The present invention relates to new diaryl acetic acid derivatives of the general formula (I) and the preparation thereof.

The new compounds of the general formula (I) according to the invention may be used as intermediates at the production of biological active compounds, preferably oxytocin antagonists described in J. Pharmacol. Exp. Ther. 2004, 309, 414; US Patent No.6,673,790.

One aspect of the present invention is the new compounds of the general formula

(I),

wherein R stands for nitro group or -COOR ¹ group, wherein R ¹ stands for hydrogen atom or for G _1-4 straight or branched alkyl group, R ² stands for hydrogen atom, C _1-4 straight or branched alkyl group and R ³ stands for a-COOR ⁴ group or -CN group, wherein R ⁴ stands for hydrogen atom or C _1-4 straight or branched alkyl group.

Preferred compounds of the general formula (I) are the folio wings: Methyl 4-chloro-3-[ 1 -(5-chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate

Methyl 4-chloro-3 -[I -(5-chloro-2-nitrophenyl)-2-methoxy-l -methyl 2- oxoethyljbenzoate

4-Chloro-3-[l-(5-chloro-2-nitrophenyl)-2-methoxy-l-methyl -2-oxoethyl]benzoic acid Methyl 4-chloro-3-[l-(5-chloro-2-nitrophenyl)-l-methyl-2-carboxyeth yl]benzoate

4-Chloro-3-[l-(5-chloro-2-nitrophenyl)-l-methyl-2-carboxy ethyl]benzoic acid

Methyl 4-chloro-3-[(5-chloro-2-nitrophenyl)-cyano-methyl]benzoate Methyl 4-chloro-3-[l-(5-chloro-2-nitrophenyl)-l-cyanoethyl]benzoate Methyl 2-(2-chloro- 5-nitrophenyl)-2-(5-chloro-2-nitrophenyl)propionate.

The compounds of the general formula (I),

wherein R stands for nitro group or -COOR ¹ group, wherein R ¹ stands for hydrogen atom or Ci _-4 straight or branched alkyl group, R ² stands for hydrogen atom, C _1-4 straight or branched alkyl group and R? stands for a-COOR ⁴ group or -CN group, wherein R ⁴ stands for hydrogen atom or Cj _-4 straight or branched alkyl group, may be prepared by reacting a compound of the general formula (II),

wherein R ⁵ stands for nitro group or -COOR ⁶ group, wherein R ⁶ stands for a straight or branched C _1-4 alkyl group, R ⁷ stands for a -COOR ⁸ or -CN groupj wherein R ⁸ stands for a straight or branched C _1-4 alkyl group, with a nitrobenzene derivative of the formula (III),

wherein X stands for a fluorine atom or a chlorine atom, in the presence of solid sodium hydride, alkali metal hydroxide, alkali metal alkoxylate, alkali metal carbonate or bicarbonate in a solvent at low temperature, and if desired reacting a compound of the general formula (IV),

wherein R ⁵ and R ⁷ have the same meaning as defined above, with an alkylating compound of the formula (R ⁹ ) _n Y, wherein R ⁹ stands for Cj _-4 straight or branched alkyl group, Y stands for halogen atom, sulphate, sulphonate or phosphate group and n stands for 1, 2 or 3, if desired hydrolyzing the ester groups of a compound of the formula (V),

wherein R ² and R ⁵ have the same meaning as defined above and R ⁷ stands for -COOR ⁸ , wherein R ⁸ stands for straight or branched Ci _-4 alkyl group in one or two steps and if desired hydrolyzing the -CN group of a compound of the formula (V), wherein R ⁷ stands for -CN group and R ² and R ⁵ are as defined above, and if desired transforming the substituents of the compound of the general formula (I) into .each other by known methods.

According to the invention sodium hydroxide or potassium hydroxide might be used as alkali metal hydroxide; sodium methoxide or potassium tertiary butoxide, as alkali metal alkoxylate; potassium carbonate, as alkali metal carbonate; sodium bicarbonate, as alkali metal bicarbonate; dimethylformamide, N-methylpyiτolidone, toluene, tetrahydrofurane, acetone, tertiary-butylalcohol, as solvent. The X leaving group preferably means fluorine or chlorine atom.

