuran, acetonitrile, dichloromethane and chlorobenzene

[0035] The step A is advantageously carried out in a temperature range from 0 °C to 100 °C, more preferably between 20 °C and 60 °C.

[0036] Step (B) comprises

[0037] Reacting a compound of formula (II) with an appropriate acid in an appropriate solvent to produce a compound of formula (III). Example of suitable and preferred acids are selected from mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and nitric acid as well as organic acids such as trifluoroacetic acid, acetic acid and para toluenesulfonic acid.

[0038] Preferably the acid is hydrochloric acid, hydrobromic acid, sulfuric acid or para toluenesulfonic acid. The ratio of acid relative to compound of formula (II) is in the range from 5:1 to 1 :1 , preferably between 3:1 and 1 :1 , more preferably between 2:1 and 1 :1.

[0039] Examples of suitable and preferred solvents (or diluents) for step B are esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons.

[0040] Examples include but are not limited to: tetra hydrofuran, 2-methyl tetra hydrofuran, acetonitrile, butyronitrile, dichloromethane, 1 ,2-dichloroethane, chlorobenzene, ethyl acetate, toluene, xylenes, dioxane, cyclopentylmethyl ether, t-butylmethyl ether, diethyl ether, anisole, fluorobenzene

[0041] The step B is advantageously carried out in a temperature range from 0 °C to 80 °C, more preferably between 10 °C and 50 °C.

[0042] Step (C) comprises

[0043] Reacting a compound of formula (III) with an appropriate ammonia source and an appropriate acid in an appropriate solvent to produce a compound of formula (IV). Example of suitable and preferred ammonia sources are selected from ammonia, such as gaseous ammonia, aqueous ammonia solution, ammonium halides such as ammonium chloride or ammonium bromide, ammonium carboxylates such as ammonium acetate, ammonium formate, and ammonium sulfate.

[0044] Preferably the ammonia source is gaseous ammonia, ammonium acetate, aqueous ammonia or ammonium chloride.

[0045] Ratio of ammonia source relative to compound of formula (III) is in the range of is in the range from 10:1 to 1 :1 , preferably between 7.5:1 and 1 :1 , more preferably between 5:1 and 1 :1.

[0046] Suitable and preferred acids are selected from mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and nitric acid as well as organic acids such as trifluoroacetic acid, acetic acid and para toluenesulfonic acid.

[0047] Preferably the acid is hydrochloric acid, sulfuric acid, acetic acid ortrifluoro acetic acid. Ratio of acid relative to compound of formula (III) is in the range from 10:1 to 1 :1 , preferably between 7:1 and 1 :1 , more preferably between 5:1 and 1 :1.

[0048] Suitable and preferred solvents (or diluents) for step C are are esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons. Examples include but are not limited to: tetra hydrofuran, 2-methyl tetra hydrofuran, acetonitrile, butyronitrile, dichloromethane, 1 ,2-dichloroethane, chlorobenzene, ethyl acetate, toluene, xylenes, dioxane, cyclopentylmethyl ether, t-butylmethyl ether, diethyl ether, anisole, fluorobenzene.

[0049] Preferably the solvent is an ether, nitrile or a halogenated hydrocarbon, for example: tetrahydrofuran, 2- methyl tetrahydrofuran, acetonitrile, dichloromethane and chlorobenzene.

[0050] The step C is advantageously carried out in a temperature range from 0 °C to 100 °C, more preferably between 40 °C and 80 °C.

[0051] In another embodiment of the present invention, a compound of formula III is provided wherein X is halogen, HSO4, acetate, trifluoroacetate, methanesulfonyl or p-toluenesulfonyl; or a resonance form of a compound of formula III.

[0052] In one embodiment, the compound of formula III can be present in at least one of these two resonance forms:

[0053] Experimental procedures and data

[0054] Example 1 : Preparation of (Z)-1 ,1 ,1-trifluoro-4-imino-6,6-dimethoxy-hex-2-en-2-ol A solution of (Z)-6,6,6-trifluoro-5-hydroxy-1 ,1-dimethoxy-hex-4-en-3-one (4.00 g, 85% purity, 14.9 mmol) in acetonitrile (60 mL) was saturated with ammonia for 15 min under 5 bar pressure (until the pressure inside the vessel is steady) and then pressurized with ammonia up to 2 bar. The reaction vessel was then heated at 50°C for 11 h. The reaction mixture was then cooled down to room temperature, the ammonia gas was released and flushed with nitrogen gas. The reaction mixture was evaporated under reduced pressure to obtain the title compound (3.89 g, 71 % purity, 81 % yield) as a brown liquid which was used in next step without further purification.

