FI103571B - Propoxibenzenderivat - Google Patents

Description

103571

Propoksibentseenijohdannaisia

The present invention relates to novel propoxybenzene derivatives useful as intermediate compounds in the synthesis of anti-bacterial compounds.

Ofloxacin, 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] -10 [1,4 ] benzoxazine-6-carboxylic acid of the formula below is known as disclosed in JP-A-1 444 043, US-A-4 382 892 and EP-B-0 047 005 as an excellent synthetic antibacterial agent and has been marketed in many countries.

The 3- (S) -methyl isomer of ofloxacin has excellent activity as a synthetic antimicrobial agent as disclosed in EP-A-0 206 283.

Ofloxacin 20 g}

FV fi ^ / ^ \ ^ COOH

XI F

This invention relates to propoxybenzene derivatives represented by the following formula: 30 °

^ OH

wherein R e represents a hydrogen atom or a group -CH = C (COO-C 1-6 alkyl-35 alkyl) 2 and Xa and Xb, which may be the same or different, represent a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and in particular a fluorine atom.

In the context of the present invention, the amino protecting group may be any of the usual known protecting groups for amino groups, and examples thereof include acyl groups such as an acetyl group or a chloroacetyl group; aralkyl groups such as triphenylmethyl group, diphenylmethyl group, benzyl group, p-methoxybenzyl group or 10 p-nitrobenzyl group; alkoxycarbonyl groups such as t-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group or p-nitrobenzyloxycarbonyl group; and a group like that.

The hydroxyl group protecting group may be any of the usual known hydroxyl group protecting groups, and examples thereof include alkyl groups such as t-butyl group, acyl groups such as formyl group, acetyl group, trifluoroacetyl group, benzyloxyacetyl; ethers or alkoxyalkyl groups such as tetrahydropyranyl group (hereinafter abbreviated as THP), methoxymethyl group, methoxyethoxymethyl group, benzyloxymethyl group; aralkyl groups such as benzyl group, p-methoxybenzyl group, p-nitrobenzyl group or triphenyl-methyl group, and the like.

Examples of substituted sulfonyl groups include the p-toluenesulfonyl group (hereinafter referred to as the tosyl group), the methanesulfonyl group or the trifluoromethanesulfonyl group, and the like.

It is an object of the present invention to provide novel compounds useful as intermediates for the synthesis of ofloxacin and its optical isomers.

The compounds of this invention are prepared by the following process.

3 103571 Synthesis of 2,3-dihalo-6-nitropropoxybenzene 2,3-dihalo-6-nitropropoxybenzenes having the following formula (I):

Da ', 10- ^ ORc wherein Rc represents a protecting group for a hydroxyl group and Xa and Xb, which may be the same or different, each represent a halogen atom, may be obtained by the administration of 2,3,4-trihalogenitrobenzene of formula (II): 20 x ^ Xno2

Xc wherein Xa, Xb and Xc, which may be the same or different, each represent a halogen atom, react with a 1,2-pro-pane diol derivative of formula (III): HOCH 2 CH (CH 3) ORc (III) wherein R c is as defined above ; Or by administering 2,3-dihalo-6-nitrophenol, which. formula (IV) is 3S <->

OH

4 103571 wherein Xa and Xb are as defined above, reacting with a compound of formula (III) or with a compound of formula (V): wherein Xc represents a halogen atom, or Xd represents a halogen atom; sulphonyloxy group.

The compounds of formulas (II) and (IV) may be prepared according to the method described in U.S. Patent 4,382,892 and EP-B-0 047 005.

The reaction of 2,3,4-trihalogenitrobenzene of formula (II) with a compound of formula (III) may be carried out in the presence of a base, which may be either an inorganic base or an organic base. Examples of inorganic bases include metal hydrides such as sodium hydride or calcium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium 20 carbonate or potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate. Examples of organic bases include trialkylamines such as triethylamine, tri-n-butylamine, N, N-diisopropylethylamine; anilines such as N, N-dimethyl-aniline or N, N-diethylaniline; heterocyclic amines such as pyridine, Ν, Ν-dimethylaminopyridine or N-methylmorpholine; metal alcoholates such as sodium methylate, sodium ethylate, sodium propylate and potassium 1-butylate; and 1,8-diazabicyclo [5.4.0] -7-undecene or N-benzyltrimethylammonium hydroxide; and bases such as these.

The molar ratio of compound (II) to compound (III) is in the range of about 1: 1 to about 1: 3, preferably 1: 1.1.

The reaction is carried out primarily in the presence of a solvent inert to the reaction. Examples of such solvents include hydrocarbons such as benzene, toluene, xylene, n-hexane, cyclohexane or n-pentane; alcohols such as methanol, ethanol, propanols and butanols; ethers such as diethyl ether, tetrahydrofuran, diox-5 or 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidone; aprotic polar solvents such as dimethylsulfoxide or sulforane and the like.

The reaction may be carried out at a temperature in the range of about 10 ° C to about 78 ° C to about 150 ° C. The reaction takes place over a period of about 10 minutes to about 4 days.

Conveniently, the optically active isomer of the compound of formula (III) may be used to prepare the optically active propoxybenzene derivatives of formula (I). Using the optically active isomer of compound (III) in this reaction, it was found that no racemization of this compound occurred and the configuration of the asymmetric carbon atom of compound (III) remained unchanged. Compound (III) was coupled to Compound (I) as a sub-structure of Compound (I), while maintaining the original configuration of the asymmetric carbon atom of Compound (III).

In another process for the preparation of compound (I), the 2,3-dihalo-6-nitrophenol of formula (IV) is reacted with compound (III) or compound (V). The reaction of compound (IV) with compound (III) can be carried out primarily in the presence of Mitsunobu reagent, a complex prepared by reacting an azodicarboxylic acid diester such as diethyl ester, dimethyl ester, dibenzyl ester, diisopropyl ester and the like. triphenylphosphine or trialkylphosphine as described in O. Mitsunobu, Synthesis. 1-28 (1981).

Note that Mitsunoburea reagent is readily degraded by moisture.

6 103571

The reaction of the compound (IV) with the compound (III) in the presence of the Mitu sunobu reagent is preferably carried out in ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. The reaction can be carried out at a temperature of 0 ° C to about 50 ° C.

An alternative reaction of compound (IV) with compound (V) can be carried out in the presence of a base, which may be either an inorganic or an organic base. Examples of the inorganic base include metal hydrides such as sodium hydride or calcium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate or potassium hydrogencarbonate. Examples of organic bases include trialkylamines such as triethylamine, tri-n-butylamine or N, N-diisopropylethylamine; anilines such as N, N-dimethylaniline or N, N-diethylaniline; heterocyclic amines such as pyridine, N, N-dimethylaminopyridine 20 or N-methylmorpholine; metal alcoholates such as sodium methylate, sodium ethylate, sodium propylate and potassium tert-butylate; 1,8-diazabicyclo [5.4.0] -7-undenene or N-benzyltrimethylammonium hydroxide and the like. The reaction may be carried out in the presence of a solvent inert to reaction 25. Examples of solvents include hydrocarbons such as benzene, toluene, xylene, n-hexane, cyclohexane or n-pentane; alcohols such as methanol, ethanol, propanols and butanols; ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; amides such as N, N-dimethyl-: formamide,?,? -dimethylacetamide or N-methyl-2-pyrrolidone; aprotic polar solvents such as dimethylsulfoxide or sulforane and the like. The reaction may be carried out at a temperature between room temperature and the boiling point of the solvent used.

