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WO2016071723A1 - Process for the preparation of a fluspirilene intermediate - Google Patents

Process for the preparation of a fluspirilene intermediate Download PDF

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WO2016071723A1
WO2016071723A1 PCT/IB2014/002330 IB2014002330W WO2016071723A1 WO 2016071723 A1 WO2016071723 A1 WO 2016071723A1 IB 2014002330 W IB2014002330 W IB 2014002330W WO 2016071723 A1 WO2016071723 A1 WO 2016071723A1
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compound
process according
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Lazzaro Feliciani
Enrico Viscardi
Giuseppe CREMONESI
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Sifavitor SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
    • C07C29/10—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of ethers, including cyclic ethers, e.g. oxiranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/17—Unsaturated ethers containing halogen
    • C07C43/174—Unsaturated ethers containing halogen containing six-membered aromatic rings
    • C07C43/176—Unsaturated ethers containing halogen containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1786—Unsaturated ethers containing hydroxy or O-metal groups containing halogen

Definitions

  • the present invention relates to a process for the preparation of a 4,4'- bis(fluorobenzene) derivative, which is an intermediate compound in the synthesis of some drugs, for example in the synthesis of fluspirilene.
  • the invention further relates to new synthetic intermediate compounds.
  • Fluspirilene is a synthetic compound used as an antipsychotic drug in the treatment of schizophrenia.
  • the present invention relates to a process for the preparation of a compound of formula (I)
  • X is a leaving group, which comprises the following steps:
  • leaving group is well known to the skilled in the art; preferred leaving groups according to the invention are halogens, such as bromine or chlorine; a mesyl group or a tosyl group.
  • Y is a halogen selected from bromine and chlorine, preferably chlorine.
  • X and Y are both chlorine.
  • the Grignard reaction of step (a) is a known reaction and may be carried out in the presence of magnesium and an organic aprotic solvent, preferably an organic aprotic polar solvent, such as a cyclic ether, for instance tetrahydrofuran (THF), 2-methyl- tetrahydrofuran (2-MeTHF) or an aliphatic ether, for example diethyl ether or cyclopentyl methyl ether.
  • an organic aprotic solvent preferably an organic aprotic polar solvent, such as a cyclic ether, for instance tetrahydrofuran (THF), 2-methyl- tetrahydrofuran (2-MeTHF) or an aliphatic ether, for example diethyl ether or cyclopentyl methyl ether.
  • step (b) may be carried out with any reagent suitable to remove the hydroxy group and form a double bond such as, for instance, p- tolensulfonic acid or sulfuric acid in an appropriate organic solvent, including toluene or cyclohexane or dichloro methane, toluene being the preferred solvent.
  • any reagent suitable to remove the hydroxy group and form a double bond such as, for instance, p- tolensulfonic acid or sulfuric acid in an appropriate organic solvent, including toluene or cyclohexane or dichloro methane, toluene being the preferred solvent.
  • the benzyl group may be removed by a reduction reaction, for example by hydrogenating the compound of formula (III) with gaseous hydrogen in the presence of a conventional catalyst, such as palladium on charcoal (Pd/C), in an organic solvent including a lower alcohol, such as C 1 -C 4 -alcohol, for instance in methanol, ethanol, isopropanol or a cyclic or aliphatic ether, such as THF, 2MeTHF, or in aromatic organic solvent as toluene.
  • a conventional catalyst such as palladium on charcoal (Pd/C)
  • an organic solvent including a lower alcohol, such as C 1 -C 4 -alcohol for instance in methanol, ethanol, isopropanol or a cyclic or aliphatic ether, such as THF, 2MeTHF, or in aromatic organic solvent as toluene.
  • a conventional catalyst such as palladium on charcoal (Pd/C)
  • Step (d) may be performed by using any appropriate agent which introduce the leaving group, such as mesyl-chloride, tosyl-chloride, brominating agent such as N- bromosuccinimide, or chlorinating agents.
  • agent which introduce the leaving group such as mesyl-chloride, tosyl-chloride, brominating agent such as N- bromosuccinimide, or chlorinating agents.
  • appropriate chlorinating agents include thionyl chloride, phosphorus tri- or penta- chloride and the like, thionyl chloride being preferred.