The hydrolysis of the group -COOR ⁶ might be carried out in a protic solvent, preferably methanol in the presence of a base, preferably benzyltrimethylammonium-hydroxide (Triton B).

The hydrolysis of the groups -COOR ⁶ and -COOR ⁸ together is preferably performed in a protic solvent, preferably isopropanol in the presence of a base, preferably alkali hydroxide, preferably potassium hydroxide.

The arylation with 2,4-dichloro-nitrobenzene is preferably carried out at a temperature between (-20 ⁰ C) and O ⁰ C, preferably (-10 ⁰ C) and (-8 ⁰ C), while using 2-chloro-4-fluoro-nitrobenzene the preferable temperature is between (-10 ⁰ C) and (+20 ⁰ C).

Compounds of the general formula (II) are new compounds, which may be prepared according to methods known -per se, e.g. by methods given in reaction schemes l and 2.

1. Reaction scheme 2. Reaction scheme

DMF, Cs ₂ CO ₃

NBS, CCI ₄ C,- ₄ alkyliodide

NaCN, 1,4-dioxane, water

NaCN, 1,4-dioxane, water alcanol, HCI

Further details of the invention are given in the examples, without limiting the invention to the examples.

EXAMPLES Preparation 1

Methyl 4-chloro-3-methylbenzoate

To a solution of 4~chloro-3-methylbenzoic acid (25 g) in DMF (550 ml) under a dry atmosphere was added portion wise 50 g of caesium carbonate and then slowly, 10,95 ml of methyl iodide. Temperature rose from 20 ⁰ C to 23 ⁰ C. The reaction mixture was stirred at room temperature overnight. The mixture was cooled to 10 ⁰ C and then 800 ml of an aqueous solution of NaHCO ₃ (2%) and 600 ml of ethyl acetate were successively added. The aqueous layer was separated, extracted again with 400 ml of ethyl acetate. The • combined organic layers were washed successively with 2x250 ml of an aqueous solution of NaHCO ₃ (2%), then 2x250 ml of aqueous solution of NaCl (2%), dried over Na ₂ SO ₄ and concentrated in vacuum. The residue was purified by distillation to afford 25.31 g of a clear yellow liquid (b.p.: 78 °C/0.08 mbar). Yield: 93%

T.L.C.: Silica gel, eluents: cyclohexane-ethyl acetate 75/25

Preparation 2

Methyl 3 -bromomethyl-4-chlorobenzoate Into an appropriate flask methyl 4-chloro-3-methylbenzoate (25.26 g), N- bromosuccinimide (24.85 g) and 20 ml of carbon tetrachloride were placed. The reaction mixture was refluxed for about 6 hours. After cooling to 25 ⁰ C, 500 ml dichloromethane and 300 ml of aqueous solution Of K ₂ CO ₃ (5 %) were added. The separated aqueous layer was extracted again with 200 ml of dichloromethane. The combined organic layers were washed with 300 ml of aqueous solution of K ₂ CO ₃ (5 %), dried over Na ₂ SO ₄ and concentrated in vacuum to give 35.66 g of pale yellow crystals. Distillation under reduced pressure allowed to separate 6.72 g of the starting methyl 4-chloro-3-methylbenzoate (b.p. 80-100 ⁰ C / 0.44-0.40 mbar) and to obtain 25.53 g of the desired product as pale yellow crystals (b.p.110 ⁰ C /0.40 mbar, m.p. 93 ⁰ C). Yield: 71 % (distilled product) T.L.C.: Silica gel, eluents: cyclohexane-ethyl acetate 85/15

Preparation 3

Methyl 4-chloro-3 -cy anomethy lbenzoate

To the solution of methyl 3-bromomethyl-4-chlorobenzoate (25.52 g) in dioxane (170 ml), cooled to 10 ⁰ C, was added sodium cyanide (7.12 g) solved in water (100 ml). The suspension was stirred vigorously overnight at 25 ⁰ C. The reaction mixture was poured into 500 ml of aqueous solution OfK ₂ CO ₃ (2%) and extracted with ethyl acetate (600 ml). The aqueous layer was extracted again with 250 ml of ethyl acetate. The combined organic layers were washed with 2x300 ml Of K ₂ CO ₃ (2%), dried over Na ₂ SO ₄ and concentrated in vacuum to give 19.69 g of the desired compound as a yellow powder (m.p. pure sample: 87 ⁰ C). Yield: 97% (raw material).

