WO2016005276A1

WO2016005276A1 - Process for preparing fluorinated iminopyridine compounds

Info

Publication number: WO2016005276A1
Application number: PCT/EP2015/065169
Authority: WO
Inventors: Jason Kennedy; Matthias RIEDRICH; Christian Funke
Original assignee: Bayer Cropscience Aktiengesellschaft
Priority date: 2014-07-07
Filing date: 2015-07-03
Publication date: 2016-01-14
Also published as: TW201613866A

Abstract

The present invention discloses the efficient preparation of alkali metal azanide salts of N-pyridyl-trifluoroacetamide derivatives from readilyavailable starting materialsand their reaction with alkylating agents to prepare iminopyridine compounds.

Description

Process for preparing fluorinated iminopyridine compounds

The present invention discloses the efficient preparation of alkali metal azanide salts of N-pyridyl- trifluoroacetamide derivatives from readily available starting materials and their reaction with alkylating agents to prepare iminopyridine compounds. Iminopyridine derivatives containing a trifluoroacetamide group have proven to be useful pest control agents (DE 3639877 Al, EP 2633756 Al). Trifluoroacetylated derivatives of 2-aminopyridine are important and versatile intermediates in the preparation of these pest control agents (WO 2013/031671 Al). The tri- fluoroacetyl-residue in such compounds is generally introduced via acylation of a derivative of 2- aminopyridine with trifluoroacetic anhydride in the presence of an amine base to give a neutral derivative (EP 1820504 Al). This procedure suffers from moderate yields (70-80%) and the use of an expensive acyl- ating agent. This procedure is also inefficient, since the anhydride contains two valuable CF3-acetate residues, of which one is then lost as an acetate salt after the reaction as waste.

While CF3CO2H and CF3COCI are more effective sources of the CF3-acetate group, amidation with these reagents is more complicated than with the anhydride: the acid needs to be activated with another reagent before amide coupling, and the acid chloride is a corrosive gas at room temperature.

Esters of trifluoroacetic acid are attractive sources of the trifluoroacetate group, since they are more active in amidation reactions than the corresponding acid and easier to handle than the acid chloride. Unfortunately, reported examples of reactions with these esters are not yet efficient enough for use in large-scale, technical production since acceptable yields are only available using a wasteful excess of the ester in the presence of a dipolar, aprotic solvent like DMF (WO 2013/031671 Al, EP 2631235 A2). Such solvents are expensive and difficult to recycle, leading to high disposal costs. Furthermore these solvents are becoming decreasingly appropriate for use in commercial productions because of tightening regulatory restrictions.

Subsequent alk lation of these neutral, acylated intermediates then proceeds with modest yields by treatment with an appropriate electrophile (e.g., 2-chloro-5-(chloromethyl)pyridine) and a super-stoichiometric amount of added base (WO 2013/031671 Al).

The present invention discloses the efficient preparation of alkali metal azanide salts of N-pyridyl- trifluoroacetamide derivatives of formula (III) from readily available starting materials of formulae (I) and (II), and the subsequent reaction of these salts with alkylating agents of formula (IV) to prepare compounds of formula (V).

(I) (II) (in) (V)

The first step of the process according to the present invention is a surprisingly straightforward synthesis of the previously unreported azanide salts of formula (III) in the presence of an alcohol-derived base of formula (VI) starting from 2-aminopyridine derivatives of formula (I) and esters of trifluoroacetic acid of formula (II), both of which are readily available and easily handled.