  • the compound of formula (I) obtained in step (d) may be isolated according to any conventional method and, if desired or necessary, it may be purified according to the known techniques.
  • the compounds obtained by the steps of the above process were isolated and characterized.
  • compounds of formula (III) and (IV) are new compounds and represent another aspect of the invention. These compounds can be used as versatile synthetic intermediates.
  • the subject-matter of the invention is a process for the preparation of 4,4'-(4-chlorobutane-l,l-diyl)bis(fluorobenzene) of formula (!') ⁇
  • a preferred subject-matter of the invention is a process for the preparation of 4,4'-(4- chlorobutane-l,l-diyl)bis(fluorobenzene) of formula (P) above, which comprises the following steps:
  • step (c) or (c') compound of formula (V) may be isolated, and if necessary purified.
  • Compound of formula (V) is a known and interesting synthetic intermediate that can be used in the preparation of different drugs.
  • step (a) or (a') are performed in inert conditions, for instance under nitrogen or argon, at the reflux temperature of the reaction mixture.
  • the reaction is usually completed in a few hours, such as 1 to 3 hours.
  • step (b) or (b') are performed in inert conditions, for instance under nitrogen or argon, at the reflux temperature of the reaction mixture.
  • the reaction is usually completed in a few hours, such as 1 to 3 hours.
  • step (c') is performed at room temperature (approx 25°C) at a pressure of approx 3-5 bar.
  • the reaction is usually completed in about 12-30 hours.
  • step (d) or (d') are performed in inert conditions, for instance under nitrogen or argon, at approx. 70-90°C.
  • the reaction is usually completed in a few hours, such as 1 to 3 hours.
  • Compound of formula (I) may then be purified by distillation at approx. 170-180°C/l-2 mBar.
  • the process of the invention provides interesting chemical intermediates, by carrying out industrially expedient reaction steps.
  • the whole process may be carried out without the need to isolate and purify the intermediate compounds, providing nevertheless a final compound, especially 4,4'-(4-chlorobutane-l,l-diyl)bis(fluorobenzene), showing a very high purity.
  • This fact is another remarkable advantage for the industrial bulk production.
  • the process of the invention therefore represents an important technical progress in the field of chemical intermediate for drugs.
  • GC GC Agilent 6890N Supelco SPBTM-5 30 m x 0.32mm x 1.0mm, 5% diphenyl / 95% dimethylpolysiloxane; FID temperature: 265°C, oven temperature: initial temperature: 50°C, initial time: 0 min, program rate 1 : 25°C/min, final temperature 1: 185°C, final hold time 1: 50 min, program rate 2: 5°C/min, final temperature 2: 260°C, final hold time 2: 20 min).
  • Example 2 The mixture was cooled to room temperature and quenched in a mixture of 1 lOg of acetic acid, 660 ml of toluene and 780 ml of water, keeping the temperature below 30°C. The aqueous phase was discarded. The organic phase was washed with water (2 x 170 ml) and evaporated to give a yellow oil. The product was used with no further purification in Example 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a process for the preparation of a 4,4'- bis(fluorobenzene) derivative, which is an intermediate compound in the synthesis of some drugs, for example in the synthesis of fluspirilene. The invention further relates to new synthetic intermediate compounds.

Description

Process for the preparation of a fluspirilene intermediate Summary of the invention
The present invention relates to a process for the preparation of a 4,4'- bis(fluorobenzene) derivative, which is an intermediate compound in the synthesis of some drugs, for example in the synthesis of fluspirilene. The invention further relates to new synthetic intermediate compounds.
Technical background
Fluspirilene is a synthetic compound used as an antipsychotic drug in the treatment of schizophrenia.
One of the key intermediates in fluspirilene synthesis is a 4,4'-(4-chlorobutane-l,l- diyl)bis(fluorobenzene) derivative bearing a leaving group on the butane moiety, especially a compound of formula I)
Figure imgf000002_0001
especially 4,4'-(4-chlorobutane-l,l-diyl)bis(fluorobenzene). The above compounds are known long since, especially the chlorine derivative. Nevertheless, there is a need to find synthetic routes for the preparation of compound of formula (I), which are simple, economic and industrially convenient.
Aims of the invention
It is an aim of the invention to provide compounds of formula (I) above, especially 4,4'-(4-chlorobutane-l,l-diyl)bis(fluorobenzene), with high yields and purity.