7 103571

The reaction can be accelerated by adding potassium iodide, sodium iodide or crown ether to the reaction mixture. The amount of such an accelerating reagent may be in the range of 1/100 to 1 molar equivalent of compound (IV).

Compound (III), a derivative of 1,2-propanediol, can be obtained by reduction of a lactic acid derivative or a lactic acid ester. The hydroxyl group of the lactic acid derivative must be protected in a suitable form before reduction. Examples of such a protecting group include a tetra-10 hydropyranyl group, a benzyl group, a p-methoxybenzyl group, a methoxymethyl group or a triphenylmethyl group and the like. The protected lactic acid derivative is then reduced with a metal hydride such as lithium aluminum hydride and sodium borohydride and a similar reducing agent to give the protected 1,2-propanediol derivative (III). This compound can be converted to the sulfonyloxy compound or halide (compound [V]) by a known method such as using sulfonyl chloride in the presence of a base or thionyl chloride, and a method similar thereto.

As it appears from the structure of lactic acid, it has an asymmetric carbon atom. The pure optical isomer and racemic mixture of both lactic acid and lactic acid esters are commercially available. Thus, in accordance with the present invention. Thus, either the optically pure or the racemic propoxybenzene derivative (I) can be readily prepared.

As shown in the following reaction scheme, the compound of formula (I) can be converted to the benzoxazine compound (XV) by reaction sequences such as (a) reduction of the nitro group, (b) methylene malonation, (c) removal of the hydroxyl protecting group, d) sulfonylation, and e) cyclizing.

8 103571

Xb ^ V ^ NOz Xb ^ V ^ N ° 2 OH p {Xc n 5 v or m

T JS

V _ V - y COOR

a) Χαγ ^] b) tC00R

Xb '^ V ^ N02 ^ XbNH2 XVI> Xb ^^ N ^

10 ° Y ° Λ V

^ "ORc I ^" ORc VI ^ "ORc VH

I "1 '

v COOR

15 XarYi t) Χαγγ vcooR e)

Xb''Y / "* N02 Xb '^ y / ^ NH2 xvi Xb' ^^^ - N ^

° 1 ° 1 ° ΛH

/ 'OH VI ^ X) H k ^ X) H X

Id) Id) 20 I y

COOR

Xb ^ yY N02 ^ XbY ^ NH2 ”XVI ^ Xb ^ V ^ N ^ ° 1 ° 1 ° 1

2 5 ^ "ORd XI /" ORd XU ^ ORd XI

| el Je)

COOR

Χαγ ^ Ν b) Xay ^ \ VCOOR

3 0 Xb '^ jV'NH XVI X Xb' ^ y ^ N '^: O ^ A. ^ yy III; HOCH2CH (CH3) ORc 35V; XdCH 2 CH (CH 3) OR c R j, substituted sulfonyl group XVI; Y-CH = C (COOR) 2 R; -CH 2 CH 3 or -CH 3 9 103571

In a series of reactions, the product obtained in each reaction can be isolated or purified by known methods such as extraction, recrystallization or chromatography on silica gel or a combination thereof.

Each of the reactions of Reaction Scheme (I) to (XV) is described in detail below.

Step a): Reduction of nitro group

Reduction of the nitro group in Compound (I) can be accomplished by catalytic reduction using cat 10 lithium such as Raney nickel, palladium on charcoal and platinum oxide and the like, with hydrosulfite or with a combined reagent of sodium borohydride and metal chlorides. Examples of solvents that can be used in these reductions are lower alcohols such as methanol, ethanol and propanols. The reduction may be carried out at a temperature between room temperature and the boiling point of the solvent. The catalytic reduction may be carried out at atmospheric pressure or under hydrogen pressure.

The amino group may be protected by attaching a suitable protecting group such as an acetyl group (upon reaction with acetyl chloride or acetic anhydride), a triphenylmethyl group (upon reaction with triphenylmethyl chloride), a tert-butoxycarbonyl-butyl-t ) or a benzyloxycarbonyl group (upon reaction with benzyloxycarbonyl chloride). Removal of the protecting group may be carried out by suitable methods known per se.

Step b): Methylene malonylation of the amino group The methylene malonylation reaction of the amino group can be carried out by reacting an amino compound such as compound (VI), (IX) or (XII) with a compound of formula (XVI): 35 Y-CH = C (COO-). C 1-4 alkyl) 2 (XVI) 10 103571 wherein Y represents an alkoxyl group, a halogen atom or a dialkylamino group having 1-6 carbon atoms in each alkyl moiety; in the presence or absence of a solvent.

A suitable amount of compound (XVI) is greater than the equimolar amount relative to the amino compound.

The solvent used in the reaction may be any inert solvent. Examples of solvents include hydrocarbons such as benzene, toluene, xylene, n-hexane, cyclohexane or n-pentane; alcohols such as methanol, ethanol, propanols and butanols; ethers such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidone; aprotic polar solvents such as dimethylsulfoxide or sulphorane, and the like.

The reaction may be carried out at a temperature of about 100 ° C to about 180 ° C when the reaction is carried out in the absence of solvent. When using a solvent, the reaction may conveniently be carried out at the boiling point of the solvent.

Step c): Removal of the hydroxy protecting group

Removal of the hydroxyl protecting group is carried out in a manner known per se. For example! Removal of the THP group is accomplished by treating the protected compounds under acidic conditions at room temperature to 100 ° C. Examples of acidic conditions include treatment with hydrogen chloride, hydrobromic acid or sulfuric acid in alcohol or pyridinium p-toluene nisulfonate in a protolytic solvent such as: lower alcohol, water, carboxylic acid, e.g.

in acetic acid.

Step d): Sulphonylation of hydroxy group

The sulfonylation reaction can be carried out by reacting 35 substituted sulfonyl halides such as p-toluene sulfonyl chloride, methanesulfonyl chloride or trifluoromethanesulfonyl anhydride with a deprotected hydroxy compound. Examples of such bases include trialkylamine such as triethylamine, tri-n-butylamine, N, N-diisopropylethylamine; anilines such as N, N-dimethylaniline or Ν, Ν-diethylaniline; heterocyclic amines such as pyridine, N, N-dimethylaminopyridine or N-methylmorpholine; and 1,8-diazabicyclo [5.4.0] -7-undecene, and bases such as these.

It is convenient to use an aprotic solvent in the reaction and examples include ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diethyl ether and the like; amides such as dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidone and the like; halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane and the like, halogenated hydrocarbons.

Step e): Classification to Benzoxazine Derivatives Some of the compounds of this invention may be cyclized to known benzoxazine derivatives of formulas (XIV) and (XV).

The sulfonyloxy compounds of formula (XII) or (XIII) can be cyclized to benzoxazine derivatives under basic conditions. For the cyclization of sulfonyloxy compounds, either an inorganic or organic base may be used. Examples of useful inorganic bases include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali-lime metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate or potassium hydrogencarbonate. Examples of useful organic bases include trialkylamines such as triethylamine, tri-n-butyl-35-amine, N, N-diisopropylethylamine; anilines such as 12 103571 N, N-dimethylaniline or N, N-diethylaniline; heterocyclic amines such as pyridine, N, N-dimethylaminopyridine or N-methylmorpholine; metal alcoholates such as sodium methylate, sodium ethylate, sodium propylate and potassium t-butylate, 1,8-diazabicyclo [5.4.0] -7-undecene or N-benzyltrimethylammonium hydroxide and the like.

