CS236696B2 - Manufacturing process of 8-halogenalkyl-4h-(1)-benzopyran-4- - Google Patents

Abstract

L'invention concerne des haloalkyl -8-4H-[1]-benzo- pyran-4-ones.

Les composés sont représentés par la formule dans laquelle AR est l'hydrogène, un radical phényle, phényle substitué - par un radical alkyle inférieur, alkoxy inférieur ou un halogène - un radical thényle, pyridyle, furyle, naphtyie, alkyle, cycloalkyle ou aralkyle, X est un halogène et Y l'hydrogène, un radical alkyle inférieur, alkoxy ou un halogène, R₁ est l'hydrogène, un radical alkoxy ou phényle.

Ils sont utilisables en tant que produits industriels intermédiaires dans la synthèse de produits pharmaceutiques et de pesticides.

Description

(54) A method for producing 8-haloalkyl-4H- [1] -benzopyran-4-one

The present invention relates to a process for the preparation of 8-haloalkyl-4H- [1] -benzopyran-4-ones and to novel intermediates useful in the preparation of these compounds.

8-haloalkyl-4H- [1] -benzopyran-4-ones can be represented by the general formula I

Y is hydrogen, (C 1 -C 4) alkyl or halogen;

R ¹ is hydrogen, C 1 -C 4 alkoxy or phenyl.

These compounds are useful, industrially useful intermediates in various syntheses, particularly in the field of pesticides and pharmaceutical products, such as (4-oxo-4H- [1] -benzopyran-8-yl) carboxylic acids and derivatives thereof. 4H- [1] -benzopyran-4-ones form a very interesting group of these compounds, which can be represented by the general formula Ia wherein:

AR is hydrogen, phenyl optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or halogen, thenyl, pyridyl, furyl, naphthyl, C1-C4 alkyl, cycloalkyl (C 3 -C 6), (C 1 -C 4) -alkyl, or (C 2 -C 4) -alkenyl;

X is halogen, especially bromine,

236896 where

Ar, R ¹ and Y are as defined above.

Halogenbenzopyranones of general formulas

I and Ia can be prepared by the process according to the invention in good yields.

The following reaction scheme illustrates the preparation of 8-bromomethyl-2-phenyl-4H- [1] from:

_______ _____

-benzopyran-4-one according to the process of the invention

CH _Z OCH ₃

In the process according to the invention, the starting compound (II) is treated in a first step

Y

COCHg-ft

OR ^Z

(II) where

Y is hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy or halogen,

^R1 is hydrogen or phenyl, and

R ² represents hydrogen or alkyl having 1 to 4 carbon atoms in the polyoxymethylene <presence of concentrated hydrochloric acid to form the formula III chlormethylfenylketonu

R ^1, R ² and Y are as defined above.

The reaction is carried out at a moderately elevated temperature of 50-60 ° C for up to 7 hours, after cooling the product obtained is extracted with benzene, the solids are filtered off, the filtrate is washed neutral, the benzene solvent is evaporated and the resulting solid is recrystallized from hexane .

In the second step, the chloromethylated intermediate (III) is condensed with methanol. The reaction is carried out under reflux for 2 hours in the presence of concentrated hydrochloric acid after addition of iron powder in small portions, after which the reaction mixture is neutralized after cooling and extracted with chloroform. This affords the methoxymethyl intermediate of formula IV

Y

where

(H1) (IV) wherein

COCH2 -R

R ^1, R ² and Y are as defined above.

In the third step, the intermediate of formula (23696) is condensed with an ester of formula (IV)

AR — COOC2H5 where

AR is as defined above.

This condensation is carried out by dropwise addition of a benzene solution of the intermediate of formula IV containing sodium hydride to the ester of formula AR-COOC2H5 and heating the reaction mixture under reflux for 2 hours.

In the final step, the resulting propane-1,3-dione of formula V is formed

O 0

where

AR, R1, R2 and Y are as defined above, cyclizes in the presence of hydrobromic acid. The cyclization is carried out by heating at 70 ° C for 3 hours in acetic acid. This provides 8-haloalkyl-4H- [1] -benzopyran-4-ones of formula I wherein X is bromo.

Finally, by known bromine reactions, X is optionally converted to another substituent within the scope of formula (I).

