Process for the preparation of 3,3-diaryl acrylic acid amides

Abstract: The invention provides a process for the preparation 3,3-diaryl acrylic acid amides of the formula in which A, B and Q are as defined in the specification, characterised by condensing a compound of formula with a compound of formula ZCH₂-CO-Q (III) in which Z represents a hydrogen or halogen atom, and, if an intermediate compound is formed of formula dehydrating the intermediate compound.

Description: The invention concerns a new process for the preparation of 3,3-diaryl acrylic acid amides of the formula in which A represents B represents and Q represents or where R₁ represents a C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, mono- or di-(C₁₋₄ alkyl)amino, C₃₋₄ alkenyl, C₃₋₄ alkynyl, C₃₋₄ alkenyloxy, C₃₋₄ alkynyloxy or C₃₋₆ cycloalkyl group; R₂ represents a C₁₋₄ alkyl or C₁₋₄ alkoxy group or a halogen atom; R₃ represents a hydrogen or halogen atom; R₄ represents a hydrogen or halogen atom or a C₁₋₄ alkyl or C₁₋₄ alkoxy group; R₅ represents a hydrogen atom, a phenyl group optionally substituted by one or more substituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, phenyl and phenoxy moieties, a C₁₋₁₂ alkyl group optionally substituted by one or more halogen atoms, a C₃₋₇ cycloalkyl group, a C₂₋₆ alkenyl or a C₂₋₆ alkynyl group each optionally substituted by a phenyl group, or a naphthyl or C₅₋₈ cycloalkenyl group; -X-Y- represents a single bond or a -O-, -S(O) p -where p is 0, 1 or 2, -N=N-, -CHR₁₀-O-, -O-CHR₁₀-, -CHR₁₀-S(O) p -, -S(O) p -CHR₁₀-, - C n H 2n - where n is an integer from 1 to 10, -HC=CH- or -C≡C- moiety; R₆ represents a C₁₋₄ alkyl, C₃₋₇ cycloalkyl, benzyl, C₃₋₄ alkenyl or C₃₋₄ alkynyl group; R₇ represents a C₁₋₄ alkyl group; R₈ represents a hydrogen atom or a C₁₋₄ alkyl or C₁₋₄ alkoxy group; and R₉ and R₁₀ independently represent a hydrogen atom or a C₁₋₄ alkyl group. Compounds of formula I are fungicidally active and are particularly useful in the control of phytopathogenic fungi, especially Plasmopara victicola and Phytophthora infestans. Particularly preferred compounds of formula I in this respect are those in which A represents a 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 3-methyl-4-methoxyphenyl, 3-ethyl-4-methoxyphenyl, 3-propyl-4-methoxyphenyl, 3,4-dimethylphenyl, 3-amino-4-methoxyphenyl, 3,5-dichloro-4-aminophenyl or 3-methoxy-4-methylphenyl group and, of these, 3,4-dimethoxyphenyl is especially preferred. It is also preferred that Q represents a morpholino group. An especially preferred compound of formula I is 3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl) acrylic acid morpholide. Compounds of formula I form the subject of European patent applications nos. 84102012.6 and 86113835.2, published as EP 0 120 321 A1 and EP 0219756 A1 respectively, and these documents describe methods for the preparation of these compounds. Additionally, W. Chodkiewicz et al, Bull. Soc. Chim. France, 1958 , pp. 1586-91 describes, inter alia, the preparation of diaryl α-ethylenic amides by condensing a diarylketone with an acetamide or N-acetyl morpholine in the presence of a strong base to form an intermediate β-hydroxyamide and then dehydrating the β-hydroxyamide by heating it in the presence of an acid, preferably a mixture of sulphuric and acetic acids, to obtain the desired diaryl α-ethylenic amide. However, it has now been surprisingly discovered that compounds of formula I can also be prepared by reacting a benzophenone with an appropriate acetamide, in a modification of a known reaction, followed, if necessary, by dehydration under alkaline conditions. According to the present invention there is therefore provided a process for the preparation of a compound of formula I, as defined above, which comprises condensing a compound of formula in which A and B have the meanings given above, with a compound of formula CH₃-CO-Q (III) in which Q has the meaning given