The cyclization can be carried out at a temperature of about room temperature to about 150 ° C in a solvent.

Examples of solvents include alcohols such as methanol, ethanol, propanols or butanols; ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, 2-methoxyethyl ether or ethylene glycol diethyl ether and the like; amides such as N, N-15 dimethylformamide, N, N-dimethylacetamide or N-methyl-2-pyrrolidone and the like; aprotic polar solvents such as dimethylsulfoxide or sulforane and the like.

The cyclization reaction can be accelerated by the addition of potassium iodide, sodium iodide or crown ether to the reaction mixture. The amount of such an accelerating reagent may be preferably 1/20 molar equivalent or more relative to the propoxybenzene derivative.

Cyclization of a hydroxy compound of formula (X); The reaction may be carried out after conversion of the compound to a halide by a halogenating agent such as thionyl chloride, phosphorus trichloride or phosphorus tribromide and the like. The cyclization can be carried out in the presence of the same base as exemplified for the cyclization of sulfonyloxy compounds of formulas (XII) and (XIII).

The hydroxy compound can also be cyclized to a benzoxazine derivative by reaction with 1 to 1.5 molar equivalents of Mitsunobu reagent in ethers such as diethyl ether, tetrahydrofuran or 1,2-di-103571 methoxyethane at a temperature of about 0 ° C to about 50 ° C.

The cyclization of the propoxybenzene compound to the benzoxazine compound results in an inversion of the configuration at the asymmetric carbon atom of the propoxy group. Thus, 3- (S) -alkylbenzoxazine derivatives are obtained by cyclization of (R) -propoxybenzene derivatives; and 3- (R) -benzoxazine derivatives are obtained from (S) -propoxybenzene derivatives.

The compound of formulas (XIV) and (XV) can be converted to an ofloxacin compound by the method described in U.S. Patent 4,382,892 or EP-B-0 047 005. The optical isomer of a compound of formulas (XIV) and (XV) may also be converted to the optical isomer of ofloxacin compound 15 as described in EP-A-0 206 283.

The present invention is illustrated in more detail with reference to the following examples, but it is to be understood that they are not intended to be limiting of the present invention.

REFERENCE EXAMPLE A-1 (1) O- (Tetrahydropyran-2-yl) lactic acid ethyl ester 29.53 g of dl-ethyl lactate, 25.54 g of 2,3-dihydropyran and 2.9 g of dl-camphor-10-sulfonic acid dissolved in 25 ml of dry diethyl ether under ice-cooling.

The mixture was stirred at room temperature overnight. To the mixture was added 150 ml of diethyl ether, and the ether solution was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound in quantitative yields.

(2) 2- O - (Tetrahydropyran-2-yl) propane-1,2-diol (III). Rc = THP) 35 To a suspension of 10.04 g of lithium aluminum hydride in 500 ml of dry diethyl ether was added, under ice-cooling, a solution of 52 g of the ester obtained in Reference Example 14 103571 Cat A-1 (1) in 150 ml. in dry diethyl ether. The mixture was stirred at room temperature for 20 minutes, then heated at reflux for 2 hours and stirred again at room temperature overnight. The mixture was externally cooled on ice and to this mixture was added with stirring 10.04 ml of water, 10.04 ml of 15% aqueous sodium hydroxide solution and 30.12 ml of water, respectively. The insoluble material formed was removed by filtration and the filtrate was concentrated to about half the original volume. The condensate was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound in quantitative yields. This product was purified by distillation in vacuo.

15 Kp: 108-114 ° C (14 mm Hg), 1 H-NMR (CDCl 3) δ: 1.13, 1.22 (all 3H, d each, J = 6.5 Hz), 1.30-1. 94 (6H, m), 2.28 (1H, dd, J = 5.5 and 7Hz), 3.26 - 4.10 (5H, m), 4.48 - 4.78 (1H, m) .

These two examples were performed according to the method described in J. Am. Chem.

Soc., 106, 4916-4922 (1984).

Example 1 2,3-Difluoro-6-nitro- [2- (tetrahydropyran-2-yl) -oxypropyl] -yloxy] -benzene (I. Xa = Xb = F, Rc = THP); To a solution of 2.04 g. triphenylphosphine in 10 mL of dry tetrahydrofuran was added dropwise with 1.36 g of diethyl azodicarboxylate under ice-cooling, and the resulting mixture was stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of 1.05 g of 2,3-difluoro-6. -nitrophenol (IV, Xa = Xb = F), 1.01 g of 2-O- (tetrahydropyran-2-yl) propane-1,2-diol (III, Rc = THP) in 5 ml of dry tetrahydrofuran, and The mixture was then stirred at room temperature overnight The solvent was removed in vacuo and benzene and saturated aqueous sodium bicarbonate were added to the residue, After shaking, the organic layer was separated and washed sequentially with water and a saturated aqueous sodium chloride solution. sodium sulfate and the solvent was then removed in vacuo. The residue was purified through 5 columns of silica gel yielding 1.85 g of the title compound.

This product contained diastereoisomeric isomers, and each diastereomer was detected as a different spot on TLC. The 1 H-NMR spectrum of the product found in TLC at the larger 10 spots, the second of two spots, is shown below.

The '1 H-NMR spectrum of the product, which was found as a smaller spot in TLC, was almost identical to the' 1 H-NMR spectrum of the larger spot.

1 H-NMR (CDCl 3) δ: 1.18-1.84 (9H, m), 3.23-4.28 (5H, m), 4.74 (1H, br s), 6.94 ( 1H, ddd, J = 5, 7.5, 9Hz), 7.65 (1H, ddd, J = 2.5, 5, 9Hz).

Example 2 2.3-Difluoro-6-amino ([2- (tetrahydropyran-2-yl) oxypropyl] oxy] benzene (VI. Xa = Xb = F. Rc = THP) To a solution of 1.82 g The compound obtained in Example 1 dissolved in 50 ml of ethanol was added with 500 mg of 5% palladium on charcoal Catalytic reduction was carried out at atmospheric pressure for about 1 hour The catalyst was removed by filtration and the solvent removed in vacuo to give the title compound. This product was used in the next step without further purification.

Example 3 2.3-Difluoro-6- (2,2-diethoxycarbonylmethyl) amino-2-30 (hydroxypropyl) oxybenzene (X. Xa = Xb = F, R = Et). To the entire product obtained in Example 2 was added 1.24 g of diethyl ethoxymethylene malonate (XVI, Y = EtO, alkyl = Et, abbreviated hereinafter EMME). The mixture was heated to 145-150 ° C with stirring. After 1.5 hours, the mixture was evaporated to remove the ethanol formed, and the mixture was heated for a further 30 minutes to 1003571 with hot stirring. After cooling, the product was isolated by chromatography on a silica gel column to give 1.33 g of the title compound, which has no tetrahydropyranyl group.

A smaller batch of product having a tetrahydropyranyl group weighing 580 mg was also obtained. This compound was converted to the title compound by treatment with pyridinium tosylate.