Preparation 4 Methyl (2-chloro-5-methoxycarbonyl-phenyl)-acetate

To a suspension of methyl 4-chloro-3-cy anomethy lbenzoate (19.68 g) well stirred in methanol (207 ml) and cooled to 0 ⁰ C was bubbled a slight stream of dry HCl gas for 3 hours, maintaining the temperature between 0 and 10 ⁰ C. The clear solution was further stirred at room temperature overnight. After concentration under reduced pressure, the white solid residue was dissolved in 600 ml of ethyl acetate and 500 ml of water. The separated organic phase was washed with 200 ml of aqueous NaCl solution (5 %), dried over Na ₂ SO ₄ and concentrated in vacuum to give 22.10 g of the desired compound as a pale yellow liquid (b.p.: 118 ⁰ C / 0.4 mbar) which crystallized at room temperature, (m.p.: 55 ⁰ C). Yield: 97 % (raw material)

Preparation 5

Methyl-2-chloro-5-nitro-phenylacetate

To a stirred suspension of (2-chloro-5-nitrophenyl)acetonitrile (18.10 g) in methanol (190 ml) at 0 ⁰ C was bubbled a slight stream of dry HCl gas for 3 h, maintaining the temperature between 0 and 10 ⁰ C. The clear solution was further

stirred at 20 ⁰ C overnight. After concentration under reduced pressure, the white solid residue was dissolved in 500 ml of ethyl acetate and 440 ml of water. The organic layer was washed with 200 ml of aqueous NaCl solution (5%), dried over Na ₂ SO ₄ and concentrated in vacuum to give 21.5 g of a brown residue. Column chromatography on 400 g of silica gel using a mixture of cyclohexane-ethyl acetate 97/3 as eluents, yielded to 14.3 g of the desired compound as a yellow liquid. ¹ H-NMR 250MHz (CDCl ₃ ): 3.79 (s, 3H) 3.92 (s, 2H) 7.61 (d, IH) 8.1-8.3 (m, 2H).

Preparation 6

Methyl 4-chloro-3 -(cyanomethyl)benzoate

A 10-litre glass reactor was equipped with a condenser, thermometer, dropping funnel and a mechanical stirrer. ^' Methyl 3-(bromomethyl)-4-chlorobenzoate (1054 g, 4.0 mol) and-benzyltriethylammonium chloride (15 g, 0.065 mol) were suspended in methanol (5220 ml). This mixture was cooled to 10 ⁰ C. To this stirred suspension was added sodium cyanide (294 g, 6.0 mol) solved in water (1500 ml) between 9-12 ⁰ C. The suspension was stirred overnight at 25 ⁰ C. The reaction mixture was poured into water (7000 ml). A precipitate formed. The mixture was stirred for 0.25 hour, and then filtered off. The solid was washed with aqueous solution of potassium carbonate (2%, 3000 ml) and water (3x2500 ml). The crude product was used without purification in the next step. (740.5 g, white crystal). Mp.: 85-86 ⁰ C. Yield: 88.3 %

Preparation 7 Methyl 4-chloro-3-(2-methoxy-2-oxoethyl)benzoate

In a 6-litre glass reactor, equipped with a reflux condenser, thermometer, pressure equalizing dropping funnel, and a mechanical stirrer was placed methyl 4-chloro-3- (cyanomethyl)benzoate (461.6 g, 2.2 mol) in methanol (759 ml, 18.7 mol). The mixture was heated to 50 ⁰ C. Chloro-trimethyl-silane (1135 ml, 9 mol) was added to this solution over 80 minutes. The mixture was refluxed for 5 hours. There was a heavy evolution of hydrogen chloride gas during this period. The mixture was left at

ambient temperature overnight. The solvent was evaporated. After cooling the residue was diluted with dichloromethane (1930 ml) and water (1930 ml). The mixture was stirred for 0.5 hour and the layers were separated. The aqueous phase was extracted with dichloromethane (1000 ml), that was combined with the organic layer, dried over Na ₂ SO ₄ , filtered and concentrated to give oil, which solidified. The residue was used in the next step without purification. (515.8 g, white crystal) Yield: 97.1 %

