NZ212440A - 3-( q -chloropropyl)-6-fluoro-1,2-benzisoxazole - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £12440 2 12440 Under the provisions of Regu« totlon 23 (I) the .

Priority Date(s): A-l:,.?/, Specification has been ante-date^ to Qfe<1r\«A. 19 i5L- Publication Date: Journal, Mo: yownw • ••« no drawimss Uf.sr..

NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION "3-(y-CHLOROPROPYL)-6-FLUOR-l,1-BENZISOXAZOLE, A PROCESS FOR ITS PREPARATION AND ITS USE AS INTERMEDIATE. " We, HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED, a corporation organised under the laws of the United States of America, of Route 202-206 North Somerville, New Jersey 08876, United States of America, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement : - - 1 (followed by 1A) 2 1244 - iA- iinrnirT nrmi m i iiiniiini i in n m i TiirnnrnnATrn »nr ni fr "mr inn Qiii«iunul I'ippllLULlUII Ul iBLLlll i'ip|jliuu>i■■ III i TiaiClff fiiTOlP (nor g?iijfn cairn1) 3-(Y-CHLOROPROPYL)-6-FLUOR-l,1-BENZISOXAZOLE, a process for its preparation and Its use as Intermediate The present Invention relates to 3-(Y-chloropropyl)-6-fluoro-1,2-benzisoxazole, a process for the preparation thereof and its use in the synthesis of compounds which are useful as neuroleptics.

The benzisoxazole having the structural formula is prepared by cyclizing an oxime derivative having the formula where R is a substituent selected from -C-alkyl, where alkyl is a straight or branched chain hydrocarbon of 1 to 5 carbon atoms, and OH NOR F ff-vtv-as -j mw jfiwraw.r? 212440 Japanese patent publloatlon J5l/l36»666 discloses a broad D class of compounds of the formula IJaa. starting materials for drugs exhibiting action on the central nervous system, (cH2ynx were R^ is hydrogen, halogen atom, lower alkoxy, or hydroxy; X is a reactive ester residue of an alcohol (e.g., chlorine, bromine, iodine, an aryl sulfonyloxy group, such as p-toluene-sulfonyloxy or benzene sulfonyloxy, or an alkyl sulfonyloxy group, such as methanesulfonyloxy; and n is an integer 1-3.

This disclosure, however, does not reveal or hint that 3-( -chloropropyl)-6-fluoro-1,2-benzisoxazole is.especially useful in the synthesis of neuroleptics, nor dofesr'dlt resttal or hint at the preparation of this precursor or a method by which to do so. t>ont publication J'l 0070 063 describes 'The Japonooc pqbont publioat f tkfiry cfeXrC"be**- 'ationjof 1,2-benzlsoxazo preparation!of 1,2-benzisoxazole derivatives of formula II, 25 * II O IT CR2R3R4 where R1 is hydrogen, hydroxy, alkoxy, alkyl, halogen, nitro; R2 is halogen; R^ is hydrogen, halogen; is hydrogen, halogen, carboxyl, alkoxycarbonyl by halogenating , PATENT Of FfCE 3 1 1,2-benzisoxazole-3-acetic acid derivatives III III R 1 CH2COR where R is hydroxy, alkoxy, halogen; and R^ is as shown under II.

No method, however, is revealed or hinted at which would yield 3-(f-chloropropyl)-6-fluoro-1,2-benzisoxazole of this invention or even closely related analogs or next adjacent homologs.

A process for preparation of a 3-( ^-substituted propyl)-15 6-fluoro-1,2-benzisoxazole is described. The process comprises cyclizing an oxirae having the formula leaving group in organic nucleophilic displacement reactions. Typical leaving groups are a halide group, comprising CI and 25 Br, a tosyl group, a mesyl group, etc. A preferred halide is CI. R is a substituent selected from -C-alkyl, where alkyl is a straigth or branched chain hydrocarbon of 1 to 6 carbon atoms, and * "OH N-OR j"c~(CH2^3*' where X is a N 0 n 0 it The starting compound for the preparation of 3-Or-sub-stituted-propyl)-6-fluoro-1,2-benzisoxazole is V-substituted 21^4-iO -*l-fluoro-2-hydroxybutyrophenone. A preferred compound is f-chloro-4-fluoro-2-hydroxybutyrophenone having a formula, C_ (ch2)3-ci A butyrophenone precursor to this benzisoxazole is prepared by reacting 3-fluorophenol, ^ with an acid chloride, such as the aicd chloride JL ii * C1-C-(CH2)^C1>in the manner described in Belgian patent 639,097.

