The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

PREPARATION OF FIPAMEZOLE
INTRODUCTION
Aspects of the present patent application relate to processes for preparing fipamezole  its pharmaceutically acceptable salts  and intermediates thereof. In particular aspects it relates to processes for preparing fipamezole hydrochloride and to intermediates used in the processes.
The drug compound having the adopted name “fipamezole” has chemical names: 4-(2-ethyl-5-fluoro-2 3-dihydro-1H-inden-2-yl)-1H-imidazole; or 4-[(2 RS)-2-ethyl-5-fluoroindan-2-yl]-1H-imidazole; and is represented structurally by Formula I.

Formula I
Fipamezole is a highly selective and long-acting adrenergic alpha-2 receptor antagonist and is currently undergoing clinical trials to treat symptoms of advanced Parkinson""s disease such as dyskinesias  motor fluctuations and cognitive impairment. It has a good oral bioavailability and is useful in the treatment of cognitive disorders.
U.S. Patent No. 5 498 623 discloses substituted imidazole derivatives including fipamezole and pharmaceutically acceptable salts thereof. It also discloses a process for the preparation of fipamezole involving nitration of 4-(2-ethyl-2 3-dihydro-1H-inden-2-yl)-1H-imidazole with urea nitrate and concentrated sulfuric acid; reduction of the resulting nitro compound to an amino compound using PtO2; and reacting the amino compound with fluoroboric acid and sodium nitrite to obtain fipamezole  which is then converted to its hydrochloride salt.
International Application Publication No. WO 04/063168 A1 discloses a process for preparing fipamezole  in which an alkali metal thiocyanate is used for the formation of an imidazole ring.
There is a continuing need for new and improved processes for the preparation of fipamezole with high purity and yield.

SUMMARY
In an aspect  the present application relates to processes for the preparation of fipamezole or salts thereof  embodiments comprising:
a) reacting 5-fluoro-1-indanone of Formula II with a lower alkyl ester reagent  in the presence of a base  to form 1-(5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula III;

Formula II Formula III
b) reacting 1-(5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula III with an ethyl halide  in the presence of a base  to form 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV;

Formula IV
c) reducing 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV with a reducing reagent to form 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V;

Formula V
d) reacting 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V with a brominating agent to form 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula VI; and

Formula VI
e) converting 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone into fipamezole or a salt thereof  using formamide  optionally in the presence of ammonia.
In this multi-step process  each step is contemplated separately or in combinations of two or more steps for the preparation of fipamezole.
In an aspect  the present application provides processes for purifying fipamezole or a salt thereof  comprising:
a) providing a mixture of fipamezole or a salt thereof in an alcohol solvent;
b) combining the solution with a ketone anti-solvent and cooling to form a precipitate; and
c) recovering purified fipamezole or a salt thereof.
In an aspect the present application provides the intermediate compounds 1-(5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula III  and 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV  and their uses in the preparation of fipamezole or a salt thereof.

Formula III Formula IV
An aspect of the invention provides a process for preparing fipamezole or a salt thereof  comprising:
a) reacting 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV with a reducing reagent  to form 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V;

Formula IV Formula V
b) reacting 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V with a brominating agent  to form 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula VI; and

Formula VI
c) converting 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone into fipamezole or a salt thereof.
An aspect of the invention provides a process for the preparation of 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV  comprising:

Formula IV
a) reacting 5-fluoro-1-indanone of Formula II with a lower alkyl ester reagent  in the presence of a base  to form 1-(5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula III; and

Formula II Formula III
b) reacting 1-(5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula III with an ethyl halide  in the presence of a base  to form 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV.
An aspect of the invention provides a compound 1-(5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula III.

Formula III
An aspect of the invention provides a compound 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV.