Example 1

Methyl -2-(2-chloro- 5-nitrophenyl)-2-(5-chloro-2-nitrophenyl)propionate Under argon atmosphere, a solution of methyl (2-chloro-5-nitrophenyl)-acetate (14.25 g) and 4-chloro-2-fluoro-nitrobenzene (10.91 g) in DMF (126 ml) was added drop wise at (—10) ⁰ C during 30 minutes to a stirred suspension of 9.7 g of sodium hydride (55-65 % dispersion in mineral oil) in DMF (165 ml). The reaction mixture was stirred at 20 ⁰ C for 4 hours, then cooled to 0 ⁰ C. Methyl iodide (11.6 ml) was then added drop wise, and the reaction mixture was allowed to stir overnight at 20 ⁰ C. The reaction mixture was quenched successively with 20 ml of methanol at 10 ⁰ C and 600 ml of aqueous solution Of NaHCO ₃ (2 %) followed by 600 ml of ethyl acetate.

A first crop of the desired compound was obtained by filtration of the media, rinsing the resulting precipitate with a mixture of methanol and acetone then with di-isopropyl ether and dried in vacuum at 45 ⁰ C to afford 10,42 g (powder, m.p.:195 ⁰ C). The rinsing filtrate and the separated ethyl acetate layer were dried over Na ₂ SO ₄ and concentrated in vacuum to lead to a second crop of the desired compound which was crystallized in toluene (6.15 g, m.p.: 195 ⁰ C),

¹ H-NMR 250MHz (DMSO): 2.25 (s, 3H) 3.67 (s, 3H) 7,65 (d, IH) 7,71 (m, 2H) 7,93 (d, IH) 8.25 (m, IH) 8,67 (d, IH).

Example 2

Methyl 2-(2-chloro-5-methoxycarbonylphenyl)-2-(5-chloro-2-nitrophen yl)- propionate

To a well stirred suspension of sodium hydride (10.8 g) in DMF (200 ml), under argon and cooled to (-5) ⁰ C, was added drop wise the solution of a mixture of methyl (2-chloro-5-me ^' thoxycarbonyl-phenyl)-acetate (22.10 g) and 4-chloro-2- fluoro-nitrobenzene (15.97 g) in DMF (150 ml), during 30 minutes. The cooling bath was removed; stirring was continued at room temperature for 4 hours, T.L.C. analysis showed that the reaction was complete. After cooling to 10 ⁰ C, methyl iodide (16.9 ml) was added drop wise. The mixture was stirred overnight at 20 ⁰ C. The reaction was quenched with 20 ml of methanol at 10 ⁰ C followed by 700 ml of aqueous solution of NaHCO ₃ (2%), extracted with 500 ml of ethyl acetate. The. separated aqueous layer was extracted again with 300 ml of ethyl acetate. The two combined organic layers were washed three times with 250 ml of NaHCO ₃ (2%), dried over Na ₂ SO ₄ and concentrated in vacuum to give 35.8 g of a brown solid. Recrystallization in 20 ml of toluene yielded 17.2 g of the desired product as a pale yellow powder (M.p.: 144 ⁰ C) 5.38 g of a second crop was obtained. Yield: 60%. T.L.C: Silica gel eluents: cyclohexane-ethyl acetate 75/25, toluene-methanol 97/3

Example 3

To a suspension of sodium hydroxide (2.4 g) in N-methylpyrrolidone (30 ml) was added in nitrogen atmosphere a solution of methyl 4-chloro-3-(2-methoxy-2- oxoethyl)benzoate (4.85 g) in N-methylpyrrolidone (10 ml) at (-8) ⁰ C. The mixture was stirred for 15 minutes at same temperature and then 2,4-dichloro-l- nitrobenzene (3.84 g) in N-methylpyrrolidone (6 ml) was added. The reaction mixture was stirred at this temperature for 2 hours, then it was poured into a mixture of aqueous hydrochloric acid and toluene. The aqueous phase was extracted with toluene. The organic phase was washed with water, dried over sodium sulphate and after filtration the filtrate was evaporated under reduced pressure to dryness. The residue was treated with small amount of methanol to give methyl 4-chloro-3-[l-(5-

chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate (50 %) as crystalline product. Mp. 84.5-85.7 ⁰ C. C ₁₇ H ₁₃ Cl ₂ NO ₆

