TW202005956A - Process for producing difluoromethyl-nicotinic-indanyl carboxamides - Google Patents

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

Method for manufacturing difluoromethyl-nicotine-dihydroindenylcarboxamide

The invention relates to a method for preparing difluoromethyl-nicotine-dihydroindenylcarboxamide by amidation.

Various pyrazole indanyl carboxamides are known to have fungicidal activity (eg WO 1992/12970, WO 2012/065947, J. Org. Chem. 1995, 60 , 1626 and WO 2012/084812).

It is also known that various pyridine dihydroindenylcarboxamides have fungicidal activity (eg 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 part of benzyl dihydroindenyl amide has fungicidal activity (WO 2010/109301).

Very generally, such fungicidal indanyl carboxamides can be linked to the carboxyl group of the activated heterocyclic acid counterpart by means of a primary amine group of the 4-aminodihydroindenyl derivative (amidation reaction) The former is coupled with the latter.

The chemical synthesis of difluoromethyl-nicotine-dihydroindenylcarboxamide has been described in, for example, EP-A 0256503, WO 2014/095675 and WO 2015/197530.

WO 2014/095675 discloses a method for preparing difluoromethyl-nicotine-dihydroindenylcarboxamide, wherein carbonyl halide or difluoromethyl-nicotinic acid is optionally in the presence of a coupling agent, as the case may be It reacts with amines in the presence of an acid remover and optionally in the presence of a diluent, wherein the disclosed method is generally carried out at a temperature of 0°C to 150°C, preferably at a temperature of 20°C to 110°C . According to WO 2014/095675, the coupling reaction is carried out by reacting the carbonyl halide with a suitable acid remover or by directly reacting difluoromethyl-nicotinic acid with the coupling agent. This is reflected in the preparation examples in which 2-(difluoromethyl)-5-methylnicotinic acid is reacted with 4-aminodihydrogen at 150°C in the presence of propanephosphonic anhydride (ie coupling agent) Indene derivatives are coupled to produce 80% of the desired difluoromethyl-nicotine-dihydroindenylcarboxamide. However, the use of suitable coupling agents such as propanephosphonic anhydride often results in high process costs and environmentally hazardous waste.

WO 2015/197530 also discloses a method for preparing difluoromethyl-nicotine-dihydroindenylcarboxamide, wherein the carbonyl halide or difluoromethyl-nicotinic acid is optionally in the presence of a coupling agent, as the case may be It reacts with the amine in the presence of an acid remover and optionally in the presence of a diluent. The method disclosed therein is generally carried out at a temperature of 0°C to 150°C, preferably at a temperature of 20°C to 110°C. According to WO 2015/197530, if the coupling reaction is carried out with a carbonyl halide, the method is carried out in the presence of a suitable acid remover. This is reflected in the preparation examples in which 2-(difluoromethyl)nicotinyl chloride is in the presence of triethylamine (ie acid remover) at room temperature with 4-aminodihydroindane derivative Coupling, after purification by chromatography, only 68% of the desired difluoromethyl-nicotine-dihydroindenylcarboxamide was produced. However, it is known that HCl is formed during the coupling reaction of acetyl chloride with amine components. This generally results in protonation of the amine component and reduced reactivity based on the amine hydrochloride salt without complete conversion. Therefore, in order to obtain the desired difluoromethyl-nicotine-dihydroindenylcarboxamide in at least acceptable yields, an acid remover is generally used to maintain the reactivity during the coupling reaction and obtain complete conversion of the starting material.

Regarding the above disadvantages, the object of the present invention is to find a simplified process which can be industrially and economically carried out for the general preparation of difluoromethyl-nicotine-dihydroindenylcarboxamide. The difluoromethyl-nicotine-dihydroindenylcarboxamide obtainable by this desired method should preferably be obtained in high yield and/or high purity. In particular, the desired method should be able to obtain the target compounds without complicated purification methods (such as column chromatography). In addition, the object of the present invention is therefore to find a method for producing difluoromethyl-nicotine-dihydroindenylcarboxamide, which method results in a lower proportion of secondary components, and it is further preferred to take into account, for example, safety and environmental concerns And/or improved reaction methods in terms of quality.