(I) (II) (ill) wherein

Y is selected from the group consisting of halogen, Ci-6 alkyl and Ci-6 alkoxy; n is chosen from 0, 1 and 2; X¹ is selected from the group consisting of OR³ and SR³;

R³ is selected from the group consisting of Ci-8 alkyl (which may be branched and/or contain ether, thi- oether, ester, alcohol, ketone, nitrile or amide groups), phenyl (which may be substituted with a Ci-8 alkyl group, halogens, or nitro groups), a 2-pyridyl group (which may be substituted with Ci-4 alkyl groups or halogens), a succinimidyl group, a benzotriazole group, a 7-azabenzotriazole group, an NN'-phosphoryl(bis(l ,3 -oxazolidin-2-one) group, or a tri(pyrrolidin- 1 -yl)phosphonium group;

R⁴ is C 1-8 alkyl (which may be branched), -(CH₂)_n-OH (n = 2-4), or -(CH₂)_n-OCH₃ (n = 2-4);

M is an alkali metal, such as Li, Na or K.

In a preferred embodiment

Y is a halogen atom selected from the group consisting of F, CI, Br, and I; n is chosen from 0 and 1 ;

X¹ is OR³;

R³ is Ci-8 alkyl (which may be branched); R⁴ is Ci-8 alkyl (which may be branched); M is an alkali metal, such as Na or K. In an especially preferred embodiment n is O; is OR³; is CM alkyl (which may be branched); is CM alkyl (which may be branched);

M is an alkali metal, such as Na or K.

In another especially preferred embodiment n is O;

X¹ is OR³;

R³ is CM alkyl (which may be branched); R⁴ is CM alkyl (which may be branched); M is Na.

This high yielding process occurs at ambient temperatures in common, inexpensive organic solvents that are easily recycled, and introduces the trifluoroacetyl residue in an efficient manner without the need for special activation agents or corrosive, gaseous reagents. Depending on the reaction medium chosen for the preparation, the product is isolated after reaction either by filtration or by removal of the solvents.

The second step of the process according to the present invention, alkylation of the azanide salts of formula (III) with compounds of formula (IV), proceeds in the absence of added base, and smoothly leads to the desired compounds of formula (V) in high yield without generating large amounts of waste. Compounds of formula (IV) can be acquired either commercially or by preparation according to literature procedures (e.g., EP 0 421 210 A2, US 5756497, WO 2014/057078 Al).

(ill) (iv) (V)

Wherein Y, n and M have the same definitions as provided above for the compounds of formula (III); X² is selected from the group consisting of halogen and sulfonate (e.g., mesylate, tolsylate, triflate, no- naflate) groups;

R¹ is selected from the group consisting of hydrogen, Ci-6 alkyl, Ci-6haloalkyl, phenyl, pyridyl; R² is selected from the group of following scaffolds where # marks its attachment point

wherein

A is CH or N;

Z is independently selected from the group consisting of F, CI, Br, I, and CF3; m is 0, 1 or 2.

In a preferred embodiment of the invention Y, n and M have the same definitions as above in the preferred embodiment of the first step of the process;

X² is halogen, in particular F, CI, Br, or I;

R¹ is selected from the group consisting of hydrogen and G-6 alkyl;

R² is selected from the group of scaffolds of formulae (VII) and (Vffl) where # marks its attachment point wherein

A is N;

Z is independently selected from the group consisting of F, CI, Br, I and CF3; m is 1 or 2.

In an especially preferred embodiment of the invention Y, n and M have the same definitions as above in the especially preferred embodiments of the first step of the process;

X² is halogen; is hydrogen; is scaffolds of formula (Vni) where # marks its attachment point wherein

A is N;

Z is selected from the group consisting of F, CI and Br; m is 1.

Depending of the nature of the substituents, the compounds of formula (V) may be present as geometrical isomers, e.g. as indicated in the following formula with regard to the N-C(0)-bond:

o

The present invention includes such isomeric forms. For the sake of clarity in the text, only one of such potential isomers is shown for compounds of formula (V).