Formula IV

DETAILED DESCRIPTION
In an aspect  the present application relates to processes for the preparation of fipamezole or a salt thereof  embodiments comprising:
a) reacting 5-fluoro-1-indanone of Formula II with a lower alkyl ester reagent  in the presence of a base  to form 1-(5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula III;

Formula II Formula III
b) reacting 1-(5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula III with an ethyl halide  in the presence of a base  to form 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV;

Formula IV
c) reducing 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV with a reducing reagent to form 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V;

Formula V
d) reacting 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V with a brominating agent to form 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula VI; and

Formula VI
e) converting 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone into fipamezole or a salt thereof  using formamide  optionally in the presence of ammonia.
Step a) involves a reaction of 5-fluoro-1-indanone of Formula II with a lower alkyl ester reagent  in the presence of a base  to form 1-(5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula III.
5-fluoro-1-indanone can be subjected to a Claisen condensation with a lower alkyl acetate in the presence of a base  to yield 2-acetyl-5-fluoro-indane-1-one.
Suitable lower alkyl esters that may be used in step a) include  without limitation thereto  ethyl acetate  n-propyl acetate  isopropyl acetate  n-butyl acetate  t-butyl acetate  and like.
Suitable bases that may be used in the reaction include  but are not limited to  sodium hydride  potassium hydride  sodium methoxide  sodium amide  and the like.
The reaction may be carried out in the presence of an inert solvent such as tetrahodrofuran (THF)  hydrocarbons  such as  for example  toluene  xylene and the like; and mixtures thereof; or the alkyl ester may be used as the solvent.
Suitably  the reaction may be carried out at temperatures ranging from about 20 to 70°C  or about 50 to 55°C.
It has been observed that a C-alkylated indanone is isolated exclusively with more than 75% yield  and substantially no O-alkylated product is observed in this reaction.
Step b) involves a reaction of 1-(5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula III with an ethyl halide  in the presence of a base  to form 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV.
Suitable ethyl halides that may be used include ethyl fluoride  ethyl chloride  ethyl bromide  and ethyl iodide.
Suitable bases that may be used include  but are not limited to: alkali metal hydroxides such as lithium hydroxide  sodium hydroxide  potassium hydroxide  and cesium hydroxide; alkaline metal hydroxides such as aluminum hydroxide  magnesium hydroxide  calcium hydroxide  and the like; alkali metal carbonates such as sodium carbonate  potassium carbonate  lithium carbonate  cesium carbonate  and the like; alkaline earth metal carbonates such as magnesium carbonate  calcium carbonate  and the like; and alkali metal bicarbonates such as sodium bicarbonate  potassium bicarbonate  and the like;
Suitable solvents that may be used in the reaction of step b) include  but are not limited to: polar aprotic solvents such as N N-dimethylformamide  N N-dimethylacetamide  N-methylpyrrolidone  pyridine  dimethylsulphoxide  sulpholane  formamide  acetamide  propanamide  and the like; tetrahydrofuran (THF); hydrocarbons  such as  for example  toluene and xylene; halogenated hydrocarbons  such as  for example  dichloromethane  dichloroethane  chloroform  chlorobenzene  and the like; and any mixtures thereof.
Suitably  the reaction may be carried out at temperatures ranging from about 20-70°C  or about 50-55°C.
After completion of the reaction  the reaction may be quenched by adding water slowly and then acidified with a mineral acid such as HCl. The product is extracted with a water immiscible organic solvent and the solvent is distilled to obtain the product as a residue.
Step c) involves reducing 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV with a reducing agent to form 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V.
The removal of the benzylic ketone of the halogenated aryl 1 3-diketone can be achieved by a chemo-selective hydrogenation reaction  carried out in a polar solvent in the presence of an acid.
Suitable reducing agents that may be used in the reaction of step c) include  but are not limited to  metal catalysts  such as  for example  nickel  platinum  palladium  iridium  ruthenium  and the like  in combination with hydrogen. These metal catalysts can be used in concentrations about 2-20% w/w  or 5-10% w/w  on an inert solid support such as charcoal or alumina.
Suitable solvents that may be used in the reaction of step c) include  but are not limited to: C1–6 straight chain or branched alcohols  such as  for example  methanol  ethanol  isopropanol  butanol  and the like; hydrocarbons  such as  for example  toluene  xylene  and the like; and any mixtures thereof.
The reaction may be carried out in the presence of an acid  such as  for example  hydrochloric acid  hydrobromic acid  sulphuric acid  phosphoric acid  acetic acid  and the like.