above, in the presence of a strong base and a solvent at a temperature from room temperature to the reflux temperature of the reaction mixture and, if an intermediate compound is formed of formula in which A, B and Q have the meanings given above, dehydrating the intermediate compound characterised in that the intermediate compound of formula IV is dehydrated by heating in an inert solvent under alkaline conditions. The above process can be represented by the following reaction scheme:- In this scheme A, B and Q are as defined above. As shown in the scheme, depending on the reaction conditions and reagents used, the above reaction may proceed directly to the final product of formula I in one step or may proceed in two steps via an intermediate of formula IV. In the latter case, a separate dehydration step is required to produce the final product of formula I. As stated above, the condensation reaction is carried out in the presence of a strong base. Suitable strong bases include alkali hydroxides, alkali carbonates, potassium tert-butylate and tert-butyl lithium. Depending on the base used and the temperature at which the reaction is carried out, compounds of formula I are sometimes formed directly by elimination of water without the need for a separate dehydration step. (cf. W. Chodkiewicz et al, Bull. Soc. Chim. France, 1958 , 1586-9). The reactions are carried out in the presence of an inert solvent, such as toluene, benzene, diethyl ether, diisopropyl ether, diglyme, tetrahydrofuran, dimethyl formamide, acetone or ethylene chloride. Alternatively, an excess of one of the reactants may also serve as a solvent. Depending on the reactivity of the reactants, the condensation reaction may be carried out at any temperature from room temperature to the reflux temperature of the reaction mixture. Compounds of formula II and formula III are either known compounds or can be produced from known compounds by known methods. The process of the invention is illustrated by the following specific examples. Example 1 (Comparative Example) Preparation of 3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid morpholide 6.92g (25 mmol) 4-chloro-3',4'-dimethoxybenzophenone, 12.9g (100 mmol) N-acetylmorpholine and 11.2g (170 mmol) powdered potassium hydroxide (85%) were mixed well and allowed to stand at room temperature for 30 minutes, with occasional stirring. The viscous mass so obtained was then added to a vigorously stirred mixture of 100 ml water and 50 ml toluene. The toluene phase was dried and separated over a column containing 50g silica gel using 150 ml each of 95:5, 90:10 and 80:20 toluene-acetone mixture as eluant. The fractions with an Rf value of 0.37 (Toluene/Acetone 7:3) were evaporated in a rotary evaporator, after which 0.8 g of the title compound were obtained by trituration with a little diisopropyl ether. By evaporating the fractions with an Rf value of 0.52, 3.4g (33.5% of theory) of 3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)-3-hydroxypropionic acid morpholide were obtained, m.pt. 150°C. For the dehydration step, this substance was then dissolved in 10 ml glacial acetic acid by warming, 0.1 ml conc. sulphuric acid were added and the mixture was then boiled under reflux for 5 minutes. After cooling to 50°C, the mixture was stirred into 100 ml water. The oil that initially separated out solidified on further stirring. The substance was then filtered off under suction, washed with water and dried. Thin layer chromatography (TLC) indicated that the final product was substantially pure. Yield: 2.9g (30% of theory) Total yield: 3.7g (38% of theory), TLC - pure. Example 2 Preparation of 3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl)acrylic acid morpholide 13.84g (50 mmol) 4-chloro-3′,4′-dimethoxybenzophenone, 7.75g (60 mmol) N-acetylmorpholine, 7.29g (65 mmol) potassium tert-butylate and 75 ml anhydrous toluene were mixed and stirred for 2 hours under nitrogen at 80°C. The solution was then cooled, extracted with 100ml water, dried and evaporated in a rotary evaporator. 