The acylation reaction between a compound of formula (I) and a compound of formula (II) in the presence of a compound of formula (VI) may be performed neat or in the presence of a solvent. In reactions where a solvent is used, solvents such as amides (e.g., DMF, DMAC), nitriles (e.g., MeCN, PrCN), alcohols (e.g., MeOH, (z)-PrOH, (n)-BuOH), ethers (e.g., Et₂0, 2-methyltetrahydrofuran, THF, MTBE), esters (e.g., EtOAc, BuOAc), aromatic hydrocarbons or halogenated derivatives thereof (e.g., toluene, xylene, chloro- benzene), hydrocarbons or halogenated derivatives thereof (e.g., methylcyclohexane, dichloromethane, di- chloroethane), sulfoxides (e.g., dimethylsulfoxide, sulfolane), or ketones (e.g., acetone, methylisobutylke- tone) may be used either singly or as a mixture of two or more thereof. The use of nitriles, ethers, or mix- tures thereof with aromatic hydrocarbons is preferred.

The reaction stoichiometry between compounds of formulae (I) and compounds of formulae (II), as well as the stoichiometry between compounds of formulae (I) and compounds of formulae (VI), may range from 0.1 equiv. to 5 equiv., although a range from 0.5-1.5 equiv. is preferred.

The reaction may be carried out between -30 °C and 150 °C, and is preferably carried out between 20 °C and 60 °C. The reaction may be carried out between 0.1 bar and 10 bar pressure, and is preferably carried out between 0.8 bar and 1.2 bar.

The alkylation reaction between compounds of formulae (III) and (IV) may be performed neat or in the presence of a solvent. In reactions where a solvent is used, solvents such as amides (e.g., DMF, DMAC), nitriles (e.g., MeCN, PrCN), alcohols (e.g., MeOH, (z)-PrOH, (n)-BuOH), ethers (e.g., Et₂0, 2- methyltetrahydrofuran, THF, MTBE), esters (e.g., EtOAc, BuOAc), aromatic hydrocarbons or halogenated derivatives thereof (e.g., toluene, xylene, chlorobenzene, pyridine, 2-chloropyridine, 3-methylpyridine, 2- chloro-5-methylpyridine), hydrocarbons or halogenated derivatives thereof (e.g., methylcyclohexane, di- chloromethane, dichloroethane), sulfoxides (e.g., dimethylsulfoxide, sulfolane), ketones (e.g., acetone, me- thylisobutylketone), or water may be used either singly or as a mixture of two or more thereof. The use of nitriles, ethers, or mixtures thereof with aromatic hydrocarbons is preferred.

The reaction stoichiometry between compounds of formulae (III) and (IV) may range from 0.1 equiv. to 4 equiv., although a range from 0.5-1.5 equiv. is preferred.

The reaction may be carried out between 0 °C and 150 °C, and is preferably carried out between 20 °C and 80 °C.

The reaction may be carried out between 0.1 bar and 10 bar pressure, and is preferably carried out between 0.8 bar and 1.2 bar.

Furthermore, the acylation and alkylation steps can be carried out in a convenient tandem operation, allowing an efficient and rapid access to the desired compounds of formula (V), c.f. Example 3. The present invention is illustrated in detail by the following examples, although the examples should not be interpreted in a manner that restricts the invention.

Examples:

Example 1: Preparation of sodium pyridin-2-yl(trifluoroacetyl)azanide

50.0 g 2-aminopyridine and 81.6 g methyl trifluoroacetate were dissolved in 150 mL toluene. 95.7 g Na- OMe (30 % in MeOH) were added dropwise at room temperature. The reaction mixture was stirred for 2 h at room temperature and concentrated under reduced pressure to give 111.2 g of sodium pyridin-2- yl(trifluoroacetyl)azanide as an off-white solid in 94.8 % yield and 96.1 % purity. fZ-NMR (600 MHz, DMSO-Λ): δ = 8.17 (dd, 1H), 7.53-7.47 (m, 2H), 6.75 (m, 1H).