It is a further aim of the invention to provide a new synthetic process for the preparation of compounds of formula (I) above, especially 4,4'-(4-chlorobutane-l,l- diyl)bis(fiuorobenzene), which are suitable for an industrial bulk production.
It is yet a further aim of the invention to provide a process which does not necessarily need to isolate the intermediate compounds of the synthesis steps, thus resulting in a cost-effective industrial process.
Description of the invention The present invention relates to a process for the preparation of a compound of formula (I)
Figure imgf000003_0001
wherein X is a leaving group, which comprises the following steps:
a. carrying out a Grignard reaction on 4,4'-difluorobenzofenone with a compound of formula (II)
Figure imgf000003_0002
wherein Y is halogen, in the presence of magnesium, in an organic solvent, providing the com ound of formula (III)
Figure imgf000003_0003
b. dehydrating the compound of formula (III), thus obtaining the compound of formula (IV)
Figure imgf000003_0004
c. removing the benzyl group from the compound of formula (IV) and concurrently hydrogenating it, providing the compound of formula (V)
Figure imgf000003_0005
d. converting the compound of formula (V) into the compound of formula (I) and, optionally, isolating it.
The term "leaving group" is well known to the skilled in the art; preferred leaving groups according to the invention are halogens, such as bromine or chlorine; a mesyl group or a tosyl group.
According to a preferred embodiment of the invention, Y is a halogen selected from bromine and chlorine, preferably chlorine.
According to a preferred embodiment, X and Y are both chlorine.
The Grignard reaction of step (a) is a known reaction and may be carried out in the presence of magnesium and an organic aprotic solvent, preferably an organic aprotic polar solvent, such as a cyclic ether, for instance tetrahydrofuran (THF), 2-methyl- tetrahydrofuran (2-MeTHF) or an aliphatic ether, for example diethyl ether or cyclopentyl methyl ether.
The dehydration reaction of step (b) may be carried out with any reagent suitable to remove the hydroxy group and form a double bond such as, for instance, p- tolensulfonic acid or sulfuric acid in an appropriate organic solvent, including toluene or cyclohexane or dichloro methane, toluene being the preferred solvent. In step (c), the benzyl group may be removed by a reduction reaction, for example by hydrogenating the compound of formula (III) with gaseous hydrogen in the presence of a conventional catalyst, such as palladium on charcoal (Pd/C), in an organic solvent including a lower alcohol, such as C1-C4-alcohol, for instance in methanol, ethanol, isopropanol or a cyclic or aliphatic ether, such as THF, 2MeTHF, or in aromatic organic solvent as toluene. The double bond is concurrently hydrogenated. Step (d) may be performed by using any appropriate agent which introduce the leaving group, such as mesyl-chloride, tosyl-chloride, brominating agent such as N- bromosuccinimide, or chlorinating agents. For instance, when X is chlorine, appropriate chlorinating agents include thionyl chloride, phosphorus tri- or penta- chloride and the like, thionyl chloride being preferred.
The compound of formula (I) obtained in step (d) may be isolated according to any conventional method and, if desired or necessary, it may be purified according to the known techniques. The compounds obtained by the steps of the above process were isolated and characterized. In particular, compounds of formula (III) and (IV) are new compounds and represent another aspect of the invention. These compounds can be used as versatile synthetic intermediates.
However, it was surprisingly noticed that the whole process may be carried out without the need to isolate and purify any of the intermediate compounds, said possibility making the process particularly interesting from an industrial point of view.
Indeed, even if no intermediate compound is isolated and purified, it was unexpectedly found that the final purity of the compound of formula (I) is nevertheless acceptable and a simple purification such as a distillation, allows to obtain the compound with a very high purity, even higher than 98% (by Gas Chromatography).