The resultant butyrophenone, e.g. y-chloro-*J-fluoro-2-hydroxybutyrophenone, is then converted into its oxime, e.g.

N-°H C-(CH2)3ci by reaction with a salt of hydroxylamine, utilizing conventional techniques and conditions. Typically hydroxylamine hydrochloride is employed in the presence of an acid acceptor, such as pyridine.

The resulting oxime, ]f'-chloro-J4-fluoro-2-hydroxybutyro- . phenone oxime, is predominantly the E-oxime in respect to its position relative to the benzene ring. This reasoning is deduced from the fact that after acetylation to E-T-chloro-1!-fluoro-2-hydroxybutyrophenone-0-acetyl oxime, the acetylated 35 oxime gives a high yield (80 %) of 3-(Jf-chloropropyl)-6-fluoro-1,2-benzisoxazole on cyclization.

NIW ZEALAND 16 MAR 1987 PATENT 0"-' The resulting oxime, e.g.

OH NCH £_<oy3ci is reacted with an acyl anhydride, acetyl halide, e.g., chloride, or benzoic anhydride or halide to form an O-acetyl or O-benzoyl compound e.g.

N-OR c— Cch2)3ci, where R is selected from -C- alkyl, where alkyl is a straight or branched chain hydrocarbon substituent having 1 to 6 carbon atoms, and 0 It is to be understood that other reagents reacting with the -OH group of the oxime may be employed to form O-alkanoyl or O-aroyl derivatives, as for example, propionic anhydride, butyric anhydride, acetic benzoic anhydride, propionyl chloride, butyroyl chloride, and benzoyl chloride.

The resulting O-alkanoyl or O-aroyl derivative is then cyclized in the presence of a base to form the desired compound ,J§pr'°w L-.g. , urn*?' 2 1 244 C _ 6 - 3-(^-chloropropyl)-6-fluoro-1,2-benzisoxazole. Typically the cyclization is carried out in the presence of potassium carbonate.

Alternate reagents of potassium carbonate to effect cyclization of the O-acyl oxime, e.g., E-ir^chloro-^-fluoro-2-hydroxybutyrophenon-O-acetyl oxime, include alkaline reagents such as sodium bicabonate, sodium carbonate, calcium carbonate, magnesium carbonate, calcium oxide, magnesium oxide and potassium hydroxide. Because of the necessity to avoid excess alkali with its potential for reaction with the chlorine atom of the chloropropyi side chain attached to the benzisoxazole ring, it is desirable to limit any alkali present to a slight excess over that required to react with the phenol group. Desirably, alkali remaining after reaction with the acetylated oxime should not cause a pH greater than 9 after dilution with water. Cyclization with reagents yielding a pH after reaction and dilution with water below 8 are preferred.

It is understood that the above-identified reactions of the reaction sequence are carried out in a conventional solvent system typically employed therefor and well known to those skilled in the art.

The overall reaction sequence from y-chloro-4-fluoro-2-hydroxy-butyrophenone to its oxime to its acetylated oxime to 3-(tf-chloropropyl)-6-fluoro-1,2-benzisoxazole is remarkable for its high yield of desired product. This yield is the more remarkable in that the JT-chloropropyl group survives intact and is available for subsequent use in reactions to prepare compounds having neuroleptic utility, such as for example 4-(JJ-chlorophenyl)-1-£3-(6-fluoro-1,2-ben-zisoxazole-3-yl)propyl]-^-hydroxypiperdine.

