KR100468936B1 - Substituted [2- (1-piperazinyl) ethoxy] methyl compound - Google Patents

Abstract

The present invention provides novel substituted [2- (1-piperazinyl) ethoxy] methyl compounds of formula (I), methods for preparing these compounds, and 2- [2- [4-[(4-chloro Phenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid or 2- [2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] ethoxy] acetic acid and / or It relates to their use for the preparation of compounds which are important intermediate products for the preparation of their pharmaceutically acceptable salts:

Formula (I)

Where

R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms,

R ₂ is a hydrogen atom or a -COR ₄ or -COR ₅ group, wherein R ₄ is selected from -OR ₆ or -OR ₇ group, wherein

R ₅ represents an allyl or alkylaryl radical,

R ₆ represents a straight or branched chain alkyl radical having 1 to 4 carbon atoms or a haloalkyl, alkylaryl, alkylnitroaryl or alkylhaloaryl radical,

R ₇ represents a haloalkyl radical.

Description

Substituted [2- (1-piperazinyl) ethoxy] methyl compound

Example I. Preparation of substituted [2- (1-piperazinyl) ethoxy] methyl compounds of formula (I).

I.1. Preparation of Compound of Formula (I) wherein R ₂ is -H

I.1.1 2- [2- (1-piperazinyl) ethoxy] acetamide

I.1.1.1.

A mixture of 13.15 g of (2-chloroethoxy) acetamide (0.1 mol) and 43 g of anhydrous piperazine (0.5 mol) in 250 ml of toluene was introduced into a round bottom flask equipped with a water-cooled condenser and a mechanical stirrer. The mixture was heated at reflux for 4 hours. The formed precipitate was filtered while warming, and the solvent in the filtrate was evaporated to dryness under reduced pressure. The evaporation residue was purified by chromatography on silica gel (eluent: mixture of dichloromethane / methanol / 28% aqueous ammonia solution (14/5 / l (v / v / v))). 7.4 g of 2- [2- (1-piperazinyl) ethoxy] acetamide was obtained in the form of a yellow oil.

Yield: 39%

Mass spectrum: 188 (MH ⁺ ), 99 (HN (C ₄ H ₈ ) N ⁺ = CH ₂ ), 44 (CONH ₂ )

I.1.1.2. (transform)

Three necked round bottom flasks with 8.6g (0.1mol) piperazine, 15.9g (0.1mol) piperazine dihydrochloride, 10.8ml (0.6mol) water and methyl ethyl ketone 86ml water-cooled condenser and mechanical stirrer Introduced into. The temperature of the mixture was brought to 65 ° C. Then 13.8 g (0.1 mol) of (2-chloroethoxy) acetamide was added in one portion. The mixture was kept at a temperature of 65 ° C. for 16 hours. The mixture was allowed to cool to room temperature and then separated by precipitation of the two phases before separation. The lower phase (oil phase incompatible with methyl ethyl ketone) was washed with 2 x 25 ml of methyl ethyl ketone. This oil was dissolved in 50 ml of ethanol and stirred for 15 minutes. The precipitate formed (piperazine dihydrochloride) was filtered and the filtrate was concentrated using a rotary evaporator at 50 ° C. and under reduced pressure. 27 g of a yellow oil were obtained, and the obtained product was subjected to preparative chromatography on silica gel (eluent: dichloromethane / methanol / 28 wt% aqueous ammonia solution / water (2/15/1/2 (v / v / v / v)). Mixture). 10.7 g of [2- (1-piperazinyl) ethoxy] acetamide was finally obtained in the form of a colorless oil, which was crystallized.

Yield: 57.1%

NMR: δ: 2.33 (4H, m); 2.43 (2H, t. 5.54 Hz); 2.67 (4H, m); 2.79 (1 H, bs); 3.53 (2H, t, 5.53 Hz), 3.78 (2H, s); 7.18 (1 H, bs); 7.53 (1 H, bs).

Mass spectrum: 188 (MH ⁺ )

I.1.2. 2- (1-piperazinyl) ethoxyacetonitrile.

Piperazine 8.6 g (0.1 mol), piperazine dihydrochloride 15.9 g (0.1 mol), 0.6 ml of water and 40 ml of ethanol were introduced into a 250 ml three necked round bottom flask equipped with a water-cooled condenser and a mechanical stirrer. I was. The temperature of the mixture was brought to 70 ° C. 11.9 g (0.1 mol) of (2-chloroethoxy) acetonitrile was dissolved in 48 ml of ethanol and then added dropwise over 15 minutes. The mixture was kept at 70 ° C. for 16 hours. The mixture was returned to room temperature and then cooled in an ice bath. The resulting precipitate was then filtered off. The filtrate was concentrated using a rotary evaporator under reduced pressure, the residue (oil + solid) was dissolved in 50 ml of ethanol and the mixture was stirred for 15 minutes. The resulting precipitate (piperazine dihydrochloride) was filtered off and the filtrate was concentrated using a rotary evaporator at 50 ° C. under vacuum. The evaporated residue was subjected to preparative chromatography on silica gel (eluent: dichloromethane / methanol / 28 wt% aqueous ammonia solution (94.5 / 5 / 0.5 (v / v / v)) followed by the same component (89/10 / l (v / v / v))). 4.7 g of 2- (1-piperazinyl) ethoxyacetonitrile were obtained in the form of an orange oil.

Yield: 27.8%

NMR: δ: 2.36 (4H, m); 2.47 (2H, t, 5.6 Hz); 2.71 (4H, m), 3.6 (2H, t, 5.6 Hz), 4.44 (2H, s).

Mass spectrum: 170 (MH ⁺ ).

I.1.3. Methyl 2- (1-piperazinyl) ethoxyacetate.

Piperazine 8.6 g (0.1 mol), piperazine dihydrochloride 17.7 g (0.1 mol), 10.8 ml (0.6 mol) water and 40 ml of ethanol, 250 ml three necked round with water-cooled condenser and mechanical stirrer It was introduced into the bottom flask. The temperature of the mixture was brought to 39 ° C. 13.8 g (0.1 mol) of methyl ester of (2-chloroethoxy) acetic acid were dissolved in 1 ml of methanol, and then added dropwise over 35 minutes. The mixture was kept at 65 ° C. for 48 hours. The mixture was cooled to room temperature and the precipitated piperazine salt was filtered off. The filtrate was concentrated using a rotary evaporator at 50 ° C. under reduced pressure. 31.6 g of a yellow oil are obtained, and the obtained product is subjected to preparative chromatography on silica gel (eluent: dichloromethane / methanol / 28 wt% aqueous ammonia solution (94.5 / 5 / 0.5 (v / v / v)), followed by the same components. (Using a mixture of 73.5 / 25 / 2.5 (v / v / v))). 9.83 g of methyl 2- (1-piperazinyl) ethoxyacetate was obtained in the form of a colorless oil.

Yield: 48.6%

NMR: δ: 2.54 (2H, t, 5.6 Hz); 2.60 (4 H, m); 2.95 (4H, m); 3.58 (2H, t, 5.6 Hz); 3.65 (3 H, s); 4.10 (2H, s).

Mass spectrum: 202 (MH ⁺ ).

I.1.4. 2- (1-piperazinyl) ethoxyacetic acid

8.6 g (0.1 mol) of piperazine, 17.7 g (0.1 mol) of piperazine dihydrochloride and 50 ml of water were introduced into a 100 ml three necked round bottom flask equipped with a water-cooled condenser and a mechanical stirrer, and then the mixture The temperature of was set to 70 ° C. 15.2 g of (2-chloroethoxy) acetic acid was added dropwise over 15 minutes. With stirring, the temperature of the mixture was brought to 80 ° C. and maintained at this temperature for 27 hours. The mixture was cooled to room temperature and water was evaporated using a rotary evaporator under reduced pressure. The evaporation residue was dissolved in 50 ml of ethanol and kept at 50 ° C. with stirring for 45 minutes. Then placed in an ice bath and stirred for 1 hour. The resulting precipitate (piperazine dihydrochloride) was then filtered and the solvent was evaporated using a rotary evaporator at 50 ° C. under reduced pressure to give 22.4 g of a yellow oil. 10 g of this mixture was purified on 130 g of Amberlite IRA-400 resin. It was eluted first with 600 ml of water and then eluted with 0.5M ammonium acetate aqueous solution. Mixture containing 2- (1-piperazinyl) ethoxyacetic acid or a salt thereof and combined with water to remove water from it using a rotary evaporator at 60 ° C. under reduced pressure to give a mixture containing white crystals and oil 18.2 g was recovered. This mixture was dissolved in 75 ml of isopropanol and the insoluble crystals were filtered off. The filtrate was acidified with 20 ml of 9N hydrochloric acid solution in ethanol. The resulting precipitate was quickly filtered, washed with isopropanol and dried using a rotary evaporator at 50 ° C. under reduced pressure. 7.1 g of a white solid were obtained, and the obtained solid was purified by sublimation of ammonium chloride salt (4 h at l35 ° C. under 0.1 mbar, then 8 h at 150 ° C. under 0.1 bar). 1.4 g of 2- (1-piperazinyl) ethoxyacetic acid dihydrochloride was obtained.

Yield: 12%

NMR: δ: 2.36 (2H, t, 4.8 Hz); 3.45 (4H, m); 3.53 (4H, m); 3.88 (2H, t, 4.8 Hz); 4.09 (2H, s); 10 (1 H, bs).

Mass spectrum: 189 (MH ⁺ ).

Elemental Analysis:

Atom C

I.2. Preparation of Compound of Formula (I) wherein R ₂ is -CH ₂ -C ₆ H ₅

Ⅰ.2.1. 2- (4-benzyl-1-piperazinyl) ethoxyacetamide.

I.2.1.1.

8.8 g (0.05 mol) of 1-benzylpiperazine, 7.6 g (0.055 mol) of (2-chloroethoxy) acetamide, 11.7 g (0.11 mol) of sodium carbonate, 0.050 g of potassium iodide and 44 ml of methyl ethyl ketone And into three 100 ml round necked flasks equipped with a mechanical stirrer. The mixture was brought to reflux and then held at this temperature for 20 hours. The mixture was cooled to room temperature and 50 ml of water was added. The methyl ethyl ketone was then removed using a rotary evaporator under reduced pressure, and then the aqueous phase was extracted with 2 x 50 ml of dichloromethane. The organic phases were combined and washed with 25 ml saturated ammonium chloride solution. The solution was dried over sodium sulphate, then filtered and concentrated under reduced pressure using a rotary evaporator. 14.15 g of brown oil was obtained as crystals, which were purified by chromatography on silica gel (eluent: mixture of dichloromethane / methanol / 28 wt% aqueous ammonia solution (97/3 / 0.3 (v / v / v))). Purification gave 11.5 g of a yellow oil.

Yield: 82.9%

After recrystallization from ethyl acetate, 2- (4-benzyl-1-piperazinyl) ethoxyacetamide was obtained in the form of a white solid.

Crystallization Yield: 81.5%

NMR: δ: 2.40 (8H, m); 2.47 (2H, t, 5.58 Hz), 3.44 (2H, s); 3.53 (2H, t, 5.57 Hz); 3.78 (2H, s); 7.19 (1 H, s, b); 7.31-7.22 (5H, m); 7.34 (1 H, bs).

Mass spectrum: 277 (MH ⁺ ).

DSC: First 74.6 ° C., maximum 78.6 ° C.

Elemental Analysis:

I.2.1.2.

8.8 g (0.05 mol) of 1-benzylpiperazine, 12.6 g (0.055 mol) of (2-iodine-ethoxy) acetamide, 11.7 g (0.11 mol) of sodium carbonate, and 44 ml of methyl ethyl ketone were added to a water-cooled condenser and mechanical stirrer. It was introduced into three 100 ml round necked flasks equipped. The mixture was brought to reflux and held at this temperature for 4 hours. The mixture was cooled to room temperature and 75 ml of water was added. Methylethyl ketone was removed under reduced pressure using a rotary evaporator. The aqueous phase was then extracted with 75 ml dichloromethane and then 50 ml. The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure using a rotary evaporator. This was crystallized to give 14.5 g of an orange oil, which was purified by chromatography on silica gel (eluent: dichloromethane / methanol / 28 wt% aqueous ammonia solution (95.6 / 4 / 0.4 (v / v / v)), followed by Purified using the same component (using a mixture of 93.6 / 6 / 0.4 (v / v / v)). 12.7 g (91.6%) of a yellow solid were finally obtained. After recrystallization from ethyl acetate, 2- (4-benzyl-1-piperazinyl) ethoxyacetamide was obtained in the form of a white solid (crystallization yield: 81.5%).

Analysis: Example I.2.1.1. Reference

Ⅰ.2.2. 2- (4-benzyl-1-piperazinyl) ethoxyacetonitrile.

8.8 g (0.05 mol) of 1-benzylpiperazine, 6.6 g (0.055 mol) of (2-chloro-ethoxy) acetonitrile, 11.5 g (0.11 mol) of sodium carbonate, 0.5 g of potassium iodide, and 50 ml of methyl ethyl ketone It was introduced into three 100 ml round necked flasks equipped with a cold condenser and a mechanical stirrer. The temperature of the mixture was brought to 80 ° C. and maintained at this temperature for 24 hours. The mixture was then cooled to room temperature, diluted with 50 ml of water and removed methyl ethyl ketone under reduced pressure using a rotary evaporator. The aqueous phase was extracted with 2 x 50 ml of dichloromethane and the organic phases combined. It was dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. 14.6 g of a brown oil are obtained, and the obtained product is purified by purification chromatography on silica gel (eluent: a mixture of dichloromethane / methanol / 28 wt% aqueous ammonia solution (97.8 / 2 / 0.2 (v / v / v))). It was. 8.4 g (64.9%) of 2- (4-benzyl-1-piperazinyl) ethoxyacetonitrile were obtained in the form of an orange oil.

NMR in deuterium substituted chloroform: δ: 2.40 (8H, m); 2.50 (2H, t, 5.68 Hz); 3.44 (2H, s); 3.61 (2H, t, 5. 67 Hz); 4.44 (2H, s); 7.28 (5 H, m).

Mass spectrum: 259 (M ⁺ ).

I.2.3. Methyl 2- (4-benzyl-1-piperazinyl) ethoxyacetate.

10 g (0.057 mol) of 1-benzylpiperazine, 9.52 g (1.1 equiv) of methyl (2-chloro-ethoxy) acetate, 13.23 g (2.2 equiv) of sodium carbonate, 0.4 g of potassium iodide and 100 ml of toluene were water-cooled condenser and machine It was introduced into a 250 ml three necked round bottom flask equipped with a stirrer. The mixture was heated at 100 ° C. for 36 h. The mixture was then cooled to room temperature and then 100 ml of water was added and precipitated to separate the organic phase. The organic phase was washed with 100 ml of water followed by 100 ml of saturated sodium chloride solution. It was dried over sodium sulphate and filtered and concentrated under reduced pressure using a rotary evaporator. 18.8 g of a brown oil are obtained, and the obtained product is purified by chromatography on silica gel (eluent: dichloromethane / methanol / 28 wt% aqueous ammonia solution (98.9 / l / 0.1 (v / v / v)), followed by the same component. (Using a mixture of 91.2 / 8 / 0.8 (v / v / v))). 10.8 g of methyl 2- (4-benzyl-1-piperazinyl) ethoxyacetate was obtained in the form of an orange oil.

Yield: 65%

NMR: δ: 2.38 (8H, m); 2.47 (2H, t, 5.87 Hz); 3.44 (2H, s); 3.56 (2H, t, 5.84 Hz); 3.64 (3H, s); 4.09 (2H, s); 7.28 (5 H, m).

Mass spectrum: 292 (M ⁺ ).

I.3 Preparation of the Compound of Formula (1) wherein R ₂ is -COOCH ₂ -C ₆ H ₅

I.3.1. Benzyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate.

6.6 g (0.03 mol) of benzyl piperazine-1-carboxylate, 7.6 g (0.033 mol) of (2-ioethethoxy) acetamide, 7 g (0.066 mol) of sodium carbonate and 33 ml of methyl ethyl ketone were water-cooled condensers and machines It was introduced into three 100 ml round necked flasks equipped with a stirrer. The mixture was brought to reflux and held at this temperature for 5 hours. After the mixture was cooled to room temperature, 75 ml of water were added and methyl ethyl ketone was removed under reduced pressure using a rotary evaporator. The aqueous phase was extracted with 75 ml dichloromethane and then 50 ml and the organic phases combined. It was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. 9.4 g of a beige solid are obtained, and the obtained product is purified by purification chromatography on silica gel (eluent: dichloromethane / methanol / 28% by weight aqueous ammonia solution (95.4 / 4 / 0.4 (v / v / v) mixture). This gave 7.7 g (79.9%) of a white solid, of which 7.5 g was recrystallized from 34 ml of acetone: 6.6 g of benzyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate was white crystald. Recovered in the form (crystallization yield: 88%).

NMR: δ: 2.41 (4H, m); 2.51 (2H, t); 3.39 (4H, m): 3.56 (2H, t, 5.48 Hz); 3.79 (2H, s); 5.08 (2H, s); 7.15 (1 H, s el.); 7.35 (6 H, m).

Mass spectrum: 321 (M ⁺ ).

DSC: first 115.09 ° C., maximum: 125.46 ° C.

First 136.04 ° C., Max: 143.86 ° C.

Elemental Analysis:

I.3.2. Benzyl 4- (2-cyanomethoxyethyl) piperazine-1-carboxylate.

6.4 g (0.029 mol) benzyl piperazine-1-carboxylate, 3.8 g (0.03 l9 mol) (2-chloroethoxy) acetonitrile, 6.8 g (0.0638 mol) sodium carbonate, 20 mg potassium iodide and 32 ml of methyl ethyl ketone Introduced into three 100 ml three necked round bottom flasks equipped with cooling condenser and mechanical stirrer. The mixture was kept at reflux temperature (80 ° C.) for 20 hours. Then 1.7 g (0.0145 mol) of (2-chloroethoxy) acetonitrile were added and maintained at reflux for an additional 24 hours. The mixture was cooled to room temperature and 75 ml of water were added and then methyl ethyl ketone was removed under reduced pressure using a rotary evaporator. The aqueous phase was extracted with 75 ml of dichloromethane and then 50 ml. The organic phases were combined and dried over sodium sulfate. This mixture was filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. 10.5 g of a dark brown liquid is obtained, and the obtained product is purified by chromatography on silica gel (eluent: dichloromethane / methanol / a mixture of 28% by weight aqueous ammonia solution (99 / l / 0.1 (v / v / v), then the same component) 98/2 / 0.1 (v / v / v))) 7.3 g (83%) of benzyl 4- (2-cyanomethoxyethyl) piperazine-1-carboxylate is yellow Obtained in liquid form.

NMR: δ: 2.39 (4H, m); 2.54 (2H, t, 5.5 Hz); 3.39 (4H, m); 3.63 (2H, t, 5.3 Hz); 4.45 (2H, s); 5.07 (2H, s); 7.35 (5 H, m).

Mass spectrum: 304 (MH ⁺ ).

1.4. Preparation of Compound of Formula (I) wherein R ₂ is -COOtBu

I.4.1. Tert-butyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate.

Water-cooled 5.6 g (0.03 mol) tert-butyl piperazine-1-carboxylate, 7.6 g (0.033 mol) (2-iodineethoxy) acetamide, 7 g (0.066 mol) sodium carbonate and 28 ml methyl ethyl ketone It was introduced into three 100 ml round necked flasks equipped with a condenser and a mechanical stirrer. The mixture was kept at reflux for 2 hours. After the mixture was cooled to room temperature, 75 ml of water was added and methyl ethyl ketone was removed under reduced pressure using a rotary evaporator. The aqueous phase was extracted with 2 x 50 ml of dichloromethane. The organic phases were combined, washed with 40 ml of saturated aqueous ammonium chloride solution, dried over sodium sulphate and filtered and then concentrated under reduced pressure using a rotary evaporator. 9.7 g of a pale yellow solid are obtained, and the obtained product is purified by chromatography on silica gel (eluent: a mixture of dichloromethane / methanol / 28 wt% aqueous ammonia solution (98/2 / 0.2 (v / v / v))). Purified. 7.8 g (90.5%) of a white solid were obtained, of which 7.7 g were recrystallized from 15.4 ml of acetone. 6.35 g of tert-butyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate was finally obtained in the form of white crystals (crystallization yield: 82.5%).

NMR: δ: 1.39 (9H, s); 2.38 (4H, m); 2.49 (2H, t): 3. 29 (4H, m); 3.55 (2H, t, 5.5 Hz); 3.75 (2H, s); 7.14 (1 H, bs); 7.38 (1 H, bs).

Mass spectrum: 287 (M ⁺ ).

DSC: first 113.7 ° C., maximum: 117.9 ° C.

Elemental Analysis:

I.4.2. Tert-butyl 4- (2-cyanomethoxyethyl) piperazine-1-carboxylate.

20 g (0.107 mol) tert-butyl piperazine-1-carboxylate, 14.12 g (0.117 mol) (2-chloroethoxy) acetonitrile, 25.04 g (0.235 mol) sodium carbonate, 0.075 g potassium iodide and methyl ethyl ketone 100 ml were introduced into a 250 ml three necked round bottom flask equipped with a water-cooled condenser and a mechanical stirrer. The mixture was refluxed for 78 hours, then the mixture was cooled to 50 ° C. and the salts were filtered off. The solvent was evaporated under reduced pressure using a rotary evaporator. The residue was dissolved in 150 ml of water and extracted with 200 ml of dichloromethane and then 100 ml. The organic phases were combined, dried over sodium sulphate, filtered and then concentrated under reduced pressure using a rotary evaporator. 30.5 g of a brown oil was obtained, and the obtained product was purified on silica gel (eluent: dichloromethane, followed by dichloromethane / methanol / 28 wt% aqueous ammonia solution (98.9 / 1 / 0.1 (v / v / v)). Mixture, followed by a mixture of the same components (97.8 / 2 / 0.2 (v / v / v))) tert-butyl 4- (2-cyanomethoxyethyl) piperazine-1-carboxyl Yield 25.8 g in the form of a yellow oil.

Yield: 89.2%

NMR in deuterium substituted chloroform: δ: 1.44 (9H, s); 2.43 (4H, m); 2.62 (2H, t, 5.4 Hz); 3.43 (4H, m); 3.71 (2H, t, 5.4 Hz); 4.28 (2H, s).

Mass spectrum: 269 (M ⁺ ).

I.4.3. Tert-butyl 4- (2-methoxycarbonylmethoxyethyl) piperazine-1-carboxylate.

Tert-butyl piperazine-1-carboxylate 7.06 g (0.0379 mol), methyl (2-chloroethoxy) acetate 6.35 g (0.0417 mol), sodium carbonate 8.83 g (0.083 mol), potassium iodide 0.025 g and toluene 80 ml Was introduced into a 250 ml three necked round bottom flask equipped with a water-cooled condenser and a mechanical stirrer. The mixture was refluxed for 78 hours. The mixture was cooled to room temperature and the salts were filtered off. The filtrate was washed with 2 x 50 ml of water and the aqueous phase was extracted with 50 ml of dichloromethane. The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure using a rotary evaporator. 12.72 g of a brown oil are obtained, and the obtained product is purified by chromatography on silica gel (eluent: dichloromethane, then dichloromethane / methanol / 28 wt% aqueous ammonia solution (98.9 / 1 / 0.1 (v / v / v)) , Followed by a mixture of the same components (97.2 / 2 / 0.2 (v / v / v)). 7.2 g of tert-butyl 4- (2-methoxycarbonylmethoxyethyl) -piperazine-1-carboxylate were obtained in the form of a yellow oil.

Yield: 62.8%

NMR in deuterium substituted chloroform: δ: 1.45 (9H, s); 2.45 (4H, m); 2.63 (2H, t, 5.6 Hz); 3.43 (4H, m); 3.68 (2H, t, 5.6 Hz); 3.74 (3H, s); 4.10 (2H, s).

Mass spectrum: 302 (M ⁺ ).

I.5. Preparation of a compound of formula (I) wherein R ₂ is -COOEt.

I.5.1. Ethyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate.

I.5.1.1.

164 g (1.04 mol) of ethyl piperazinecarboxylate, 156.9 g (1.14 mol) of (2-chloroethoxy) acetamide, 241.7 g (2.28 mol) of sodium carbonate, 1 g of potassium iodide and 200 ml of water-cooled condenser and mechanical stirrer It was introduced into a two-necked three-necked round bottom flask equipped with a flask. The mixture was refluxed for 3 hours 30 minutes. The mixture was cooled to 50 ° C. and 200 ml of isopropanol were added. The reaction mixture was filtered and the filter residue was washed with 150 ml of isopropanol. The filtrate was concentrated under reduced pressure using a rotary evaporator to give 277.2 g of crude product, which was recrystallized from 500 ml of ethyl acetate. 219.2 g (81.6%) of ethyl (2-carbamoylmethoxyethyl) piperazine-1-carboxylate was obtained in the form of a white solid.

NMR: δ: 1.24 (3H, t, 7.05 Hz); 2.46 (4H, m); 2.57 (2H, t, 5.2 Hz); 3.44 (4H, m); 3.62 (2H, t, 5.2 Hz); 3.95 (2H, s); 4.1 (2H, 9, 7.1 Hz); 5.72 (1 H, bs); 7.34 (1 H, bs).

Mass spectrum: 260 (MH ⁺ ).

DSC: First 106.5 ° C., up to 109.7 ° C.

Elemental Analysis:

I.5.1.2.

15.13 g (0.11 mol) of (2-chloroethoxy) acetamide in 25 ml of toluene, 14.6 ml (0.1 mol) of ethyl piperazinecarboxylate, 23.3 g (0.22 mol) of sodium carbonate and 1.0 g of potassium iodide were added to a water-cooled condenser and It was introduced into a two-necked three-necked round bottom flask equipped with a mechanical stirrer. The mixture was heated at reflux for 4 hours and cooled to room temperature. The reaction was continued for 16 hours while stirring. 100 ml of isopropanol was added and the solid formed was filtered off. The solvent was evaporated to dryness from the filtrate under reduced pressure. After evaporating the solvent, the obtained product was recrystallized from toluene. 21.35 g of ethyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate were obtained.

Yield 82%.

Mass spectrum: 260 (MH ⁺ ), 214 (M ⁺ -OEt).

I.5.2. Potassium 2- (4-carboxyethyl-1-piperazinyl) ethoxyacetate.

200 g (0.77 mol) of ethyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate prepared in Example I.5.1., 216.4 g (3.86 mol) of potassium hydroxide and 800 ml of ethanol were It was introduced into a three-necked two-necked round bottom flask equipped with a cold condenser and a mechanical stirrer. The mixture was refluxed for 24 hours. The mixture was cooled to room temperature and the salts were filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator and the oil obtained was dissolved in 300 ml of isopropanol. The salt was filtered over dicalite and the solution was concentrated again under reduced pressure using a rotary evaporator. While stirring, the oil was dissolved in 1.25 L of ethyl acetate and a precipitate formed. The mixture was cooled in an ice bath for 2 hours and then filtered, and the white solid obtained was dried in an oven. 231.8 g of product containing inorganic salts were obtained.

Example II. Deprotection of substituted [2- (1-piperazinyl) ethoxy] methyl compounds of formula (I), wherein R ₂ is not a hydrogen atom.

II.2. 2- (1-piperazinyl) ethoxyacetamide.

II.2.1.

13.9 g (0.05 mol) of 2- (4-benzyl-1-piperazinyl) ethoxyacetamide prepared in Example I.2.1 and l39 ml of ethanol were added to 250 ml of water-cooled condenser and mechanical stirrer. Three necked round bottom flasks were introduced. Then 1.4 g (10% by weight) of palladium on charcoal and 15.8 g of ammonium formate were added. The mixture was heated at 30 ° C. for 30 minutes, then at 40 ° C. for 1 hour and again at 60 ° C. for 30 minutes. The mixture was cooled to 40 ° C., filtered through diatomaceous earth (decalite) and the palladium was washed with ethanol. The filtrate was concentrated under reduced pressure using a rotary evaporator. 9.5 g (100%) of 2- (1-piperazinyl) ethoxyacetamide was obtained in the form of a colorless oil which crystallized.

The analytical value corresponds to that obtained with the compound prepared in Example I.1.1.

II.3. From compounds of formula (I) wherein R ₂ is -COOCH ₂ -C ₆ H ₅ .

II.3.1. 2-1- (piperazinyl) ethoxyacetamide.

6.45 g (0.02 mol) of benzyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate prepared in Example I.3.1, 0.654 g of palladium on charcoal and 65 ml of ethanol were prepared in a Parr tube. tube). The resulting mixture was stirred for 4 h at a pressure of 310.26 kPa and at room temperature. It was filtered through decalite, washed with ethanol and the filtrate was concentrated under reduced pressure using a rotary evaporator. 3.75 g (100%) of 2- (1-piperazinyl) ethoxyacetamide was recovered in the form of a colorless oil which crystallized.

The analytical value corresponds to that obtained with the compound prepared in Example I.1.1.

II.4. From compounds of formula (I) wherein R ₂ is -COOtBu.

II.4.1. 2- (1-piperazinyl) ethoxyacetamide.

14 ml of a 3M hydrochloric acid solution in ethyl acetate and 1.4 g (0.005 mol) of tert-butyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate prepared in Example I.4.1. It was introduced into a 50 ml three necked round bottom flask equipped with a cooling condenser and a mechanical stirrer. The mixture was stirred for 2 hours at room temperature and the precipitate was filtered off and washed with ethyl acetate. 1.3 g (100%) of 2- (1-piperazinyl) ethoxyacetamide dihydrochloride was obtained.

NMR: δ: 3.4 (2H, t, 4.7 Hs); 3.49-3.66 (8H, m); 3.81 (2H, t, 4.7 Hz); 3.87 (2H, s); 6.2 (5H exchangeable, bm); 7.2-7.7; 10.2.

Mass spectrum: 188 (MH ⁺ ).

II.4.2. 2- (1-piperazinyl) ethoxyacetonitrile.

2.7 g (0.010 mol) of tert-butyl 4- (2-cyanomethoxyethyl) piperazine-1-carboxylate prepared in Example I.4.2 was equipped with a water-cooled condenser, a dropping funnel and a mechanical stirrer. Was dissolved in 70 ml of dichloromethane in three 250 ml round necked flasks. 1.7 ml (1.2 equiv) of trimethylsilyl iodide dissolved in 15 ml of dichloromethane was added over 30 minutes. By the end of the addition, the formation of a precipitate was observed. 5 ml of dichloromethane was added to the reaction mixture. After 20 minutes at room temperature, 1 ml of trimethylsilyl iodide dissolved in 10 ml of dichloromethane was added over 10 minutes. The mixture was stirred for an additional hour at room temperature and left at room temperature for 16 hours. Then 20 ml of methanol was added and the resulting mixture was stirred for 10 minutes. The solvent was removed at 50 ° C. under reduced pressure using a rotary evaporator to yield 3.5 g of a brown solid, which was dissolved in 40 ml of dichloromethane. The mixture was stirred at 35 ° C. for 10 minutes. The precipitate formed was filtered off, washed with 2 × 5 ml of dichloromethane and dried. 1.6 g (94.6%) of 2- (1-piperazinyl) ethoxyacetonitrile dihydrochloride was obtained in the form of a yellow oil.

NMR: δ: 3.88 (10H, m); 3.87 (2H, t, 4.9 Hz); 4.57 (2H, s); 8.8 (2H, bs).

Mass spectrum: 169 (M ⁺ ).

Elemental Analysis:

II.4.3, methyl 2- (1-piperazinyl) ethoxyacetate.

2 g (0.0066 mol) of tert-butyl 4- (2-methoxycarbonylmethoxyethyl) piperazine-1-carboxylate prepared in Example I.4.3. Was equipped with a water-cooled condenser and a mechanical stirrer. It was dissolved in 5 ml of ethyl acetate in three 50 ml round neck flasks. While stirring, 20 ml of a 3M hydrochloric acid solution in ethyl acetate was added in one portion. The mixture was stirred for 30 minutes at room temperature, then 5 ml of 3M hydrochloric acid solution in ethyl acetate was added and stirring continued for 30 minutes. The precipitate was filtered off and washed with 2 × 5 ml of ethyl acetate. 1.68 g (92%) of methyl 2- (1-piperazinyl) ethoxyacetate dihydrochloride was obtained in the form of a beige solid.

NMR: δ: 3.4 (2H, t, 4.8 Hz); 3.47-3.65 (8H, m); 3.67 (3H, s); 3.92 (2H, t, 4.8 Hz); 4.21 (2H, s); 10.1 (2H, bs).

Mass spectrum: 202 (M ⁺ ).

II.4.4. Ethyl 2- (1-piperazinyl) ethoxyacetate.

2 g (0.0066 mol) of tert-butyl 4- (2-methoxycarbonylmethoxyethyl) piperazine-1-carboxylate prepared in Example I.4.3. Was equipped with a water-cooled condenser and a mechanical stirrer. Dissolve in 10 ml of ethanol in 50 ml three necked round bottom flask. While stirring, 11 ml of a 3.8 M hydrochloric acid solution in ethanol was added in one portion. The mixture was stirred for 30 minutes at room temperature and an additional 11 ml of 3.8 M hydrochloric acid in ethanol was added. The mixture was refluxed for 4 hours and the solvent removed under reduced pressure using a rotary evaporator. 1.86 g (97.3%) of ethyl 2- (1-piperazinyl) -ethoxyacetate dihydrochloride was obtained in the form of a pale yellow oil, which was crystallized.

NMR: δ: 1.21 (3H, t, 7.1 Hz); 3.37 (2H, t, 4.8 Hz); 3.46 (4H, m); 3.55 (4H, m); 3.91 (2H, t, 4.8 Hz); 4.14 (2H, q, 7.1 Hz); 4.18 (2H, s): 10.1 (1H, bs); 12 (1 H, bs).

Mass spectrum: 216 (M ⁺ ).

II.5. From a compound of formula (I) wherein R ₂ is -COOEt,

II.5.1. 2- (1-piperazinyl) ethoxyacetic acid.

20 g (0.077 mol) of ethyl 4- (2-carbamoylmethoxyethyl) -piperazine-1-carboxylate prepared in Example 1.2 was charged in a round bottom flask equipped with a water-cooled condenser and a mechanical stirrer, 37 It was suspended in a mixture of 20 ml of an aqueous solution containing 20% by weight of hydrochloric acid and 20 ml of water and brought to a temperature of 50 DEG C while stirring. The mixture was reacted at this temperature for 5 hours. The reaction mixture was cooled to 0 ° C. and the pH of the mixture was adjusted to 6 using 50% aqueous sodium hydroxide solution. After toluene was added, water was evaporated from the reaction mixture under reduced pressure. Then toluene was evaporated using a rotary evaporator and the evaporation residue was dissolved in 100 ml of isopropanol. The salt formed was filtered and acidified by adding 28 ml of 6N aqueous hydrochloric acid solution to the filtrate. After addition of 50 ml of toluene, water was evaporated from the reaction mixture under reduced pressure. The toluene was then evaporated using a rotary evaporator and the evaporation residue was dissolved in 50 ml of acetone. The white crystals formed were filtered and acetone was evaporated from the filtrate under reduced pressure. An oil was obtained which was used without further purification.

The oil thus obtained was dissolved in 75 ml of a 5.5N potassium hydroxide solution in ethanol and the mixture was kept at reflux for 28 hours. 100 ml of water was added and ethanol was evaporated under reduced pressure, and then the pH of the mixture was adjusted to 7 using 36 ml of 6N aqueous hydrochloric acid solution. After evaporation to remove water under reduced pressure, the evaporation residue was dissolved in isopropanol and the solids were filtered off. The solvent was evaporated from the filtrate and the residual oil thus obtained was dissolved in 30 ml of 6N hydrochloric acid aqueous solution. Water was removed again by evaporation under reduced pressure and the solid was dissolved in 100 ml of toluene, then the mixture was filtered and washed with toluene. 9.4 g of 2- (1-piperazinyl) ethoxyacetic acid dihydrochloride were obtained.

Yield (65%)

Mass spectrum: 189 (MH ⁺ ) 171 (M-OH), 99 (HN (C ₄ H ₈ ) N ⁺ = CH ₂ ).

Example III. Conversion of R ₁ groups to carboxylic acids in compounds of formula (I).

III.1. 2- (4-benzyl-1-piperazinyl) ethoxyacetic acid.

III.1.A. 13.9 g (0.05 mol) of 2- (4-benzyl-1-piperazinyl) ethoxyacetamide was dissolved in l 5 ml of water in a 100 ml three necked round bottom flask equipped with a water-cooled condenser and a mechanical stirrer. . 31 ml (0.375 ml) of 37% aqueous hydrochloric acid solution was added and the mixture was heated at 60 ° C. for 1 h. Water was removed using a rotary evaporator at 60 ° C. under reduced pressure. The white solid obtained was dissolved in 75 ml of acetone and stirred at room temperature for 1 hour. The mixture was filtered and 19.7 g of 2- (4-benzyl-1-piperazinyl) ethoxyacetic acid dihydrochloride was obtained in the form of white crystals.

refine:

1) Recrystallization: 5 g of a white solid was dissolved in high temperature conditions in 55 ml of a mixture of isopropanol / water (9/1 (v / v)). 2 g of 2- (4-benzyl-1-piperazinyl) ethoxyacetic acid product was recovered in a yield of 44.8%.

2) Sublimation: 2 g of finely crushed white crystals ) Placed in a sublimation device. The device was placed under vacuum (0.2 mmHg) and heated at 150 ° C. for 11 hours. 1.65 g of pure 2- (4-benzyl-1-piperazinyl) ethoxyacetic acid product was recovered in 92.8% yield.

NMR: δ: 3.39 (6H, m); 3.65 (4H, m); 3.88 (2H, t, 4.6 Hz); 4.09 (2H, s); 4.34 (2H, s, d); 7.44 (3H, m); 7.64 (2H, m).

Mass spectrum: 278 (M ⁺ ).

Generation of free bases:

5 g of white crystals were dissolved in 25 ml of water. The pH of the solution was adjusted to 7 by adding 25 ml of 1N aqueous sodium hydroxide solution. Water was removed using a rotary evaporator at 60 ° C. under reduced pressure and the evaporation residue was dissolved in 50 ml of isopropanol. The mixture was stirred for 2 h at 50 ° C. using a rotary evaporator. The salts were filtered off and the filtrate was concentrated in vacuo at 50 ° C. using a rotary evaporator to give 4 g of orange oil. This oil was dissolved in 40 ml of acetone and the solution was stirred at 50 ° C. The salts were filtered off and the filtrate was concentrated to give 3.4 g (96.3%) of 2- (4-benzyl-1-piperazinyl) ethoxyacetic acid in the form of a brown oil.

NMR: δ: 2.51 (4H, m); 2.78 (6H, m); 3.54 (2H, s); 3.66 (2H, t, 5.4 Hz); 3.92 (2H, s); 7.28 (5 H, m).

Mass spectrum: 279 (MH ⁺ ).

DSC: First 234.05 ° C., up to 237.7 ° C.

Elemental Analysis:

III.1.B. 2- (1-piperazinyl) ethoxyacetic acid.

2 g (0.0057 mol) of 2- (4-benzyl-1-piperazinyl) ethoxyacetic acid dihydrochloride, 0.2 g of palladium on charcoal and 50 ml of a solution of ethanol / water (8/2 (v / v)) in par tubes Located. The mixture was stirred for 5 hours at room temperature and a pressure of 310.26 kPa. The mixture was filtered through decalite, washed with 25 ml of a solution of ethanol / water (8/2 (v / v)) and the filtrate was concentrated under reduced pressure using a rotary evaporator to recover 1.6 g of an orange solid. This solid was dissolved in 10 ml of ethanol and stirred for 1 hour. After filtration and drying, 1.2 g of 2- (1-piperazinyl) ethoxyacetic acid dihydrochloride was recovered as a yellow crystalline form in a yield of 80.6%.

Analytical values corresponded to those obtained with the compound prepared in Example I.1.4.

III.2. 1-stage hydrolysis and deprotection

Example I.4.3. 1 g (0.00348 mol) of tert-butyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate, prepared in the above, and 2 ml of water were placed in a 10 ml Erlenmeyer flask. 2 ml of 37% hydrochloric acid solution was added and the resulting mixture was heated in a 60 ° C. oil bath for 1 hour and water was removed using a rotary evaporator under reduced pressure. The residue was dissolved in toluene. After evaporation, 1.1 g of a pale yellow solid was obtained. This finely pulverized solid was placed in a booky sublimation apparatus. The apparatus was placed under vacuum (0.3 mm Hg) and heated at 150 ° C. for 8 hours. 800 mg of 2- (1-piperazinyl) ethoxyacetic acid dihydrochloride was obtained as a white crystalline form in 88% yield.

Analytical values corresponded to those obtained with the compound prepared in Example I.1.4.

Example IV. Preparation of Compounds of Formula (II).

IV.1. From (4-chlorophenyl) phenylmethane chloride.

IV.1.1. 2-[(4-[(4-chlorophenyl) phenylmethyl) -1-piperazinyl] ethoxy] acetamide.

2.4 g (0.01 mol) of (4-chlorophenyl) phenylmethane chloride, 4.1 g (0.022 mol) of 2- (1-piperazinyl) ethoxyacetamide prepared in Example I.1. 1, and 10 ml of acetonitrile Was introduced into a 100 ml three necked round bottom flask with a water-cooled condenser and a mechanical stirrer. The mixture was refluxed for 3 hours. The mixture was cooled to rt and concentrated using a rotary evaporator under reduced pressure. The residue was dissolved in 25 ml of water and the pH of the solution was adjusted to 14 using 1N NaOH solution. Then the mixture was extracted with 2 × 25 ml of dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated using a rotary evaporator at 50 ° C. and under reduced pressure. 4.1 g of a brown oil is obtained, and the obtained product is purified by chromatography on silica gel (eluent: dichloromethane / methanol / a mixture of 28 wt% aqueous ammonia solution (98/2 / 0.2 (v / v / v)), followed by dichloromethane. / Methanol (97/3 (v / v)))). 3.2 g (82.5%) of 2-[(4-[(4-chlorophenyl) phenylmethyl) -1-piperazinyl] ethoxy] acetamide were obtained in the form of a colorless oil, which crystallized.

IV.1.2. 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid.

(4-chlorophenyl) phenylmethane) 5.9 g (0.025 mol) chloride, potassium 2- (1-piperazinyl) 11.3 g (0.05 mol) oxyacetate and 50 ml acetonitrile with water-cooled condenser and mechanical stirrer Into a 100 ml three necked round bottom flask. The mixture was refluxed for 16 h. The mixture was cooled to room temperature, the acetonitrile was separated after precipitation had occurred and the brown solid was dissolved in 50 ml of water. The aqueous and acetonitrile phases were combined and concentrated using a rotary evaporator under reduced pressure. The residue (brown solid) was dissolved in 50 ml of water and the pH of the solution was adjusted to 4-5 using 8 ml of 6N aqueous hydrochloric acid solution. The mixture was then extracted with 2 x 50 ml of dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered and concentrated at 50 ° C. in vacuo. 9.5 g of a brown oil was obtained, which was dissolved in 100 ml of acetone. 2 g of Norit (firewood) was added and the mixture was stirred at 50 ° C. for 15 minutes. After filtration, an orange solution was obtained, to which 4.6 ml of concentrated (37%) HC1 was added. Acetone was evaporated using a rotary evaporator under reduced pressure, and the oily brown residue was dissolved in 100 ml of acetone, and formation of a precipitate was observed. The suspension was stirred at 50 ° C. for 30 minutes and then at room temperature for 2 hours. Filtration and drying at 50 ° C. yielded 5.6 g (48.5%) of 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid in the form of a white solid. It was.

IV.2. From bis (4-fluorophenyl) methane chloride.

IV.2.1. (2- [4- [bis (4-fluorophenyl) methyl] -1-perrazinyl] ethoxy) acetamide.

2.43 g (0.0102 mol) of bis (4-fluorophenyl) methane chloride, 3.84 g (0.022 mol) of 2- (1-piperazinyl) ethoxyacetamide and 10 ml of acetonitrile with water-cooled condenser and mechanical stirrer Into a 50 ml three necked round bottom flask. The mixture was refluxed for 3 hours and the mixture was cooled to room temperature. The mixture was concentrated in vacuo and the residue was dissolved in 100 ml of water and 100 ml of dichloromethane. The pH of the aqueous phase was adjusted to 14 using 1N NaOH solution. After precipitation occurred, the organic phase was separated and then reextracted with 50 ml of dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator at 50 ° C. 4.02 g of a yellow oil is obtained, and the obtained product is purified by chromatography on silica gel (eluent: dichloromethane / methanol / 28 wt% aqueous ammonia solution (98.9 / 1 / 0.1 (v / v / v)), followed by the same component. (Using a mixture of 95.6 / 4 / 0.4 (v / v / v))). 2.5 g (63.1%) of (2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] ethoxy) acetamide were obtained in the form of an orange oil.

IV.2.2. (2- [4- [bis (4-fluorophenyl) methyl] -1-perrazinyl] ethoxy]) acetic acid.

6 g (0.025 mol) of bis (4-fluorophenyl) methane chloride, 1 g (0.075 mol) of potassium 2- (1-piperazinyl) ethoxyacetate and 100 ml of acetonitrile were 250 ml with a water-cooled condenser and a mechanical stirrer. It was introduced into three necked round bottom flasks. The mixture was refluxed for 10 hours and then cooled to room temperature. The mixture was concentrated using a rotary evaporator under reduced pressure and the residue was dissolved in 100 ml of water. The pH of the aqueous phase was adjusted to 4-5 using 5 ml of 6N HCl solution. The mixture was extracted with 2 x 50 ml of dichloromethane. The organic phases were combined and concentrated at 50 ° C. in vacuo. The oil obtained was dissolved in 50 ml of acetone and stirred at room temperature for 30 minutes. Insoluble matter was filtered off and the filtrate was concentrated using a rotary evaporator under reduced pressure. 8.5 g of brown oil is obtained, and the obtained product is purified by chromatography on silica gel (eluent: dichloromethane / methanol / a mixture of 28 wt% aqueous ammonia solution (89 / 1O / l (v / v / v)), followed by the same component. (Using a mixture of 78/20/2 (v / v / v))). 3.4 g (34.8%) of (2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] ethoxy]) acetic acid were obtained in the form of a colorless oil.

IV.3. From (4-chlorophenyl) phenylmethane bromide.

IV.3.1 (2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] ethoxy) acetamide.

2.85 g (0.01 mol) of (4-chlorophenyl) phenylmethane bromide, 4.1 g (0.022 mol) of 2- (1-piperazinyl) ethoxyacetamide and 10 ml of acetonitrile with water-cooled condenser and mechanical stirrer Into a 50 ml three necked round bottom flask. The mixture was refluxed for 2 hours and then the mixture was cooled to room temperature. The mixture was concentrated using a rotary evaporator under reduced pressure and the residue was dissolved in 25 ml of water and 50 ml of dichloromethane. The pH of the aqueous phase was adjusted to 14 using 1N NaOH solution. After precipitation took place the organic phase was separated and then reextracted with 50 ml of dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated at 50 ° C. using a rotary evaporator. 4.14 g of a yellow oil are obtained, and the obtained product is purified by chromatography on silica gel (eluent: dichloromethane / methanol / a mixture of 28 wt% aqueous ammonia solution (98.9 / 1 / 0.1 (v / v / v)), followed by the same component. (Using a mixture of 95.6 / 4 / 0.4 (v / v / v))). 3.4 g (86.5%) of (2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] ethoxy) acetamide were obtained in the form of a colorless oil, which was crystallized.

The present invention provides novel compounds, i.e., substituted [2- (1-piperazinyl) ethoxy] methyl compounds of formula (I), methods for preparing these compounds and compounds of formula (II) It relates to their use.

[Formula I]

[Formula II]

Where

R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms,

R ₂ is a hydrogen atom or a -COR ₄ or -R ₅ group wherein R ₄ is -OR ₆ or -R ₇ (wherein R ₆ is a linear or branched alkyl radical having 1 to 4 carbon atoms, halo Alkyl, alkylaryl, alkylnitroaryl or alkylhaloaryl radicals, R ₇ represents a haloalkyl radical), R ₅ represents an allyl or alkylaryl radical,

X ₁ and X ₂ independently represent a hydrogen, fluorine, chlorine or bromine atom.

When R ₁ represents a -COOH group, X ₁ represents a chlorine atom at position 4 and X ₂ represents a hydrogen atom, the compound of formula (II) is represented by 2- [2- [4-[( 4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid:

[Formula III]

R ₁ represents a -CONH ₂ , -CN, -COOM or -COOR ₃ group wherein M is an alkali metal and R ₃ represents an alkyl radical having 1 to 4 carbon atoms and X ₁ represents a chlorine atom at position 4 When X ₂ represents a hydrogen atom, the compound of formula (II) is 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] of formula (III); Acetic acid and their pharmaceutically acceptable salts are important intermediate products.

2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride is described in Canadian Patent No. 1,199,918 and allergic syndrome, for example It has been introduced as a medicament for the treatment of chronic and acute allergic rhinitis, allergic conjunctivitis, pruritis, urticaria. When used for therapeutic purposes, these products have been shown to have significantly fewer side effects on the central nervous system, such as drowsiness, attenuation of mental activity, etc. [DP TASHKIN et al., Annals of Allergy, Part II, 59 , (1987), 49-52, as well as FM GENGO et al., Annals of Allergy, Part II, 59 , (1987), 53-57].

When R ₁ is a -COOH group and X ₁ and X ₂ each represent a fluorine atom at position 4, the compound of formula (II) is represented by 2- [2- [4- [bis (4- Fluorophenyl) methyl] -1-piperazinyl] ethoxy] acetic acid:

[Formula IV]

R ₁ represents a -CONH ₂ , -CN, -COOM or -COOR ₃ group wherein M is an alkali metal and R ₃ represents an alkyl radical having 1 to 4 carbon atoms, and X ₁ and X ₂ are 4 times When each of the positions represents a fluorine atom, the compound of formula (II) is 2- [2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] ethoxy] of formula (IV). Acetic acid and pharmaceutically acceptable salts are important intermediate products.

2- [2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] ethoxy] acetic acid dihydrochloride is also known under the international trade name efletirizine. . The use of efetirizine to treat rhinitis or nasal conjunctivitis of allergic origin has been described in several recent publications in the 51 ^st Annual Meeting or American Academy of Allergy and Immunology, reproduced in J. Allergy Clin. Immunol., 95/1 (1995), part 2, Abstract 229 and XV ^th Congress of Allergology and Clinical Immunology, reproduced in Allergy & Clin. Immunol. News, (1994) suppl. No. 2, abstracts 428, 1136, 1496 and 1864. These documents show that intranasal administration of epletirizine can effectively treat rhinitis or nasal conjunctivitis of allergic origin.

Canadian Patent No. 1,199,918 describes the preparation of 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its dihydrochloride. In this preparation, the starting material is 1-[(4-chlorophenyl) phenylmethyl] piperazine, which is reacted with methyl (2-chloroethoxy) acetate or 2- (2-chloroethoxy) acetamide to methyl, respectively. 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate (R ₁ is -COOCH ₃ and X ₁ is -Cl (position 4) and X ₂ is -H) or 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetamide (R ₁ is -CONH ₂ and X Compound of formula (II) wherein ₁ is -Cl (position 4) and X ₂ is -H). Hydrolysis of these methyl esters and acetamides with inorganic bases (potassium hydroxide or sodium hydroxide) then forms sodium salts or potassium salts, and these salts are readily converted to cetirizine and its dihydrochloride.

Applicant's Canadian Patent No. 1,320,732 discloses 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and another for preparing dihydrochloride thereof. Synthetic routes are shown.

According to the patent, 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its dihydrochloride are 2- [4-[(4 -Chlorophenyl) phenylmethyl] -1-piperazinyl] ethanol is reacted with alkali metal haloacetate in the presence of an alkali metal alkoxide and the alkali metal salt obtained is subjected to the corresponding acid, suitably dihydro thereof. Prepared by a process characterized in that it is converted to chloride.

Applicant's Canadian Patent No. 1,317,300 also provides for the preparation of 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its dihydrochloride. Another method of synthesis is provided.

According to the patent, 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid and its dihydrochloride are 2- [2- [4- [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile of formula (II) wherein R ₁ is -CN, X ₁ is -Cl (position 4) and X ₂ is -H Compound) is hydrolyzed to a base or an acid in an aqueous, alcoholic or aqueous-alcoholic medium and the acid obtained is suitably converted to its dihydrochloride.

2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetonitrile used as starting material was 1-[(4-chlorophenyl) phenylmethyl] piperazine. Is obtained by reacting with 2-haloethoxyacetonitrile.

This reaction is carried out in the presence of an acid acceptor such as an alkali metal carbonate, and optionally in an inert organic solvent such as an alcohol (e.g., n-butanol, etc.), preferably in small amounts to promote the reaction at a temperature within the reflux temperature range. Is carried out in the presence of an alkali metal iodide.

The inventors aimed at increasing the therapeutic value of cetirizine and compounds with similar structures, and were directed to 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] Studies have been conducted to develop new synthetic routes of ethoxy] acetic acid and their pharmaceutically acceptable salts, obtaining such compounds from reagents that are known and / or readily accessible by these routes, and with more sufficient purity These compounds have been provided in economically acceptable yields. In addition, to simplify the industrialization of the process, the applicant has further aimed to develop synthetic routes with fewer steps than known processes.

It would also be advantageous if these other compounds could be prepared according to essentially similar methods, provided they provide the therapeutic value of other compounds of formula (II) such as, for example, epletirizine.

As a result, it is necessary to find precursors which can be produced on the one hand easily and economically, and on the other hand, which can be converted to the compound of formula (II) easily and in high yield.

Applicant has found a kind of compound that completely satisfies the object of the present invention, ie substituted [2- (1-piperazinyl) ethoxy] methyl compound.

As such, the subject of the invention is a substituted [2- (1-piperazinyl) ethoxy] methyl compound of formula (I) as a novel compound:

Formula (I)

Where

R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms,

R ₂ is a hydrogen atom or a -COR ₄ or -R ₅ group, wherein R ₄ is -OR ₆ or -R ₇ (wherein R ₆ is a linear or branched alkyl radical having 1 to 4 carbon atoms, halo Alkyl, alkylaryl, alkylnitroaryl or alkylhaloaryl radicals, R ₇ represents a haloalkyl radical, and R ₅ represents an allyl or alkylaryl radical.

These compounds can be readily obtained by the reaction of substituted [2-haloethoxy] methyl of formula (VI) with piperazine of formula (V):

[Formula V]

[Formula VI]

X-CH ₂ -CH ₂ -O-CH ₂ -R ₁

Where

R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms,

R ₂ is a hydrogen atom or a -COR ₄ or -R ₅ group wherein R ₄ is -OR ₆ or -R ₇ (wherein R ₆ is a linear or branched alkyl radical having 1 to 4 carbon atoms, haloalkyl , An alkylaryl, alkylnitroaryl or alkylhaloaryl radical, R ₇ represents haloalkyl), R ₅ represents an allyl or alkylaryl radical,

X represents a halogen atom.

Typically, compounds of formula (VI) in which X represents a chlorine or iodine atom are used, but this reaction can also be carried out with the corresponding bromide. When X represents an iodine atom, it has been observed that it is advantageous to treat for very low temperatures (less than 40 ° C.) and for relatively short periods of time (eg 2 hours).

Such reactions can be carried out in the presence of acid acceptors such as tertiary organic bases (e.g. triethylamine) or inorganic bases (e.g. sodium carbonate), aliphatic alcohols, aliphatic ketones (e.g. methyl ethyl ketone), aromatic hydrocarbons (e.g. toluene or xylene). It is generally carried out by heating to 30-180 ° C. for a few hours in a solvent selected from or alternatively in water. If an excess of piperazine (greater than 3 equivalents to [2-haloethoxy] methyl) is used, it is not necessary to add an additional acid acceptor since piperazine itself acts as an acid acceptor. Advantageously, piperazine and its dihydrochloride can also be used in equivalent amounts.

In general, to prepare substituted [2- (1-piperazinyl) -ethoxy] methyl compounds of the invention, it is simple to use piperazine of formula (V) in which R ₂ represents a hydrogen atom for obvious reasons. desirable. Nevertheless, it may be wise to protect one of the amine functional groups of piperazine during this reaction with conventional protecting groups for such functional groups to prevent piperazine from reacting twice with the compound of formula (VI). have.

As protecting groups for amine functional groups, any protecting group known to those skilled in the art for this purpose can be used.

Thus, it is possible to select a protecting group which can be selectively cleaved according to the following scheme after the compound of formula (I) is formed:

Among the particularly suitable protection methods in this case, for example, haloalkyl, alkylhaloaryl, alkylaryl, alkylnitroaryl, and amides such as alkylhaloaryl carbamate, trifluoroacetamide, or alternatively Can be used a tertiary amine such as N-allylamine or N-alkylarylamine. With these groups, the reaction for deprotection of the amine functional groups of piperazine can be carried out by simple heating, catalytic hydrogenation or hydrolysis with bases or acids, according to techniques well known in the art.

According to one variant, when R ₁ is a -CONH ₂ , -CN, -COOM or -COOR ₃ group wherein M is an alkali metal and R ₃ represents an alkyl radical having 1 to 4 carbon atoms, Using a reaction for deprotection of amine functionality, when the R ₁ group is converted to a -COOH group and R ₁ represents a -COOH group, it is separated under conditions such that this -COOH group is preserved during the reaction for deprotection of the amine function. Groups as protecting groups for amine functional groups, which may be employed, may also be selected.

This reaction can be carried out according to the following scheme:

Among the particularly suitable protection methods in this case, for example, an alkyl carbamate group can be used.

Along with such carboxylated groups, the amine functionality of piperazine can be deprotected by heating for several hours in alcoholic or aqueous media in the presence of an inorganic base or by any other conventional method known to those skilled in the art.

In the two schemes above,

R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms,

R ₂ is a hydrogen atom or a -COR ₄ or -R ₅ group, wherein R ₄ is -OR ₆ or -R ₇ (wherein R ₆ is a linear or branched alkyl radical having 1 to 4 carbon atoms, halo Alkyl, alkylaryl, alkylnitroaryl or alkylhaloaryl radicals, R ₇ represents a haloalkyl radical, and R ₅ represents an allyl or alkylaryl radical.

Substituted [2- (1-piperazinyl) ethoxy] methyl compounds of formula (I) thus prepared are compounds of formula (II) that can be prepared in sufficient purity, economically acceptable yields, and in fewer steps (Or compounds of formulas (III) and (IV) when R ₁ represents a -COOH group), which has the main value and, when initiated from such precursors, simplifies industrial processes and reduces production costs. It shows a significant advantage in this regard.

As a result, the present invention also provides a compound of formula (II) wherein R ₁ is -COOH by reacting a compound of formula (I) wherein R ₂ represents hydrogen with a diphenylmethyl halide of formula Group to represent compounds of formulas (III) and (IV)):

Where

R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group wherein M is an alkali metal and R ₃ is an alkyl radical having 1 to 4 carbon atoms;

X 'represents a halogen atom selected from the group consisting of chlorine, bromine and iodine,

X ₁ and X ₂ independently represent a hydrogen, fluorine, chlorine or bromine atom.

This reaction is about 60 in an inert solvent selected from the group consisting of aliphatic alcohols, aliphatic ketones (eg methyl ethyl ketone), aromatic hydrocarbons (eg toluene or xylene), aliphatic nitriles (eg acetonitrile) It is carried out by reacting the diphenylmethyl halide of formula (VI) with a compound of formula (I) at a molar fraction of 4: 1 to 1: 4 for a few minutes to several hours at a temperature of from 160 ° C. The reaction may also be carried out in the presence of an acid acceptor such as a tertiary organic base (eg triethylamine) or an inorganic base (eg sodium carbonate). This reaction can optionally be carried out in the presence of an alkali metal iodide.

As described above, the compound of formula (II) (R ₁ represents a -CONH ₂ , -CN, -COOM or -COOR ₃ group, wherein M is an alkali metal and R ₃ is an alkyl radical having 1 to 4 carbon atoms , X ₁ represents a chlorine atom at position 4 and X ₂ represents a hydrogen atom) are already known, these are 2- [2- [4-[(4-chlorophenyl) phenylmethyl]-of formula (III) It has already been described that the conversion to 1-perrazinyl] ethoxy] acetic acid is carried out in an aqueous, alcoholic or aqueous-alcoholic medium using a base or an acid. Furthermore, the compound of formula (II) in which R ₁ represents a -COOH group and X ₁ represents a chlorine atom at position 4 and X ₂ represents a hydrogen atom is 2- [2- [4-[(4) in formula (III). -Chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetic acid. Thus, alkyl 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate (R ₁ is -COOR ₃ and X ₁ is -Cl at position 4 And a compound of formula (II) wherein X ₂ is -H) or 2- [2- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetamide (R ₁ is Compound of formula (II) wherein -CONH ₂ , X ₁ is -Cl ₁ at position 4 and X ₂ is -H), 2- (2- [4-[(4-chlorophenyl)) of formula (III) For subsequent conversion to phenylmethyl] -1-piperazinyl] ethoxy] acetic acid see Canadian Patent No. 1,199,918, 2- [2- [4-[(4-chlorophenyl) phenylmethyl]- Canadian Patent No. 1,317,300 to convert 1-piperazinyl] ethoxy] acetonitrile (compound of formula (II) wherein R ₁ is -CN, X ₁ is -Cl at position 4 and X ₂ is -H); Reference is made to the call.

Similar processes are carried out for the conversion of other compounds of formula (II).

The following examples illustrate the invention but are not limited thereto. In these examples, the melting point was measured by differential scanning calorimetry (D.S.C.) at a temperature gradient of 20 ° C./min. Mass spectra were recorded on a Finnigan MAT TSQ 700 apparatus. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker device at 250 MHz in dimethyl sulfoxide using tetramethylsilane as internal standard. Chemical shifts are expressed in δ (ppm). The letters s, d, dd, t, q, b and m represent singlet, doublet, two doublet, triplet, quadruple, broad peak and multiplet, respectively.

Claims (11)

Substituted [2-1-piperazinyl) ethoxy] methyl compound of formula (I): Formula (I) Where R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms, R ₂ is a hydrogen atom or a -COR ₄ or -R ₅ group wherein R ₄ is -OR ₆ or -R ₇ (wherein R ₆ is a linear or branched alkyl radical having 1 to 4 carbon atoms, carbon atoms A haloalkyl radical or benzyl radical having 1 to 4 linear or branched alkyl, R ₇ represents a haloalkyl radical having linear or branched alkyl of 1 to 4 carbon atoms, and R ₅ Represents an allyl radical or benzyl radical. The method of claim 1, 2- (1-piperazinyl) ethoxyacetic acid, 2- [2- (1-piperazinyl) ethoxy] acetamide, 2- (1-piperazinyl) ethoxyacetonitrile, Methyl 2- (1-piperazinyl) ethoxyacetate, Ethyl 2- (1-piperazinyl) ethoxyacetate, 2- (4-benzyl-1-piperazinyl) ethoxyacetamide, 2- (4-benzyl-1-piperazinyl) ethoxyacetonitrile, Methyl 2- (4-benzyl-1-piperazinyl) ethoxyacetate, Benzyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate, Benzyl 4- (2-cyanomethoxyethyl) piperazine-1-carboxylate, Tert-butyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate, Tert-butyl 4- (2-cyanomethoxyethyl) piperazine-1-carboxylate, Tert-butyl 4- (2-methoxycarbonylmethoxyethyl) piperazine-1-carboxylate, Ethyl 4- (2-carbamoylmethoxyethyl) piperazine-1-carboxylate, and Substituted [2- (1-piperazinyl) ethoxy] methyl compound, characterized in that it is selected from potassium 2- (4-carboxyethyl-1-piperazinyl) ethoxyacetate. The substituted [2- (1-piperazinyl) according to claim 1, wherein the protecting group R ₂ for the amine functional group is a linear or branched alkyl carboxylate group having 1 to 4 carbon atoms, or a benzyl group. Oxy] methyl compound. A piperazine of the formula (V) is reacted with a substituted [2-haloethoxy] methyl of the formula (VI) to produce a substituted [2- (1- Process for preparing piperazinyl) ethoxy] methyl compound: Formula (V) Formula (VI) Where R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms, R ₂ is a hydrogen atom or a -COR ₄ or -R ₅ group wherein R ₄ is -OR ₆ or -R ₇ (wherein R ₆ is a linear or branched alkyl radical having 1 to 4 carbon atoms, carbon atoms Represents a haloalkyl radical having 1-4 alkyl, or a benzyl radical, R ₇ represents a haloalkyl radical having 1 to 4 carbon atoms, R ₅ represents an allyl radical or benzyl radical, X represents a halogen atom. 5. A method according to claim 4, wherein the halogen atom represented by X is a chlorine or iodine atom. The method according to claim 4, wherein the protecting group R ₂ for the amine functional group is a linear or branched alkyl carboxylate group having 1 to 4 carbon atoms, or benzyl group. A method of preparing a compound of formula (II) by reacting a substituted [2- (1-piperazinyl) ethoxy] methyl compound of formula (I) with a diphenylmethyl halide of formula (VII) : Formula (I) Formula (II) Formula Where R ₁ represents a -CONH ₂ , -CN, -COOH, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms, R ₂ represents a hydrogen atom, X ₁ and X ₂ independently represent a hydrogen, fluorine, chlorine or bromine atom, X 'represents a halogen atom selected from chlorine, bromine or iodine. Claim 7 wherein, R ₂ is a substituted [2- (1-piperazinyl)] methyl compounds of formula (Ⅰ) represents a hydrogen atom, R ₂ is a hydrogen atom, -COR ₄ or -R ₅ in {Wherein R ₄ is —OR ₆ or —R ₇ wherein R ₆ is a linear or branched alkyl radical having 1 to 4 carbon atoms, a haloalkyl radical having 1 to 4 carbon atoms, or a benzyl radical; And R ₇ represents a haloalkyl radical having alkyl having 1 to 4 carbon atoms, and R ₅ represents an allyl radical or a benzyl radical. Characterized in that it is the product of a reaction that separates the R ₂ groups of a ferrazinyl) ethoxy] methyl compound. 8. A compound of formula 7 according to claim 7, wherein the compound of formula II is hydrolyzed with an acid or a base in an aqueous, alcoholic or aqueous-alcoholic medium, thereby yielding 2- [2- [4-[(4-chlorophenyl) phenylmethyl ] -1-piperazinyl] ethoxy] acetic acid or a pharmaceutically acceptable salt thereof. Formula (II) Where R ₁ represents a -CONH ₂ , -CN, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms, X ₁ represents a chlorine atom at position 4 and X ₂ represents a hydrogen atom. 8. A compound of formula 7 according to claim 7, wherein the compound of formula II is hydrolyzed with an acid or a base in an aqueous, alcoholic or aqueous-alcoholic medium to give 2- [2- [4- [bis (4-fluorophenyl) Methyl] -1-piperazinyl] ethoxy] acetic acid or a pharmaceutically acceptable salt thereof. Formula (II) Where R ₁ represents a -CONH ₂ , -CN, -COOM or -COOR ₃ group, where M is an alkali metal, R ₃ is an alkyl radical having 1 to 4 carbon atoms, X ₁ and X ₂ each represent a fluorine atom at position 4. The method according to claim 5, wherein the protecting group R ₂ for the amine functional group is a linear or branched alkyl carboxylate group having 1 to 4 carbon atoms, or a benzyl group.