After completion of the reaction the catalyst may be removed by filtration. The organic layer containing the product may be distilled to obtain the product as a residue  or it may be used in the next step directly.
Step d) involves reacting 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V with a brominating agent  to form 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula VI.
Suitable brominating agents include liquid bromine  aqueous HBr  acetic acid HBr  N-bromosuccinamide (NBS)  and the like.
Suitable solvents that may be used in the reaction of step d) include  but are not limited to  C1–6 straight chain or branched alcohols  such as  for example  methanol  ethanol  isopropanol  butanol  and the like.
In an embodiment  2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone is prepared using bromine and methanol at a temperature in the range of about 0-40°C for about 2 to 6 hours  to minimize formation of a dibromo impurity.
Step e) involves converting 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone into fipamezole or a salt thereof  using formamide  optionally in the presence of ammonia.
In an embodiment  the conversion of 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone to fipamezole is carried out using formamide and ammonia.
In embodiments  suitable temperatures for the reaction range from about 70-180°C  or about 145-155°C  and the reaction is carried out for about 1 to 4 hours  or 1 to 2 hours. Longer times also can be used.
In a specific embodiment of the process  ammonia gas is sparged into a reaction mixture comprising 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone and formamide at 150-155°C  for about 1 to 2 hours.
After completion of the reaction  the reaction mixture is cooled to 0-10°C and pH may be adjusted to about 2-3  using concentrated HCl. The reaction mixture is washed with a water immiscible solvent  such as dichloromethane. The aqueous layer is made basic with aqueous ammonia and the product is extracted with an organic solvent  such as ethyl acetate. The organic layer may be concentrated to obtain a residue  or it may be used directly in the next step.
Fipamezole that is obtained may be converted into a pharmaceutically acceptable salt by reaction with an acid in a suitable solvent  such as  for example  acetone  methyl ethyl ketone  methyl isobutyl ketone  methanol  ethanol  isopropanol  and the like.
Pharmaceutically acceptable acids include hydrochloric acid  hydrobromic acid  sulphuric acid  phosphoric acid  acetic acid  and many others.
In this multi-step process  each step is contemplated separately or in combinations of any two or more steps  for the preparation of fipamezole.
In an aspect  the present application also provides processes for purifying fipamezole or a salt thereof  embodiments comprising:
a) providing a mixture of fipamezole or a salt thereof in an alcohol solvent;
b) combining the solution with a ketone anti-solvent and then cooling the mixture to form a precipitate; and
c) recovering purified fipamezole or a salt thereof.
The step of providing a solution includes dissolving fipamezole or a salt thereof in an alcohol solvent  or obtaining a solution from a step in which fipemazole is synthesized. Any forms of fipamezole or a salt thereof  such as crystalline forms  amorphous form  or mixtures of amorphous and crystalline forms in any proportions  obtained by any method  are acceptable for forming the solution.
Suitable alcohol solvents that may be used include C1–6 straight chain or branched alcohols  such as  for example  methanol  ethanol  isopropanol  butanol  and the like.
Suitable ketone anti-solvents include acetone  methyl ethyl ketone  methyl isobutyl ketone  and the like.
In embodiments  the mixtures of fipamezole and alcohol are provided at the reflux temperature of the alcohol solvent used. The ketone anti-solvent may be added at reflux or at a lower temperature. Alternatively  the solution can be added to a ketone anti-solvent  at any temperatures up to the boiling point. The solution is then cooled to temperatures ranging about 0-30°C  or 20-25°C.
The method by which a solid material is collected from the final mixture can be any of techniques such as decantation  filtration by gravity or by suction  centrifugation  and the like. The solid so isolated can carry a small proportion of occluded mother liquor. If desired  the solid can be washed with a suitable solvent or mixtures of solvents in various proportions to wash out the mother liquor.
Drying can be suitably carried out using equipment such as a tray dryer  vacuum oven  air oven  fluidized bed dryer  spin flash dryer  flash dryer and the like. The drying may be carried out at temperatures about 35°C to about 70°C. The drying can be carried out for any time periods necessary for obtaining a desired purity  such as from about 1 to about 25 hours  or longer.
In embodiments  there is provided fipamezole or a salt thereof having high purity  containing less than about 0.5%  or less than about 0.1%  by weight of process-related impurities  as characterized using techniques such as high performance liquid chromatography (“HPLC”).
In aspects  the present application provides the intermediate compounds 1-(5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula III  and 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV  and their uses in the preparation of fipamezole or a salt thereof.