The method according to the invention described below can achieve these objectives.

Surprisingly, it has now been shown that the amidation reaction of acyl halide with 4-aminodihydroindene derivatives can be carried out in the absence of an acid remover, and even leads to unpredictably higher yields of difluoromethyl- Nicotine-dihydroindenylcarboxamide.

Therefore, the method according to the invention not only enables the production of difluoromethyl-nicotine-dihydroindenylcarboxamide to be cost-effective, but also achieves a higher yield.

In addition, since no purification method is required to obtain the final product, less waste is generated, making the method according to the invention more eco-friendly. In particular, according to the method of the present invention, since no coupling agent is used during the coupling reaction, the generation of environmentally hazardous waste is reduced.

Furthermore, the method according to the present invention provides for the selective production of difluoromethyl-nicotine-dihydroindenylcarboxamide, so that it can be synthesized in a direct way with less undesirable secondary components, and the method according to the present invention More efficient and more energy efficient.

In particular, another advantage of the method according to the invention is the simplicity of the post-treatment of difluoromethyl-nicotine-dihydroindenylcarboxamide. This is in view of both: the product itself can be simply filtered off after the reaction is completed, and in view of the conversion of the product salt into free active ingredients.

The invention provides a method for preparing the compound of formula (I),

其中R¹ 代表(C₁-C₄)烷基；R² 代表氫或(C₁-C₈)烷基；R³ 代表氫或(C₁-C₈)烷基；R⁴ 代表氫、鹵素、(C₁-C₄)烷基、(C₁-C₄)鹵烷基；該方法包括步驟(a)，其中式(II)化合物

Where R ¹ represents (C ₁ -C ₄ )alkyl; R ² represents hydrogen or (C ₁ -C ₈ )alkyl; R ³ represents hydrogen or (C ₁ -C ₈ )alkyl; R ⁴ represents hydrogen, halogen , (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl; the method includes step (a), wherein the compound of formula (II)

在無酸去除劑的存在下與式(III)化合物反應。

Reacts with compound of formula (III) in the absence of acid remover.

The residues R ¹ , R ² , R ³ and R ⁴ listed in formulae (I), (II) and (III) (also referred to as formulae (I)-(III)) as defined herein are preferred, The best and best definitions are explained below.

Preferably in the following cases: R ¹ represents (C ₁ -C ₄ ) alkyl; R ² represents hydrogen or (C ₁ -C ₈ ) alkyl; R ³ represents hydrogen or (C ₁ -C ₈ ) alkyl R ⁴ represents hydrogen, halogen, (C ₁ -C ₄ )alkyl or (C ₁ -C ₄ )haloalkyl.

Preferably also in the following cases: R ¹ represents methyl or n-propyl; R ² and R ³ represent methyl; R ⁴ represents hydrogen or fluorine.

In the following cases, the most preferred systems are: R ¹ represents methyl or n-propyl; R ² and R ³ represent methyl; R ⁴ represents hydrogen.

The best system is in the following cases: R ¹ represents n-propyl; R ² and R ³ represent methyl; R ⁴ represents hydrogen.

The best case is also in the following cases: R ¹ , R ² and R ³ represent methyl; R ⁴ represents hydrogen.

The best case is also in the following cases: R ¹ , R ² and R ³ represent methyl; R ⁴ represents fluorine.

In the definition of the symbols listed in the above formula, collective terms that generally represent the following substituents are used:

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

Alkyl groups : having 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms, saturated, straight-chain or branched hydrocarbon groups, such as (but not limited to) C ₁ -C ₆ alkyl groups such as Methyl, ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl (n-butyl), 1-methylpropyl (secondary butyl), 2-methyl Propyl (isobutyl), 1,1-dimethylethyl (tertiary butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2 ,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl Group, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2- Dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 1,2-trimethylpropyl , 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. In particular, the group is a C ₁ -C ₄ alkyl group such as methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (secondary butyl) ), 2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tertiary butyl).