When in formula (III) Y is a substituent particularly attached at the 5-position, the chloromethylated intermediate is obtained under good conditions. For R2 and Y, each of which is hydrogen, Roberto TRAVÉ (Gazz. Chim. Ital., 80, 502-509, 1950) describes chloromethylation at the 5-position or dichloromethylation at the 3, 5 positions. the product of formula III, wherein Y as R ² is hydrogen, from which the product of formula IV and V can be converted to a compound of formula I. However, insufficient selectivity in chloromethylation as well as some difficulties in isolating the products have led to the search a selective process that could be used to prepare said compounds on an industrial scale.

The process for preparing novel intermediates in the preparation of 8-haloalkyl-4H- [1] -benzopyran-4-ones is also within the scope of the invention.

The following examples illustrate the invention in greater detail without limiting its scope.

Example 1

8-bromomethyl-2-phenyl-4H- [1] -benzopyran-4-one (C _ie H _for O2Br, molecular weight 315,17)

a) 1- (3-chloromethyl-2-hydroxyphenyl) ethanone (C9H9O2Cl, molecular weight 184,62)

A mixture of 2.723 kg (20 moles) of 1- (2-hydroxyphenyl) ethanone (II), 600.6 g (20 moles) of polyoxymethane and 15 liters of concentrated hydrochloric acid is heated at 50-60 ° C for 7 hours. The extract was washed neutral with aqueous sodium bicarbonate solution and the solvent was evaporated under reduced pressure.

The residue was dissolved in 2.25 L of carbon tetrachloride and 1.5 L of hexane warmed, then left overnight at 5 ° C, whereupon the precipitated 1- (5-chloromethyl-2-hydroxyphenyl) ethanone precipitate was filtered off.

The filtrate is evaporated under reduced pressure and then distilled, taking care that the temperature of the cooking vessel does not exceed 200 degrees Celsius. The fraction was collected at 130-146 ° C under a pressure of 10 mmHg, which crystallized at room temperature and was a mixture of 1- (5-chloromethyl- and 3-chloromethyl-2-hydroxyphenyl) ethanone. This fraction was heated to about 80 ° C (until melting) and slowly poured into hexane (500 ml per 100 g) with vigorous stirring. After stirring for 30 minutes, the precipitated 1- (5-chloromethyl-2-hydroxyphenyl) ethanone precipitate was filtered off. The filtrate is left overnight, the insoluble oil is decanted and the residue is concentrated slightly. The precipitate formed is filtered off and dried at room temperature. Melting point 45 ° C.

IC spectrum: [nu] C-O: 1640 cm <^4>

NMR Spectrum (CC1 ₄₎ δ (ppm):

2.6 (3H, singlet).

4.62 (2H, singlet);

6.94 (1H, triplet).

7.5 to 7.8 (2H, multiplet)

12.6 (1H, singlet, exchangeable with D2O).

b) 1- (2-Hydroxy-3-methoxymethylphenyl) ethanone (CmH4-O ;; MW 180.2)

A mixture of 184.6 g (1 mol) of 1- (3-chloromethyl-2-hydroxyphenyl) ethanone (III), 1.5 liters of methanol and 103 ml of concentrated hydrochloric acid was heated to reflux. Then 167.5 g of iron powder are added in small portions over 1 hour 20 minutes. The mixture was then heated at reflux for 2.5 hours and allowed to cool overnight. After filtration, the filtrate is concentrated under reduced pressure to a volume of approximately 500 ml, neutralized with aqueous sodium bicarbonate flow, extracted with chloroform, washed with water, the solvents are evaporated under reduced pressure and the residue is distilled. Boiling point at 40 Pa is 89-91 ° C. The yield is 88 why.

IR: VC = O 1640 ^cm-1

NMR spectrum (CCl4) δ (ppm):

2.58 (3H, singlet);

3.40 (3H, singlet).

4.46 (2H, singlet),

6.90 (1 H, triplet),

7.3 to 7.7 (2H, multiplet)

12.6 (1H, singlet, exchangeable with D2O).

c) 1- (2-hydroxy-3-methoxymethylphenyl) -3-

phenylpropane-1,3-dlonol (C 1 H 4 O 4 mol);

wt. 284.31)

A mixture of 207 g (1.38 mol) of ethyl benzoate, 740 ml of anhydrous benzene and 124 g (2.58 mol) of a 50% sodium hydride suspension in oil was heated to reflux. A solution of 167 g (0.93 mol) of 1- (2-hydroxy-3-methoxymethylphenyl) ethanone (IV) in 415 ml of anhydrous benzene is then added dropwise over 2 hours. The mixture was heated at reflux for 2 hours, cooled and added dropwise with 300 ml of ethanol. Approximately 700 mL of solvent was evaporated, the residue was cooled and taken up with 1.5 L of benzene and 1.8 L of 3N hydrochloric acid.

