Chemical process

Abstract: Processes for the preparation of compounds (X), (XI) and (XII): where M is an alkali metal or alkaline earth metal and n is 1 or 2, and for obtaining compound (X) in a substantially pure form. These compounds are useful intermediates in the manufacture of fungicides.

Description: This invention relates to a process for preparing 3-(α-methoxy)methylenebenzofuranone which is useful as an intermediate in the preparation of certain fungicides. It is known that 3-(α-methoxy)methylenebenzofuran-2(3H)-one can be made by methylation of 3-formylbenzofuran-2(3H)-one with either diazomethane or methanolic sulphuric acid [J.A. Elix and B.A. Ferguson in Australian Journal of Chemistry 26 (5) 1079-91 (1973)]. Attempts to formylate benzofuran-2(3H)-one are reported to have been unsuccessful [A.D. Harmon and C.R. Hutchinson in Journal of Organic Chemistry 40 (24) 3474-3480 (1975)]. According to the present invention there is provided a process for the preparation of a compound of formula (X), and stereoisomers thereof, by: i) reacting a compound of formula (XIII) with trimethyl orthoformate (preferably in the presence of an activating agent such as an acid anhydride); or ii) reacting a compound of formula (XVII) with an acid anhydride and trimethyl orthoformate at a suitable temperature; or iii) cyclising a compound of formula (XVII) and reacting the product so formed with trimethyl orthoformate (preferably in the presence of an activating agent such as an acid anhydride) or a dimethoxymethyl carboxylate; or iv) reacting a mixture of compounds of formulae (XIII) and (XVII) with an acid anhydride and trimethyl orthoformate; or v) reacting a compound of formula (XIII) with a dimethoxymethyl carboxylate (such as dimethoxymethyl acetate). The compound of general formula (X) can exist in the form of two geometric isomers, referred to as ( E )- and ( Z )-isomers. The process of the present invention predominantly produces the ( E )-isomer. The foregoing process of the invention is shown diagrammatically in Scheme I. The compound of formula (X) can be prepared by reacting a compound of formula (XIII) with trimethyl orthoformate in a suitable solvent (for example trimethyl orthoformate or an inert solvent such as a hydrocarbon solvent, for example toluene), at a suitable pressure, preferably in the range 1-5 atmospheres, usually atmospheric pressure, and at a suitable temperature (preferably in the range 20-180°C, suitably 90-130°C (for example 95-110°C)). It is preferred that an acid anhydride (preferably an alkyl acid anhydride (for example acetic anhydride or iso -butyric anhydride)) is used with the trimethyl orthoformate in this reaction, and in this case the suitable solvent can be the acid anhydride, trimethyl orthoformate, or a mixture of the two and/or an inert solvent such as a hydrocarbon solvent, for example toluene. Alternatively, the compound of formula (X) can be prepared by a 2-step process. The first step comprises cyclising a compound of formula (XVII), suitably by heating it, preferably in the presence of another suitable acid (for example glacial acetic acid) which is preferably present in a catalytic amount, optionally in a suitably high boiling point and inert solvent (such as a hydrocarbon solvent (for example toluene or a xylene)) at a suitable temperature, preferably 20-250°C, suitably 50-200°C, for example 90-150°C, and at a suitable pressure in the range 0.1-10 atmospheres, preferably at atmospheric or autogenic pressure. It is preferred that when a solvent is used, the temperature at which this cyclisation is carried out is the boiling point of said solvent or its azeotrope with water. It is further preferred that any water generated by the cyclisation is removed during the course of the reaction. The second step comprises reacting the product of cyclisation of the compound of formula (XVII) with trimethyl orthoformate in a suitable solvent (for example trimethyl orthoformate and/or an inert solvent such