Elementary analysis: Calculated: C:51.28, H:3.29, N:3.52, 01:17.81 Found: C:50.87, H:3.14, N: 3.44, Cl: 17.85

Example 4

To a suspension of sodium hydroxide (1.6 g) in N-methylpyrrolidone (30 ml) was added a solution of methyl 4-chloro-3-(2-methoxy-2-oxoethyl)benzoate (4.85 g) in N-methylpyrrolidone at (- 8) ⁰ C (10 ml). The mixture was stirred for 15 minutes at same temperature and then 2,4-dichloro-l -nitrobenzene (3.84 g) in N- methylpyrrolidone (6 ml) was added. The reaction mixture was stirred at this temperature for 2 Hours. It was poured into a mixture of aqueous hydrochloric acid and toluene. The aqueous phase was extracted with toluene. The organic phase was washed with water dried over sodium sulphate and after filtration the filtrate was evaporated under reduced pressure to dryness. The residue was treated with small amount of methanol to give methyl 4-chloro-3-[l-(5-chloro-2-nitrophenyl)-2- methoxy-2-oxoethyl]benzoate (4.1 g) as crystalline product, which did not give any melting point depression after mixing with the sample, prepared according to example 1.

Example 5

The reaction was carried out in the same way as in example 3, but instead of sodium hydroxide sodium hydride was used as base to give methyl 4-chloro-3-[l-(5-chloro- 2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate (2.76 g).

Example 6

The reaction was carried out in the same way as in example 3, but instead of sodium hydroxide potassium tertiary butoxide was used as base to give methyl 4-chloro-3- [1 -(5-chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate ( 1.7 g).

Example 7

The reaction was carried out in the same way as in example 3, but instead of sodium hydroxide potassium carbonate was used as base to give methyl 4-chloro-3-[l-(5- chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate (0.9 g).

Example 8

The reaction was carried out in the same way as in example 3, but instead of sodium hydroxide sodium methoxide was used as base to give methyl 4-chloro-3-[l-(5- chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate (2.9 g).

Example 9

The reaction was carried out in the same way as in example 5, but instead of N- methylpyrrolidone N,N-dimethylformamide was used as solvent to give methyl 4- chloro-3-[l-(5-chloro-2 ¹ nitrophenyl)-2-methoxy-2-oxoethyl]benzoate (2,51 g).

Example 10

The reaction was carried out in the same way as in example 6, but instead of N- methylpyrrolidone N,N-dimethylformamide was used as solvent to give methyl 4- chloro-3-[l-(5-chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]be nzoate (1.3 g).

Example 11

The reaction was carried out in the same way as in example 7, but instead of N- methylpyrrolidone N,N-dimethylformamide was used as solvent to give methyl 4- chloro-3-[l-(5-chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]be nzoate (1.0 g).

Example 12

The reaction was carried out in the same way as in example 5, but instead of N- methylpyrrolidone toluene was used as solvent to give methyl 4-chloro-3-[l-(5- chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate (1.2 g).

Example 13

The reaction was carried out in the same way as in example 5, but instead of N- methylpyrrolidone tetrahydrofurane was used as solvent to give methyl 4-chloro-3- [l-(5-chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate (1.2 g).

Example 14

The reaction was carried out in the same way as in example 7, but instead of N- methylpyrrolidone acetone was used as solvent to give methyl 4-chloro-3-[l~(5- chloro-2-nitrophenyl)-2-methoxy-2-oxoethyl]benzoate (0.9 g).