The mixture was stirred for 1 hour, decanted, the aqueous phase extracted with benzene, washed with water and evaporated under reduced pressure. The product obtained is recrystallized from 2 liters of hexane. 215 g (yield 81%) of the title compound of melting point about 55 ° C are obtained.

IC spectrum: VC = O: 1610 cm &lt; -1 &gt;.

d) 8-bromomethyl-2-phenyl-4H- [1] -benzopyran-4-one (C ₁₆ HuO ₂ Br, mol.

315.17)

A mixture of 361 g (1.40 mol) of 1- (2-hydroxy-3-methoxymethylphenyl) -3-phenylpropane-1,3-dione (V), 1.4 L of acetic acid and 917 ml of 62% hydrobromic acid was heated at 70 ° C for 3 hours. The reaction mixture was poured into 5 liters of cold water, filtered, washed with water and recrystallized from acetone. 207.4 g (yield 47%) of the title compound are obtained as a white solid, m.p. 182-183 ° C.

IC spectrum: VC = 0: 1650 cm &lt; -1 &gt;.

NMR spectrum (dimethylsulfoxide) δ (ppm):

5.02 (2H, singlet),

7.02 (1H, singlet).

7.3 to 8.3 (8H, multiplet).

Analysis:

calculated:

% C, 60.98;% H, 3.51;% Br, 25.36; found:

% C, 61.12;% H, 3.35;% Br, 25.35.

Example 2

8-bromomethyl-6-chloro-2-phenyl-4H- [1] benzopyran-4-one (C ₁₀ H _U5 BrClO2, mol. Wt. 349.62)

a) 1- (5-chloro-2-hydroxy-3-methoxymethyl-phenyl) -ethanone (C _{1 () U} H C1O3, mol. wt. 214.65)

A solution of sodium methylate prepared from 28.6 g (1.245 mol) of sodium and 930 ml of methanol was charged to the reactor. A solution of 252.6 g (1.153 mol) was then added. 1- (5-chloro-3-chloromethyl-2-hydroxyphenyl) ethanone (III) in 230 ml methanol. The mixture was heated under reflux for 2 hours, the solvent was evaporated and the residue was dissolved in dilute acetic acid. The solution is extracted with ethyl acetate and, after drying and evaporation, the oil obtained is distilled under reduced pressure. 69.4 g (28% yield) of the title compound of b.p. 121-131 [deg.] C (80 Pa) are obtained.

IR: [nu] C-O (ketone): 1650 cm ^<-1>

NMR spectrum (CDCl3) δ (ppm):

2.6 (3H, singlet);

3.4 (3H, singlet).

4.5 (2H, singlet);

7.4 to 7.7 (2H, broad),

5.12 (1H, exchangeable with D ₂ O).

(b) 8-bromomethyl-6-chloro-2-phenyl-4H- [1] -

-benzopyran-4-one (C ₁₆ H ₁₀ BrClO ₂ , mol.

wt. 349.62)

The procedure is as in Example 1c) but using 69 g (0.32 mol) of 1- (5-chloro-2-hydroxy-3-methoxymethylphenyl) ethanone (IV), prepared according to a), and 72, 3 g (0.48 mol) of ethyl benzoate. 1- (5-Chloro-2-hydroxy-3-methoxymethylphenyl) -3-phenylpropanedione (V) is isolated as an intermediate, m.p. 100 DEG C., then treated with 300 ml of acetic acid and 210 ml of hydrobromic acid. 61.2 g (yield 54.7%) of the title compound of melting point 210 DEG C. (from toluene) are obtained.

IR: VC = 0 (pyron): 1640 cm &lt; -1 &gt;.

NMR Spectrum (CDCl3) δ (ppm):

(2H, singlet),

7.1 (1H, singlet).

7.3 to 8.3 (7H, multiplet).

