SK281056B6 - Process for the preparation of 3-(alpha-methoxy)methylenebenzofuranones and intermediates therefor - Google Patents

Abstract

4-Halo-6-phenoxy-pyrimidines of formula (I) are obtd. by (c) reacting a 3-methoxymethylene-benzofuranone of formula (II) with a methoxide of formula (XV); and (d) reacting with a dihalopyrimidine of formula (III); (where Z1, Z2 = halo; R = a metal; R1-R4 = H, halo, 1-4C alkyl, 1-4C alkoxy, acetoxy, or acyl; and W = (MeO)2CHCHCOOMe or MeOCH=CCOOMe. A more complete prepn. of (I) comprises either (b') reacting a benzofuranone of formula (XIV) with CH(OMe)3 or with a dimethoxymethyl carboxylate; (c') reaction with (XV); and (d) reaction with (III); or (a") lactonising a 2-hydroxyphenylacetic acid of formula (IX); and (b"), (c"), (d") treating the prod. as (XIV) in (b'), (c'), (d") above.

Description

The invention relates to a process for the production of certain 3- (α-methoxy) methylenebenzofuranones which can be used as intermediates for the production of phenoxypyrimidine compounds, which can be further used in the manufacture of fungicides.

BACKGROUND OF THE INVENTION

It is known that 3- (α-methoxy) methylenebenzofuran-2 (3H) -one can be prepared by methylating 3-formylbenzofuran-2 (3H) -one either with diazomethane or with methanolic sulfuric acid [J. A. Elix and B. A. Ferguson in the Australian Journal of Chemistry 26 (5), 1079-91 (1973)].

Attempts to formulate benzofuran-2 (3H) -one have been reported to have failed [A. D. Harmon and C.R. Hutchinson in Joumal of Organic Chemistry 40 (24), 3474-3480 (1975)].

SUMMARY OF THE INVENTION

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

wherein R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, an acetoxy group or an acyl group such as (C 1 -C 6) alkanoyl, for example acetyl, or benzoyl, in which the phenyl moiety is optionally substituted by halogen, (C 1 -C 4) alkoxy or (C 1 -C 4) alkyl group, characterized in that: sa compound of formula (xiv)

in which R ^{@ 1} , R ^{@ 2} , R ^{@ 3} and R ^{@ 4 are} as defined above, are reacted with trimethyl orthoformate.

Said reaction is preferably carried out in the presence of an activating agent, for example an acid anhydride.

The alkyl groups and alkyl portions of the alkoxy groups have either a straight or branched chain and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

Halogen atoms include fluorine, bromine and iodine atoms, and preferably chlorine.

A compound of formula (XIV) can be prepared by cyclizing a compound of formula (IX) wherein R ¹ , R ² , R ³ and R ^{4 are} as defined above. The product so formed is then reacted with trimethyl orthoformate to obtain a compound of formula (II).

The process for preparing a compound of formula (II) may also be carried out by reacting at a suitable temperature a mixture of a compound of formula (IX) and a compound of formula (XIV), optionally a compound of formula (IX) itself, with an acid anhydride and trimethyl orthoformate. .

It is preferred that all of R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms.

The reaction of a compound of formula (XIV) with trimethyl orthoformate is conveniently carried out in a suitable solvent, for example trimethyl orthoformate, or in an inert solvent such as a hydrocarbon solvent, for example toluene, at a suitable pressure, preferably in the range 0.1 to 0.5 MPa. at atmospheric pressure and at a suitable temperature, preferably in the range of 20 to 180 ° C, suitably 90 to 130 ° C, for example 95 to 110 ° C. It is preferred to use an acid anhydride, preferably an alkyl acid anhydride such as acetic anhydride or isobutyric anhydride with trimethyl orthoformate, in which case a suitable solvent may be an acid anhydride, trimethyl orthoformate or a mixture of the two solvents and / or an inert solvent such as a hydrocarbon solvent, e.g. .

