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)

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)

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)

wherein Y is halogen, in the presence of magnesium, in an organic solvent, providing the com ound of formula (III)

b. dehydrating the compound of formula (III), thus obtaining the compound of formula (IV)

c. removing the benzyl group from the compound of formula (IV) and concurrently hydrogenating it, providing the compound of formula (V)

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 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. 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 (!')·

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)

in the presence of magnesium, in THF, providing the compound of formula (III)

b'. dehydrating the compound of formula (III) with p-toluensulfonic acid, in toluene, thus obtaining the com ound of formula (IV)

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)

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]+.