Example 3

8-Bromomethyl-6-methyl-2-phenyl-4H- [1] -benzopyran-4-one (S, N);

(a) 1- (2-hydroxy-3-methoxymethyl-5-methylphenyl-ethanone ₎

The procedure is as in Example 1b) but using 1- (3-chloromethyl-2-hydroxy-5-methylphenyl) ethanone (III), bp 110-116 ° C (0.5 mm Hg). 190.7 g (49% yield) of the title compound of b.p. 95-103 ° C (80 Pa) are obtained.

1C spectrum: VC-O (ketone): 1650 cm ^-1

NMR Spectrum (CCI +) _; δ (ppm):

1.8 (3H, singlet)

2.1 (3H, singlet);

2.9 (3H, singlet);

6.8 to 7 (broad, 2H).

12.5 (1H, exchangeable with D ₂ O).

(b) 8.-Bromomethyl-6-methyl-2-phenyl-4H- [1] -benzopyran-4-one (Ο ₁₇ Η _{3 3} ΒγΟ ·>, mol.

The procedure is as in Example 1c), but using 204 g (1.05 mol) of 1- (2-hydroxy-3-methoxymethyl-5-methylphenyl) ethanone (IV), prepared according to a), and 210 g (1.4 mol) of ethyl benzoate. After isolation, the oil obtained was treated with 520 ml of acetic acid and 410 ml of 62% hydrobromic acid. This gave 108 g (yield

31.2% J of the title compound o; mp 186 ° C (from acetone).

IR: [nu] C-O (pyron). 1640 cm * ¹

NMR spectrum (dimethylsulfoxide) δ (ppm):

3.2 (3H, singlet), (2H, singlet), (1 H, singlet),

7.3 to 8.3 (7H ·, multiplet);

Example 4

8-br cm-methyl-2- (2-thenyl) -4H- [1] -benzopyran-4-one (C 1 H 9 Brj, mol% 321.2)

The procedure was as in Example 1c) but using 118 g (0.65 mol). 1- (2-hydroxy-3-methoxymethylphenyl) ethanone (IV) and 127 g (0.82 mol) of α-ethylthenoate. The crude oil obtained is treated with 450 ml of 62% hydrobromic acid and 600 ml of acetic acid. Following the procedure of Example 1d), 80.1 g (40% yield) of the title compound are obtained, m.p. 174 DEG C. (from ethanol).

IR: [nu] C-O (pyron): 1640 cm <^-1>

NMR (CDC1 ₃₎ <5 (ppm);

4.8 (2H, singlet);

6.7 (1H, singlet);

7.1 to 8.3 · (6H, multiplet).

Example 5

- (bromomethyl) -3-methoxy-2-phenyl-4H- [1] -benzopyran-4-one (2-carboxylic acid), mol., mass 345,40)

(a) 3-hydroxy-8-methyl-2-phenyl-4- [1] -benzopyran-4-one (C ₁₆ H ₁₂ O ₃ , mol% 252,27)

To a solution of 90.1 g (0.6 mol) of 1- (2-hydroxy-3-methylphenyl) ethanone (II) and 63.7 g (0.6 mol) of benzaldehyde in 1.2 liters of ethanol is added at a temperature of not exceeding 30 ° C a solution of 81.6 g (2.04 mol) of sodium hydroxide pellets in 163 ml of water. After stirring overnight at room temperature, 204 ml of 20% aqueous sodium hydroxide solution diluted with 4 L of ethanol were added. The mixture was cooled in an ice bath and rapidly. 825 ml (15%) hydrogen peroxide solution was added.

The reaction mixture was stirred at 25 ^° C for 4 hours, then acidified with 30% sulfuric acid and poured into 15 L of ice-water. The resulting mixture is left overnight, and the precipitate formed is filtered off and recrystallized from toluene. 18.3 g (yield 12%) of the title compound of melting point 180 DEG C. are obtained.

IR spectrum: _O h = 3300 cm ^-1, VC = O (pyrone) 1625 cm ^-1

NMR (CDC1 _3):

2.66 (3H, singlet);

6.7 [1H, exchangeable with DO),

7.2 to 7.7 (5H, multiplet)

8.0 to 8.5 (3H, multiplet).

b) 3-Methoxy-8-methyl-2-phenyl-4H - [1,1] -benzopyran-4-one (C 1 H ₄ O ₃ , mol% 266.30)

A mixture of 18 g (0.071 mol) of 3-hydroxy-8-methyl-2-phenyl-4H- [1] -benzopyran-4-one, prepared according to a), 9.86 g (0.071 mol) of potassium carbonate, 100 ml of acetone and 9.9 g (0.078) of dimethyl sulfate were heated under reflux for 16 hours. The mixture is filtered while hot, the filtrate is cooled, the precipitate formed is filtered off and recrystallized from acetone. 14.5 g (76% yield) of the title compound of melting point 143 DEG C. are obtained.

