WO2019224175A1

WO2019224175A1 - Process for producing difluoromethyl-nicotinic-indanyl carboxamides

Info

Publication number: WO2019224175A1
Application number: PCT/EP2019/063051
Authority: WO
Inventors: Florian ERVER; Frank Memmel
Original assignee: Bayer Aktiengesellschaft
Priority date: 2018-05-23
Filing date: 2019-05-21
Publication date: 2019-11-28
Also published as: TW202005956A

Abstract

The present invention relates to a method for preparing difluoromethyl-nicotinic-indanyl carboxamides of the formula (I) by amidation in which the substituents R¹, R², R³ and R⁴ have the definitions as specified in the description.

Description

Process for producing difluoromethyl-nicotinic-indanyl carboxamides

The present invention relates to a method for preparing difluoromethyl-nicotinic-indanyl carboxamides by amidation.

It is known that various pyrazole indanyl carboxamides have fungicidal activity (e.g. WO 1992/12970, WO 2012/065947, J. Org. Chem. 1995, 60, 1626 and WO 2012/084812).

It is also known that various pyridine indanyl carboxamides have fungicidal activity (e.g. EP-A 0256503; JP-A 1117864; J. Pesticide Sci. 1993, 18, 245-251 ; WO 2014/095675; WO 2015/197530).

In addition, it is known that some benzoyl indanyl amides have fungicidal activity (WO 2010/109301).

Very generally, such fungicidal indanyl carboxamides can be produced via the coupling of a 4-aminoindane derivative with an activated heterocyclic acid counterpart by linking the primary amino group of the former with the carboxyl group of the latter (amidation reaction).

Chemical syntheses of difluoromethyl-nicotinic-indanyl carboxamides have been described e.g. in EP-A 0256503, WO 2014/095675 and WO 2015/197530.

WO 2014/095675 discloses a process for the preparation of difluoromethyl-nicotinic-indanyl carboxamides in which a carbonyl halide or difluoromethyl-nicotinic acid is reacted with an amine optionally in the presence of a coupling agent, optionally in the presence of an acid scavenger and optionally in the presence of a diluent, wherein the disclosed process is generally carried out at temperatures of from 0°C to l50°C, preferably at temperatures of from 20°C to H0°C. According to WO 2014/095675, the coupling reaction is performed either using a carbonyl halide in reaction with a suitable acid scavenger or using the difluoromethyl-nicotinic acid directly in reaction with a coupling agent. This is reflected in the preparation examples, wherein 2-(difLuoromethyl)-5-methylnicotinic acid is coupled with a 4-aminoindane derivative in the presence of propanephosphonic anhydride, i.e. a coupling agent, at 150°C, yielding 80% of the desired difluoromethyl-nicotinic-indanyl carboxamide. However, the use of suitable coupling agents such as propanephosphonic anhydride often leads to high process costs and to environmentally hazardous waste.

WO 2015/197530 also discloses a process for the preparation of difluoromethyl-nicotinic-indanyl carboxamides in which a carbonyl halide or a difluoromethyl-nicotinic acid is reacted with an amine optionally in the presence of a coupling agent, optionally in the presence of an acid scavenger and optionally in the presence of a diluent, wherein the disclosed process is generally carried out at temperatures of from 0°C to 150°C, preferably at temperatures of from 20°C to 110°C. According to WO 2015/197530, the process is carried out in the presence of a suitable acid scavenger if the coupling reaction is performed with a carbonyl halide. This is reflected in the preparation examples, wherein 2-(difluoromethyl)nicotinoyl chloride is coupled with a 4-aminoindane derivative in the presence of triethylamine, i.e. an acid scavenger, at room temperature, yielding only 68% of the desired difluoromethyl-nicotinic-indanyl carboxamide after purification via chromatography. However, it is known that HC1 is formed during a coupling reaction of an acid chloride with an amine component. This generally leads to protonation of the amine component and to incomplete conversion based on the decreased reactivity of the amine hydrochloride salt. Therefore, in order to obtain the desired difluoromethyl-nicotinic-indanyl carboxamide in an at least acceptable yield, an acid scavenger is usually deployed to maintain reactivity during the coupling reaction and to obtain complete conversion of starting materials.