Mp: 52-55 ° C, MS; m / e = 373 (m +) 10 1 H-NMR (CDCl 3) δ: 1.22-1.46 (9H, m), 3.55 (1H, d, J = 4.5 Hz), 3.88 - 4.43 (7H, m), 6.75 - 7.08 (2H, m), 8.48 (1H, d, J = 14.5 Hz).

Reference Example B-1

Diethyl (7,8-difluoro-3-methyl-3,4-dihydro-2H- [1,4] -15-benzoxazin-4-yl) methylene malonate (XV, Xa = Xb = F, R = Et)

To a solution of 341 mg triphenylphosphine in 5 ml dry tetrahydrofuran was added dropwise 226 mg diethyl azodicarboxylate and the mixture was stirred under ice-cooling for 20 minutes. To this solution was added a solution of 373 mg of the compound obtained in Example 3 in 3 ml of dry tetrahydrofuran, and the mixture was stirred at room temperature overnight.

The solvent was removed in vacuo and the residue purified by chromatography on a silica gel column to give the title compound in quantitative yield. This product was identical to an authentic sample (obtained as described in JP-A-85-126 190) (the term "JP-A" as used herein refers to "published Japanese patent application for the non-investigated 30 countries") in its physical properties.

Mp: 68 ° C.

1 H-NMR (CDCl 3) δ: 1.20-1.41 (9H, m), 3.90-4.44 (7H, m), 6.71-6.85 (2H, m), 7.76 (1H, s).

17 103571

Example 4 2,3-Difluoro-6- (2,2-diethoxycarbonylmethyl) -amino-2-p-toluenesulfonyl-hydroxypropyl) oxy-benzene (XIII. Xa =

Xb = F. Rd = Ts. R = Et15 To a solution of 747 mg of the compound obtained in Example 3 in 2 ml of pyridine was added 710 mg of p-toluenesulfonyl chloride, and the mixture was stirred under ice-cooling for 24 hours and then at room temperature for 4 hours. To the mixture was added ethyl acetate and 1N. hydrogen chloride-10 acid. The mixture was shaken and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by chromatography on a silica gel column to give 1.0 g of the title compound.

Mp: 61-62 ° C.

1 H-NMR (CDCl 3) δ: 1.34, 1.36 (3H each, t each, J = 7Hz), 1.50 (3H, d, J = 7Hz), 2.40 (3H, s) ), 4.12-4.40 (6H, m), 4.94 (1H, sextet-like), 6.83-6.97 (2H, 20m), 7.26, 7.76 (2H each, d each, J = 9Hz), 8.34 (1H, d, J = 14Hz).

Reference Example C-1

Diethyl (7.8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-4-yl) methylene malonate (XV, Xa = Xb = F,: 25 R = Et)

To a solution of 791 mg of the compound obtained in Example 4 in 5 ml of dry Ν, Ν-dimethylformamide (hereinafter abbreviated as DMF) was added 207 mg of potassium carbonate and a catalytic amount of 18-crown-6-ether, and the mixture was heated at 80 ° C. 8.5 hours. Ethyl acetate and water were added to the mixture. The mixture was shaken and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by Kro-35 chromatography on a silica gel column to give the title compound as crystals in quantitative yield.

18 103571

The physical values of the product were identical to the authentic sample described in Reference Example B-1.

Example 5 2.3-Difluoro-6-nitro- (2-hydroxypropyl) oxy-benzene 5 (VIII. Xa = Xb = F)

A mixture of 6.35 g of 2,3-difluoro-6-nitro - {[2- (tetrahydropyran-2-yl) oxypropyl] oxy} benzene (I, Xa = Xb = F, Rc = THP), 60 ml dry ethanol and 640 mg of pyridinium tosylate were stirred at room temperature for 10 nights and then heated to reflux for 1 hour.

The solvent was removed in vacuo. To the residue was added ethyl acetate and 1N. hydrochloric acid. The mixture was shaken and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and water, then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the oily title compound. This product was used in the next reaction without purification. 1 H-NMR (CDCl 3) δ: 1.25 (3H, d, J = 6 Hz), 3.00 (1H, br d, 20 J = 2.5 Hz), 3.99 - 4.43 (3H , m), 7.03 (1H, ddd, J = 7.9, 9.5 (Hz), 7.74 (1H, ddd, J = 2.5, 5.5, 7 Hz).

Example 6 2.3-Difluoro-6- (2,2-dimethoxycarbonyl-ethylene) -amino (2-hydroxypropyl) oxybenzene (X, Xa = Xb = F, R = Me) To a solution of 3.17 g of the compound obtained in Example 5 In 45 ml of ethanol, 780 mg of 5% palladium on charcoal was added, and the catalytic reduction was carried out at atmospheric pressure at room temperature. The catalyst was removed by filtration and the solvent removed in vacuo. To the residue was added 2.44 g of dimethylmethoxymethylene malonate (XVI, Y = OMe, alkyl = Me) and the mixture was heated at 140 ° C with stirring as follows: atmospheric pressure for 1 hour, then vacuum for 1 hour and then atmospheric pressure for 1 hour. After cooling to 35, the mixture was purified by chromatography on a silica gel column to give 4.0 g of the title compound.

Mp: 107-108 ° C

1 H-NMR (CDCl 3) δ: 1.29 (3H, d, J = 6.5 Hz), 3.45 (1H, d, J J 4.5 Hz), 3.80, 3.88 ( 3H each, s each), 6.76 -7.12 (2H, m), 8.53 (1H, J = 14.5 Hz).

Example 7 2,3-Difluoro-6- (2,2-dimethoxycarbonylmethyl) amino- [2- (p-toluenesulphonyloxypropyl) oxy] benzene (XIII, 10a = Xb = F. Rd = Ts. R = Me)

To a solution of 2.07 g of the compound obtained in Example 6 in 4.2 ml of pyridine was added 1.49 g of p-toluenesulfonyl chloride, and the mixture was stirred for 3 days at an external temperature of 5 ° C.

Ethyl acetate was added to the mixture, and the solution was washed successively with 1 N. hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by chromatography on a silica gel column to give 2.76 g of the title compound.

Mp: 89-90 ° C.

1 H-NMR (CDCl 3) δ: 1.50 (3H, d, J = 6.5 Hz), 2.40 (3H, s), 3.80, 3.85 (3H each, s each), δ , 04 - 4.42 (2H, m),

* 4.80 - 5.14 (1H, m), 6.76 - 7.12 (2H, m), 7.28, 7.80 (2H)

each, d each, J = 8 Hz), 8.41 (1H, J = 14 Hz). Reference Example C-2

Dimethyl (7,8-difluoro-3-methyl-3,4-dihydro-2H-f 1,41-benzoxazin-4-yl) methylene malonate (XV, Xa = Xb = F, 30R = Me)

A mixture of 749 mg of the compound obtained in Example 7, 207 mg of potassium carbonate and 5 ml of dry DMF was heated at 80 ° C for 8 hours. The mixture was diluted with ethyl acetate and the resulting mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by chromatography on a silica gel column to give 455 mg of the title compound.