IR: [nu] C-O (pyron): 1645 cm <^-1>

NMR Spectrum (CDCl3):

2.6 (3H, singlet);

236695

3.97 (3H, singlet), 7.1-7.7 (5H, multiplet), 7.9-8.4 (3H, multiplet).

- [1] -benzopyran-4-one (C17H13B1O3, molecular weight 345,20)

A mixture of 11 g (0.041 mol) of 3-methoxy-8-methyl-2-phenyl-4H- [1] -benzopyran-4-one, prepared according to b), 8.03 g (0.045 mol) of N-succinimide, 350 ml of carbon tetrachloride and 0.2 g of azobisisobutyronitrile are heated under reflux for 8 hours under irradiation with ultraviolet radiation. The reaction mixture was filtered hot while the filtrate was left in the refrigerator overnight. The precipitate formed is filtered off, washed with water and recrystallized from ethyl acetate. 6.2 g (43% yield) of the title compound of melting point 157 DEG C. are obtained.

IR spectrum: v C = O 1630 ^cm-1

NMR Spectrum (CDCl3):

3.95 (3H, singlet).

4.83 (2H, singlet);

7.2 to 7.9 (5H, multiplet)

8.1 to 8.5 (3H, multiplet).

Example 6

8-bromomethyl-6-methoxy-2-phenyl-4H '[1] benzopyran-4-one (C 1 H 4 BrOa), mol.

345.20)

a) 1- (3-Chloromethyl-2-hydroxy-5-methoxyphenyl) ethanone (C 10 H _for C 10 O ₃ , mol% 214.65)

A mixture of 1- (2-hydroxy-5-methoxyphenyl) ethanone (47 g, 0.283 mol), polyoxymethylene (8.5 g, 0.283 mol) and concentrated hydrochloric acid (215 ml) was heated at 50 DEG C. for 7 hours. It is taken up in benzene, insoluble materials are filtered off, the benzene solution is washed neutral, the benzene is evaporated off under reduced pressure and the solid obtained is recrystallized from hexane to give 37.1 g (yield 61%) of the title compound, m.p. Deň: 32 ° C.

IR: [nu] C-O: 1650 cm <^4>

NMR (CDC1 _3):

2.63 (3H, singlet);

3.85 (3H, singlet);

4.7 (2H, singlet);

7.2 to 7.4 (2H, multiplet)

12.6 (1H, singlet).

The procedure is as in Example 1b) but using 36.8 g (0.171 mol) of 1- (3-chloromethyl-2-hydroxy-5-methoxyphenyl) ethanone (III) prepared according to a). 24.7 g (69% yield) of the title compound of b.p. 110 DEG-114 DEG C. (40 Pa) are obtained.

IR: vC = O: 1650 cm ⁴ Voh: 3000-3600 cm -1

NMR Spectrum (CDCl3):

2.57 (3H, singlet);

3.42 (3H, singlet);

3.77 (3H, singlet);

4.5 (2H, singlet),

7.1 (1H, doublet, J = 3Hz);

7.25 (1H, doublet, J = 3Hz),

12.0 (1H, singlet).

c) 1- (5-2lhycdro.xy] metho.xyl3-methoxymethyl-phenyl-3-phenylpropan-l, 3-dione (C 1 -C ₈ H ₁₈ O 3, mol. wt. 314.34)

81.6 g (1.7 mol) of a 50% sodium hydride suspension in oil were washed three times with benzene. The hydride is suspended in 600 ml of anhydrous dioxane, the suspension is heated to 80 DEG C. and a solution of 114 g (0.542 mol) of 1- (2-hydroxy-5-methoxy-3-methoxymethylphenyl) ethanone is added dropwise over 1.5 hours. (IV), prepared according to b), and 122 g (0.813 mol) of ethyl benzoate in 150 ml of anhydrous dioxane. The mixture was then heated at 80 ° C for 3 hours, cooled, diluted with 3.5 L of hexane, filtered and the filter cake washed with benzene. The solid was then added portionwise with vigorous stirring to a mixture of 1 liter of water, 1 liter of acetic acid and 1.5 liters of chloroform. After decantation, the reaction mixture is extracted with chloroform, washed neutral, dried and evaporated under reduced pressure. 200 g of an oil are obtained, which oil is used as is in the following stage.