Example 15

To a suspension of sodium hydroxide (2.4 g) in N-methylpyrrolidone (30 ml) was added a solution of methyl 4-chloro-3-(2-methoxy-2-oxoethyl)benzoate (4.85 g) in N-methylpyrrolidone (10 ml) at (-8) ⁰ C. The mixture was stirred for 15 minutes at same temperature and then 2,4-dichloro-l -nitrobenzene (3.84 g) in iV-methyl- pyrrolidone

(6 ml) was added. The reaction mixture was stirred at this temperature for 2 hours, then methyl iodide (3.8 ml) was added and the reaction mixture was stirred for additional 4 hours. The mixture was poured into a mixture of aqueous hydrochloric acid and toluene. The aqueous phase was extracted with toluene. The organic phase was washed with water dried over sodium sulphate and after filtration the filtrate was evaporated under reduced pressure to dryness. Treating the residue with small amount of methanol gave methyl 4-chloro-3-[l-(5-chloro-2-nitrophenyl)-2- methoxy-l-methyl-2-oxoethyl]benzoate (5.12 g, 62.1%) as crystalline product. Mp.:139-140.5 ⁰ C. C ₁₈ H ₁₅ Cl ₂ NO ₆ Elementary analysis: Calculated: C: 52.4, H: 3.67, N: 3.4, Cl: 17.2

Found: C: 52.4, H: 3.56, N: 3.58, Cl: 17.19

Example 16

The reaction was carried out in the same way as in example 15, but instead of N- methylpyrrolidone N,N-dimethylformamide was used as solvent to give methyl 4- chloro-3-[l-(5-chloro-2-nitrophenyl)-2-methoxy-l-methyl-2-ox oethyl]benzoate (44 %).

Example 17

The reaction was carried out in the same way as in example 15, but instead (-8) ⁰ C the reaction was carried out at 0 ⁰ C to give methyl 4-chloro-3-[l-(5-chloro-2- nitrophenyl)-2-methoxy-l-methyl-2-oxoethyl]benzoate (56 %).

Example 18

The reaction was carried out in the same way as in example 15, but instead of sodium hydroxide sodium hydride was used as base to give methyl 4-chloro-3-[l- (5-chloro-2-nitrophenyl)-2-methoxy-l-methyl-2-oxoethyl]benzo ate (40 %).

Example 19

The reaction was carried out in the same way as in example 15, but instead of sodium hydroxide potassium tertiary butoxide was used as base to give methyl 4- chloro-3-[l-(5-chloro-2-nitrophenyl)-2-methoxy-l-methyl-2-ox oethyl]benzoate (31 %).

Example 20

The reaction was carried out in the same way as in example 15, but instead of sodium hydroxide sodium methoxide was used as base to give methyl 4-chloro-3- [l-(5-chloro-2-nitrophenyl)-2-methoxy-l-methyl-2-oxoethyl]be nzoate (38 %).

Example 21

To a suspension of sodium hydroxide (2.4 g) in N-methylpyrrolidone (30 ml) was added a solution of methyl 4-chloro-3-(2-methoxy-2-oxoethyl)benzoate (4.85 g) in

N-methylpyrrolidone (10 ml) at (—8) ⁰ C. The mixture was stirred for 15 minutes at

same temperature and then 2-fluoro-4-chloro-l -nitrobenzene (3.5 g) in JV-methyl- pyrrolidone (6 ml) was added. The reaction mixture was stirred at this temperature for 2 hours, then methyl iodide (3.8 ml) was added and the reaction mixture was stirred for additional 4 hours. The mixture was poured into a mixture of aqueous hydrochloric acid and toluene. The aqueous phase was extracted with toluene. The organic phase was washed with water, dried over sodium sulphate and after filtration the filtrate was evaporated under reduced pressure to dryness. Treating the residue with small amount of methanol gave methyl 4-chloro-3-[l-(5-chloro-2- nitrophenyl)-2-methoxy-l-methyl-2-oxoethyl]benzoate (6.2 g) as crystalline product. Mp.: 138.4-139.5 ⁰ C. C ₁₈ H ₁₅ Cl ₂ NO ₆