Example 2: Preparation of A-[(2£')-l-[(6-chloropyridin-3-yl)methyl]pyridin-2(l/ )-ylidene]-2^^- trifluoroacetamide

11.3 g sodium pyridin-2-yl(trifluoroacetyl)azanide were suspended in a solution of 8.1 g 2-chloro-5- (chloromethyl)pyridine in 15 mL acetonitrile at room temperature. The reaction mixture was stirred for 18 h at 50 °C. After this time 75 mL ¾0 were added at room temperature and the product was filtered off, washed with water, and dried under reduced pressure. Following this procedure 14.2 g N-[(2£)-l -[(6- chloropyridin-3-yl)methyl]pyridin-2(lH)-ylidene]-2,2,2-trifluoroacetamide could be isolated in 88.5 % yield and 97.9 % purity.

^!H-NMR (600 MHz, DMSO- ₆) δ = 8.71 (dd, 1H), 8.53 (d, 1H), 8.32 (dd, 1H), 8.08 (m, 1H), 7.88 (dd, 1H), 7.53 (d, 1H), 7.21 (m, 1H), 5.61 (s, 2H).

Example 3: Preparation of A-[(2£')-l-[(6-chloropyridin-3-yl)methyl]pyridin-2(l/ )-ylidene]-2^^- trifluoroacetamide following a one-pot procedure

5.0 g 2-aminopyridine, 8.2 g methyl trifluoroacetate and 8.6 g 2-chloro-5-(chloromethyl)pyridine were dissolved in 15 mL acetonitrile. 11.5 g NaOMe (30 % in MeOH) were added dropwise at room temperature and the reaction mixture was stirred for 18 h at 50 °C. After this time 75 mL ¾0 were added at room tem- perature and the product was filtered off, washed with water and dried under reduced pressure. Following this procedure 13.5 g N-[(2i?)-l-[(6-chloropyridin-3-yl)methyl]pyridin-2(lH)-ylidene]-2,2,2- trifluoroacetamide could be isolated as an off-white solid in 77.9 % yield and 96.9 % purity. This product gave a ¾ NMR spectrum that was identical to the spectrum obtained from the product in Example 2.

Claims

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

(V)

in which

Y is selected from the group consisting of halogen, Ci-6 alkyl and Ci-6 alkoxy;

n is chosen from 0, 1 and 2;

R¹ is selected from the group consisting of hydrogen, Ci-6 alkyl, Ci-6haloalkyl, phenyl, pyridyl; R² is selected from the group of following scaffolds where # marks its attacliment point

(VII) (VIII)

wherein

A is CH or N;

Z is independently selected from the group consisting of F, CI, Br, I, CF3;

m is 0, 1 or 2,

wherein a compound of formula (III) - lo

(III)

in which M is an alkali metal, and Y and n have the meanings given above, is reacted with a compound of formula (IV)

(IV)

wherein

X² is selected from the group consisting of halogen and sulfonate groups; and R¹ and R² have the meanings given above,

optionally in the presence of a solvent.

2. Process for the preparation of a compound of formula (III)

(III)

wherein a compound of formula (I) N H ₂

(I) in which

Y, and n are defined as in claim 1, is reacted with a compound of formula (II)

X^CF₃

O

(II) in which

X¹ is selected from the group consisting of OR³ and SR³;

R³ is selected from the group consisting of Ci-8 alkyl (which may be branched and/or contain ether, thioether, ester, alcohol, ketone, nitrile or amide groups), phenyl (which may be substituted with a Ci-s alkyl group, halogens, or nitro groups), a 2-pyridyl group (which may be substituted with Ci-4 alkyl groups or halogens), a succinimidyl group, a benzotriazole group, a 7-azabenzotriazole group, an N,N'-phosphoryl(bis(l ,

3-oxazolidin-2-one) group, or a tri(pyrrolidin-l -yl)-phosphonium group; in the presence of a compound of formula (VI)

R— OM

(VI) in which

R⁴ is Ci-g alkyl (which may be branched), -(CH₂)_n-OH (n = 2-4), or -(CH₂)_n-OCH₃ (n = 2-4) and M is defined as in claim 1 , optionally in the presence of a solvent. Process for the preparation of a compound of formula (V)