According to a preferred embodiment, the subject-matter of the invention is a process for the preparation of 4,4'-(4-chlorobutane-l,l-diyl)bis(fluorobenzene) of formula (!')·
Figure imgf000005_0001
A preferred subject-matter of the invention is a process for the preparation of 4,4'-(4- chlorobutane-l,l-diyl)bis(fluorobenzene) of formula (P) above, which comprises the following steps:
a'. carrying out a Grignard reaction on 4,4'-difluorobenzofenone with 1- (benzyloxy)-3-chloropropane of formula IP)
Figure imgf000005_0002
in the presence of magnesium, in THF, providing the compound of formula (III)
Figure imgf000006_0001
b'. dehydrating the compound of formula (III) with p-toluensulfonic acid, in toluene, thus obtaining the com ound of formula (IV)
Figure imgf000006_0002
c'. removing the benzyl group from the compound of formula (IV) and concurrently hydrogenating it by using gaseous hydrogen and Pd/C in isopropanol, providing the compound of formula (V)
Figure imgf000006_0003
d'. converting the compound of formula (V) into 4,4'-(4-chlorobutane-l,l- diyl)bis(fluorobenzene) of formula (Γ), with thionylchloride, in toluene.
According to another aspect of the invention, the above processes may be ended at the end of step (c) or (c') and compound of formula (V) may be isolated, and if necessary purified. Compound of formula (V) is a known and interesting synthetic intermediate that can be used in the preparation of different drugs.
So, it is another subject matter of the invention the preparation of 4,4'-(4- hydroxybutane-l,l-diyl)bis(fluorobenzene) which comprises carrying out steps (a) to (c) or steps (a') to (c') as above defined, optionally isolating compound of formula (V) and, if needed or desired, purifying it.
According to a preferred embodiment, step (a) or (a') are performed in inert conditions, for instance under nitrogen or argon, at the reflux temperature of the reaction mixture. The reaction is usually completed in a few hours, such as 1 to 3 hours.
According to another preferred embodiment, step (b) or (b') are performed in inert conditions, for instance under nitrogen or argon, at the reflux temperature of the reaction mixture. The reaction is usually completed in a few hours, such as 1 to 3 hours.
According to another preferred embodiment, step (c') is performed at room temperature (approx 25°C) at a pressure of approx 3-5 bar. The reaction is usually completed in about 12-30 hours.
According to a further preferred embodiment, step (d) or (d') are performed in inert conditions, for instance under nitrogen or argon, at approx. 70-90°C. The reaction is usually completed in a few hours, such as 1 to 3 hours. Compound of formula (I) may then be purified by distillation at approx. 170-180°C/l-2 mBar.
The skilled in the art is perfectly able to follow the development of the reactions by using the conventional techniques.
As it can be easily understood, the process of the invention provides interesting chemical intermediates, by carrying out industrially expedient reaction steps.
Moreover, as stated above, the whole process may be carried out without the need to isolate and purify the intermediate compounds, providing nevertheless a final compound, especially 4,4'-(4-chlorobutane-l,l-diyl)bis(fluorobenzene), showing a very high purity. This fact is another remarkable advantage for the industrial bulk production.
The process of the invention therefore represents an important technical progress in the field of chemical intermediate for drugs.
Details of every reaction step are provided in the following Experimental Section, for illustrative purposes only.
Experimental Section
The compounds were characterized by:
1H-NMR (Varian Gemini, 200 MHz; chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet); MS (Thermo Finnigan LCQ Advantage);
GC (GC Agilent 6890N Supelco SPBTM-5 30 m x 0.32mm x 1.0mm, 5% diphenyl / 95% dimethylpolysiloxane; FID temperature: 265°C, oven temperature: initial temperature: 50°C, initial time: 0 min, program rate 1 : 25°C/min, final temperature 1: 185°C, final hold time 1: 50 min, program rate 2: 5°C/min, final temperature 2: 260°C, final hold time 2: 20 min).
Example 1
Preparation of 4-(benzyloxy)-l,l-bis(4-fluorophenyl)butan-l-ol [step (a) compound (III)]
To a stirred suspension of magnesium turnings (22.9 g, 0.942 mol) in dry THF (130 ml) under nitrogen was added a solution of ((3-chloropropoxy)methyl)benzene (169 g, 0.915 mol) in dry THF (714 ml) maintaining a gentle reflux. The reaction was kept at reflux temperature for 1-2 hours. A solution of bis(4-fluorophenyl)methanone (100 g, 0.458 mol) in dry THF (260 ml) was added slowly to the Grignard reagent, keeping the reaction at reflux temperature. The reaction heated for additional 1-2 hours. The mixture was cooled to room temperature and quenched in a mixture of 1 lOg of acetic acid, 660 ml of toluene and 780 ml of water, keeping the temperature below 30°C. The aqueous phase was discarded. The organic phase was washed with water (2 x 170 ml) and evaporated to give a yellow oil. The product was used with no further purification in Example 2.