[0055] 1H NMR (400 MHz, DMSO-cfe) 6 9.89 (br s, 1 H), 8.94 (br s, 1 H), 5.34 - 5.37 (m, 1 H), 4.66 (t, J=5.8 Hz, 1

[0056] H), 3.27 (s, 6 H), 2.61 (d, J=5.7 Hz, 2 H)

[0057] Example 2: Preparation of [2-(trifluoromethyl)pyran-4-ylidene]ammonium chloride

[0058] To a solution of (Z)-1 ,1 ,1 -trifluoro-4-imino-6,6-dimethoxy-hex-2-en-2-ol (3.70 g, 75% purity, 12.2 mmol) in acetonitrile (37 mL) was added 4M HCI in dioxane (6.11 mL, 24.4 mmol) at room temperature and the resulting reaction mixture was stirred for2 h. The reaction mixture was then evaporated under reduced pressure at 40°C to obtain the title compound (3.30 g, 72% purity, 97% yield) as a brown solid which was used as such for the next step.

[0059] 1H NMR (400 MHz, DMSO-d6) 6 11.25- 1 1.48 (m, 2 H), 8.66 (d, J=5.6 Hz, 1 H), 7.81 (d, J=2.3 Hz, 1 H), 7.31 (dd, J=5.6 Hz, 2.4 Hz, 1 H).

[0060] Example 3: Preparation of[2-(trifluoromethyl)pyran-4-ylidene]ammonium 4-methylbenzenesulfonate To a solution of (Z)-1 ,1 ,1-trifluoro-4-imino-6,6-dimethoxy-hex-2-en-2-ol (1.00 g, 75.5% purity, 3.32 mmol,) in acetonitrile (10 mL) was added p-toluenesulfonic acid (1.17g, 6.65 mmol) at room temperature and the reaction mixture was stirred for 2 h. The reaction mixture was then evaporated under reduced pressure at 40°C to obtain the title compounds (1.870 g, 52.5% purity, 88% yield) as a brown sticky solid which was used as such for the next step.

[0061] 1H NMR (400 MHz, DMSO-cfe) 5 10.73 (br s, 1 H), 10.57 (br s, 1 H), 8.67 (d, J=5.6 Hz, 1 H), 7.59 (d, J=2.3 Hz, 1 H), 7.51 (d, J=8.0 Hz, 2 H), 7.18 (dd, J=5.6, 2.41 Hz, 1 H), 7.13 (d, J=7.9 Hz, 2 H), 2.29 (s, 3 H)

[0062] Example 4: Preparation of[2-(trifluoromethyl)pyran-4-ylidene]ammonium hydrogen sulfate

[0063] To a solution of (Z)-1 ,1 ,1-trifluoro-4-imino-6,6-dimethoxy-hex-2-en-2-ol (1 .00 g, 75.51% purity, 3.32 mmol,) in acetonitrile (10 mL) was added sulfuric acid (0.37 mL, 6.65 mmol) at room temperature (suspension was observed). The reaction mixture was stirred at 24°C for 1 h. After full consumption of starting material, the reaction mixture was evaporated under reduced pressure at 40°C to obtain the title compound (1 .62 g, 48% purity, 90% yield) as a brown sticky solid which was used as such for the next step.

[0064] 1H NMR (400 MHz, DMSO-d6) 5 11.25- 1 1.48 (m, 2 H), 8.66 (d, J=5.6 Hz, 1 H), 7.81 (d, J=2.3 Hz, 1 H), 7.31 (dd, J=5.6, 2.4 Hz, 1 H)

[0065] Example 5: Preparation of [2-(trifluoromethyl)pyran-4-ylidene]ammonium bromide

[0066] To a solution of (Z)-1 ,1 ,1-trifluoro-4-imino-6,6-dimethoxy-hex-2-en-2-ol (1 .00 g, 75.51% purity, 3.32 mmol,) in acetonitrile (10 mL) was added hydrobromic acid in acetic acid (33%, 1.15 ml., 6.65 mmol) at room temperature. The reaction mixture was stirred at 24°C for 2 h. After full consumption of starting material, the reaction mixture was evaporated under reduced pressure at 40°C to obtain the title compound (1 .37 g, 34 % purity, 58% yield) as a brown sticky solid which was used as such for the next step.1H NMR (400 MHz, DMSO-cfe) 6 10.79 (br s, 1 H), 10.62 (br s, 1 H), 8.69 (d, J=5.6 Hz, 1 H), 7.63 (d, J=2.3 Hz, 1 H), 7.15 - 7.30 (m, 1 H).

[0067] Example 6a: Preparation of 3-(trifluoromethyl)pyridin-4-amine

[0068] A solution of [2-(trifluoromethyl) pyran-4-ylidene] ammonium chloride (3.3 g, 73% purity, 11 .91 mmol), ammonium acetate (4.78g, 59.53mmol,) and acetic acid (3.41 ml, 59.53 mmol) in acetonitrile (16mL) followed by was heated at 70°C for 2h. After full consumption of the starting material the reaction mixture was cooled to ambient temperature and diluted with water and ethyl acetate. Phases were separated and the aqueous layers extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude residue was treated with 1 N NaOH, extracted with MTBE (25 ml x 2) and combined organic layers were concentrated under reduced pressure. The residue was treated with 2N HCI (pH <1) and extracted with ethyl acetate (25 mL). The aqueous layer was basified with NaOH and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.28 g, 91 % purity, 60% yield) as a brown solid.