With regard to the disadvantages outlined above, it is accordingly an object of the present invention to find a simplified method that can be carried out industrially and economically for the general preparation of difluoromethyl-nicotinic-indanyl carboxamides. The difluoromethyl-nicotinic-indanyl carboxamides obtainable by such desired method should preferably be obtained in high yield and/or high purity. In particular, the desired method should enable the target compounds to be obtained without the need for complex purification methods such as column chromatography. Furthermore, it is accordingly an object of the present invention to find a process for producing difluoromethyl-nicotinic- indanyl carboxamides which results in a lower proportion of side components and in addition preferably allows for an improved reaction regime, for example in terms of aspects relevant to safety, the environment and/or quality.

The hereinbelow-described process according to the invention achieves these objects.

Surprisingly, the amidation reaction of an acid halide with a 4-aminoindane derivative has now been proven to be performable without the presence of an acid scavenger, leading even to unexpected higher yields of the difluoromethyl-nicotinic-indanyl carboxamides.

Therefore, the process according to the invention allows the production of difluoromethyl-nicotinic- indanyl carboxamides not only in a cost-efficient manner but also in higher yields.

In addition, less waste is produced since no purification methods are necessary to obtain the final product, making the process according to the invention more ecologically friendly. In particular, the process according to the invention reduces the production of environmentally hazardous waste since no coupling agents are used during the coupling reaction. Furthermore, the process according to the invention affords the selective production of difluoromethyl- nicotinic-indanyl carboxamides allowing their synthesis in a straightforward fashion in which fewer undesired side components are formed so that the process according to the invention is more efficient and more energy-saving. In particular, another advantage of the process according to the invention is the simplicity of the work up of the difluoromethyl-nicotinic-indanyl carboxamides. This in view of both, the product itself after completion of the reaction, which can be simply filtered off, but also in view of the transformation of the product salt into the free active ingredient.

The present invention provides a process for the preparation of a compound of the formula (I)

in which

R¹ represents(Ci-C4)alkyl;

R² represents hydrogen or (Ci-Cs)alkyl;

R³ represents hydrogen or (Ci-Cs)alkyl; R⁴ represents hydrogen, halogen, (Ci-C alkyl, (Ci-C haloalkyl; comprising a step (a) wherein a compound of the formula (II)

is reacted with a compound of the formula (III)

in the absence of an acid scavenger.

Preferred, particularly preferred and most preferred definitions of the residues R¹, R², R³and R⁴ listed in the herein-defined formulae (I), (II) and (III) (further referred to as formulae (I)-(III)) are elucidated below.

It is preferable when in each case:

R¹ represents (Ci-C OaLkyl;

R² represents hydrogen or (Ci-Cs)aLkyl;

R³ represents hydrogen or (Ci-Cs)aLkyl; R⁴ represents hydrogen, halogen, (Ci-C4)alkyl or (Ci-C4)haloalkyl;

It is also preferable when in each case:

R¹ represents methyl or n-propyl;

R² and R³ represent methyl;

R⁴ represents hydrogen or fluorine. It is particularly preferable when in each case:

R¹ represents methyl or n-propyl;

R² and R³ represent methyl;

R⁴ represents hydrogen.

It is most preferable when in each case: R¹ represents n-propyl;

R² and R³ represent methyl;

R⁴ represents hydrogen.

It is also most preferable when in each case: R¹, R² and R³ represent methyl;

R⁴ represents hydrogen.

It is also most preferable when in each case:

R¹, R²and R³ represent methyl;

R⁴ represents fluorine. In the definitions of the symbols given in the above formulae, collective terms which are generally representative of the following substituents were used:

Halogen: fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine and most preferably chlorine or bromine.