For analysis purpose, 1 gram of crude product was purified by chromatography over silica gel.
1H NMR (200 MHz, CDC13): δ 7.27-7.43 (m, 8H), 7.03-7.20 (m, 1H), 6.88-7.03 (m, 4H), 4.50 (d, J = 2.2 Hz, 2H), 3.51 (t, J = 5.8 Hz, 2H), 2.39 (t, J = 7.0 Hz 2H), 1.55 - 1.73 (q, J = 5.9 Hz, 2H).
EI-MS m/z: 368[M]+.
Example 2
Synthesis of 4,4'-(4-(benzyIoxy)but-l-ene-l,l-diyl)bis(fIuorobenzene) [step (b) - compound (IV)]
To a solution of crude 4-(benzyloxy)-l,l-bis(4-fluorophenyl)butan-l-ol obtained in the previous Example in toluene (936 ml) under nitrogen was added p-toluensulfonic acid monohydrate (4.4 g, 0.023 mol). The mixture was stirred for 1-2 hours at reflux removing water from the reaction. The solution was cooled to room temperature and washed with a solution of sodium bicarbonate (5.3 g in 87 ml of water), then with water (87 ml). The solvent was evaporated to give a yellow oil The product was used with no further purification in Example 3.
For analysis purpose, 1 gram of crude product was purified by chromatography over silica gel.
1H NMR (200 MHz, CDC13): δ 7.27-7.38 (m, 4H), 7.06-7.21 (m, 5H), 6.88-7.05 (m, 4H), 6.06 (t, J = 7.4 Hz, 1H), 4.50 (d, J = 1.5 Hz, 2H), 3.55 (td, J - 6.6-1.5 Hz, 2H), 2.15-2.53 (m, 2H).
EI-MS m/z: 350[M]+.
Example 3
Synthesis of 4,4-bis(4-fluorophenyl)butan-l-ol [step (c) - compound (V)]
A solution of crude 4,4'-(4-(benzyloxy)but-l-ene-l,l-diyl)bis(fluorobenzene) obtained in the previous Example in isopropanol (1090 ml) was hydrogenated at room temperature (25°C ±5°C) at 3-5 bar over palladium on charcoal (32.7 g, 5% Pd, 50% water) for 24 hours. The catalyst was filtered and the solution was evaporated to give a colorless oil. The product was used with no further purification in Example 4. For analysis purpose, 1 gram of crude product was purified by chromatography over silica gel.
1H NMR (200 MHz, CDC13): δ 7.06-7.23 (m, 4H), 6.81-7.06 (m, 4H), 3.74-3.98 (m, 1H), 3.64 (td, J - 6.4-3.1 Hz, 2H), 1.93-2.17 (m, 2H), 1.51 (ddd, J = 13.9-11.5-6.4 Hz, 2H), 1.39 (d, J = 3.1 Hz, 1H).
EI-MS m/z: 262[M]+
Example 4
Synthesis of 4,4'-(4-chIorobutane-l,l-diyl)bis(fluorobenzene) [step (d) - compound (I)]
A solution of 4,4-bis(4-fluorophenyl)butan-l-ol obtained in the previous Example (218 g) and catalytic pyridine (0.10 g) in toluene (570 ml) under nitrogen was heated at 80°C ±10°C. Thionyl chloride (57 g, 0.480 mol) was slowly added in 1 -2 hours to the solution, keeping the temperature at 80°C ±10°C. The reaction was further refluxed for 2-3 hours, till completion. Solvent was evaporated, 270 ml of toluene were added and the solvent was evaporated to afford a brown oil. The residue was distilled under vacuum (170-180°C /1-2 mBar). The title compound was obtained as a colorless oil (80 g).
Purity > 98 (GC)
Overall synthesis yield: 62.4%.
1H NMR (200 MHz, CDC13): δ 7.06-7.24 (m, 4H), 6.85-7.07 (m, 4H), 3.89 (t, J = 7.9 Hz, 1H), 3.53 (t, J = 6.4 Hz, 2H), 1.99-2.28 (m, 2H), 1.72 (dt, J = 17.3-6.6 Hz, 2H).
EI-MS m/z: 280[M]+.