Mp: 146-147 ° C

1 H-NMR (CDCl 3) δ: 1.32 (3H, d, J = 7Hz), 3.81, 3.85 δ (3H each, s each), 3.94-4.63 (3H, m ), 4.80-5.14 (1H, m), 6.80 (2H, q-like m), 7.82 (1H, s). Example 8 2.3-Difluoro-6-nitro- (2-p-toluenesulfonyl-oxy-propyl) -oxybenzene (XI, Xa = Xb = F. Rd = Ts) 10 To a solution of 4.5 g of the compound obtained in Example 5 in 8.6 ml: of pyridine, 4.36 g of p-toluenesulfonyl chloride was added and the mixture was stirred under ice-cooling for 4 hours and then at room temperature for 4 hours. To the mixture was added ethyl acetate and 2N. hydrogen chloride-15 acid. The mixture was shaken and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by chromatography on a silica gel column to give 6.52 g of the title compound.

Mp: 67-69 ° C.

1 H-NMR (CDCl 3) δ: 1.44 (3H, d, J = 6Hz), 2.41 (3H, s), 4.08-4.40 (2H, m), 4.76-5. , 08 (1H, m), 7.30 (1H, sextet-like), 7.67 (1H, ddd, J = 2.5, 5.5, 8.5 Hz), 25 7.32, 7.80 (2H each, d each, J = 8 Hz).

Example 9 2.3-Difluoro-6-amino (2-p-toluenesulfonyl-oxy-propyl) -oxyl-benzene (XII, Xa = Xb = F, Rd = Ts)

To a solution of 2.32 g of the compound of Example 8 in 50 ml of ethanol was added 1 g of 5% palladium on charcoal, and catalytic reduction was carried out at atmospheric pressure at room temperature for about 1 hour. The catalyst was removed by filtration and the solvent removed in vacuo to give the title compound 35. This product was used in the next reaction without purification.

21 103571

Example 10 2,3-Difluoro-6- (2,2) -diethoxycarbonylpropyl) amino- (2-p-toluenesulfonoxypropyl) oxy benzene (XIII,

Xa = Xb = F. Rd = Ts. R = Et) A mixture of the entire product obtained in Example 9 and 1.30 g of EMME was heated at 140-150 ° C with stirring as follows: at atmospheric pressure for one hour, then under vacuum for one hour. The reaction mixture was purified by chromatography on a silica gel column to give 1.64 g of the title compound. This compound was identical to that obtained in Example 3.

Reference Example D1 7,8-Difluoro-3-methyl-3,4-dihydro-2H-11,4-benzoxazine (XIV. Xa = Xb = F) To a solution of 720 mg of the compound obtained in the same manner as in Example 9. In 5 ml of DMF, 276 mg of potassium carbonate and a catalytic amount of 18-crown-6-ether were added. The mixture was heated at 80 ° C overnight. Ethyl acetate and water were added to the mixture. The mixture was shaken and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by chromatography on a silica gel column to give 267 mg of the title compound. The physical values of the product were identical to the authentic sample obtained as described in U.S. Patent 4,382,892 and EP-B-0 047 005.

Mp: 52 ° C (identical to authentic compound).

Reference Example A-230 (1) (S) -ethyl-O- (tetrahydropyran-2-yl) lactate

A mixture of 50.06 g of (S) - (-) - ethyl lactate, 50.48 g of 2,3-dihydropyran, 5.8 g of dl-camphor-10-sulfonic acid and 250 ml of dry diethyl ether was stirred under ice-cooling. 30 minutes and then at room temperature-35 overnight. To the mixture was added 300 ml of diethyl ether and the ether solution was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The resulting solution was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound in quantitative yields.

(2) 2-O- (Tetrahydropyran-2-yl) - (S) -propane-1,2-diol (IIIS. Rc = THP)

To a suspension of 20.1 g of lithium aluminum hydride in 1000 ml of dry diethyl ether, a solution of the total ester obtained in Reference Example A-2 (1) in 200 ml of dry diethyl ether was added dropwise and stirred under ice-cooling. The mixture was stirred at room temperature for 1 hour, then heated at reflux for 2 hours and again at room temperature overnight. The mixture was externally cooled on ice and 20.1 ml of water, 20.1 ml of 15% aqueous sodium hydroxide solution, 61.5 ml of water were added to the mixture, respectively and with stirring. The insoluble material formed was removed by filtration, and the filtrate was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo.

The residue was distilled in vacuo to give the title compound as a mixture of diastereomers.

Kp: 88-93 ° C (5 mm Hg) 1 H-NMR (CDCl 3) δ: 1.13 and 1.22 (3H total, d each, 25 J = 6.5 Hz) 1.36-1.96 (6H, m), 3.30-4.12 (5H, m), 4.50-4.60, 4.68-4.80 (1H, m).

Example 11 2,3-Difluoro-6-nitro - ([(S) -2- (tetrahydropyran-2-yl) -oxy-propyloxy] benzene (IS, Xa = Xb = F, Rc = THP) The title compound was obtained as an oil as a product, according to the procedure described in Example 1, starting from 12.26 g of 2,3-difluoro-6-nitrophenol (IV, Xa = Xb = F), 11.78 g of 2-O- (tetrahydropyran-2-yl). ) - (S) -propane-1,2-diol (IIIS, Rc = THP) and 1,3 molar equivalent (based on pheneno-35) Mitsunobu reagent The product weighing 20.4 g was a mixture of diastereomers .

23 103571 1 H NMR (CDCl 3) δ: 1.28, 1.32 (3H total, d each, J = 6Hz), 1.40-1.86 (6H, m), 3.36-4. 42 (5H, m), 4.68 - 4.86 (1H, m), 7.00 (1H, ddd, J = 7.9, 9.5 Hz), 7.68 (1H, ddd, J = 2.5, 5, 9 Hz).

5 Example 12 2.3-Difluoro-6-nitro (Γ (S) - (2-hydroxypropyl) -1-oxylbenzene (VIIIS. Xa = Xb = F)

Removal of the tetrahydropyranyl group was carried out using 6.35 g of the product obtained in Example 11 and 640 mg of pyridine tosylate according to the procedure described in Example 5. An oily product was obtained and the product was used without further purification in the following reaction.

1 H-NMR (CDCl 3) δ: 1.26 (3H, d, J = 6Hz), 2.88 (1H, d, J = 2.5Hz), 3.96-4.44 (3H, m) , 7.03 (1H, ddd, J = 7.9, 9.5 15 Hz), 7.75 (1H, ddd, J = 2.5, 5.5, 7 Hz).

Example 13 2.3-Difluoro-6-nitro- (f (S) -2-p-toluenesulfonyl-hydroxypropyl) -1-oxy) benzene (XIS, Xa = Xb = F, Rd = Ts) from 4.35 g of the product obtained in Example 12. 6.9 g of the title compound were obtained according to the tosylation procedure described in Example 8 cat.

Mp: 68-69.5 ° C.

1 H-NMR (CDCl 3) δ: 1.44 (3H, d, J = 6Hz), 2.42 (3H, s), 4.08-4.40 (2H, m), 4.76-5. , 08 (1H, m), 7.03 (1H, ddd, J = 7.9, 9.5 Hz), 7.68 (1H, ddd, J = 2.5, 5.5, 7 Hz) . Example 14 and Reference Example D-2 (R) - (+) - 7,8-Difluoro-3,4-dihydro-3-methyl-2H-f, 41-benzo-oxazine (XIVR, Xa = Xb) = F)

According to the methods described in Example 30, Cat 9 and Reference Example D1, 775 mg of 2,3-difluoro-6-nitro {[(S) -2-p-toluenesulfonyloxypropyl] oxy} benzene (XIS, Xa = Xb. = F, Rd = Ts) gave 280 mg of the title compound. The product was identical to the authentic sample (obtained as described in Agric. Biol. Chem., 51, (5), 351265-1270 (1987)) in terms of physical values.