Elementary analysis: Calculated: C:52.4, H:3.67, N:3.4, Cl: 17.2

Found: C:52.18, H:3.94, N:3.3, Cl:17.22

Example 22

Methyl 4-chloro-3-[ 1 -(5-chloro-2-nitrophenyl)-2-methoxy- 1 -methyl-2- oxoethyljben-zoate (13 g) was suspended in 2-propanol (40 ml) and the stirred suspension was heated to reflux. With continuous stirring the solution of potassium hydroxide (12.4 g) in water (13 ml) was added drop wise to the suspension. The mixture was boiled with stirring for one hour and then it was cooled to room temperature. The solid product was filtered and washed with 2-propanol. The wet product was solved in water (25 ml) and this solution was dropped to the mixture of concentrated hydrochloric acid (11 ml) and water (26 ml). The precipitated product was filtered and washed with water. It yielded 11.2 g of diacid, mp: 224-226 ⁰ C. C ₁₆ H ₁₁ Cl ₂ NO ₆

Elementary analysis: Calculated: C: 50.02, H:2.89, N:3.65, Cl: 18.46

Found: C:49.17, H:2.74, N:3.44, Cl: 18.36

Example 23 Methyl 4-chloro-3-[ 1 -(5-chloro-2-nitrophenyl)-2-methoxy- 1 -methyl-2- oxoethyl]ben-zoate (10 g) and Triton B (30 ml) in methanol (100 ml) were refluxed

for 4 hours. The solvent was removed in vacuum. The residue was diluted with water (50 ml), acidified with hydrochloric acid. The solution was poured off from the separated oil. The residue was treated with methanol (30 ml), the precipitate was filtered off, washed and dried. It yielded 4.4 g (45.5%) 4-chloro-3-[l-(5-chloro-2- nitrophenyl)-2-methoxy-l-methyl-2-oxoethyl]benzoic acid. Mp.: 260-262 ⁰ C ^• decomp. C ₁₇ H ₁₃ Cl ₂ NO ₆

Elementary analysis: Calculated: C:51.28, H:3.29, N:3,52, Cl: 17.81

Found: C:51.28, H:3.21, N:3.38, Cl: 17.71

Example 24

3-[l-carboxy-l-(5-chloro-2-nitiOphenyl)ethyl]-4-chloroben zoic acid (10 g) was stirred with thionyl chloride (20 ml). After the completion of the acyl chloride formation the excess of reagent was evaporated under reduced pressure. The residue was treated with methanol (50 ml) and was refluxed for one hour. The precipitated solid material was filtered off, washed with hot methanol and dried. It yielded 2-[2- chloro-5-(methoxycarbonyl)phenyl]-2-(5-chloro-2-nitrophenyl) propionic acid (6.9 g, 65%). Mp.: 220-229 ⁰ C decomp. C ₁₇ H ₁₃ Cl ₂ NO ₆ Elementary analysis: Calculated: C:51.28, H:3.29, N:3,52, Cl: 17.81

Found: C:51.23, H:3.39, N:3.30, Cl:17.71

Example 25

To a suspension of sodium hydroxide (240 g) in N-methyl-pyrrolidone (3000 ml) was added drop wise a solution of methyl 4-chloro-3-(2-methoxy-2- oxoethyl)benzoate (485,3 g) in N-methyl-pyrrolidone (1000 ml) at (-8) ⁰ C. The mixture was stirred for 15 minutes at the same temperature and then 2,4-dichloro-l- nitrobenzene (384 g) in N-methyl-pyrrolidone (600 ml) was added. The reaction mixture was stirred at this temperature for 2 hours. During this period the mixture was wormed up to 10 ⁰ C and then methyl iodide (376 ml) was added to it. The mixture was stirred for additional 2 hours and was poured into a mixture of aqueous

hydrochloric acid, crushed ice and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulphate and after filtration the filtrate was evaporated under reduced pressure to dryness. Treating the residue with methanol gave methyl 4-chloro-3-[l-(5-chloro-2- nitrophenyl)-2-methoxy-l-methyl-2-oxoethyl]benzoate as an almost white crystalline product.