d) 8-bromomethyl-6-methoxy-2-phenyl-4H1 [1] -benzopyran-4-one (C 1 H 4 B 2) (mol. wt. 345.20)

The procedure is as in Example 1d) but using the 1- (2-hydroxyl-5-methyl-3-methoxymethylphenyl) -3-phenylpropane-1,3-dione (V) prepared in the previous paragraph. 112.8 g (yield 60%, total) of the title compound of melting point 194 DEG C. are obtained.

IR spectrum: v C = O (pyrone) 1650 cm ⁴

NMR spectrum (dimethylsulfoxide):

3.9 (3H, singlet),

5.1 (2H, singlet);

7.0 ’to 8.3 (8H, multiplet).

b) 1- (2-Hydroxy-5-methoxy-3-methoxymethylphenyl) ethanone (CH 2 OH), mol.

210.23)

236695

8-Bromomethyl-2-cyclohexyl-4H- [1] -benzopyran-4-one (S, N, N), mol% 321.22).

a) 11Cyclohexyl-3- (2-hydroxy-3-methoxymethylphenyl) -propane-1,3-dione (C1; H _2; > 04, mol. weight 290,36)

Following the procedure of Example 6c), from 53.3 g (0.296 mol) of 1- (2-hydroxy-3-methoxymethylphenyl) ethanone (IV) and 92.4 g (0.59 mol) of cyclohexylcarbonyl ethyl ester, however, the reaction mixture is refluxed for 3 hours instead of at 80 ° C for 3 hours and the oil is distilled after final evaporation to give 18 g (yield 21 why) of the title compound of boiling point 140-180 ° C. pressure 66.7 Pa).

b) B-Bromomethyl-4-cyclohexyl-4H- [1] -benzopyran-4-one (S, N), mol% 321,22)

The procedure is as in Example 1d), but using 18 g (0.062 mol) of 1-cyclohexyl-1- (2-yloxy-3-methoxymethylphenyl) -propane-1,3-dione (V) prepared under paragraph a). 15.2 g (76% yield) of the title compound of melting point 130 DEG C. (from acetone) are obtained.

IR: nu - O (pyrone) 1645 cm ^-1

NMR Spectrum (CDCl3):

1.1 to 3.0 (11H, multiplet)

4.7 (2H, singlet);

6.2 (1H, singlet).

7.3 (1H, triplet, J = 8Hz);

7.65 (1H, double doublet, J 1 = 8 Hz, J 2 = = 2 Hz),

8.15 (1H, double doublet, J ₁ = 8 Hz, J ₂ = 2 Hz).

Example 8

8lbrommylhy - 2-HH-mУlhyl · [1-j lbenzrp raml4lom (C _u H <) BrO ₂ moles. bmot. 253,10)

a) 2-Methyl? <y methoyymethy-3-benzoic acid (C _ia H ₁₂ O ;, mol. wt. 196.20)

To a solution of 315.3 g (1.5 mol) of 2-methyl-3-methoxy-meth-1-benzoic acid methyl ester in 1.2 liters of methanol is added

118.8 g (1.8 mol) of drained pellet hydroxide in 300 ml of water and the mixture was refluxed for 3 hours. The methanol was evaporated under reduced pressure, the residue was diluted with water and washed with ether. The aqueous phase was cooled, acidified with 6N hydrochloric acid and extracted with ether. The ether phase was washed with water, dried, evaporated under reduced pressure and the resulting solid recrystallized from cyclohexane. 278.3 g (94% yield) of the title compound of m.p. 68 DEG-69 DEG C. are obtained.

IR: Vc = O (acid): 1700 cm ^-1

NMR Spectrum (CDCl3):

3.47 (3H, singlet);

3.97 (3H, singlet).

4.6 (2H, singlet).

7.23 (1H, triplet, J = 8Hz).