Haloalkyl : having 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms, straight-chain or branched alkyl (as specified above), of which Some or all of the hydrogen atoms are replaced with halogen atoms as specified above, such as (but not limited to) C ₁ -C ₃ -haloalkyl groups such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl , Fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 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 method

The method according to the present invention can be performed as shown in the process (1):

In Scheme 1, the substituents R ¹ , R ² , R ³ and R ⁴ of formulae (I)-(III) each have substituents that have been related to the description of the compounds of formulae (I)-(III) The general, better, better, better or best meaning of the definition.

The compounds of formulae (II) and (III) used as starting materials are known and can be obtained as described in WO 2014/095675 and WO 2015/197530. It is reacted in the absence of acid removing agent and coupling agent to obtain the compound of formula (I).

The amount of the compounds of formula (II) and (III) can be varied within a wide range. Preferably, the compound of formula (II) is reacted with a stoichiometric compound of formula (III).

Preferably, the reaction is carried out at a temperature ranging from 25°C to 130°C.

Particularly preferably, the method is carried out in the temperature range of 60°C to 130°C.

More preferably, the method is carried out in the temperature range of 60°C to 95°C.

As already mentioned above, one of the advantages of the method according to the invention is that not only can the unexpectedly high yield of the desired compound of formula (I) be obtained, but also the post-treatment of the reaction product is very straightforward and simple: in the amidation process, the released The hydrogen chloride of this product 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 filtered out.

Therefore, the reaction of the compound of formula (II) and the compound of formula (III) according to the first step (a) above to obtain the compound of formula (I) is particularly preferably performed at a temperature ranging from 60°C to 130°C. In the optional subsequent step (b), after completing step (a), the temperature is reduced to a temperature of -20°C to 55°C, where the first temperature range used in step (a) is very suitable for the The amination reaction and the second temperature range used in step (b) therein are very suitable for the crystallization of the product hydrochloride. The completion of step (a) can be confirmed by HPLC analysis of the reaction mixture.

More preferably, steps (a) and (b) are first in the temperature range of 60°C to 95°C (step (a)), and secondly in the temperature range of -20°C to 60°C (step (b)) continuously get on.

烷、二乙基醚、二甘二甲醚、甲基三級丁基醚(MTBE)、三級戊基甲基醚(TAME)、2-甲基-THF；烷烴或環烷烴或經烷基取代之環烷烴類，例如正己烷、正庚烷、環己烷、異辛烷或甲基環己烷；腈類如乙腈(ACN)或丁腈；酮類如丙酮、甲基異丁基酮(MIBK)；芳烴類如甲苯、二甲苯、苯基甲基醚、1,3,5-三甲苯；酯類如乙酸乙酯、乙酸異丙酯、乙酸丁酯、乙酸戊酯；碳酸酯如碳酸伸乙酯、碳酸伸丙酯；醯胺類如N,N-二甲基乙醯胺(DMAc)、N,N-二甲基甲醯胺(DMF)、N-甲基吡咯啶酮；鹵烴和鹵化芳烴類，特別是氯烴類如四氯乙烯、四氯乙烷、二氯丙烷、二氯甲烷(二氯甲烷，DCM)、二氯丁烷、氯仿、三氯乙烷、三氯乙烯、五氯乙烷、二氟苯、三氟苯、1,2-二氯乙烷、氯苯、溴苯、二氯苯，特別是1,2-二氯苯、氯甲苯、三氯苯；氟化脂族和芳族化合物類如三氯三氟乙烷、三氟甲基苯和4-氯三氟甲基苯。亦可使用溶劑混合物。 Generally, the reaction can be carried out in one or more of the following solvents: ethers such as tetrahydrofuran (THF), di