Formula III Formula IV
In an aspect  the present application also includes pharmaceutical formulations comprising fipamezole or a pharmaceutically acceptable salt thereof  prepared by a process of the present application  together with one or more pharmaceutically acceptable excipients.
Certain specific aspects and embodiments of this disclosure are described in the examples below  which are provided only for the purpose of illustration and are not intended to limit the scope of the disclosure in any manner.

EXAMPLE 1: Preparation of 5-fluoro-1-indanone (Formula II).
A) Preparation of 3-chloro-1-(4-fluorophenyl)-propan-1-one.
AlCl3 (9.02 g) and dichloromethane (DCM  50 mL) are charged into a round bottomed flask under a nitrogen atmosphere. Chloropropionyl chloride (7.93 g) is added over 20 minutes at 25-30°C. Fluorobenzene (5 g) is added over about 15 minutes at 30°C. The mixture is maintained at 25-30°C for about 12 hours. After reaction completion  water (50 mL) is added slowly and the mixture is stirred for 15 minutes. The aqueous layer is separated and extracted with DCM (50 mL). The combined organic layers are dried with sodium sulphate and distilled under vacuum below 50°C. n-Hexane (15 mL) is added to the residue and stirred for 20 minutes. The solid is filtered and washed with 10 mL of n-hexane (10 mL). The wet solid is dried  to obtain 6.9 g of 3-chloro-1-(4-fluorophenyl)-propan-1-one.
B) Preparation of 5-fluoro-1-indanone (Formula II).
3-Chloro-1-(4-fluorophenyl)-propan-1-one (10 g) and concentrated sulfuric acid (60 mL) are charged into a 250 mL round bottom flask equipped with nitrogen gas flow and heated to 120°C. The mixture is stirred for about 30 minutes at 115-120°C. Reaction completion is confirmed using thin layer chromatography (TLC). The reaction mixture is poured into ice water (30 mL) followed by stirring for about 15 minutes. The mass is extracted with chloroform (150 mL) and the organic layer is concentrated under reduced pressure below 50°C. The obtained residue is purified by column chromatography using silica gel and n-hexane/ethyl acetate as a gradient eluent  to obtain 3.7 g of the title compound.

EXAMPLE 2: Preparation of 2-acetyl-5-fluoroindan-1-one (Formula III).
Into a 250 mL round bottom flask equipped with nitrogen gas flow are placed sodium hydride (1.6 g  60% dispersion in mineral oil)  THF (15 mL)  5-fluoro-1-indanone (3 g)  and ethyl acetate (3.52 g)  and the mixture is stirred at 30°C for about 15 minutes. The mixture is heated to 50°C and maintained for about 3 hours under a nitrogen atmosphere. After reaction completion  the mixture is cooled to 30°C  ice water (40 mL) is added  and pH is adjusted to about 5 using 10% aqueous HCl (4 mL). The mixture is extracted with ethyl acetate (90 mL) and the organic layer is concentrated under reduced pressure below 55°C. Isopropanol (15 mL) is added to the residue and stirred for about 1 hour at 30°C. The solid is filtered and washed with isopropanol (15 mL)  to obtain 2.3 g of the title compound as a solid.
1HNMR (CDCl3  400 MHz): 2.16(s  3H)  3.52(s  2H)  7.0-7.89(3H  m  ArH)  14.52-14.90 (s  CH-OH).
Mass: M+1 (M.Wt.: 193).