The compounds of formula (II) may also be prepared by a two-step process. In the first step, the compound of formula (IX) is cyclized, conveniently by heating, preferably in the presence of another suitable acid, for example glacial acetic acid, which is preferably present in a catalytic amount, optionally in an inert high boiling solvent such as hydrocarbon solvents, e.g. toluene or xylene, at a suitable temperature, preferably at 20 to 250 ° C, suitably at 50 to 200 ° C, for example at 90 to 150 ° C and at a suitable pressure in the range of 0.01 to 1 MPa, preferably at atmospheric or autogenous pressure . When a solvent is used, it is preferred that the temperature at which the cyclization is carried out is the boiling point of said solvent or its azeotropic mixture with water. It is further preferred that any water formed during cyclization be removed during the reaction.

The second step consists in reacting the cyclization product of the compound of formula (IX) with trimethylorthoformate in a suitable solvent, for example trimethylorthoformate and / or in an inert solvent such as a hydrocarbon solvent such as toluene, and at a suitable temperature, preferably at 20 ° C. to 180 ° C, conveniently at 90 to 130 ° C, for example at 95 to 110 ° C, to give a compound of formula (II). It is further preferred that an acid anhydride, preferably an alkyl acid anhydride, for example acetic anhydride or isobutyric anhydride, is used with trimethyl orthoformate in this reaction. In this case, a suitable solvent may be an acid anhydride or a mixture of trimethyl orthoformate and an acid anhydride.

Both steps of this two-step process can be combined into a "single-pot" process.

The compound of formula (II) may also be prepared by reacting a compound of formula (IX) with an acid anhydride, preferably an alkyl acid anhydride, e.g. acetic anhydride or isobutyric anhydride and trimethyl orthoformate, optionally in a suitable solvent, e.g. trimethyl orthoformate or a mixture of the two solvents and / or optionally in an inert solvent such as a hydrocarbon solvent, for example toluene or xylene,

at a suitable temperature, preferably at 20 to 250 ° C, suitably at 50 to 200 ° C, for example at 90 to 150 ° C and at a suitable pressure in the range of 0.01 to 1 MPa, preferably at atmospheric or autogenous pressure.

The compound of formula (II) may also be prepared by reacting a mixture of compounds of formulas (XIV) and (IX) with trimethyl orthoformate and an acid anhydride, preferably an alkyl acid anhydride, for example acetic anhydride, or isobutyric anhydride, optionally in a suitable a solvent, for example acetic anhydride or trimethyl orthoformate or a mixture of the two solvents or a mixture of one or both of an inert solvent such as a hydrocarbon solvent, for example toluene or xylene, at a suitable temperature, preferably at 20 to 250 ° C, suitably at 50 to 200 ° C, for example at 90 to 150 ° C and at a suitable pressure, preferably in the range of 0.01 to 1 MPa, usually at atmospheric or autogenous pressure.

Under suitable conditions, the acid anhydride, for example acetic anhydride, may be reacted with trimethyl orthoformate to form a dimethoxymethyl carboxylate, for example dimethoxymethyl acetate. Accordingly, a compound of formula (II) may also be prepared by reacting a compound of formula (XIV) with a dimethoxymethyl carboxylate, preferably dimethoxymethyl acetate, at a suitable temperature, preferably in the range of 20 to 180 ° C, suitably 90 to 130 ° C, e.g. Mp 95-100 ° C.

In all variations of the preparation of the compound of formula (II), it is preferred that the apparatus in which the process is carried out is adapted to allow removal of volatile by-products.

Compounds of formula (IX) can be obtained by standard methods described in the literature. In addition to the described methods for producing compounds of formula (XIV) from compounds of formula (IX), methods described in the literature may be used to produce compounds of formula (XIV).

Compounds of formula (II) may be used to produce phenoxypyrimidine compounds of formula (6)

in which

W is (CH ₃ O) ₂ CHCHCO ₂ CH ₃ or CH ₂ OCH = CCO ₂ CH 3.

Z ¹ represents a halogen atom and R ¹ , R ² , R ³ and R ⁴ are as defined above.

The process for the preparation of compounds of formula (I) is the subject of our co-pending Slovak patent application PV483-93.

The compounds of formula (I) are further used as intermediates for the production of fungicides.