7.7 (1H, doublet, J = 8 Hz, J = 2 Hz),

8.05 (1H, doublet, J = 8 Hz, J = 2 Hz).

b) 1- (2-metУo: χyl3 metho.xymeth-LF-hydroxyphenyl) ethane (0 _{н Н>} 40 ₃ mol. wt. 194.23)

To a solution of 264.9 g (1.35 mol) of k-selins

2-π-methoxy-3-myrhoxymethylbromine prepared in (a) in 1.35 liters of chloroform and 2.7 ml of dimethylformamide is added 148.5 ml (2.02 mol) of thionyl chloride and the mixture is gradually heated to boiling point heating is controlled according to the evolution of the gases, which temperature is maintained for 2 hours. After cooling, the chloroform and excess of triphenyl chloride were evaporated under reduced pressure and the resulting 2-methoxy-3-methoxy-methylbenzamic acid chloride was dissolved in 270 ml of anhydrous ether. This solution was added dropwise to a boiling solution of 1.62 moles of ethoxymagnesium ethyl formate (prepared according to Org. Syn. Coll., Vol. IV, page 708) and the mixture was heated under reflux for 3 hours. It is then cooled in an ice bath, hydrolyzed with 5% sulfuric acid to give two clear phases, decanted, extracted with ether, washed with water and evaporated under reduced pressure.

The residue was dissolved in 460 ml of acetic acid, 300 ml of water and 58 ml of concentrated sulfuric acid and heated at reflux for 4 hours. After cooling, the reaction mixture was extracted with ether. The aqueous phase was cooled in an ice bath and basified with 10% sodium hydroxide solution, then extracted with ether. The combined ether phases were washed first with aqueous sodium bicarbonate solution, then with water, then dried and evaporated under reduced pressure. The remainder was distilled. 173.3 g (yield 66%) of the title compound of b.p. 100-105 ° C (0.5 mm Hg) are obtained.

IR: nC-O: 1690 tin- ¹

NMR spektrumf CDC1 _3):

2.63 (3H, singlet);

3.5 (3H, singlet).

3.8 (3H, singlet).

4.55 (2H, singlet).

7.0 to 7.8 (4H, multiplet).

c) 1- (2-methoxy-3-methoxymethylphenyl-1) 236693

-butane-1,3-dione ( _{13 13} И _ø 0 ₄ , mol.

236,27]

The procedure is as in Example 6c], but using 0.8 mole of sodium hydride, 77.77 g (0.4 mole) of 1- (2-methoxy-3-methoxymethylsulfanyl) ethanone (IV) and 59 ml (0, 2). The oil obtained after work-up is distilled under reduced pressure to give 53.7 g (yield 56%) of the title compound, b.p. 110-140 ° C (40 Pa).

IR: [nu] C-O: 1320 cm &lt; -1 ^&gt;.

NMR Spectrum (CDCl3):

2.12 (3H, singlet),

3.4 (3H, singlet),

3.73 (3H, singlet).

4.47 (2H, singlet),

6.3 (1H, singlet);

7.0 to 7.8 (3H, multiplet), (1H, exchangeable with D ₂ O); (enoic form) -diketone.

d) 8-Tzommethy2-2-methyl-4H-1 1% --benzopyran-4-one (C ₉ H _u Bi? O 2, mol. wt. 253.10)

The procedure was as in Example 1d), but using 27.4 g (0.116 mol) of 1- (2-methaxyl-4-methoxymethylphenyl) butane-1,3-dione (V). 18 g (61% yield) of the title compound of melting point 126 DEG-128 ^DEG C. (from a mixture of cyclohexane and ethyl acetate) are obtained.

IR: nu - O: 1670 cm ¹

NMR Spectrum (CDCl3):

2.45 (3H, singlet);

4.73 (2H, singlet).

6.27 (1H, singlet).

7.1 to 7.5 (1H, m / m),

7.77 (1H, double doublet, J = 8 'Hz, J ₂ = 2 Hz)

8.2 (1H, double doublet, J = 8 Hz, J = 2 Hz). '

Example 9

8-Bromobutyl-2- (phenylmethyl) -4H- [1] benzylpyran-4-zn (C (H ^ ^B ^, mol% 329.20)

a) 1- (2-Hydroxy-3-methoxymethylphenyl) -4-phenylbutane-1,3-dione (C ^H ^O O, mol% 298.34)

The procedure is as in Example 1c), but using 37 g (0.2 mol) of 1- (2-hydroxy-3-methoxymethylphenyl ethane) (1V) and

Replace 49.2 g (0.3 mol) of phenylacetic acid ethyl ester and 3 N hydrochloric acid with 50% acetic acid. Evaporation of the solvent gave 68 g of an oil which was used in the next step without further purification.

b) 8-bromomethyl-2- (phenylmethyl) -4H- [1,1'-benzopyrae-4-zinc (C 1 H 4 B 2), mol.