Alkanes, diethyl ether, diglyme, methyl tertiary butyl ether (MTBE), tertiary pentyl methyl ether (TAME), 2-methyl-THF; alkane or cycloalkane or via alkyl Substituted cycloalkanes such as n-hexane, n-heptane, cyclohexane, isooctane or methylcyclohexane; nitriles such as acetonitrile (ACN) or butyronitrile; ketones such as acetone and methyl isobutyl ketone (MIBK); aromatic hydrocarbons such as toluene, xylene, phenyl methyl ether, 1,3,5-trimethylbenzene; esters such as ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate; carbonates such as Ethylene carbonate and propyl carbonate; Acylamines such as N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone; Halogenated hydrocarbons and halogenated aromatic hydrocarbons, especially chlorinated hydrocarbons such as tetrachloroethylene, tetrachloroethane, dichloropropane, dichloromethane (dichloromethane, DCM), dichlorobutane, chloroform, trichloroethane, trichloroethane Vinyl chloride, pentachloroethane, difluorobenzene, trifluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, especially 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene Benzene; fluorinated aliphatic and aromatic compounds such as trichlorotrifluoroethane, trifluoromethylbenzene and 4-chlorotrifluoromethylbenzene. Solvent mixtures can also be used.

Preferably, the solvents used in steps (a) and (b) are organic solvents that are immiscible with water.

Particularly preferably, the solvent used in steps (a) and (b) is selected from xylene, chlorobenzene or toluene.

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

The above-mentioned solvent-wet product hydrochloride can be very directly and simply converted into free active ingredients as appropriate: the higher crystallization tendency of the product hydrochloride can be advantageously used to separate the content contained in the starting material and during the amidation reaction Polymer impurities formed. This is accomplished by first washing the filtered product hydrochloride with a water-immiscible organic solvent, and then replacing the washing with a water-miscible organic solvent. This allows subsequent washing with water to release the product from the hydrochloride salt. Therefore, after completing steps (a) and (b), replacement washing is performed as the optional subsequent step (c), in which the water-immiscible organic solvent performing steps (a) and (b) is exchanged for the first Dihydrate miscible organic solvent.

After completing step (c), the solvent-wet product hydrochloride (wherein the exchanged solvent is now an organic solvent miscible with water) is then suspended in water, mixed, filtered and washed with water, and finally dried In order to separate hydrogen chloride and obtain free active ingredients.

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

烷、丙酮、甲基異花青素、二甲氧基乙烷、糠基醇、甲酸、乙酸、丙酸、丁酸、乙二醇、三乙二醇、1,3-丙二醇、1,5-戊二醇、丙二醇、甘油、1,2-丁二醇、1,3-丁二醇、1,4-丁二醇、2-丁氧基乙醇、二乙醇胺、甲基二乙醇胺、乙胺、二伸乙三胺、吡啶、N,N-二甲基甲醯胺、N-甲基-2-吡咯啶酮或二甲基亞碸。 Preferably, the solvent used in step (c) is one or more of the following solvents: THF, acetonitrile, methanol, ethanol, isopropanol, n-propanol, 1,4-bis

Alkane, acetone, methylisocyanidin, dimethoxyethane, furfuryl alcohol, formic acid, acetic acid, propionic acid, butyric acid, ethylene glycol, triethylene glycol, 1,3-propanediol, 1,5 -Pentanediol, propylene glycol, glycerin, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2-butoxyethanol, diethanolamine, methyldiethanolamine, ethylamine , Diethylenetriamine, pyridine, N,N-dimethylformamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide.

Particularly preferably, the solvent used in step (c) is THF.

Particularly preferably, steps (a) and (b) are performed in the presence of an organic solvent that is immiscible with water, and step (c) is performed in the presence of an organic solvent that is miscible with water.

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

Preferably, the temperature of step (c) is in the range of -20°C to 55°C, and particularly preferably in the range of -20°C to 20°C.

Depending on the type of substituents, the compounds prepared according to the method of the invention may appear in the form of geometric and/or optical isomers or their corresponding isomeric mixtures of various compositions. Such isomers are, for example, mirror isomers, non-mirror isomers or geometric isomers. Therefore, the invention described herein includes pure stereoisomers and mixtures of each such isomer.

The present invention is explained in detail by the following examples, but the examples should not be interpreted in a way to limit the present invention.