as a hydrocarbon solvent, for example toluene) and at a suitable temperature (preferably 20-180°C, suitably 90-130°C, for example 95-110°C) to give the compound of formula (X). It is further preferred that an acid anhydride (preferably an alkyl acid anhydride (for example acetic anhydride or iso -butyric anhydride)) is used with the trimethyl orthoformate in this reaction. In this case the suitable solvent can be the acid anhydride or a mixture of trimethyl orthoformate and the acid anhydride. It is probable that the product of the cyclisation of the compound of formula (XVII) is the compound of formula (VIII). The two steps of this 2-step process can be combined in a "one-pot" process. Alternatively the compound of formula (X) can be prepared by reacting a compound of formula (XVII) with an acid anhydride (preferably an alkyl acid anhydride (for example acetic anhydride or iso -butyric anhydride)) and trimethyl orthoformate, optionally in a suitable solvent (for example acetic anhydride or trimethyl orthoformate or a mixture of the two and/or optionally an inert solvent such as a hydrocarbon solvent, for example toluene or a xylene), at a suitable temperature (preferably 20-250°C, suitably 50-200°C, for example 90-150°C), and at a suitable pressure in the range 0.1-10 atmospheres, preferably at atmospheric or autogenic pressure. Alternatively the compound of general formula (X) can be prepared by reacting a mixture of compounds of formulae (XIII) and (XVII) with trimethyl orthoformate and an acid anhydride (preferably an alkyl acid anhydride (for example, acetic anhydride or iso -butyric anhydride)), optionally in a suitable solvent (for example, acetic anhydride or trimethyl orthoformate or a mixture of the two or a mixture of one or both with an inert solvent such as a hydrocarbon solvent, for example toluene or a xylene), at a suitable temperature (preferably 20-250°C, suitably 50-200°C, for example 90-150°C) and at a suitable pressure, preferably in the range 0.1-10 atmospheres, usually atmospheric or autogenic pressure. Under suitable conditions an acid anhydride (for example acetic anhydride) can react with trimethyl orthoformate to form a dimethoxymethyl carboxylate (for example dimethoxymethyl acetate). Therefore, in another alternative, the compound of formula (X) can be prepared by reacting a compound of formula (XIII) with a dimethoxymethyl carboxylate (preferably dimethoxymethyl acetate) at a suitable temperature, preferably in the range 20-180°C, suitably 90-130°C (for example 95-100°C). In another aspect the present invention provides a process for the preparation of the compound of formula (X), and stereoisomers thereof, the process comprising reacting a compound of formula (XIII) with a dimethoxymethyl carboxylate at a suitable temperature, preferably in the range of 20-180°C, suitably 90-130°C (for example 95-110°C). For all processes for the preparation of the compound of formula (X) it is preferred that the apparatus in which the process is carried out is adapted to allow the removal of volatile by-products. The compound of formula (X) is 3-(α-methoxy)-methylenebenzofuran-2(3H)-one. EXAMPLES The following Examples illustrate the invention. All reactions were performed under an atmosphere of nitrogen. Where shown, NMR data are selective; no attempt is made to list every signal. The following abbreviations are used throughout: mpt = melting point m = multiplet MS = mass spectrum s = singlet EXAMPLE 1 This Example illustrates a preparation of 3-(α-methoxy)methylenebenzofuran-2(3H)-one. Benzofuran-2(3H)-one (10.2g), acetic anhydride (30 cm 3 ) and trimethyl orthoformate (12.1g) were stirred at 100-105°C for 12 hours. During this time, low boiling point liquids were collected using a Dean and Stark apparatus. The reaction mixture was allowed to cool and was concentrated under reduced pressure (using a water bath temperature of 60°C) to give a brown solid. This was dissolved in dichloromethane (100cm 3 ) and this solution