EXAMPLE 3: Preparation of 2-acetyl-2-ethyl-5-fluoroindan-1-one (Formula IV).
Into a 500 mL round bottom flask equipped with nitrogen gas flow  potassium carbonate (18.03 g)  DMF (125 mL)  and 2-acetyl-5-fluoro-indan-1-one (25 g) are charged and stirred for about 10 minutes at 25-35°C. The mixture is heated to 50-55°C and maintained for about 1 hour  to form an off-white anion complex. Ethyl iodide (24.5 g) is added and the mixture is maintained for about 6 hours at 50-55°C. After reaction completion  the mixture is cooled to 25-35°C. The mixture is filtered to remove solid material. Water (250 mL) is added to the filtrate and pH is adjusted to about 3 with concentrated HCl (25 mL). The product is extracted with toluene (375 mL) and the organic layer is washed with water (125 mL). The organic layer is concentrated under reduced pressure below 55°C. The residue obtained is purified by column chromatography  using silica gel and 3% ethyl acetate in n-hexane as the mobile phase  to obtain 21 g of the title compound.
Purity by GC: 98.6%.
1HNMR (CDCl3  400 MHz): 0.830(t  3H)  1.805(q  2H)  2.188(s  1H)  2.83-2.93 (2H  dd  the indan ring H2-1 or H2-3)  6.80-7.08 (3H  m  ArH).
Mass: M+1 (M.Wt.: 220).

EXAMPLE 4: Preparation of 2-(2-ethyl-5-fluoroindan-2-yl)-ethanone (Formula V).
Palladium on charcoal (5% by weight  5 g )  ethanol (100 mL)  acetic acid (50 mL)  and 2-acetyl-2-ethyl-5-fluoro-indan-1-one (5 g) are charged into a stainless steel vessel at 25-35°C. The mixture is maintained at 50-60°C under 340-415 kPa (50-60 psi) hydrogen pressure for about 6 hours. Reaction completion is confirmed using TLC. The mixture is filtered and the filtrate is concentrated under reduced pressure below 50°C  to obtain 4.6 g of the title compound.
1HNMR (CDCL3  400 MHz): 0.830(t  3H)  1.805(q  2H)  2.188(s  1H)  2.83-2.93 (2H  dd  the indan ring H2-1 or H2-3)  3.35-3.46 (2H  dd  the indan ring H2-1 or H2-3)  6.80-7.02-7 (3H  m  Ar-H).
Mass: M+1 (M.Wt.: 206).

EXAMPLE 5: Preparation of 2-bromo-1-(2-ethyl-5-fluoroindan-2-yl) ethanone (Formula VI).
Methanol (30 mL) and 2-(2-ethyl-5-fluoroindan-2-yl)-ethanone (5 g) are charged into a 250 mL round bottom flask equipped with nitrogen gas flow and the mixture is cooled to -10°C to 0°C. A mixture of bromine (3.9 g) and methanol (12.5 mL) is slowly added at -5°C to 0°C. The mixture is stirred for about 4 hours. After completion of the reaction  water (25 mL) and sodium sulfite (1.25 g) are added and the mixture is allowed to reach 30°C and stirred for about 10 minutes. The mixture is extracted with toluene (37.5 mL) and the organic layer is washed with aqueous sodium bicarbonate solution (10%  25 mL). The organic layer is concentrated under reduced pressure below 55°C. The residue obtained is purified by column chromatography using silica gel and ethyl acetate/n-Hexane as a mobile phase  to obtain 4.2 g of the title compound.