The following examples further illustrate the invention but do not limit it in any way. Example 7 is present to compare the method of the invention with another method.

DETAILED DESCRIPTION OF THE INVENTION

All reactions are carried out under a nitrogen atmosphere.

The NMR data are selective. It was not considered necessary to record each signal.

Example 1

This example illustrates the preparation of 3- (α-methoxy) methylenebenzofuran-2 (3H) -one.

10.2 g of benzofuran-2 (3H) -one, 30 cm ^{3 of} acetic anhydride a

12.1 g of trimethyl orthoformate are stirred for 12 hours at 100-105 ° C. During this time, low boiling liquids are removed using a Dean-Stark apparatus.

The reaction mixture was allowed to cool and concentrated under reduced pressure using a water bath temperature of 60 ° C to give a brown solid. This material is dissolved in 100 cm @ ^{3 of} dichloromethane, washed twice with 50 cm @ ^{3 of} water and concentrated under reduced pressure using a water bath temperature of 60 DEG C. to give 13.5 g of crude product. A portion of this crude product was added to the crude product from similar experiments and all the crude product was taken up in methanol and treated with activated carbon. Then, the methanolic solution was refluxed for 30 minutes, cooled to below 10 ° C, filtered and the residue washed with cold methanol. The residue was dried at 50 ° C under vacuum to give an off-white solid, mp 102-103 ° C.

The following physical values were found in the product from a similar experiment;

1 H-NMR (CDCl 3, 250 MHz): δ 7.6 (1H, s), 7.6-7.1 (4H, m), 4.15 (3H, s) ppm, ¹³ C-NMR (CDCl 3) , 62.9 MHz): δ 169.9, 160.1, 152.0, 128.3, 123.9, 123.0, 122.8, 110.4, 103.9, 63.9 ppm.

Mass spectrometry: molecular ion m / z 176.

Example 2

This example illustrates an alternative preparation of 3- (α-methoxy) methylenebenzofuran-2 (3H) -one.

15.2 g of o-hydroxyphenylacetic acid, 95 cm ^{3 of} toluene and 5 cm ^{3 of} glacial acetic acid are mixed and heated to reflux for 4 hours. After this time, no undissolved starting material is present. During this time, 2.2 ml of water was isolated in the Dean-Stark apparatus. The reaction mixture was then cooled and allowed to stand overnight.

40 cm @ ^{3 of} acetic anhydride are then added to the reaction mixture and 100 cm @ ³ of low boiling solvents (predominantly toluene) are distilled off. After cooling to below 50 ° C, 15.9 g of trimethyl orthoformate are added to the reaction mixture, followed by heating at 100-105 ° C for 20 hours. Analysis by gas chromatography revealed that approximately 5% of the 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.

g of benzofuran-2 (3H) -one, 11.3 g of o-hydroxyphenylacetic acid, 60 cm ^{3 of} acetic anhydride and 23.7 g of trimethyl orthoformate were heated at 100-105 ° C for 14 hours. During this time some volatile products were isolated using a Dean-Stark apparatus. Analysis of the reaction mixture revealed that approximately 5% of the starting material was still present.

The reaction mixture was concentrated under reduced pressure to a water bath temperature of 70 ° C to give 28.24 g of crude product. This product was combined with the crude product from a similar experiment and recrystallized from methanol to give the title compound at the beginning of this example.

SK 281056 Β6

Example 4

This example illustrates an alternative preparation of 3- (α-methoxy) methylenebenzofuran-2 (3H) -one.

7.95 g of trimethyl orthoformate, 25 cm ³ of isobutyric anhydride and 7.6 g of o-hydroxyphenylacetic acid are mixed and heated to 100 ° C for 19 hours. During this time, low boiling liquids are isolated using a Dean-Stark apparatus.

The reaction mixture was then concentrated under reduced pressure using a water bath temperature of 85 ° C to yield

8.64 g of black oil. This black oil is taken up in 20 ml of hot methanol and cooled to yield

4.16 g of the title compound as a crystalline product.