11.5g of a viscous oil were obtained, which were then heated with 50 ml diisopropyl ether whilst stirring. The oil crystallised on cooling and rubbing. The crystals were then filtered off under suction, washed with a little diisopropyl ether and dried. Yield : 9.25g (48% of theory) M.pt : 122-148°C TLC-pure, R.f. value: 0.38 in 7:3 toluene/acetone. Example 3 Preparation of 3-(4-chlorophenyl)-3-(3,4-dimethoxyphenyl) acrylic acid morpholide 5.53g (20 mmol) 4-chloro-3′,4′-dimethoxybenzophenone, 3.23g (25 mmol) N-acetylmorpholine, 3.29g (50 mmol) powdered potassium hydroxide (85%) and 30 ml absolute tetrahydrofuran were stirred under reflux for 5 hours under nitrogen. After cooling, the liquid paste so obtained was added to a well stirred mixture of 100 ml water and 50 ml toluene. The toluene phase was dried and separated over a column containing 50g silica gel, using 100 ml each of 95:5, 90:10 and 80:20 toluene-acetone mixture as eluant. The fractions containing a substance with an Rf-value of 0.38 (Toluene/Acetone 7:3) were then evaporated in a rotary evaporator. The oil thus obtained solidified on trituration with a little diisopropyl ether. M.pt: 125-145°C Yield: 3.25g (42% of theory)

Claims: A process for the preparation of a compound of formula in which A represents B represents and Q represents or where R₁ represents a C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, mono- or di-(C₁₋₄ alkyl)amino, C₃₋₄ alkenyl, C₃₋₄ alkynyl, C₃₋₄ alkenyloxy, C₃₋₄ alkynyloxy or C₃₋₆ cycloalkyl group; R₂ represents a C₁₋₄ alkyl or C₁₋₄ alkoxy group or a halogen atom; R₃ represents a hydrogen or halogen atom; R₄ represents a hydrogen or halogen atom or a C₁₋₄ alkyl or C₁₋₄ alkoxy group; R₅ represents a hydrogen atom, a phenyl group optionally substituted by one or more substituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, phenyl and phenoxy moieties, a C₁₋₁₂ alkyl group optionally substituted by one or more halogen atoms, a C₃₋₇ cycloalkyl group, a C₂₋₆ alkenyl or C₂₋₆ alkynyl group each optionally substituted by a phenyl group, or a naphthyl or C₅₋₈ cycloalkenyl group; -X-Y- represents a single bond or a -O-, -S(O) p - where p is 0, 1 or 2, -N=N-, -CHR₁₀-O-, -O-CHR₁₀-, -CHR₁₀-S(O) p -, -S(O) p -CHR₁₀-, -C n H 2n - where n is an integer from 1 to 10, -HC=CH- or -C≡C- moiety; R₆ represents a C₁₋₄ alkyl, C₃₋₇ cycloalkyl, benzyl, C₃₋₄ alkenyl or C₃₋₄ alkynyl group; R₇ represents a C₁₋₄ alkyl group; R₈ represents a hydrogen atom or a C₁₋₄ alkyl or C₁₋₄ alkoxy group; and R₉ and R₁₀ independently represent a hydrogen atom or a C₁₋₄ alkyl group; which comprises condensing a compound of formula in which A and B have the meanings given above, with a compound of formula CH₃-CO-Q (III) in which Q has the meaning given above, in the presence of a strong base and a solvent at a temperature from room temperature to the reflux temperature of the reaction mixture, and, if an intermediate compound is formed of formula in which A, B and Q have the meanings given above, dehydrating the intermediate compound characterised in that the intermediate compound of formula IV is dehydrated by heating in an inert solvent under alkaline conditions. A process according to claim 1 in which the strong base is selected from alkali hydroxides, alkali carbonates, potassium tert-butylate and tert-butyl lithium. A process according to claim 1 in which the solvent is selected from toluene, benzene, diethylether, diisopropyl ether, diglyme, tetrahydrofuran, dimethyl formamide, acetone and ethylene chloride.

Inventors: CURTZE JUERGEN, CURTZE, JUERGEN, Curtze, Jürgen 
Applicants: SHELL INT RESEARCH, SHELL INTERNATIONALE RESEARCH MAATSCHAPPIJ B.V.
Application year: 1988
Main classification: C07D295
IPC codes: C07C323, C07D265, C07C245, C07D295, C07C315, C07C67, C07C231, C07C313, C07C317, C07C237, C07C241, C07C235