Yield: 580.4 g (70.4%), mp.: 139-140.5 ⁰ C. Purity by HPLC: 99.3% C ₁₈ H ₁₅ Cl ₂ NO ₆ Elementary analysis: Calculated: C: 52.4, H: 3.67, N: 3.4, Cl: 17.2

Found: C: 52.4, H: 3.56, N: 3.58, Cl: 17.19

Example 26

The reaction was carried out in the same way as in example 3, but instead of 2,4- dichloro-nitrobenzene 2-fluoro-4-chloro-nitrobenzene was used. Yield: 500.6 g (67.7%), mp.: 139.7-140.5 ⁰ C. Purity by HPLC:99.6%

Example 27 N-methyl-pyrrolidone (150 ml) and small beads of sodium hydroxide (12 g, 0.3 mol) were placed into a 500 ml Sovirel apparatus, equipped with thermometer, stirrer, dropping funnel and gas inlet tube. The suspension was cooled to (—8) ⁰ C and a solution of methyl 4-chloro-3-(2-methoxy-2-oxoethyl)benzoate in N-methyl- pyrrolidone (50 ml) was dropped to it. The mixture was stirred for 15 minutes and then 2,4 dichloro-nitrobenzene (18.4 g) solved in N-methyl-pyrrolidone (50 ml) was added to it drop wise at the same temperature. With continuous stirring the mixture was let to warm up to 10 ⁰ C during three hours and then it was poured to a mixture of crushed ice, saturated sodium chloride solution, 2N HCl and ethyl acetate. After separation of the layers the aqueous phase was extracted with ethyl acetate. The organic phase was dried and evaporated under reduced pressure. The residue was

treated with small amount of methanol to give methyl 4-chloro-3-[l-(5-chloro-2- nitrophenyl)-2-methoxy-2-oxoethyl]benzoate. Mp.: 85-86.5 ⁰ C Yield: 26 g, 65%

Example 28

Preparation of methyl 4-chloro-3-[(5-chloro-2-nitrophenyl)-cyano-methyl]benzoate To a suspension of 2 g sodium hydroxide in N-methyl-pyrrolidone (30 ml) was added at (-8) ⁰ C a solution of methyl 4-chloro-3-(cyanomethyl)benzoate (5.8 g) in N-methyl-pyrrolidone (15 ml). The mixture was stirred for 15 minutes at same temperature and then 2,4-dichloro-l -nitrobenzene (5.3 g), solved in N-methyl- pyrrolidone (15 ml) was added. The reaction mixture was stirred at this temperature for 2 hours, and then it was poured into a mixture of aqueous hydrochloric acid and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic ^■ phase was washed with water dried over sodium sulphate and evaporated under reduced pressure. Treating the residue with small amount of methanol yielded 5.9 g (58.4%) crystalline product. Mp.: 156.8-158.8 ⁰ C. Crystallization of the product from methanol yielded 4.95 g (49%) white crystals. Mp: 159.2-160.7 ⁰ C. C ₁₆ H ₁₀ Cl ₂ N ₂ O ₄ Elementary analysis Calculated C: 52.63, H: 2.76, N: 7.67, Cl: 19.42 ^■ Found C: 52.35, H: 2.69, N: 7.55, Cl: 19.32

Example 29

Preparation of methyl 4-chloro-3-[l-(5-chloro-2-nitrophenyl)-l- cyanoethyl]benzoate To a suspension of sodium hydroxide (240 g) in N-methyl-pyrrolidone (3000 ml) was added at (-8) ⁰ C methyl 4-chloro-3-(cyanomethyl)benzoate (419 g) solved in N-methyl-pyrrolidone (1000 ml). The mixture was stirred for 15 minutes at same temperature and then 2,4-dichloro-l -nitrobenzene (384 g), solved in N-methyl- pyrrolidone (1000 ml) was added at this temperature. The reaction mixture was stirred at this temperature for 2 hours, and then methyl iodide (376 ml) was added. The reaction mixture was stirred for additional 4 hours, and then it was poured into

a mixture of aqueous hydrochloric acid, saturated sodium chloride solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulphate and evaporated under reduced pressure. Treating the residue with small amount of methanol yielded a crystalline product.

Yield: 580 g, (76.5 %), mp: 159.4-160.2 ⁰ C. C ₁₇ H12C1 ₂ N ₂ O ₄

Elementary analysis Calculated C: 53.85, H: 3.19, N: 7.39, Cl: 18.70

Found C:53.96, H: 3.16, N: 7.41, Cl: 18.64