329.20)

The procedure was as in Example 1d) but using 1- (2-hydroxy-4-methoxymethylmethyl) -4-phenylbutene-1,3-dione (V) prepared according to a). 47.5 g (72%) of the title compound are obtained, m.p. 128 DEG C. (toluene / hexane).

IR spectrum: v C = O (pyrone) 1670 ^'_ 1 cm

NMR (CDC1 _3):

4.0 (2H, singlet),

4.63 (2H, singlet);

6.23 (1H, singlet).

7.1 to 7.55 (6H, multiplet)

7.7 (1H, doublet dvoiitý, _t J = 8 Hz, J 2 - J = 2 Hz)

8.2% (1H, doublet, h = 8% Hz, J2 = 2 Hz).

Example 10

8-bromo-methyl-2- (2-phenylethenyl) -4H- [1] benzyl-4-z (C 1 H 4 BrO 2), mol.

341.21).

a) 1% (2-hexyloxy-3-methoxymethylphenyl) -5% -fb ^, E4-petetine-1,3-dione (C ^H ^O O, mol% 310.35)

The procedure is as in Example 6c), but using 60 g (0.333 mol) of 1- (2-hydroxy-3-methoxy-methylphenellethaeze) (IV) in 88 g (0.499 mol) of ethyl 3- (4-hydroxy) ethyl ester. 92 ° C (hexane / ether).

IR: [nu] C-O: 1640 cm <^4>

NMR (CDC1 _3):

3.46 (3H, singlet);

4.6 (2H, singlet);

6.33 (1H, singlet).

6.4 to 7.9 (10H, multiplet)

12.6 (1H, exchangeable with D2O),

14.7 (1H, exchangeable with D2O); (Elder form) -] 8-bromomethyl-2- (2 - (-) - (-) - (-) -) - (-) - (-) - O ^ H ^ BtO ·,, molecular weight 341.21)

The procedure is as in Example 1d), but using 10.2 g (0.033 mol) of 1- (2-hydroxy-3-methoxymethylthyl) -5-phenyl / 1,4-pentene-1,3-dione (IN). 8.4 g (75% yield) of the title compound of melting point 212 DEG C. (from toluene) are obtained.

IR: nu - O (pyrone) 1660 cm ^4, VC = O: 1640 cm-1

238696

NMR Spectrum [CDCl3]: 4.83 (2H, singlet), 6.4 (1H, singlet),

6.8 (1H, doublet, J = 16Hz),

7.1 to 7.9 (8H, multiplet)

8.2 (1H, doublet of doublets, = 8 Hz, J2 = 2 Hz).

Claims (1)

SUBJECT A process for the preparation of 8-haloalkyl-4H- [1] -benzopyran-4-ones of the general formula I wherein AR is hydrogen, phenyl, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or halogen, thenyl, pyridyl, furyl, naphthyl, C1-C4 alkyl, cycloalkyl C 3 -C 6, C 1 -C 4 aralkyl or C 2 -C 4 aralkenyl. X is halogen, especially bromine, Y is hydrogen, (C 1 -C 4) alkyl or halogen; R 1 is hydrogen, C 1 -C 4 alkoxy or phenyl, characterized in that the starting compound of formula (II): R 1 and Y are as defined above and R 2 is hydrogen or C 1 -C 4 alkyl, treated with polyoxymethylene in the presence of concentrated hydrochloric acid at 50 to 60 ° C for up to 7 hours, the chloromethylated intermediate of formula III obtained OF THE INVENTION where R1, R'2 and Y are as defined above, condensed with methanol in the presence of concentrated hydrochloric acid with the addition of iron powder to form the methoxymethyl intermediate of formula IV Ctl ^ OCH ^ (IV) where &quot; R1, R2 and Y are as defined above, in a benzene solution containing sodium hydride is condensed with an ester of formula AR — COOC2H5 where AR is as defined above, and the resulting propan-1,3-dione of formula (V) O 0 CH 2 OCH, * ⁽ V) where Ar, R ^1, R 2 and Y have the above meaning, is cyclized in the presence · HBr heated at 70 ° C for 3 hours in acetic acid with the product of general formula I where X represents bromine and in · the compound of other substituents X are optionally introduced.