[0069] 1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.08 (d, J=5.6 Hz, 1 H), 6.89 (d, J=2.1 Hz, 1 H), 6.65 (dd, J=5.6, 2.1

[0070] Hz, 1 H), 6.57 (s, 2 H)

[0071] Example 6b: Preparation of 3-(trifluoromethyl)pyridin-4-amine

[0072] The same procedure as in example 6a was used starting from [2-(trifluoromethyl)pyran-4- ylidene]ammonium 4-methylbenzenesulfonate (1 .50 g, 2.3 mmol, 52.5% purity) to yield the title compound (0.75 g, 32 % purity, 63% yield) Example 6c: Preparation of 3-(trifluoromethyl)pyridin-4-amine

[0073] The same procedure as example 6a was used starting from [2-(trifluoromethyl)pyran-4-ylidene]ammonium hydrogen sulfate (1 .60 g, 2.96 mmol, 48 % purity) to yield the title compound (0.96 g, 31 % purity, 62% yield)

[0074] Example 6d: Preparation of 3-(trifluoromethyl)pyridin-4-amine

[0075] The same procedure as in example 6a was used starting from [2-(trifluoromethyl)pyran-4-ylidene] ammonium bromide (1.30 g, 1.8 mmol, 34% purity) to yield the title compound (0.84 g,24% purity, 69% yield).

Claims

Claims:1 . A process for the preparation of a 2-trifluoromethyl-4-aminopyridine compound of formula (IV)lv,or a salt thereof, which process comprises:A) reacting a compound of formula (I)1wherein R is C1-C4 alkoxy or both R groups together form a five or six membered carbocycle with ammonia in an appropriate solvent to produce a compound of formula (II)wherein R is as defined for a compound of formula (I);B) reacting a compound of formula (II) with an appropriate acid in an appropriate solvent to produce a compound of formula (III)111wherein X is halogen, HSO4, acetate, trifluoroacetate, methanesulfonyl or p- toluenesulfonyl; andC) reacting a compound of formula (III) with an appropriate ammonia source in an appropriate solvent to produce a compound of formula (IV).

2. The process according to claim 1 , wherein the compound of formula (IV) is prepared in a one pot procedure without isolation of compound of formula (III).

3. The process according to claim 1 , wherein the ammonia source is selected from gaseous ammonia, aqueous ammonia solution, ammonium halides such as ammonium chloride or ammonium bromide, ammonium carboxylates such as ammonium acetate, ammonium formate, and ammonium sulfate.

4. The process according to claim 3, wherein the ammonia source is selected from gaseous ammonia, aqueous ammonia, ammonium acetate, or ammonium chloride.

5. The process according to any one of claims 1 - 4, wherein the reaction is conducted under a positive pressure of ammonia between 1.5 and 10 bar.

6. The process according to any one of claims 1 - 5, wherein the solvent (or diluent) for step A is selected from esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons.

7. The process according to any one of claims 1 - 6, wherein step A is carried out in a temperature range from 0 °C to 100 °C.

8. The process according to claims 1 , wherein the acid for step B is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, trifluoroacetic acid, acetic acid and para toluenesulfonic acid.

9. The process according to claims 8, wherein the ratio of acid relative to the compound of formula (II) in the reaction step B is in the range from 5:1 to 1 :1 .

10. The process according to any one of claims 1 or 8 - 9, wherein the solvent (or diluent) for step B is selected from esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons.11 . The process according to any one of claims 1 or 8 - 10, wherein step B is carried out in a temperature range from 0 °C to 80 °C.

12. The process according to claim 1 , wherein the ratio of the ammonia source relative to the compound of formula (III) in the reaction step C is in the range of is in the range from 10:1 to 1 :1 .

13. The process according to claims 1 or 12, wherein the acid for step C is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, trifluoroacetic acid, acetic acid and para toluenesulfonic acid.

14. The process according to any one of claims 1 or 12 - 13 wherein the ratio of acid relative to compound of formula (III) in the reaction step C is in the range from 10:1 to 1 :1 .

15. The process according to any one of claims 1 or 12 - 14 wherein the solvents (or diluents) for step C are selected from esters, nitriles, ethers, and aliphatic, aromatic or halogenated hydrocarbons.

16. The process according to any one of claims 1 or 12 - 15 wherein step C is carried out in a temperature range from 0 °C to 100 °C.

17. A compound of formula III,111wherein X is halogen, HSO4, acetate, trifluoroacetate, methanesulfonyl or p- toluenesulfonyl; or a resonance form of a compound of formula III.

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