J'•)■ 'i- r- rtiiriffr'tttfyirrtftrfiM 2 1244 By condensing 3-(Y-chloropropyl)-6-fluoro-1,2-benzisoxazole with readily available 4-hydroxy-4-phenylpiperidines of the formula in the presence of an acid acceptor, a displacement pro-motor and a suitable solvent, 1-[3-(6-fluoro-1,2-benz-isoxazol-3-yl)propyl]-4-phenyl-4-hydroxypiperidines of "the formula 0H _ JCH2)3-N / . N 0' are obtained which are useful as neuroleptics. 21244 EXAMPLE 1 lf*-Ch I oro-^l-f luoro-2-hydroxy buy rophenone To 350 ml (2.8 mols) cold boron trifluoride etherate is added 100 g (0.89 mole) of 3-fluorophenol and 252 g (200 5 ml 1.78 mole) of M-chlorobutyry1 chloride. The resulting solution is stirred for twenty hours at 130°C.

The mixture is cooled and poured into one liter of mixed ice and water. After stirring for ten minutes, the water mixture is extracted three times with 200 ml of ether 10 each time. The ether extracts are combined and washed three times with water. The ether extract is dried by washing with a saturated solution of sodium chloride in water and is then dried over anhydrous magnesium sulfate.

The magnesium sulfate is filtered from the dry ether 15 solution and the ether is evaporated. The resultant oil is vacuum distilled and a fraction is collected at 110 - 150°C (1.0 mm, pot at 170 - 250°C) weighing 115 g (50 % of the theoretical yield). This material is recrystallized from a mixed solvent solution (hexane/ether at 8 : 1 ratio) to 20 obtain white crystals of )p-chloro-14-fluoro-2-hydroxybuty-rophenone, melting at 68 - 70°C.

EXAMPLE 2 E-y-chloro-^-fluoro-2-hydroxybutyrophenone oxime To 25 ml of pyridine is added 11.2 g (0.052 mole) of y-chloro-^-fluoro-2-hydroxybutyrophenone of Example 12 and g (0.06 mole) of hydroxylamine hydrochloride. This 30 mixture is stirred overnight (20 hours) at ambient temperature. It is then poured into 100 ml of dilute hydrochloric aicd, stirred for five minutes, and is extracted with ether. The ether solution is washed two times with water before it is dried by washing with a saturated solution - <? - r^s 1 244 or sodium chloride in water followed by final drying over anhydrous magnesium sulfate.

The magnesium sulfate is filtered from the ether solution, and the ether is evaporated. The white solid ob-5 tained is recrystallized from.a mixed hexane and ether solvent to obtain 11.5 g (95 % of the theoretical yield) of white crystals melting at 68 - 70°C. A sample of this material is again recrystallized from hexane/ether to yield white crystals of E-Jf^chloro-^-fluoro^-hydroxybutyrophe-10 none oxime, melting at 74 - 6°C.

Analysis; Calculated for C1QHnClFN02: 51.84 %C 4.79 *H 6.05 *N Found: 52.20 %C 4.77 *H 6.00 *N EXAMPLE 3 E~y-chloro-4-fluoro-2-hydroxybtuyrophenone-0-acetyl oxime To 5.5 ml (0.06 mole) of acetic anhydride is added 20 10.0 g (0.043 mole) of E-lT-chloro-4-fluoro-2-hydroxybutyro-phenone oxime.

This mixture is heated at 60°C for one and one-half hours. The resulting mixture is cooled to room temperature and is dissolved in 100 ml of ether. The ether solution is 25 washed twice with a sodium bicarbonate solution in water. It is then washed twice with water. The ether solution remaining is dried by washing with a saturated solution of sodium chloride in water before finally drying it over anhydrous magnesium sulfate.