Alkyl: saturated, straight-chain or branched hydrocarbyl radical having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C₆-alkyl such as methyl, ethyl, propyl (n-propyl), 1 -methylethyl (iso-propyl), butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2- methylpropyl (iso-butyl), l,l-dimethylethyl (tert-butyl), pentyl, 1 -methylbutyl, 2-methylbutyl, 3- methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, l ,l -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, l ,l -dimethylbutyl, 1 ,2-dimethylbutyl, l ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, l ,l,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl- 1 -methylpropyl and 1 -ethyl-2 -methylpropyl. Particularly, said group is a C 1 -C4-alkyl group, e.g. a methyl, ethyl, propyl, 1 -methylethyl (isopropyl), butyl, 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl) or l,l-dimethylethyl (tert-butyl) group.

Haloalkyl: straight-chain or branched alkyl groups having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups are replaced by halogen atoms as specified above, for example (but not limited to) Ci-C3-haloalkyl such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro fluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1- bromoethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1 ,1,1- trifluoroprop-2-yl.

Detailed description of the process The process according to the invention can be conducted as shown in scheme (1):

In scheme 1 , the substituents R¹, R², R³ and R⁴ of the formulae (I)-(III) each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I)-(III).

Compounds of formula (II) and (III) used as starting materials are known and can be obtained as described e.g. in WO 2014/095675 and WO 2015/197530. They are reacted in the absence of an acid scavenger and in the absence of a coupling agent to obtain the compound of the formula (I).

The employed amount of the compounds of the formulae (II) and (III) may be varied over a wide range. Preferably, the compound of the formula (II) is reacted with the compound of the formula (III) in stoichiometric amounts.

Preferably, the reaction is carried out at a temperature in the range of from 25°C tol30°C.

Particularly preferably, the process is carried out at a temperature in the range of from 60°C to l30°C.

More preferably, the process is carried out at a temperature in the range of from 60°C to 95°C. As already mentioned above, one of the advantages of the process according to the present invention is not only that the desired compound of the formula (I) is obtainable in unexpected high yields, but also that the work-up of the reaction product is very straightforward and simple: In the amidation process the released hydrogen chloride forms a hydrogen chloride salt with the product, which begins to crystallize at temperatures below 60°C. Advantageously, the desired product hydrochloride precipitates during cooling to 22°C and can be easily fdtered off.

Therefore particularly preferably, the reaction of the compound of formula (II) with the compound of the formula (III) according to the above-described first step (a) to obtain the compound of the formula (I), is carried out at a temperature in the range of from 60°C to l30°C. In an optional subsequent step (b), after completion of step (a), the temperature is lowered to temperatures of from -20°C to 55°C, wherein the first temperature range used for step (a) is ideal for the amidation reaction and wherein the second temperature range used for step (b) is ideal for crystallization of the product hydrochloride. Completion of step (a) can be confirmed by HPLC analysis of the reaction mixture.

More preferably, the steps (a) and (b) are carried out consecutively first at a temperature in the range of from 60°C to 95°C (step (a)) and second at a temperature in the range of from -20°C to 60°C (step (b)).

Generally, the reaction can be conducted in one or more of the following solvents: ethers such as tetrahydrofuran (THF), dioxane, diethyl ether, diglyme, methyl tert-butyl ether (MTBE), tert- amyl methyl ether (TAME), 2-methyl-THF; alkanes or cycloalkanes or alkyl-substituted cycloalkanes, for example «-hexane, «-heptane, cyclohexane, isooctane or methylcyclohexane; nitriles such as acetonitrile (ACN) or butyronitrile; ketones such as acetone, methyl isobutyl ketone (MIBK); aromatic hydrocarbons such as toluene, xylenes, anisole, mesitylene; esters such as ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate; carbonates such as ethylene carbonate, propylene carbonate; amides such as N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N- methylpyrrolidone; halohydrocarbons and halogenated aromatic hydrocarbons, particularly chlorohydrocarbons such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, trifluorobenzene, 1 ,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, especially 1 ,2 -dichlorobenzene, chlorotoluene, trichlorobenzene; fluorinated aliphatic and aromatic compounds such as trichlorotrifluoroethane, benzotrifluoride and 4- chlorobenzotrifluoride. It is also possible to use solvent mixtures.