Claims

Claims
1. A process for the preparation of a compound of formula (I)
Figure imgf000011_0001
wherein X is a leaving group, which comprises the following steps:
a. carrying out a Grignard reaction on 4,4'-difluorobenzofenone with 1- (benzyloxy)-3-chloropro ane of formula (II)
Figure imgf000011_0002
wherein Y is halogen, in the presence of magnesium, in an organic solvent, providing the compound of formula (III)
Figure imgf000011_0003
b. dehydrating the compound of formula (III), thus obtaining the compound of formula (IV)
Figure imgf000011_0004
c. removing the benzyl group from the compound of formula (IV) and concurrently hydrogenatin it, providing the compound of formula (V).
Figure imgf000011_0005
d. converting the compound of formula (V) into the compound of formula (I) and, optionally, isolating it.
2. The process according to claim 1, characterized in that Y is chlorine or bromine.
3. The process according to claim 1 or 2, characterized in that step (a) is carried out in the presence of magnesium and an organic aprotic solvent.
4. The process according to any one of claims 1 to 3, characterized in that said aprotic solvent is selected from cyclic or aliphatic ethers, tetrahydrofuran (THF) and diethyl ether.
5. The process according to any one of claims 1 to 4, characterized in that step
(b) is carried out with p-tolensulfonic acid or sulfuric acid, in toluene.
6. The process according to any one of claims 1 to 5, characterized in that step
(c) is carried out by hydrogenating the compound of formula (III) with gaseous hydrogen in the presence of a catalyst in a solvent in a C1-C4-alcohol, a cyclic or aliphatic ether, or an aromatic organic solvent.
7. The process according to claim 6, characterized in that said solvent is isopropanol or toluene.
8. The process according to claim 6 or 7, characterized in that said catalyst is Pd/C.
9. The process according to any one of claims 1 to 8, characterized in that step
(d) is carried out with a compound selected from mesyl-chloride, tosyl-chloride, N- bromosuccinimide, thionyl chloride, phosphorus tri-chloride and phosphorus penta- chloride.
10. The process according to any one of claims 1 to 9, characterized in that the compound of formula (I) is 4,4'-(4-chlorobutane-l,l-diyl)bis(fluorobenzene) of formula (Γ)
Figure imgf000012_0001
11. The process according to claim 10, which comprises: a', carrying out a Grignard reaction on 4,4'-difluorobenzofenone with 1- (benzyloxy)-3-chloro ropane of formula (IF)
Figure imgf000013_0001
in the presence of magnesium, in THF, providing the compound of formula (III)
Figure imgf000013_0002
dehydrating the compound of formula (III) with p-toluensulfonic acid, toluene, thus obtaining the compound of formula (IV)
Figure imgf000013_0003
c'. removing the benzyl group from the compound of formula (IV) and concurrently hydrogenating it, by using gaseous hydrogen and Pd/C in isopropanol, providing the com ound of formula (V)
Figure imgf000013_0004
d'. converting the compound of formula (V) into 4,4'-(4-chlorobutane-l,l- diyl)bis(fluorobenzene) with thionylchloride. in toluene.
12. A process for the preparation of compound of formula (V)
Figure imgf000014_0001
which comprises carrying out steps (a) to (c) according to any of claims 1 to 10.
13. The process of claim 12, which comprises carrying out steps (a') to (c') according to claim 11.
14. The compound 4-(benzyloxy)-l,l-bis(4-fluorophenyl)butan-l-ol of formula (III)
Figure imgf000014_0002
15. The compound 4,4'-(4-(benzyloxy)but-l-ene-l,l-diyl)bis(fluorobenzene) of formula (IV)
Figure imgf000014_0003
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4352811A (en) * 1981-11-12 1982-10-05 Hoechst-Roussel Pharmaceuticals Inc. 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles
EP0065814A1 (en) * 1981-05-12 1982-12-01 Imperial Chemical Industries Plc 1,1-Bis phenylalkan-1-ols and processes for their preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0065814A1 (en) * 1981-05-12 1982-12-01 Imperial Chemical Industries Plc 1,1-Bis phenylalkan-1-ols and processes for their preparation
US4352811A (en) * 1981-11-12 1982-10-05 Hoechst-Roussel Pharmaceuticals Inc. 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles

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