EXAMPLE 6: Preparation of fipamezole hydrochloride.
Formamide (12 mL) and 2-bromo-1-(2-ethyl-5-fluoroindan-2-yl) ethanone (4 g) are charged into a 100 mL round bottom flask equipped with nitrogen gas flow and the mixture is heated to about 150°C. The mixture is stirred for about 3 hours and then ammonia gas is sparged into the reaction mixture for about 2 hours at 150-155°C. After completion of the reaction  the mixture is cooled to 0-5°C and water (20 mL) is added. The pH is adjusted to about 2 using concentrated HCl (4 mL). The mixture is allowed to reach 25-35°C and is washed with dichloromethane (8 mL). The aqueous layer pH is adjusted to about 9-10 using aqueous ammonia solution (25%  8 mL) and the aqueous layer is extracted with ethyl acetate (40 mL). The organic layer is separated and washed with water (20 mL) and aqueous sodium chloride solution (10%  50 mL). The organic layer is concentrated under reduced pressure below 55°C  to obtain 3.1 g of residue.
Hydrogen chloride in ethanol (7% w/v  31 mL) is added to the residue and stirred for about 1 hour at 25-30°C. The mixture is concentrated under reduced pressure below 55°C  to obtain 3.2 g of fipamezole HCl.
Purity by HPLC: 98.94%.

EXAMPLE 7: Purification of fipamezole hydrochloride.
Isopropyl alcohol (9.6 mL) and fipamezole HCl from Example 6 (3.2 g) are charged into a 100 mL round bottom flask equipped with nitrogen gas flow and the mixture is heated to reflux. The mixture is stirred for about 40 minutes and then acetone (32 mL) is added at reflux temperature. The mixture is then cooled to 25-30°C and stirring is continued for about 6 hours. The formed solid is filtered and washed with cold acetone. The wet solid is dried  to produce 2.1 g of purified fipamezole HCl as a white solid.
Purity by HPLC: 99.8%.

EXAMPLE 8: Preparation of 5-fluoro-1-indanone (Formula II).
A) Preparation of 3-fluorocinnamic acid.
Malonic acid (15 g)  pyridine (35 mL)  and 4-fluorobenzaldehyde (10 g) are charged into a 500 mL round bottom flask equipped with nitrogen gas flow at 25°C. Piperidine (0.6 g) is added and the mixture is stirred for 10 minutes at 25-35°C. The mixture is heated to 110°C and stirred for about 5 hours at 110-115°C. After completion of the reaction  the mixture is cooled to 25°C and the reaction is quenched by adding a mixture of ice water (210 mL) and concentrated HCl (56 mL). The mixture is stirred for about 15 minutes. The obtained solid is filtered and washed with water (20 mL). The wet solid is charged into a flask containing a mixture of water (132 mL) and methanol (66 mL) and heated to 60°C. The mixture is stirred for about 30 minutes and then cooled to 25-35°C. The solid is filtered and dried below 50°C  to obtain 12 g of 3-fluorocinnamic acid as a solid.
B) Preparation of 3-(3-fluorophenyl)propanoic acid.
Palladium on charcoal (5% w/w  2.5 g)  methanol (50 mL)  THF (50 mL)  and 3-fluorocinnamic acid (10 g) are charged into a stainless steel vessel at 25-35°C. The mixture is maintained at 25-35°C under 415-485 kPa (60-70 psi) hydrogen pressure for about 4 hours. Reaction completion is confirmed using TLC. The mixture is filtered and the solid washed with THF (25 mL). The filtrate is concentrated under reduced pressure below 50°C  to obtain 10 g of 3-(3-fluorophenyl)propanoic acid.
C) Preparation of 5-fluoro-1-indanone (Formula II).
Polyphosphoric acid (200 g) is charged into a 500 mL round bottom flask equipped with nitrogen gas flow and heated to about 90°C. 3-(3-Fluorophenyl)propanoic acid (10 g) is added at 90°C and the mixture is further heated to 110°C. The mixture is stirred for about 30 minutes at 100-110°C. After completion of the reaction  the mixture is cooled to 0-5°C and cold water (1000 mL) is added. The mixture is extracted with ethyl acetate (200 mL). The organic layer is separated and washed with aqueous sodium bicarbonate solution (10%  100 mL). The organic layer is concentrated under reduced pressure below 55°C  to obtain 8.5 g of the title compound as a solid.

