Title of Invention	A PROCESS FOR THE PREPARATION OF NOVEL INTERMEDIATE
Abstract	A process for the preparation of the compound of formula (I), namely 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile in which the compound corresponding to formula (II), namely (1-bromo-cyclohexyl)-(4-methoxy-phenyl)-methanone, is subjected to treatment with a cyanation agent.

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FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION [See sections 10] , RULE 13] APOCESS FOR THE PREPARATION OF NOVEL INTEREDATE ALEMBIC LIMITED; ALEMBIC ROAD; VADODARA-390003 GUJARAT. INDIA , AN INDIAN COMPANY The following specification pargoripjhi describes the nature on the invention, and the manner in which it is to be performed. This invention relates to a novel intermediate which is valuable in the synthesis of a known medicament by a more advantageous route. The invention further relates to processes by which such an intermediate may first be itself prepared and thereafter may be converted into the known anti¬depressant (±)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol *w. - I of structural formula (IX): and pharmacologically-acceptable . salts thereof, e.g. Venlafaxine hydrochloride, supplied by American Home Products, Inc., under the trade name Effexor®. Venlafaxine selectively inhibits the neuronal uptake of serotonin-norepinephrine and to a lesser extent dopamine. Studies indicate that it has comparable or possibly slightly greater efficacy to other selective serotonin reuptake inhibitors (SSRI's). It appears to be as effective as standard antidepressants such as imipramine. Venlafaxine's unique chemical structure and neuro-pharmacological activity give it a broader spectrum of activity than Previously known methods for the preparation of Venlafaxine include e.g. that taught in EP 0,112,669, which discloses the preparation of various 2-aryl-2-(1-hydroxycyclohexyl)ethylamine derivatives via a-aryl-a-(1-hydroxy-cyclohexyl) acetonitriles or a-aryl-N,N-dimethyl-a-(1-hydroxycyclohexyl) acetamide as chemical intermediates. These chemical intermediates are prepared by condensing a-arylacetonitriles or a-aryl-N,N-dimethyl acetamides with cyclohexanone. GB 2,227,743 discloses the preparation of 2-(1-hydroxycyclohexylethyl-thioacetamide) derivatives for the synthesis of Venlafaxine. The thioacetamido derivative is prepared from 4-methoxyacetophenone via Kindler modification of the Willgerodt reaction. Zhou Jinpei et al. (Zhongguo Yaoke Daxue Xuebao (Journal of China) 1999, 30(4), 249-250) have reported the synthesis of Venlafaxine using methoxy-benzene as a starting material. The route involves 5 steps and gives 11% overall yield. In this route anisole is treated with chloroacetyl chloride under Friedel-Crafts acylation conditions followed by substitutions of a-halo-p.-methoxyacetophenone by dimethylamine which is reduced by potassium borohydride to give a p-hydroxydimethylamine derivative. This intermediate, on treatment with PBr3 followed by magnesium in tetrahydrofuran (THF), and subsequent treatment with cyclohexanone, yields Venlafaxine. These known synthetic routes tend to involve the use of hazardous, costly and moisture sensitive reagents. For example, the synthesis described in EP 0,112,669 requires a very low reaction temperature (-50°C to -70°C), and a hydrogenation step which uses expensive rhodium catalyst. Materials in this route are not easily available, and the reaction conditions are harsh, with high demands on equipment, and high production costs. The process taught in GB 2,227,743 uses a ratio of 50:1 Raney nickel to thioamide in its hydrogenation step, and also requires the use of toxic solvents such as dioxane for the reduction of thioamide. These reagents and conditions make this process commercially unattractive. Zhou Jinpei's process requires the use of costly chemicals such as potassium borohydride and PBr3, as well as the purification of an important intermediate via distillation under high vacuum, which further adds to the cost. We have now evolved a synthetic route for the preparation of Venlafaxine which starts from easily available materials, and employs mild reaction conditions and simple after-treatment procedures, thus making it suitable for large-scale production. In this new route, hazardous, moisture-sensitive, and highly inflammable reagents are completely avoided, as are costly chemicals such as rhodium catalyst and potassium borohydride. Certain alternatives are available in the early stages of this route, which is indeed advantageous since it opens the way to the use of different reaction strategies, from a range of starting materials, which may be selected according to cost and availability. All of these alternative routes however pass through the same novel epoxy nitrile intermediate. According to the present invention, there is provided the epoxy-nitrile compound of structural formula (I): namely 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile. • The present invention also provides a process for the preparation of the compound of formula (I), in which (1-bromo-cyclohexyl)-(4-methoxy-phenyl)-methanone of structural formula (II): is subjected to treatment with a cyanation agent, so as to yield the epoxy nitrile intermediate of formula (I). The cyanation agent employed is preferably sodium cyanide or potassium cyanide, although other cyanation agents may be used, such as trimethyl silyl cyanide, cuprous cyanide, other alkali and alkaline earth metal cyanides, or other cyanating agents known from