24 103571

Reference Example A-3 (1) (R) -methyl-O- (tetrahydropyran-2-yl) lactate

A mixture of 31.23 g of (R) - (+) - methyl lactate (available from DAISEL CHEMICAL INDUSTRIES, LTD.),? 30.28 g of 2,3-dihydropyran, 3.48 g of dl-camphors-10-sulfone acid and 150 ml dry diethyl ether were stirred under ice-cooling for 30 minutes and then at room temperature overnight. To the mixture was added 300 mL of diethyl ether, and the resulting ether solution was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the oily title compound in quantitative yields.

1 H NMR (CDCl 3) δ: 1.20, 1.26 (3H total, d, J = 6.5 Hz), 1.36-2.22 (6H, m), 3.74 (3H, s), 3.32-4.02 (2H, m), 4.22, 4.44 (1H total, q each, J = 7Hz), 4.64 -4.78, 4.90-5. 02 (1H total, m).

121 2-O- (Tetrahydro-propran-2-yl) - (R) -propane-1,2-diol (IIIR, R = THP)

To a suspension of 25.7 g of lithium aluminum hydride in 800 ml of dry diethyl ether was added dropwise, with ice-cooling and stirring, a solution of 57.09 g of the compound obtained in Reference Example A-3 (1) in 200: 25 ml. dry diethyl ether. The mixture was stirred at room temperature for 1 hour, then heated at reflux for 2 hours and left at room temperature overnight. The mixture was cooled on ice externally and 25.7 ml of water, 25.7 ml of 15% aqueous sodium hydroxide solution and 77.1 ml of water were added successively with stirring. The insoluble matter was removed by filtration and the filtrate was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue was distilled in vacuo to give the title compound as a mixture of diastereomers.

35 Kp: 86-90.5 ° C (4.5-5 mmHg), 40.21 g.

103571 1 H-NMR (CDCl 3) δ: 1.13, 1.22 (3H total, d each, J = 6.5 Hz), 1.33-1.97 (6H, m), 2.21 (1H, t-like, J = 5.5 Hz), 3.28-4.13 (5H, m), 4.48-4.81 (1H, m).

EXAMPLE 15 2,3-Difluoro-6-nitro (f (R) -2- (tetrahydropyran-2-yl-oxypropyl) oxy) benzene (IR. Xa = Xb = F. R = THP) The oily title compound was obtained in Example 1. according to the method described, 12.21 g of 2,3-difluoro-6-nitrophenol (IV, Xa = Xb = F), 11.76 g of 2-O- (tetra-10 hydropyran-2-yl) - ( R) -propane-1,2-diol (IIIR, Rc = THP) and 1.3 molar equivalent (based on phenol) of Mitsu-Nobu reagent The weight of the product obtained was 20.49 g.

1 H-NMR (CDCl 3) δ: 1.28, 1.32 (3H total, d each, J = 6Hz), 1.40-1.94 (6H, m), 3.34-4.44 ( 5H, m), 4.68-15 4.86 (1H, m), 7.00 (1H, ddd, J = 7.9, 9.5 Hz), 7.68 (1H, ddd, J = 2 , 5, 5, 9 Hz).

Example 16 2.3-Difluoro-6-nitro- (Γ (R) - (2-hydroxypropyl) -1-oxybenzene (VIIIR, Xa = Xb = F) 20 Following the procedure described in Example 5, from 6.35 g in Example 15 4.62 g of the oily title compound were obtained.

1 H-NMR (CDCl 3) δ: 1.26 (3H, d, J = 6Hz), 2.89 (1H, d, J = 2.5Hz), 3.95-4.46 (3H, m), 7.03 (1H, ddd, J = 7.9, 9.5 Hz), 7.75 (1H, ddd, J = 2.5, 5.5, 7 Hz).

Example 17 2.3-Difluoro-6-nitro-! Γ (R) - (2-p-Toluenesulfonyl-hydroxypropyl) -1-oxybenzene (X 1. Xa = X b = F. Rd = Ts)

According to the tosylation procedure described in Example 8, 4.62 g of the compound obtained in Example 16, 4.53 g of p-toluenesulfonyl chloride and 12 ml of pyridine gave 6.74 g of the title compound.

Mp: 67.5-68 ° C.

1 H-NMR (CDCl 3) δ: 1.43 (3H, d, J = 6Hz), 2.41 (3H, s), δ 4.08-4.40 (2H, m), 4.76-. 5.08 (1H, m), 7.04 (1H, ddd, J = 7.9, 9.5 Hz), 7.67 (1H, ddd, J = 2.5, 5.5, 7 Hz) , 7.32, 7.80 (2H each, d each, J = 8.5 Hz).

26 103571

Example 18 2,3-Difluoro-6-amino- (f (R) - (2-p-toluenesulfonyl-oxy-propyl) -oxy) -benzene (XIIR, Xa = Xb = F. Rd = Ts)

To a solution of 581 mg of the compound of Example 17 obtained in 20 ml of ethanol was added 200 mg of 5% palladium on charcoal. The catalytic reduction was carried out at atmospheric pressure at room temperature. After the theoretical amount of hydrogen was bound, the catalyst was removed by filtration and the solvent removed in vacuo. The residue was purified by chromatography on silica gel to give 520 mg of the title compound.

Mp: 37-38 ° C.

1 H-NMR (CDCl 3) δ: 1.34 (3H, d, J = 6.5 Hz), 2.44 (3H, s), 3.50 (2H, br s), 4.02-4. 14 (2H, m), 4.80-5.14 (1H, m), δ 6.38 (1H, ddd, J = 2.5, 5.5, 7Hz), 6.71 (1H, ddd) , J = 7.9, 9.5 Hz), 7.32, 7.80 (2H each, d each, J = 8.5 Hz).

Reference Example D-3 (S) - (-) - 7,8-Difluoro-3-methyl-3,4-dihydro-2H-1,1,41 benz-20-oxazine (XIVS. Xa = Xb = F)

According to the procedures of Example 18 and Reference Example D-1, 775 mg of 2,3-difluoro-6-nitro {[(R) - (2-p-toluenesulfonyloxypropyl)] oxy} benzene (XIR, Xa =

Xb = F, Rd = Ts) gave 262 mg of the title compound. The physical values of the product were identical to those of the authentic sample obtained in Agric. Biol. Chem., 51, (5), 1265-1270 (1987) and EP-A-0 206 283.

Example 19 2,3-Difluoro-6-amino- (f (R) -2- (tetrahydropyran-2-yl) oxypropyloxy) benzene (VIR. Xa = Xb = F, Rc = THP).

To a solution of 476 mg of 2,3-difluoro-6-nitro-. {[(R) -2-Tetrahydropyran-2-yl) oxypropyl] oxy} benzene (IR, Xa = Xb = F, Rc = THP) in 20 mL of ethanol, add 200 mg of 5%: of palladium on charcoal. The catalytic reduction was carried out at atmospheric pressure at room temperature. After the theoretical amount of hydrogen was bound, the catalyst was removed by filtration and the solvent removed from the filtrate in vacuo. The residue was purified by chromatography on a silica gel column to give 385 mg of an o-5 oily compound as a mixture of diastereomers.