WE CLAIM:

1. A process for preparing fipamezole or salt thereof  comprising
a) reacting 1-(2-ethyl-5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula IV with a reducing reagent  to form 1-(2-ethyl-5-fluoro-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula V;

Formula IV Formula V
b) reacting 1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula V with a brominating agent  to form 2-bromo-1-(2-ethyl-5-fluoro-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula VI; and

Formula VI
c) converting 2-bromo-1-(2-ethyl-5-fluoro-2 3 dihydro-1H-2-indenyl)-1-ethanone into fipamezole or a salt thereof.

2. The process of claim 1  wherein a reducing agent comprises a metal catalyst in combination with hydrogen.

3. The process of claim 2  wherein a metal catalyst comprises nickel  platinum  palladium  iridium and ruthenium.

4. The process of claim 2  wherein a metal catalyst is present on a solid inert support.

5. The process of claim 1  wherein converting of c) comprises reacting with formamide  optionally in the presence of ammonia.

6. A process for the preparation of 1-(2-ethyl-5-fluoro-1 -oxo-2 3-dihydro-1-H-2-indenyl)-1-ethanone of Formula IV  comprising:

Formula IV
a) reacting 5-fluoro-1-indanone of Formula Il with a lower alkyl ester reagent  in the presence of a base  to form 1 -(5-fluoro-1-oxo-2 3-dihydro-1H-2-indenyl)-1-ethanone of Formula III; and

Formula II Formula III
b) reacting 1-(5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula III with an ethyl halide  in the presence of a base  to form 1-(2-ethyl-5-fluoro-1-oxo-2 3 dihydro-1H-2-indenyl)-1-ethanone of Formula IV.

7. The process of claim 6  wherein a lower alkyl ester reagent comprises ethyl acetate  n-propyl acetate  isopropyl acetate  n-butyl acetate  or t-butyl acetate.

8. The process of claim 6  wherein a base in a) comprises sodium hydride  potassium hydride  sodium methoxide  or sodium amide.

9. The process of claim 6  wherein an ethyl halide comprises ethyl fluoride  ethyl chloride  ethyl bromide  or ethyl iodide.

10. The process of claim 12  wherein a base used in b) comprises an alkali metal hydroxide  alkaline metal hydroxide  alkali metal carbonate  alkaline earth metal carbonate  or alkali metal bicarbonate.

11. A process for purifying fipamezole or a salt thereof  comprising:
a) providing a solution of fipamezole or a salt thereof in an alcohol solvent;
b) combining the solution with a ketone anti-solvent and cooling to form a precipitate; and
c) recovering purified fipamezole or a salt thereof.

12. The process of claim 11  wherein an alcohol solvent comprises a C-1-6 straight chain or branched alcohol.

13. The process of claim 11  wherein a ketone anti-solvent comprises acetone  methyl ethyl ketone  or methyl isobutyl ketone.

14. The process of claim 11  wherein a purified fipamezole or salt thereof contains less than about 0.5% by weight of process-related impurities.

15. A compound 1-(5-fluoro-1 -oxo-2 3-dihydro-1H-2-indenyl)-1 -ethanone of Formula III.

Formula III

16. A compound 1-(2-ethyl-5-fluoro-1 -oxo-2 3 dihydro-1H-2-indenyl)-1 -ethanone of Formula IV.

Formula IV