Preferably, the solvent used in step (a) and (b) is a water-immiscible organic solvent. Particularly preferably, the solvent used in step (a) and (b) is selected from xylenes, chlorobenzene or toluene.

More preferably, the solvent used in step (a) and (b) is toluene.

The above-described solvent-wet product hydrochloride can optionally be transformed into the free active ingredient very straightforward and simple: Advantageously, the higher crystallization tendency of the product hydrochloride can be used to separate polymeric impurities contained in the starting materials and formed during the amidation reaction. This is achieved by washing the filtered product hydrochloride with firstly a water-immiscible organic solvent and secondly by a replacement-wash with a water-miscible organic solvent. This allows subsequent washing with water in order to release the product from the hydrochloride salt. Therefore, after completion of step (a) and (b), a replacement wash is performed as an optional subsequent step (c), in which the water-immiscible organic solvent in which step (a) and step (b) are conducted, is exchanged to a second water-miscible organic solvent.

Subsequently after completion of step (c), the solvent-wet product hydrochloride, wherein such exchanged solvent is now a water-miscible organic solvent, is suspended in water, mixed, filtered and washed with water and finally dried in order to separate off hydrogen chloride and to obtain the free active ingredient.

Generally, step (c) can be conducted in a water-miscible organic solvent.

Preferably, the solvent used in step (c) is one or more of the following solvents: THF, acetonitrile, methanol, ethanol, isopropanol, n-propanol, 1 ,4-dioxan, acetone, methyl isocyanide, dimethoxyethane, furftiryl alcohol, formic acid, acetic acid, propanoic acid, butyric acid, ethylene glycol, triethyleneglycol, 1 ,3 -propanediol, l,5-pentanediol, propylene glycol, glycerol, 1 ,2-butanediol, 1,3- butanediol, l ,4-butanediol, 2-butoxyethanol, diethanolamine, methyl diethanolamine, ethylamine, diethylenetriamine, pyridine, N,N dimethylformamide, N-methyl-2-pyrollidone or dimethylsulfoxide.

Particularly preferably, the solvent used in step (c) is THF. Particularly preferably, step (a) and (b) are conducted in the presence of a water-immiscible organic solvent and step (c) is conducted in the presence of a water-miscible organic solvent.

More preferably, step (a) and (b) are conducted in toluene and step (c) is conducted in THF.

Preferably, the temperature of step (c) is in the range of from -20°C to 55°C, particularly preferably in the range of from -20°C to 20°C. Depending on the type of substituents, the compound produced with the process according to the invention can occur as geometric and/or optical isomers or as their corresponding isomeric mixtures in various compositions. These isomers are, for example, enantiomers, diastereomers or geometric isomers. As a consequence, the invention described herein includes both the pure stereoisomers and every mixture of these isomers.

The present invention is elucidated in detail by the example which follows, although the example should not be interpreted in such a manner that it restricts the invention.