The magnesium sulfate is removed by filtration after drying is complete and the ether is evaporated from the dry ether solution to give a solid which is recrystallized from a nixed hexane/ether solvent to obtain 9.0 g (76 % of the theoretical yield) of E-Jfchloro-4-fluoro-2-hydroxybutyro-35 phenone-0-acetyloxime possessing a melting point of 84 -87°C. A sample of this material is recrystallized from a 244 C -to - ; mixed hexane/ether solvent. The crystals of E-fcchloro-4-fluoro-2-hydroxy-butyrdphenone-0-acetyloxime which are obtained melt at 86 - 88°C.

Analysis: Calculated for CjgH, 3C1FNC>3: 52.66 %C 4.79 5.12 $N Found: 52.56 JtC 4.81 JtH 5.05 %N EXAMPLE 4 3-C y-chloropropylJ-6-fluoro-1,2-benzlsoxazole The cyclization of the acetylated oxime of Example 3 is effected by adding 6.5 g (0.024 mole) of E-)f-chloro-4-fluoro2-hydroxy-butyrophenone-0-acetyl oxime to 20 ml of dry 15 dimethylformamide (DMF) and 4.14 g (0.03 mole) of potassium carbonate. This mixture is stirred for five hours at room temperature. It is poured into 500 ml of water, stirred for five minutes, and Is then extracted with a mixed solvent of ether/ethyl acetate. The extracted organic layer is washed 20 two times with water and once with a saturated solution of sodium chloride in water. The organic layer is finally dried over anhydrous magnesium sulfate.

After drying, the magnesium sulfate is removed by filtration and the solution is evaporated to remove ether and 25 ethyl acetate. The product is an oil. This oil is distilled to yield 4.0 g (80 % of the theoretical yield) of an oil of 3-(K'-chloropropyl)-6-fluoro-1,2-benzisoxazole boiling at 130°C/0.5 mm.

Analysis: Calculate Found: 56.21 JSC 4.25 ?H 6.52 JtN Calculated for C1QHgClFN0: 56.22 %C 4.25 %H 6.56 %N

Claims (3)

7. 124-4 EXAMPLE 5 4-(4-Chlorophenyl-l-f 3-(6-fluoro-l^-benzlsoxazole-S-yl)-propyl]-4-hydroxyplperldlne 5 In 30 ml dry DMF is added 4-(4-chlorophenyl)-4-hydroxypiperidine (3*0 g, 0.014 mole) 3-(T-chlorophenyl)-6-fluoro-l ,2-benzisoxazole (2.99 6, 0.014 mole), NaHCO^ (8.0 g, 0.1 mole), and 0.01 g of KI. After stirring at 10 90°C for one hour, the mixture is evaporated to an oil, which is stirred with 100 ml water for five minutes and then extracted with ether. The ether solution is washed twice with water and then dried (saturated NaCl, anhydrous MgSOjj) . After filtering, the solvent is evaporated to 15 yield 4.7 g of a solid, m.p. 130°C. The solid material is recrystallized from ether to yield 3,5 g (64%) m.p. 143-5°C. This material is recrystallized from ether to yield 3.0 g of a solid of 4-(4-chlorophenyl)-l-[3-(6-fluoro-l,2-benzisoxazole-3-yl)propyl]-4-hydroxypiperidine, 20 m.p. 148-50°C. ANALYSIS: Calculated for C21H22C1PN202: 64.855&C 5-70%H 7 .21JCN 25 Pound: 64.75S&C 5-64%H 7«15%N WHAT '75 CLAIM IS: - IX- 2i2440 "If fV~

1. The compound .3-C}f-chloropropyl>6-fluoro-1,2-benzisoxazole .

2. a process for preparing 3-(JT-chloropropyl)-6- 5 fluoro-1,2-benzisoxazole which comprises cyclizing an oxime derivative having the formula of N-OJl 10 -S-CoyjO. where B is a substituent selected from the group consisting 15 of 20 C-alkyl, where alkyl is a straight or branched chain hydrocarbon substituent of 1 to 6 carbon atoms, and 25 <>

3. The process as defined in claim Q_ wherein said cyclization is carried out in the presence of an alkaline reagent. HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED By Wflf/Their Attorneys, HENRY HUGHES LIMITED, NEW ZEALAND 1 16 MAR 1987 PATENT