1 H-NMR (CDCl 3) δ: 1.23, 1.33 (3H overall, d each, J = 6Hz), 1.36-1.98 (6H, m), 3.36-4.32 ( 5H, m), 4.70-4.90 (1H, m), 6.39 (1H, ddd, J = 2.5, 5.5, 7Hz), 7.72 (1H, ddd, J = 7.9, 9.5 Hz).

Example 20 2,3-Difluoro-6- (2,2-diethoxycarbonylphenyl) -amino- (R (-R) -2-hydroxypropyl) oxy-benzene (XR, Xa = Xb = F, R = Et) 2,3-Difluoro-6- amino {[(R) -2- (tetrahydropyran-2-yl) propyl] oxy} benzene (VIR, Xa = Xb = F, Rc = THP), obtained from 6.35 g 2.3 -difluoro-6-nitro {[(R) -2- (tetrahydropyran-2-yl) oxypropyl] oxy} benzene (IR,

Xa = Xb = F, Rc = THP) according to the procedure described in Example 19, and 4.37 g of EMME were heated at 20 to 150 ° C under atmospheric pressure for 1.5 hours with stirring. The mixture was then heated at the same temperature under vacuum for 30 minutes. 60 ml of dry ethanol and 640 mg of pyridinium tosylate were added to the mixture, and the mixture was stirred at room temperature overnight. The solvent was removed; Under vacuum and the residue was dissolved in ethyl acetate. This solution was washed successively with 1N. hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo-30. The residue was purified by chromatography on a silica gel column to give 5.56 g of the title compound.

Mp: 88-90 ° C.

1 H-NMR (CDCl 3) δ: 1.25-1.45 (9H, m), 3.54 (1H, d, J = 4.5 Hz), 3.86-4.46 (7H, m) , 6.76 - 7.10 (2H, m), 8.49 (1H, 35 d, J = 14.5 Hz) 28 103571

Reference Example B-2 (S) -Diethyl- (7.8-difluoro-3-methyl-3,4-dihydro-2H-11,4-benzoxazin-4-yl) methylene malonate (XVS, Xa = Xb = F. R = Et In accordance with the procedure described in Reference Example B1, 560 mg of the compound obtained in Example 20 was cyclized in the presence of a 1.3 molar equivalent amount of Mit-sunobu reagent. The title compound was obtained in quantitative yields.

1 H NMR (CDCl 3) δ: 1.22-1.42 (9H, m), 3.90-4.44 (7H, m), 6.74-6.88 (2H, m), δ , 78 (1H, s).

Example 21 2,3-Difluoro-6- (2,2-diethoxycarbonylphenyl) amino (f (R) -2-p-toluenesulfonyl-oxy-propyl) oxy-benzene 15 (XIIIR, Xa = Xb = F, Rd = Ts, R = Et).

The tosylation reaction was carried out according to the procedure described in Example 4, and 2.43 g of the compound obtained in Example 20, 4.5 ml of pyridine and 1.49 g of p-toluenesulfonyl chloride gave 3.2 g of the title compound.

Mp: 68-69 ° C.

1 H-NMR (CDCl 3) δ: 1.33, 1.36 (3H each, t each, J = 7Hz), 1.50 (3H, d, J = 7Hz), 2.40 (3H, s ), 4.02-4.42 (6H, m), 4.96 (1H, sextet-like), 6.85-7.00 (2H, 25m), 7.28, 7.79 (2H each) , d each, J = 9Hz), 8.37 (1H, d, J = 14Hz).

Reference Example C-3 (S) -diethyl- (7,8-difluoro-3-methyl-3,4-dihydro-2H-1 H -41-benzoxazin-4-yl) methylene malonate (XVS. Xa = Xb = 30 F. R = Et): The oily title compound was obtained in quantitative yield in the cyclization reaction according to the method described in Reference Example C1, from 791 mg of the compound obtained in Example 21, 207 mg of potassium carbonate and 18-crown-6 ether.

29 103571

Example 22 2.3-Difluoro-6-amino - (f (R) -2-hydroxypropyloxy) benzene (IXR. Xa = Xb = F)

To a solution of 3.1 g of 2,3-difluoro-6-nitro-5 {[(R) -2-hydroxypropyl] oxy} benzene (VIIIR, Xa = Xb = F) in 50 ml of ethanol was added 500 mg 5% palladium on charcoal. The catalytic reduction was carried out at atmospheric pressure at room temperature. After hydrogen uptake was complete, the catalyst was removed by filtration and the solvent removed from the filtrate in vacuo. The residue was purified by chromatography on a silica gel column to give 2.47 g of the title compound.

Mp: 47-48 ° C.

1 H-NMR (CDCl 3) δ: 1.21 (3H, d, J = 6.5 Hz), 3.25 - 4.30 δ (6H, m), 6.43 (1H, ddd, J = 2 , 5.5, 7.7 Hz), 7.76 (1H, ddd, J = 7.9, 9.5 Hz).

EXAMPLE 23 2,3-Difluoro-6- (2,2-dimethoxycarbonyl-sulfenyl) -amino- (Γ (R) -2-hydroxypropyloxy) benzene (XR, Xa = Xb = F, 20R = Me)

According to the procedure described in Example 6, 9.30 g of the compound obtained in Example 16 gave 11.32 g of the title compound.

Mp: 104-105 ° C.

1 H NMR (CDCl 3) δ: 1.28, (3H, d, J = 6.5 Hz), 3.44 (1H, d, J = 4.5 Hz), 3.79, 3.87 (3H each, s each), 6.76 -7.11 (2H, m), 8.52 (1H, J = 14.5 H2).

EXAMPLE 24 2.3-Difluoro-6- (2,2-dimethoxycarbonylphenyl) amino-3 O (R) -2- (p-toluenesulfonyloxypropyl) oxy benzene (XIIIR. Xa = Xb = F. Rd = Ts. R = Me).

According to the procedure described in Example 4, 10.52 g of the compound obtained in Example 23 gave 13.52 g of the title compound.

35 Mp: 92-93 ° C.

103571 1 H-NMR (CDCl 3) δ: 1.51 (3H, d, J = 6.5 Hz), 2.41 (3H, s), 3.82, 3.88 (3H each, s each) , 4.07-4.44 (2H, m), 4.83-5.16 (1H, m), 6.80-7.15 (2H, m), 7.32, 7.85 (2H each) , d each, J = 8Hz), 8.46 (1H, d, J = 14.5Hz) Reference Example C-4 (S) -dimethyl-1- (7,8-difluoro-3-methyl) - 3,4-Dihydro-2H-1,1,4-benzoxazin-4-yl) methylene malonate (XVS, Xa =

Xb = F. R = Me)

According to the method described in Reference Example C-1, 4.99 g of the compound obtained in Example 24 gave 3.12 g of the title compound.

Mp: 108-109 ° C.

1 H-NMR (CDCl 3) δ: 1.32 (3H, d, J = 7Hz), 3.81, 3.85 (3H each, s each), 3.94-4.63 (3H, m) , 6.80 (2H, q 15), 7.82 (1H, s).