Example 5

This example illustrates the preparation of 3 - [(α-methoxy) -methylene] -5-chlorobenzofuran-2 (3H) -one.

g (0.02 mol) of 5-chlorobenzofuran-2 (3H) -one, 16.7 g (0.16 mol) of acetic anhydride and 4.24 g (0.04 mol) of trimethyl orthoformate are heated at 100 ° C for 2 hours. hours. After this time, the reaction mixture was cooled to 20 ° C and then concentrated under reduced pressure in a 70 ° C water bath to give 3.7 g of the crude product as a dark red tar.

This tar was dissolved in 5 mL of hot methanol and allowed to cool. A solid crystallizes out of this solution.

The above procedure of dissolving the crude product in hot methanol and then collecting the solid was repeated twice to give 0.3 g of the title compound as a light yellow-brown solid, mp 128-130 ° C.

'H-NMR (CDCl3, 250 MHz): δ 7.6 (1H, s), 7.6-7.0 (3H, m), 4.2 (3H, s) ppm.

Example 6

This example illustrates the preparation of 3 - [(α-methoxy) -methylene] -5-acetoxybenzofuran-2 (3H) -one.

ml of acetic anhydride and 1 g (0.0067 mol) of 5-hydroxybenzofuran-2 (3H) -one were stirred at room temperature under nitrogen for 10 minutes. After this time, 1.06 g (0.01 mol) of trimethyl orthoformate was added and the resulting reaction mixture was heated at 100 ± 5 ° C for 12 hours. The reaction mixture was then allowed to cool to room temperature and a pink solid separated.

The reaction mixture was concentrated under reduced pressure in a 70 ° C water bath to give a pink solid residue. This pink solid was dissolved in 50 mL of dichloromethane and the resulting solution was washed with 50 mL of cold water. The organic layer was then concentrated under reduced pressure in a 70 ° C water bath to give 1.15 g of the title compound as needles pink crystals, mp 206-210 ° C.

'H-NMR (CDCl3, 250 MHz): δ 7.6 (1H, s),

7.4 - 6.9 (3H, m), 4.2 (3H, s) ppm ^{, 3} C-NMR (CDCl 3, 100.6 MHz): δ 169.8, 169.5, 160.7, 149.0 , 146.6, 123.2, 121.0, 116.3, 110.6, 103.4, 6.8,

21.1 ppm.

Example 7

This example illustrates an alternative preparation of 3- (α-ethoxy) methylenebenzofuran-2 (3H) -one.

6.7 g (0.05 mol) of benzofuran-2 (3H) -one are dissolved in 40 g of toluene under nitrogen at 20-25 ° C. 12.15 g (0.075 mol) of diethoxymethylacetate are added and the reaction solution is heated at 100-105 ° C for 28 hours with the distillation of low-boiling by-products. Toluene and unreacted diethoxymethylacetate were distilled off to give 9.53 g of a yellow solid which was recrystallized from methanol and dried at 50 ° C to give the title compound as a solid, m.p. 102 ° C.

1 H-NMR (CDCl 3, 62.9 MHz): δ 1.5 (3H, t), 4.4 (2H, q), 7.1-7.6 (4H, m), Ί, Ί (1H , s) ppm, ⁿ C-NMR (CDCl3, 62.9 MHz): δ 169.8, 158.9, 151.5, 127.8, 123.6, 122.7, 110.0, 103.2, 72.8, 15.5 , 4 ppm.

Mass spectrometry: molecular ion m / z 190.

Claims (3)

Process for the preparation of 3- (α-methoxy) methylenebenzofuranones of the general formula (II) in which R ¹ , R ² , R 1 and R ⁴ , independently of one another, represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 C 1 -C 4 alkoxy, acetoxy, C 1 -C 6 alkanoyl or benzoyl in which the phenyl moiety is optionally substituted by halogen, C 1 -C 4 alkoxy or C 1 -C 4 alkyl The compounds of formula (XIV) in which R ^{@ 1} , R ^{@ 2} , R ^{@ 3} and R ^{@ 4 are} as defined above are reacted with trimethyl orthoformate. Process according to claim 1, characterized in that it is carried out in the presence of an acid anhydride. Process according to claim 1, characterized in that a compound of formula (XIV) is used in which all the substituents R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms.