Process for the synthesis of piperazinyl-ethoxy-bromophenyl derivates and their application in the production of compounds containing them

Abstract

Process for the industrial synthesis of the compound of formula (I): ##STR00001##

Claims

1. A process for preparing a compound of formula (I): ##STR00032## wherein: R.sub.1 and R.sub.2, independently of one another, represent a halogen atom, a linear or branched (C.sub.1-C.sub.6)alkyl group, a linear or branched (C.sub.1-C.sub.6)alkoxy group, a linear or branched (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy group, a hydroxyl group or a cyano group, and R.sub.3 represents a linear or branched (C.sub.1-C.sub.6)alkyl group, comprising the step of reacting a compound of formula (IV): ##STR00033## with a compound of formula (V): ##STR00034## wherein X.sup.− represents a monovalent anionic counter-ion, in a solvent, at high temperature in the presence of a base to yield the compound of formula (I).

2. The process according to claim 1, wherein the solvent is polar aprotic.

3. The process according to claim 1, wherein the temperature is above 135° C.

4. The process according to claim 1, wherein the base is a carbonate salt.

5. The process according to claim 1, wherein the compound of formula (I) is isolated as a monohydrohalide salt or a dihydrohalide salt.

6. The process according to claim 1, wherein 1,4-diazabicyclo[2.2.2]octane is employed in the process to obtain the compound of formula (V).

7. The process according to claim 1, wherein 1,4-diazabicyclo[2.2.2]octane is employed in the process to obtain the compound of formula (I).

8. The process according to claim 1, wherein the compound of formula (IV): ##STR00035## wherein R.sub.1 and R.sub.2, independently of one another, represent a halogen atom, a linear or branched (C.sub.1-C.sub.6)alkyl group, a linear or branched (C.sub.1-C.sub.6)alkoxy group, a linear or branched (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy group, a hydroxyl group or a cyano group, is obtained by a regioselective monobromination reaction of a compound of formula (VI): ##STR00036## in a solvent in the presence of a brominating agent selected from bromine, sodium bromide/trichloroisocyanuric acid and bromine/sodium acetate.

9. The process according to claim 8, wherein the reaction is carried out in the presence of 1 equivalent of brominating agent.

10. The process according to claim 8, wherein the brominating agent is bromine.

11. The process according to claim 8, wherein the solvent is selected from acetic acid, dichloromethane, a mixture of methanol and sulfuric acid, and a mixture of acetic acid and dichloromethane.

12. The process according to claim 8, wherein the reaction is carried out by diluting the compound of formula (VI) with about 10 to about 20 volumes of organic solvents or mixture of organic solvents.

13. The process according to claim 8, wherein the compound of formula (VI): ##STR00037## wherein R.sub.1 and R.sub.2, independently of one another, represent a halogen atom, a linear or branched (C.sub.1-C.sub.6)alkyl group, a linear or branched (C.sub.1-C.sub.6)alkoxy group, a linear or branched (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy group, a hydroxyl group or a cyano group, is obtained by a hydroxylation reaction of a compound of formula (VII): ##STR00038## in a solvent in the presence of a metal transition complex and a base.

14. The process according to claim 13, wherein the metal transition complex is a palladium complex comprising a palladium catalyst and a ligand.

15. The process according to claim 14, wherein the reaction is carried out in the presence of at least 0.01 equivalent of palladium catalyst.

16. The process according to claim 14, wherein the reaction is carried out in the presence of at least 0.03 equivalent of ligand.

17. The process according to claim 13, wherein the base is a hydroxide salt.

18. The process according to claim 13, wherein the solvent is 1,4-dioxane or a mixture of water and 1,4-dioxane.

19. The process according to claim 13, wherein conversion of the compound of formula (VII) into the compound of formula (IV) is carried out directly without isolating compound of formula (VI).

20. A process for preparing a compound of formula (II): ##STR00039## wherein: R.sub.1 and R.sub.2, independently of one another, represent a halogen atom, a linear or branched (C.sub.1-C.sub.6)alkyl group, a linear or branched (C.sub.1-C.sub.6)alkoxy group, a linear or branched (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy group, a hydroxyl group or a cyano group, R.sub.3 represents a linear or branched (C.sub.1-C.sub.6)alkyl group, and R.sub.4 and R.sub.5 represent a hydrogen, a linear or branched (C.sub.1-C.sub.6)alkyl group, or R.sub.4 and R.sub.5, together with the oxygen atoms carrying them, form a ring which may be substituted by one to four linear or branched (C.sub.1-C.sub.6)alkyl group, comprising the step of reacting a compound of formula (I), which compound of formula (I) is obtained by the process according to claim 1: ##STR00040## with a boronic ester of formula (VIII): ##STR00041## wherein R represents a hydrogen atom, a hydroxy group, a linear or branched (C.sub.1-C.sub.6)alkoxy group, or a (C.sub.0-C.sub.6)alkyl-B(OR.sub.4)(OR.sub.5) group to yield the compound of formula (II).

21. The process according to claim 20, wherein the reaction consists of the action of the compound of formula (VIII), wherein R represents a hydrogen atom, a hydroxy group, or a linear or branched (C.sub.1-C.sub.6)alkoxy group, in an organic solvent or a mixture of organic solvents in the presence of a base.

22. The process according to claim 20, wherein the reaction consists of the action of the compound of formula (VIII), wherein R represents a (C.sub.0-C.sub.6)alkyl-B(OR.sub.4)(OR.sub.5) group, in an organic solvent or a mixture of organic solvents in the presence of a base and a palladium complex.

23. A process for preparing a compound of formula (II): ##STR00042## wherein: R.sub.1 and R.sub.2, independently of one another, represent a halogen atom, a linear or branched (C.sub.1-C.sub.6)alkyl group, a linear or branched (C.sub.1-C.sub.6)alkoxy group, a linear or branched (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy group, a hydroxyl group or a cyano group, R.sub.3 represents a linear or branched (C.sub.1-C.sub.6)alkyl group, and R.sub.4 and R.sub.5 represent a hydrogen, a linear or branched (C.sub.1-C.sub.6)alkyl group, or R.sub.4 and R.sub.5 form with the oxygen atoms carrying them a ring which may be substituted by one to four linear or branched (C.sub.1-C.sub.6)alkyl group, wherein a compound of formula (VII): ##STR00043## is subjected to a hydroxylation reaction in the presence of a metal transition complex and a base in a solvent, to yield a compound of formula (VI): ##STR00044## which compound of formula (VI) is subjected to a regioselective monobromination reaction, in the presence of a brominating agent in a solvent, to yield a compound of formula (IV): ##STR00045## which compound of formula (IV) is reacted in a solvent at high temperature in the presence of a base and a compound of formula (V): ##STR00046## wherein X.sup.− represents a monovalent anionic counter-ion, to yield a compound of formula (I): ##STR00047## which compound of formula (I) undergoes a borylation reaction in the presence of a boronic ester of formula (VIII): ##STR00048## wherein R represents a hydrogen atom, a hydroxy group, a linear or branched (C.sub.1-C.sub.6)alkoxy group, or a (C.sub.0-C.sub.6)alkyl-B(OR.sub.4)(OR.sub.5) group, to yield the compound of formula (II).

24. The process according to claim 20, wherein R.sub.1 represents a linear or branched (C.sub.1-C.sub.6)alkyl group, R.sub.2 represents a halogen atom and R.sub.3 represents a methyl group.

25. The process according to claim 2, wherein R.sub.1 and R.sub.3 represent a methyl group and R.sub.2 represents a chlorine atom.

26. The process according to claim 25, which further comprises converting the compound of formula (II) to 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethyoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]methoxy}phenyl)propanoic acid or 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

27. The process according to claim 5, wherein 1,4-diazabicyclo[2.2.2]octane is employed in the process to obtain the compound of formula (II), and wherein the process further comprises converting the compound of formula (II) to 2-{[5-{3-chloro-2methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]methoxy}phenyl)propanoic acid or 2-{[5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}-6-(4fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid.

Description

EXAMPLE 1: PREPARATION OF 2-CHLORO-3-METHYLPHENOL (HYDROXYLATION REACTION)

(1) A solution of 1-bromo-2-chloro-3-methylbenzene (5.00 g; 24.33 mmol) in dioxane (12.5 mL) and a solution of potassium hydroxide (2.25 g; 40.14 mmol) in water (12.5 mL) were degassed with nitrogen for 15 minutes. The solutions were combined. t-BuXPhos (827 mg; 1.95 mmol) and Pd.sub.2(dba.sub.3) (446 mg; 0.48 mmol) were added and the reaction mixture was heated in a sealed tube at 100° C. for 35 minutes. The reaction mixture was cooled to 20° C. and washed with tert-butyl methyl ether. The aqueous phase was back extracted with a 1 N NaOH solution, acidified to pH 4 with a 3 N hydrochloric acid solution and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated to provide the title compound as a pale yellow solid (2.8 g, 80% yield).

(2) .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 6.97-7.11 (m, 1H); 6.73-6.90 (m, 2H); 5.88 (brs, 1H); 2.37 (s, 3H)

EXAMPLE 2: PREPARATION OF 4-BROMO-2-CHLORO-3-METHYLPHENOL (REGIOSELECTIVE MONOBROMINATION REACTION)

(3) A solution of bromine (1089 g; 6.82 mol) in dichloromethane (1.94 L; 2 vol.) was added at 0° C. to a solution of 2-chloro-3-methylphenol (972 g; 6.82 mol), which can be obtained as described in Example 1 above, in a mixture of dichloromethane (5.35 L; 5.5 vol.) and acetic acid (2.43 L; 2.5 vol.). After stirring for 15 minutes at 0° C., the reaction mixture was warmed at room temperature and was washed with water and with a 5% KHCO.sub.3 solution then dried over sodium sulfate. After filtration, the product was obtained by concentration to dryness and was carried as is in the next step (1.44 kg; 95%).

(4) .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.35 (d, J=8.8 Hz, 1H); 6.78 (d, J=8.6 Hz, 1H); 5.64 (brs, 1H); 2.49 (s, 3H)

(5) .sup.13C NMR (101 MHz, CDCl.sub.3): δ ppm 150.7, 135.9, 131.2, 121.1, 115.3, 114.5, 20.8 LC-MS [ESI.sup.−] m/z: 219.0, 219.8 [M+H].sup.+

EXAMPLE 3: PREPARATION OF 4-BROMO-2-CHLORO-3-METHYLPHENOL (REGIOSELECTIVE MONOBROMINATION REACTION—OTHER CONDITIONS)

(6) A solution of brominating agent (1 eq.) in solvent was added at 0° C. to a solution of 2-chloro-3-methylphenol (100 mg) in solvent. After stirring for 15 minutes at 0° C., the reaction mixture was washed with water and with a 5% KHCO.sub.3 solution then dried over sodium sulfate. After filtration, the product was obtained by concentration to dryness and was carried as is in the next step. The structure of the expected product was confirmed by .sup.1H NMR and delta values are the same as the one found for Example 2 above.

(7) TABLE-US-00001 TABLE 1 Experimental conditions used for the preparation of 4-bromo-2-chloro-3-methylphenol Dilution Entry Brominating agent Solvent (vol) Yield 1 N-bromosuccinimide methanol + sulfuric acid 15 78% 2 bromine acetic acid 15 89% 3 bromine dichloromethane 15 83% 4 bromine acetic acid 25% v/v in 15 88% dichloromethane 5 bromine acetic acid 25% v/v in 10 92% dichloromethane

EXAMPLE 4: PREPARATION OF 4-BROMO-2-CHLORO-3-METHYLPHENOL (ONE-POT HYDROXYLATION AND REGIOSELECTIVE MONOBROMINATION REACTIONS)

(8) A solution of 1-bromo-2-chloro-3-methylbenzene (354 g; 1.72 mol) and potassium hydroxide (242 g; 4.30 mol) in 1,4-dioxane (710 mL; 2.0 vol.) and water (2150 mL; 6.0 vol.) was degassed, under stirring, with nitrogen for 15 minutes. t-BuXphos (29.2 g; 0.069 mol) and Pd.sub.2(dba).sub.3 (15.8 g; 0.017 mol) were added and the suspension was heated to reflux (90-95° C.) for 60 minutes. Reaction completion was confirmed by HPLC. The resulting suspension was cooled to 20-25° C. tert-Butyl methyl ether (800 mL) was added and the biphasic mixture was stirred for 10-15 minutes. The catalyst residue was removed by filtration over a pad of Celite and the cake was rinsed with tert-butyl methyl ether and 1 N potassium hydroxide solution. The aqueous phase was washed three times with tert-butyl methyl ether then was acidified to pH 1-2 with 12 N hydrochloric acid solution. The solution was extracted three times with dichloromethane then the volume of the solution was adjusted (1153 mL; 5.0 vol. relative to the phenol) with dichloromethane in order to telescope at the appropriate concentration with the next step. The concentration of 2-chloro-3-methylphenol in the solution was determined by quantitative GC-FID analysis (128.1 mg/mL; 230.6 g; 1.617 mol.).

(9) The solution of 2-chloro-3-methylphenol was charged to a 5.0 L reactor and acetic acid (584 mL; 2.5 vol. relative to the phenol) was added. The solution was then cooled to −10° C./−15° C. under nitrogen and a solution of bromine (258.5 g; 1.617 mol) in dichloromethane (477 mL; 2.1 vol. relative to the phenol) was added in 70 minutes between −13° C. and −7° C. Additional bromine (3.5 g; 0.022 mol) in dichloromethane (20 mL; 0.06 vol.) was added. Water (1.4 L) was added in 10 minutes between −11° C. and 2° C. The solution was warmed to 20-25° C. and sodium bisulfite (50 g; 0.48 mol) was added. The solution was stirred for 15-20 minutes. Phases were separated and then the aqueous phase was extracted with dichloromethane. Pooled organic phases were washed twice with water, twice with 10% potassium bicarbonate solution and brine. The solution was dried over magnesium sulfate. The cake was washed with dichloromethane. Solvents were evaporated under vacuum and residual 1,4-dioxane was azeotroped with heptanes to give the product of the title as a pale brown solid (353 g, crude yield: 92.6%).

(10) .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.35 (d, J=8.8 Hz, 1H); 6.78 (d, J=8.6 Hz, 1H); 5.64 (brs, 1H); 2.49 (s, 3H)

(11) .sup.13C NMR (101 MHz, CDCl.sub.3): δ ppm 150.7, 135.9, 131.2, 121.1, 115.3, 114.5, 20.8 LC-MS [ESI.sup.−] m/z: 219.0, 219.8 [M+H].sup.+

EXAMPLE 5: PREPARATION OF 1-[2-(4-BROMO-2-CHLORO-3-METHYLPHENOXY)ETHYL]-4-METHYLPIPERAZINE (RING-OPENING OF 1-ALKYL-1-AZONIABICYCLO[2.2.2]OCTANE)

(12) A solution of methyl 4-methylbenzene-1-sulfonate (592 g; 3.18 mol) in anisole (320 mL) was added over 15 minutes to a solution of 1,4-diazabicyclo[2.2.2]octane (389 g; 3.47 mol) in anisole (6.4 L). After stirring for 1 hour at 70° C., under vigorous agitation, Cs.sub.2CO.sub.3 (1130 g; 3.466 mol) was added portion wise over 5 minutes. A solution of 4-bromo-2-chloro-3-methylphenol (640 g; 2.89 mol), obtained as described in Examples 2 or 3 above, in anisole (0.64 L) was added over 10 minutes. The reaction mixture was stirred for 6 hours at 140° C. After cooling to room temperature, tert-butyl methyl ether and ethyl acetate were added and the mixture was washed with water and brine, dried with sodium sulfate and the resulting product solution was kept for the next step.

(13) A mixture of tert-butyl methyl ether (1.28 L) and ethanol (219 mL; 3.75 mol) was added over 30 minutes to a solution of acetyl chloride (272 g; 3.46 mol) keeping the temperature mixture below 25° C. After stirring for 30 minutes, the resulting solution was added to the organic phase obtained above over 1 hour at room temperature. After stirring the resulting suspension for 1 hour, the product was collected by filtration and washed with tert-butyl methyl ether. The solid was dissolved in dichloromethane and 1 N aqueous NaOH solution was added until alkaline. After separation, the aqueous layer was washed with dichloromethane and combined organic layers were dried with sodium sulfate and evaporated. After adding 2-methyltetrahydrofurane and filtration over a Celite pad, the cake was washed with 2-methyltetrahydrofurane and the solvent was evaporated to yield an amber oil (894 g; 89%).

(14) .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.33 (d, J=8.8 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 4.09 (t, J=5.8 Hz, 2H); 2.83 (t, J=5.8 Hz, 3H); 2.63 (brs, 4H); 2.47 (s, 4H); 2.37-2.45 (in, 2H); 2.25 (s, 3H)

EXAMPLE 6: PREPARATION OF 1-[2-(4-BROMO-2-CHLORO-3-METHYLPHENOXY)ETHYL]-4-METHYLPIPERAZINE AS MONOHYDROCHLORIDE SALT (RING-OPENING OF 1-ALKYL-1-AZONIABICYCLO[2.2.2]OCTANE)

(15) A solution of methyl 4-methylbenzene-1-sulfonate (435 g; 2.34 mol) in anisole (235 mL) was added over 15 minutes to a solution of 1,4-diazabicyclo[2.2.2]octane (286 g; 2.55 mol) in anisole (4.7 L). The white thick suspension was heated to 70° C. for 60 minutes. Cesium carbonate (831 g; 2.55 mol) was added in one portion then a solution or 4-bromo-2-chloro-3-methylphenol (470 g; 2.12 mol), obtained as described in Examples 2 or 3 above, in anisole (470 mL) was added in 12 minutes at 70° C. The brown suspension was heated to 140° C. for 6 hours and the reaction completion was confirmed by HPLC. Water, tert-butyl methyl ether and ethyl acetate were added and the biphasic mixture was stirred for 10 minutes. The layers were separated and then the aqueous phase was extracted with a 1:1 mixture of tert-butyl methyl ether and ethyl acetate. Pooled organic phases were washed with brine then dried over sodium sulfate for about 30 minutes. The suspension was filtered over a Buchner filter and then the cake was washed with tert-butyl methyl ether. The solution of free base was kept aside.

(16) Acetyl chloride (200 g; 2.55 mol) was added to a cooled (0-5° C.) mixture of ethanol (127 g; 2.76 mol) and tert-butyl methyl ether (940 mL) in 35 minutes between 3° C. and 12° C. The solution was stirred for 30 minutes then it was added to the solution of free base in 60 minutes between 20° C. and 25° C. The white suspension was stirred for 60 minutes at 20-25° C. then the solid was collected by filtration over a Buchner filter and the cake was washed twice with tert-butyl methyl ether. The cake was charged back in the flask and triturated in tert-butyl methyl ether for 60 minutes. The suspension was filtered over a Buchner filter and the cake was washed twice with tert-butyl methyl ether. The solid was dried under vacuum at 70-75° C. until constant weight was observed to give the product of the title as an off-white solid (761 g, yield: 93.2%) with a purity of 97.1% by GC-FID.

(17) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 11.10 (brs, 1H); 7.54 (d, J=8.8 Hz, 1H); 7.01 (d, J=9.1 Hz, 1H); 4.27 (brs, 2H); 3.39 (brs, 10H); 2.72 (brs, 3H); 2.44 (s, 3H)

EXAMPLE 7: PREPARATION OF 1-[2-(4-BROMO-2-CHLORO-3-METHYLPHENOXY)ETHYL]-4-METHYLPIPERAZINE AS DIHYDROCHLORIDE SALT

(18) In a 22 L round bottom flask setup in distillation mode, was charged 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine, HCl salt (1490 g; 3.88 mol), obtained as described in Example 6 above, and water (14.9 L). Water was partially distilled (2.98 L) to remove residual anisole by azeotrope at 50-55° C. and 40-45 Torr. The solution was cooled to 45° C. then 12 N hydrochloric acid (646 mL; 7.76 mol) was added in 5 minutes. The solution was allowed to cool slowly to 20-25° C. over the week-end. The suspension was then chilled to 0-5° C. and was filtered over a Buchner filter and the flask was rinsed with cold (0-5° C.) water (250 mL). The cake was washed twice with acetone. Solid was charged back in the flask and triturated in acetone for 90 minutes. The suspension was filtered over a Buchner filter and the cake was washed twice with acetone. The solid was dried under vacuum at 75-80° C. for 24 hours to give the product of the title as a white solid (1471 g, yield: 90.2%) with a purity of 99.9% by GC-FID.

(19) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 10.91-13.60 (m, 2H); 7.56 (d, J=8.8 Hz, 1H); 7.03 (d, J=9.1 Hz, 1H); 4.45 (brs, 2H); 3.58 (brs, 10H); 2.79 (brs, 3H); 2.44 (s, 3H)

(20) .sup.13C NMR (101 MHz, CD.sub.3OD), D.sub.2O): δ ppm 153.7, 137.9, 132.0, 124.6, 118.0, 113.7, 65.3, 56.9, 51.2, 50.8, 43.7, 20.8

EXAMPLE 8: PREPARATION OF 1-{2-[2-CHLORO-3-METHYL-4-(TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PHENOXY]ETHYL}-4-METHYLPIPERAZINE (BORYLATION REACTION)

(21) 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine (800.0 g; 2.30 mol), obtained as described in Example 5 (or obtained from transformation of Examples 6 or 7 into freebase), and 2-methyltetrahydrofurane (5.6 L) were charged to a 12 L three-necked round bottom flask under nitrogen. The solution was cooled to between −72° C. and −76° C. using an acetone-dry ice bath. A solution of 2.5M n-butyllithium in hexanes (1196 mL; 2.99 mol) was added over 1.5 hour, keeping the temperature between −62° C. and −74° C. The resulting yellow solution was stirred at between −72° C. and −76° C. for 1 hour. 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (556 g; 2.99 mol) was then added over 45 minutes, keeping the reaction mixture between −65° C. and −76° C. The reaction mixture was stirred at a temperature of −65° C. to −76° C. for 1 hour. Reaction completion was observed by HPLC. The reaction mixture was then warned to −25° C. Methanol (200 mL) was then added over 15 minutes. The solution was poured in a solution of ammonium chloride (369 g; 6.90 mol) in water (4 L). The phases were separated. The organic phase was washed with water and then directly evaporated to dryness to give colorless oil. Heptane (2.80 L) was added to dilute the oil at 35-40° C. and crystallization soon occurred. The suspension was stirred for 1 hour at 35-40° C., then cooled to 5° C. for 1 hour. The solids were collected by filtration, then washed with heptanes. The wet cake was dried under high vacuum at 40-50° C. until constant weight to give the product or the title as a white solid (2.200 kg, 85% yield over a total of 3 batches).

(22) .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.61 (d, J=8.3 Hz, 1H); 6.72 (d, J=8.3 Hz, 1H); 4.14 (t, J=5.9 Hz, 2H); 2.85 (t, J=5.9 Hz, 2H); 2.64 (brs, 3H); 2.58 (s, 4H); 2.38-2.50 (m, 4H); 2.25 (s, 3H); 1.30 (s, 12H)

EXAMPLE 9: PREPARATION OF 1-{2-[2-CHLORO-3-METHYL-4-(TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PHENOXY]ETHYL}-4-METHYLPIPERAZINE (MIYAURA-TYPE BORYLATION REACTION)

(23) A solution of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine (20.1 g; 58 mmol), obtained as described in Example 5 (or obtained from transformation of Examples 6 or 7 into freebase), in 1,4-dioxane (200 mL) was degassed with nitrogen during 20 minutes. Potassium acetate (19.3 g; 197 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (17.8 g; 70 mmol) were added and the suspension was degassed again for 20 minutes. Pd(PPh.sub.3).sub.2Cl.sub.2 (814 mg; 1.16 mmol) was added and the suspension was heated to 100° C. for two hours. Reaction completion was confirmed by HPLC. The suspension was cooled to 20-25° C. and toluene (100 mL) was added. The suspension was filtered over Celite (15 g) and the cake was rinsed with toluene (40 mL). Activated charcoal (4.0 g) was added to the solution and stirred for 1 hour. The suspension was filtered over Celite (15 g) and silica gel (15 g) then the cake was rinsed with toluene (40 mL). The solution was concentrated to dryness, heptane (100 mL) was added, concentrated to dryness and this operation was repeated once more. The residue was dissolved in heptane (150 mL) and treated with activated charcoal (4.0 g) for 60 minutes. The suspension was filtered over Celite (15 g) and the cake was rinsed twice with heptane (2×20 mL). The solution was concentrated to dryness, heptane (40 mL) was added to the residue and the product was crystallized at 20-25° C. over four hours. The suspension was cooled to 0-5° C. for one hour and the product was collected by filtration. The cake was washed with cold (0-5° C.) heptane (20 mL) and the solid was dried at 35-40° C. until constant weight to afford 10.1 g of product as a white solid. Mother liquors were concentrated to dryness then heptane (20 mL) was added to the residue and the product was crystallized at 20-25° C. over four hours. The suspension was cooled to 0-5° C. over one hour and the product was collected by filtration. The cake was washed with cold (0-5° C.) heptane (10 mL) then the solid was dried at 35-40° C. until constant weight to afford 5.6 g of product as a white solid. Two crops were combined to give a total of 15.7 g (69% yield).

(24) .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.64 (d, J=8.3 Hz, 1H); 6.76 (d, J=8.3 Hz, 1H); 4.18 (t, J=5.8 Hz, 2H); 2.88 (t, J=5.9 Hz, 2H); 2.25-2.83 (m, 14H); 1.34 (s, 12H)

EXAMPLE 10: PREPARATION OF 1-{2-[2-CHLORO-3-METHYL-4-(TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)PHENOXY]ETHYL}-4-METHYLPIPERAZINE (MIYAURA-TYPE BORYLATION REACTION)

(25) In a solution of 1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine dihydrochloride salt (1000 g; 1 eq.; obtained as described in Example 7) in ethyl acetate (10 vol.), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (784 g; 1.3 eq.), potassium acetate (1284 g; 5.5 eq.) and Pd(PPh.sub.3).sub.2Cl.sub.2 (50 g; 0.03 eq.) were added under nitrogen. Under stirring, the suspension was heated to reflux for 16 hours. After cooling to 20° C., the reaction mixture is then filtrated and cake was washed with ethyl acetate (1.5 vol). The organic layer is then washed with L-acetyl-cysteine aqueous solution at 5%, buffered at pH 7 with AcOK (10 vol.). After layers separation, organic layer was concentrated at 2 volumes and then proceeded to a solvent switch toward acetonitrile at 30° C. under vacuum. The temperature was then decreased to −10° C. and crystallization occurred. After filtration, the solid was dried at 40° C. to afford the product of the title as a white solid (48% yield).

(26) .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 7.64 (d, J=8.3 Hz, 1H); 6.76 (d, J=8.3 Hz, 1H); 4.18 (t, J=5.8 Hz, 2H); 2.88 (t, J=5.9 Hz, 2H); 2.25-2.83 (m, 14H); 1.34 (s, 12H)

EXAMPLE 11: PREPARATION OF 4-BROMO-2-CHLORO-3-METHYLPHENOL IN LARGE SCALE (ONE-POT HYDROXYLATION AND REGIOSELECTIVE MONOBROMINATION REACTIONS)

(27) In a reactor, water (390 L, 6.0 vol.) and potassium hydroxide (52.2 Kg, 790.8 mol) was added and dissolved. When the heat of dissolution was subsided, 1,4-dioxane (130 L, 2 vol.) and 3-bromo-2-chlorotoluene (65 Kg, 316.3 mol) was charged then, the solution was degassed, under stirring, with nitrogen for 30 minutes. t-BuXphos (5.38 Kg, 12.65 mol) and Pd.sub.2(dba).sub.3 (2.90 Kg, 3.16 mol) were added and the suspension was heated to reflux for 90 minutes. Reaction completion was confirmed by GC then the reaction mixture was cooled to 20˜25° C. t-Butylmethyl ether (146 L) was added and the biphasic mixture was stirred for 20 minutes. The reaction mixture was filtered over a Celite pad, the filter cake was rinsed with t-butylmethyl ether (39 L, 0.6 vol.) and 1 N potassium hydroxide solution (78 L, 1.2 vol.) then the phases were separated. The aqueous phase was washed three times with t-butylmethyl ether (3×110.5 L, 3×1.7 vol.) then was acidified to pH 1˜2 with 12 N hydrochloric acid under 25˜30° C. The solution was extracted three times with dichloromethane (1×110.5 L, 1.7 vol. and 2×42.3 L, 2×0.65 vol.). The combined organic layer was transferred to a reactor.

(28) Acetic acid (107.3 L, 1.65 vol.) was added to the solution of 2-chloro-3-methylphenol. The solution was cooled to −10˜−5° C. under nitrogen and a solution of bromine (51.1 Kg, 319.5 mol) in dichloromethane (88 L, 1.35 vol.) was added for 1.5 hours between −10° C. and −2° C. Water (260 L, 4.0 vol.) was added and the mixture was warmed to 20˜25° C. Sodium bisulfate (9.9 Kg, 94.9 mol) was added then the solution was stirred for 20 minutes. Phase was splitted then the aqueous phase extracted with dichloromethane. The combined organic phases were washed twice with water, twice with 10% potassium bicarbonate solution and 20% sodium chloride solution. The solution was dried over magnesium sulfate then filtered and the cake was washed with dichloromethane. The solvents were removed by vacuum distillation. The residual 1,4-dioxane was azeotroped with heptane to give 70.1 Kg of product of the title. (crude yield: 100.1%)

(29) .sup.1H NMR (600 MHz, CDCl.sub.3): 2.50 (s, 3H), 5.57 (s, 1H), 6.78 (d, 1H), 7.35 (d, 1H)

EXAMPLE 12: PREPARATION OF 1-[2-(4-BROMO-2-CHLORO-3-METHYLPHENOXY)ETHYL]-4-METHYLPIPERAZINE MONOHYDROCHLORIDE IN LARGE SCALE (RING-OPENING OF 1-ALKYL-1-AZONIABICYCLO[2.2.2]OCTANE)

(30) In a reactor, was charged anisole (701 L, 10.0 vol.) and 1,4-diazabicyclo[2.2.2]octane (42.6 Kg, 379.6 mol) and stirred under nitrogen. Methyl p-toluenesulfonate (64.8 Kg, 348.0 mol) was added by portions. The reaction mixture was heated to 70° C. for 1 hour. Cesium carbonate (123.7 Kg, 379.6 mol) was added in one portion then a solution of 4-bromo-2-chloro-3-methylphenol (70.1 Kg, 316.33 mol; obtained as described in Example 11) in anisole (50 Kg) was added at 70° C. The brown solution was heated to 140° C. for 6 hours and the reaction completion was confirmed by GC. After the reaction mixture was cooled to room temperature, water, t-butylmethyl ether and ethyl acetate were added and the biphasic solution was stirred for 10 minutes. The layers were separated and the organic phases were washed with 20% sodium chloride aqueous solution then dried over magnesium sulfate. The suspension was filtered over a Buchner filter and then the cake was washed with t-butylmethyl ether. The solution of free base was charged in a reactor and kept aside for later.

(31) In a reactor, t-butylmethyl ether (140.2 L, 2.0 vol.) and ethanol (19.0 Kg, 412.4 mol) was charged and cooled to 0˜5° C. Acetyl chloride (29.8 Kg, 379.6 mol) was added under 10˜15° C. The solution was stirred for 30 minutes then it was added to the solution of free base between 15° C. and 25° C. The white suspension was stirred for 60 minutes at 20˜25° C. then filtered with Buchner filter and the cake was washed with t-butylmethyl ether.

(32) The filter cake and t-butylmethyl ether were charged back in the reactor and stirred for 60 minutes. The suspension was filtered over a Buchner filter and the cake was washed with t-butylmethyl ether. The solid was dried under vacuum at 70˜75° C. for 16 hours to give the product of the title as an white solid (101 Kg, yield: 83.1%)

(33) .sup.1H NMR (600 MHz, DMSO-d.sub.6): 2.42 (s, 3H), 2.70 (s, 3H), 2.8-3.8 (br, 10H), 4.25 (br, 2H), 6.95 (d, 1H), 7.52 (d, 1H)

EXAMPLE 13: PREPARATION OF 1-[2-(4-BROMO-2-CHLORO-3-METHYLPHENOXY)ETHYL]-4-METHYLPIPERAZINE DIHYDROCHLORIDE IN LARGE SCALE

(34) In a reactor, was charged water (1010 L, 10 vol.) and 1-[2-(4-Bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine monohydrochloride (101 Kg, 262.9 mol; obtained as described in Example 12). Water was partially distilled to remove residual anisole by azeotrope at 45˜50° C. and 55˜60 Torr. 12 N Hydrochloric acid (43.8 L, 525.8 mol) was added to the aqueous solution at 45° C. The solution was cooled slowly to 15˜20° C. during 3 hours and stirred additionally for 12 hours. The suspension was filtered over Buchner filter and the cake was washed with cold water (17 L, 0.17 vol.) and acetone (200 L, 2 vol.). The solid was charged back to the reactor then acetone was added and the suspension was stirred for 60 minutes and filtered with Buchner filter. The filter cake was washed with acetone and dried under vacuum at 75˜80° C. for 24 hours to give the product of the title (99.5 Kg, 90.0%) as a white solid with a purity of 99.4% by GC-FID

(35) .sup.1H NMR (600 MHz, DMSO-d.sub.6): 2.43 (s, 3H), 2.78 (s, 3H), 3.2-3.9 (br, 10H), 4.47 (br, 2H), 7.02 (d, 1H), 7.56 (d, 1H)