was washed with water (2x50 cm 3 ) and concentrated under reduced pressure (using a water bath temperature of 60°C) to give a crude product (13.5g). Some of this crude product was added to crude product from similar experiments, and the total crude product was taken up in methanol and treated with activated carbon. After this, the methanolic solution was refluxed for 30 minutes, cooled to below 10°C, filtered and the residue was washed with cold methanol. The residue was dried at 50°C under vacuum to give an off-white solid with a mpt of 102-103°C. The product from a similar experiment gave the following physical data: 1 H NMR (CDCl 3 , 250MHz): δ 7.6(1H,s); 7.6-7.1(4H,m), 4.15(3H,s) ppm. 13 C NMR (CDCl 3 , 62.9MHz): δ 169.9,160.1, 152.0, 128.3, 123.9, 123.0, 122.8, 110.4, 103.9, 63.9 ppm. MS: molecular ion m/z 176. EXAMPLE 2 This Example illustrates an alternative preparation of 3-(α-methoxy)-methylene-benzofuran-2(3H)-one. o -Hydroxyphenylacetic acid (15.2g), toluene (95cm 3 ) and glacial acetic acid (5cm 3 ) were mixed and heated to reflux for 4 hours, after which time there was no undissolved starting material. During this time water (2.2ml) was collected in a Dean and Stark apparatus. The reaction mixture was then cooled and allowed to stand overnight. Acetic anhydride (40cm 3 ) was then added to the reaction mixture and the low boiling solvents (mostly toluene) (100 cm 3 ) were distilled off. After cooling to below 50°C, trimethyl orthoformate (15.9g) was added to the reaction mixture which was then heated to 100-105°C for 20 hours. Analysis by gas chromatography showed that about 5% of starting material remained. The reaction mixture was worked-up and purified as in Example 1. EXAMPLE 3 This Example illustrates an alternative preparation of 3-(α-methoxy)-methylenebenzofuran-2(3H)-one. Benzofuran-2(3H)-one (10g), o -hydroxyphenylacetic acid (11.3g), acetic anhydride (60cm 3 ) and trimethyl orthoformate (23.7g) were heated to 100-105°C for 14 hours. During this time some volatile products were collected in a Dean and Stark apparatus. Analysis of the reaction mixture showed that there was still about 5% of starting material present. The reaction mixture was concentrated under pressure (water bath at 70°C) to give a crude product (28.24g). This was combined with crude product from a similar experiment and recrystallised from methanol to give the title compound. EXAMPLE 4 This Example illustrates an alternative preparation of 3-(α-methoxy)-methylenebenzofuran-2(3H)-one. Trimethyl orthoformate (7.95g), iso -butyric anhydride (25cm 3 ) and o -hydroxyphenylacetic acid (7.6g) were mixed and heated to 100°C for 19 hours. During this time low boiling point liquids were collected using a Dean and Stark apparatus. The reaction mixture was then concentrated under reduced pressure (using a water bath temperature of 85°C) to leave a black oil (8.64g). The black oil was taken up in hot methanol (20ml) and on cooling this solution gave the title compound as a crystalline product (4.16g).

Claims: A process for the preparation of a compound of formula (X): which comprises: i) reacting a compound of formula (XIII): with trimethyl orthoformate; or ii) reacting a compound of formula (XVII): with an acid anyhydride and trimethyl orthoformate at a suitable temperature; or iii) (a) cyclising a compound of formula (XVII): and (b) reacting the product so formed with either trimethyl orthoformate or a dimethoxymethyl carboxylate; or iv) reacting a mixture of compounds of formula (XIII) and (XVII): with an acid anhydride and trimethylorthoformate; or v) reacting a compound of formula (XIII): with a dimethoxymethyl carboxylate.

Inventors: COX BRIAN GEOFFREY, DEBOOS GARETH ANDREW, FIELDEN JAN MICHAEL, JONES JOHN DAVID, WILKINSON PAUL, COX, BRIAN GEOFFREY, DEBOOS, GARETH ANDREW, FIELDEN, JAN MICHAEL, JONES, JOHN DAVID, WILKINSON, PAUL
Applicants: SYNGENTA LTD, SYNGENTA LIMITED
Application year: 1991
Main classification: C07D307
IPC codes: C07D307, C07D239