Preparation Example

Preparation of racemic -2-(difluoromethyl)-N-(1,1-dimethyl-3-propyl-indan-4-yl)pyridine-3-carboxamide

In a 2000 ml four-necked round bottom flask equipped with a distillation head, a dropping funnel, a mechanical stirrer and a thermometer, make 110 g (95.9% purity, 0.609 mole, 1.00 equivalent) of 2-(difluoromethyl)pyridine- 3-Formic acid was suspended in 510 ml of toluene under nitrogen. Thereafter, 0.7 ml (6.09 millimoles, 0.01 equivalent) of N,N-diethylformamide was added all at once. With stirring, the mixture was heated to an internal temperature of 90°C. 94 grams (0.792 moles, 1.30 equivalents) of sulfenyl chloride was added to this mixture within 1 hour. The yellow suspension turned into a brown solution. The solution was stirred at 90°C for an additional 30 minutes by quenching the sample in situ with ethanol and detecting the corresponding ethyl 2-(difluoromethyl)nicotinate until HPLC monitoring indicated complete conversion to 2-(difluoromethyl) ) Nicotine chloride. Then 40 ml of volatiles were distilled from the reaction mixture at 90°C and 950 mbar. After this, 160 g (99% purity, 0.640 mole, 1.05 equivalent) of racemic-1,1-dimethyl in 40 ml of toluene was metered in under vigorous stirring and an internal temperature of 80° C. -3-propyl-indanyl-4-amine. Thereafter, stirring was continued at this temperature for 1 hour to achieve complete conversion. The resulting brown suspension was then cooled to an internal temperature of 22°C. The solid material was filtered off and washed once with 150 ml of toluene. After that, the replacement and washing of the toluene wet filter cake was performed with 150 ml of tetrahydrofuran. The wet solid was then suspended in 1000 ml of deionized and stirred at 22°C for 2 hours. The fine suspension is then filtered. The solid was washed with 2×1000 ml of deionized. The filter cake was then dried at 60°C and 65 mbar for 16 hours, leaving 204 g (99% purity, 0.566 mol, 93% yield) of an off-white solid. ¹ H-NMR (600 MHz; DMSO-d6) δ = 10.37 (bs, 1H), 8.84 (d, J = 6.0 Hz, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 6.0, 6.0Hz, 1H), 7.25-7.21 (m, 2H), 7.23 (t, J = 54Hz, 1H), 7.08 (dd, J = 6.0, 6.0Hz, 1H), 3.42-3.36 (m, 1H) ,2.07(dd, J =6.0,12.0Hz,1H),1.86-1.79(m,1H),1.66(dd, J =6.0,12.0Hz,1H),1.42-1.16(m,2H),1.32(s , 3H), 1.19 (s, 3H), 0.85 (t, J = 6.0Hz, 3H).

Claims (10)

A method for preparing the compound of formula (I),

Where R ¹ represents (C ₁ -C ₄ )alkyl; R ² represents hydrogen or (C ₁ -C ₈ )alkyl; R ³ represents hydrogen or (C ₁ -C ₈ )alkyl; R ⁴ represents hydrogen, halogen , (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )haloalkyl; the method includes step (a), wherein the compound of formula (II)

Reacts with compound of formula (III) in the absence of acid remover.

According to the method of claim 1 of the patent application scope, wherein R ¹ is n-propyl, R ² and R ³ are methyl, and R ⁴ is hydrogen. According to the method of claim 1 of the patent application scope, wherein R ¹ , R ² and R ³ are methyl groups, and R ⁴ is hydrogen. The method according to any one of items 1 to 3 of the patent application range, wherein the reaction is carried out in a temperature range of 25°C to 130°C, especially in a temperature range of 60°C to 130°C. The method according to any one of items 1 to 4 of the patent application scope, wherein the reaction is carried out in a temperature range of 60°C to 95°C. The method according to any one of items 1 to 5 of the patent application scope, which additionally includes step (b) performed after step (a) is completed, wherein the temperature is reduced to the range of -20°C to 55°C. The method according to any one of items 1 to 6 of the patent application range, wherein the reaction is carried out in the presence of an organic solvent immiscible with water. According to the method of claim 7, the solvent is toluene. The method according to any one of items 1 to 8 of the patent application scope, which additionally includes step (c) performed after step (b), in which the water-immiscible organic solvent is exchanged for water-miscible organic Solvent. The method according to item 9 of the patent application scope, wherein the water-immiscible organic solvent is tetrahydrofuran.