Preparation example

Preparation of rac- 2-(difluoromcthyl )-/V-( 1 .1 -dimethyl-3-propyl-indan-4-yl )pyndine-3-carboxamide

In a 2000 mL four-necked round-bottomed flask, equipped with a distillation head, a dropping funnel, a mechanical stirrer and a thermometer, was suspended under nitrogen 110 g (95.9 % purity, 0.609 mol, 1.00 eq) of 2-(difLuoromethyl)pyridine-3-carboxylic acid in 510 mL of toluene. Afterwards 0.7 mL (6.09 mmol, 0.01 eq) of /V,/V-diethylformamide was added in one portion. The mixture was heated to 90°C internal temperature under stirring. To this mixture was dosed 94 g (0.792 mol, 1.30 eq) ofthionyl chloride over 1 h. The yellow suspension turned into a brown solution. The solution was stirred for further 30 min at 90°C, until HPLC monitoring indicated complete conversion towards 2- (difluoromethyl)nicotinoyl chloride via in situ quenching the sample with ethanol and detection of corresponding ethyl 2-(difLuoromethyl)nicotinate. Then 40 mL of volatiles were distilled off the reaction mixture at 90°C and 950 mbar. This was followed by dosed addition of 160 g (99% purity, 0.640 mol, 1.05 eq) of rac- 1,1 -dimethyl-3 -propyl- indan-4-amine dissolved in 40 mL of toluene within 1 h at 80°C internal temperature under vigorous stirring. Afterwards stirring at this temperature was continued for 1 h to achieve complete conversion. The resulting brown suspension was then cooled toward 22°C internal temperature. The solid material was fdtered off and washed once with 150 mL of toluene. Afterwards a replacement- wash of the toluene wet filter cake was performed with 150 mL of tetrahydrofuran. The wet solid was then suspended in 1000 mL of deion. water and was stirred at 22 °C for 2 h. The fine suspension was then filtered. The solid was washed with 2 x 1000 mL of deion. water. The filter cake was then dried at 60°C, 65 mbar for 16 h to leave 204 g (99% purity, 0.566 mol, 93% yield) of an off-white solid. ¹H-NMR (600 MHz; DMSO-d6) d = 10.37 (bs, 1H), 8.84 (d, ./ = 6.0 Hz, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 6.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.23 (t, J = 54 Hz, 1H), 7.08 (dd, J = 6.0, 6.0 Hz, 1H), 3.42-3.36 (m, 1H), 2.07 (dd, J = 6.0, 12.0 Hz, 1H), 1.86-1.79 (m, 1H), 1.66 (dd, J= 6.0, 12.0 Hz, 1H), 1.42-1.16 (m, 2H), 1.32 (s, 3H), 1.19 (s, 3H), 0.85 (t, J= 6.0 Hz, 3H).

Claims

Claims:

1. Process for the preparation of a compound of formula (I)

in which

R¹ represents(Ci-C₄)alkyl;

R² represents hydrogen or (C i-Cx)alkyl;

R³ represents hydrogen or (C i-Cx)alkyl;

R⁴ represents hydrogen, halogen, (Ci-C₄)alkyl, (Ci-C₄)haloalkyl; comprising a step (a) wherein a compound of the formula (II)

is reacted with a compound of the formula (III)

in the absence of an acid scavenger.

2. The process according to claim 1, wherein R¹ is n-propyl, R² and R³ are methyl and R⁴ is hydrogen.

3. The process according to claim 1, wherein R¹, R²and R³ are methyl and R⁴ is hydrogen.

4. The process according to one of the claims 1 to 3, wherein the reaction is carried out at a temperature in the range of from 25°C tol30°C, in particular in the range of from 60°C to l30°C.

The process according to one of the claims 1 to 4, wherein the reaction is carried out at a temperature in the range of from 60°C to 95°C.

6. The process according to one of the claims 1 to 5, further comprising a step (b) which is performed after completion of step (a), wherein the temperature is lowered to a range of from - 20°C to 55°C.

7. The process according to one of the claims 1 to 6, wherein the reaction is conducted in the presence of a water-immiscible organic solvent.

8. The process according to claim 7, wherein the solvent is toluene.

9. The process according to one of the claims 1 to 8, further comprising a step (c) which is performed after step (b), wherein the water-immiscible organic solvent is exchanged to a water- miscible organic solvent.

10. The process according to claim 9, wherein the water- immiscible organic solvent is tetrahydrofuran.