Example 25 2,3-Difluoro-6-nitro (2-hydroxypropyl) oxy-benzene (VIII. Xa = Xb = F) A suspension of 207 mg of 20% sodium hydride (60%) in anhydrous ice was cooled in ice. as a solvent to remove the mineral oil, in 4 mL of anhydrous toluene, a solution of 793 mg of 2-O-tetrahydropyranylpropane-1,2-diol (III, Rc = THP) in 3 mL of anhydrous toluene was added dropwise and the mixture was stirred at 25 mass at 30 minutes. To the mixture was added dropwise a solution of 797 mg of 2,3,4-trifluoronitrobenzene (II, Xa = Xb = Xc = F) in 3 mL of dry toluene, with stirring and ice-cooling. The mixture was stirred at an external temperature of 5 ° C for 24 hours. Water and ethyl acetate were added to the mixture and the resulting mixture was shaken.

The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give 2,3-difluoro-6-nitro - {[2- (tetrahydropyran-2-yl) oxypropyl] oxy} benzene (I, Xa = Xb = F, Rc = 35 THP) in quantitative yields. This compound was dissolved in 13.5 ml of anhydrous ethanol and 145 mg of pyridinium tosylate was added to this solution. The mixture was stirred at room temperature for 24 hours and then heated to reflux for 1 hour. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. This solution was washed with 5 1N. hydrochloric acid, 5% aqueous sodium hydrogen carbonate solution and water, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by chromatography on a silica gel column to give 902 mg of the oily title compound-10.

1 H-NMR (CDCl 3) δ: 1.25 (3H, d, J = 6Hz), 3.00 (1H, br d, J = 2.5Hz), 3.99-4.43 (3H, m), 7.03 (1H, ddd, J = 7.9, 9.5 Hz), 7.74 (1H, ddd, J = 2.5, 5.5, 7 Hz).

Example 26 2.3-Difluoro-6-nitro- (Γ (R) -2-hydroxypropyl] oxylbenzene (VIIIR. Xa = Xb = F) In an ice-cooled suspension of 720 mg of sodium hydride (60%) in 12 ml: of anhydrous toluene, a solution of 2.88 g of 2-O-tetrahydro-20-ropyranyl (R) -propane-1,2-diol (IIIR, Rc = THP) in 12 ml of dry toluene was added dropwise, and was stirred at the same temperature for 30 minutes and at room temperature for 10 minutes. The mixture was added dropwise to a solution of 2.66 g of 2,3,4-trifluoronitrobenzene in 12 ml of dry to-25 luen, with stirring and ice-cooling. at ambient temperature for 24 hours, ice water and benzene were added to the mixture and the resulting mixture was shaken The organic layer was separated and dried over anhydrous magnesium sulfate The solvent was removed in vacuo to give 2,3-difluoro-6-nitro - {[(R) -2- ( tetrahydro-pyran-2-yl) oxypropyl] oxy} benzene (IR, Xa = Xb = F, Rc = TH P) in quantitative yield This compound was dissolved in 38 ml of dry ethanol and 450 mg of pyridinium tosylate was added thereto. The mixture was heated to reflux for 35 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. This solution was washed with pe 1010771 dear 1N hydrochloric acid, 5% aqueous sodium hydrogen carbonate and water, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography to give 3.20 g of the oily title compound.

1 H-NMR (CDCl 3) δ: 1.26 (3H, d, J = 6Hz), 2.89 (1H, br-d, J = 2.5Hz), 3.95-4.46 (3H , m), 7.03 (1H, ddd, J = 7.9, 9.5 Hz), 7.75 (1H, ddd, J = 2.5, 5.5, 7 Hz).

Example 27 2,3-Difluoro-6-nitro (((S) -2-hydroxypropyl) oxy) benzene (VIIIS, Xa = Xb = F)

According to the method described in Example 26, 2.88 g of 2-O-tetrahydropyranyl- (S) -propane-1,2-diol 15 (IIIS, Rc = THP) and 2.66 g of 2,3,4- Trifluoronitrobenzene (II, Xa = Xb = Xc = F) gave 3.03 g of the oily title compound.

1 H-NMR (CDCl 3) δ: 1.26 (3H, d, J = 6Hz), 2.88 (1H, d, J = 2.5Hz), 3.96-4.44 (3H, m) ), 7.03 (1H, ddd, J = 7.9, 20. 9.5 Hz), 7.75 (1H, ddd, J = 2.5, 5.5, 7 Hz).

For the products obtained in Examples 26 and 27, high performance liquid chromatography (HPLC) confirmed that no isomerization had occurred. The products were converted to 3,5-dinitrobenzoyl derivatives by reaction with 3,5-dinitrobenzoyl chloride and pyridine. The resulting 3,5-dinitrobenzoyl derivatives were subjected to HPLC to determine optical purity. The HPLC column used was a CHIRALSEL OD column from DAISEL CHEMICAL INDUSTRIES LTD.

Reference Example A-4: (1) (R) -methyl-O- (tetrahydropropran-2-yl) lactate

A mixture of .156.15 g of (R) - (+) - methyl lactate, 151.42 g of 2,3-dihydropyran, 17.42 g of dl-camphor-10-sulfonic acid and 150 ml of dry 1,2- dichloroethane was stirred under ice-cooling overnight. To this mixture was added 900 ml of 1,2-dichloroethane and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the oily title compound in the most quantitative yield of ca.

(2) 2-O- (Tetrahydro-propran-2-yl) - (R) -propane-1,2-diol (IIIR, Rb = THP)

To a suspension of 85.12 g of sodium borohydride in 750 ml of 1,2-dichloroethane was added dropwise a solution of the compound obtained in Reference Example A-4 (1) in 243 ml of methanol while maintaining an internal temperature of 30 ° C. below. Then, 122 ml of methanol was added at the same temperature. The mixture was stirred at room temperature for 1 hour. To the mixture was added 2,200 mL of water and the organic layer was separated. The aqueous layer was extracted with 1,2-dichloroethane. The combined organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue was distilled in vacuo to give 174 g of the title compound. The physical values of the products obtained in this Reference Example A-4 were identical to those of the products obtained in Reference Example A-3 (2).

Although the invention has been described in detail and with reference to its specific embodiments, it will be apparent to one skilled in the art that various changes and modifications may be made therein without departing from the spirit and scope thereof.

Claims (3)

103571 1. A propoxybenzene derivative of the formula Xb'I <VkNHRc ^ OH 10 wherein R e represents a hydrogen atom or a group -CH = C (COO-C 1-6 alkyl) 2 and Xa and Xb which may be the same or different each a halogen atom. The 6-amino-2,3-di-15-fluoro- (2-hydroxypropyl) oxy] benzene of claim 1. The 2,3-difluoro-6- (2,2-dialkoxycarbonylethenyl) amino [(2-hydroxypropyl) oxy] benzene of claim 1. «103571 A propoxybenzene derivative of the formula X, 10-color Re betecknar en zateatom eller en group -CH = C (COO-C 1-6 -alkyl) 2 ooh Xa and Xb may be substituted for the halogen atom. 6-Amino-2,3-difluoro - [(2-hydroxypropyl) oxy] -15-benzene patent No. 1. 3. A patent application for 2,3-difluoro-6- (2,2-dialkoxycarbonylenethenyl) amino [(2-hydroxypropyl) oxy] benzene.