the literature. The reaction can be readily performed in solution in methanoj^at room temperature. Alternatively, solvents such as ethanol, isopropyl alcohol, acetonitrile, dimethyl formamide, dimethyl sulphoxide, dimethyl acetamide, hexamethylene phosphoric triamide (HMPT), ethyl acetate, or sulfolane, may be used, as may benzene, toluene, cyclohexane, dichloromethane, or chloroform, in the presence of a phase_Jxansfer catalyst. The phase transfer catalyst is required when using these non-polar solvents, as the solubility of inorganic cyanides therein is practically nil. The catalyst therefore acts so as to carry the cyanide ion to the organic phase for reaction. The reaction may be carried out at a temperature in the range of from -10°C to 60°C. Preferably the reaction temperature is in the range of from 20°C to 25°C. The reaction time may be in the range of from 2 to 48 hours, or more preferably is in the range of from 6 to 8 hours. The ratio of solvent to (1-bromo-cyclohexyl)-(4-methoxyphenyl)-methanone (II) may be in the range of from 1:1 to 100:1. Preferably the ratio used is substantially 25:1. Preferably, the process additionally comprises a further step of previously preparing the compound of formula (II), by subjecting cyclohexyl-(4-methoxy-phenyl)-methanone of structural formula (III): to treatment with an a-keto-halogenating agent, so as to give the compound of formula (II). A reaction for the preparation of the bromo-ketone (II) is reported in Bull Soc Chim France (1962) 90-6 The a-keto-halogenation is preferably effected using phenyltrimethyl u,,imonium perbromide. Alternatively, a brominating agent may be selected from liquid bromine, N-bromo succinimide, 1,3-dibromo-5,5-dimethyl-hydantoin, quaternary ammonium and phosphonium perbromides, N-chlorosuccinimide, and other halogenating agents known in the literature. The solvent used may be selected from methanol, acetic acid, benzene, toluene, chloroform, carbon tetrachloride, tetrahydrofuran (THF), acetonitrile, ethanol, dichloromethane, dioxane, t-butanol, and substituted benzenes. The reaction is preferably carried out at a temperature of substantially 68°C, for a time of about 6 hours. The ratio of solvent to ketone may be in the range of from 1:1 to 100:1, but preferably is substantially 20:1. At this point it should be noted that the starting point for the above-described stage in the overall syntheses, namely cyclohexyl-(4-methoxy-phenyl)-methanone of formula (III), is itself a known compound, disclosed in Izv.Akad.Nauk Turkm.SSR.Ser.Fiz-Tekhn.,Khim.i Geol.Nauk 1963, No.1,115-6. The overall process of the present invention therefore may include an additional step_of subjecting methoxy-benzene of structural formula (IV): to Friedel-Crafts acylation treatment so as to yield the,compound of formula (III), Thus, the cyclohexyl-(4-methoxy-phenyl)-methanone (III) may for instance be synthesized by Friedel-Crafts reaction between cyclohexane-carbonyl chloride and methoxy-benzene in the present of aluminium trichloride: Alternatively, boron trifluoride or sodium aluminium chloride may also be used as the Friedel-Crafts reagent, in place of aluminium trichloride. The solvent is selected from methoxy-benzene and halogenated or nitrated benzenes, and may be used in a ratio relative to the cyclohexane-carbonyl chloride in the range of from 5:1 to 50:1. The reaction temperature may be in the range of from -20°C to 40°C. However, unless there are other, external reasons that argue for the use of methoxy-benzene as the primary starting material for the overall syntheses, we currently believe that the intermediate cyclohexyl-(4-methoxy- phenyl)-methanone (III) may usually be better produced in an alternative . manner. It is thus preferred that the previously-outlined process of this invention should instead furtherncomprise an additional step of subjecting cyclohexyl-(4-methoxy-phenyl)-methanol of structural formula (V): to oxidation so as to yield the cyclohexyl-(4-methoxy-phenyl)-methanone (III). . Oxidation is preferably performed using chromic acid, which may desirably be formed in situ by the reaction of sodium dichromate dihydrate with sulphuric acid. Alternatively, an oxidising agent may be selected from alkali and alkaline earth metal chromates and dichromates, chromic anhydride, manganese dioxide, alkali and alkaline earth metal manganates, permanganates, nitric acid, alkali and alkaline earth metal persulphates, quaternary ammonium and phosphonium manganates and permanganates, chromates and other oxidising agents known in the literature. The oxidation is preferably carried out at a temperature in the range of from 25°C to 30°C, for a time of substantially 3 hours. This alternative process preferably further comprises the initial step of subjecting 4-methoxy-benzaldehyde of structural formula (VI): to treatment with a cyclohexyl magnesium halide, C6H11-Mg-X (where X= chlorine, bromine or iodine) so as to yield cyc!ohexyl-(4-methoxy-phenyl)- methanol (V). The reaction is preferably carried out using cyclohexyl magnesium bromide in THF at a temperature in the range of from 10°C to 15°C for a period of substantially one hour. The cyclohexyl magnesium bromide may desirably be formed in situ by the reaction of cyclohexyl bromide with magnesium turnings. Alternatively, the 4-methoxy-benzaldehyde (VI) may be treated with an organometallic reagent such as cyclohexyl lithium or dialkylcupro lithium. Besides THF, the solvent used may also be selected from diethyl ether, dibutyl ether, dipropyl ether, di-isoproyl ether, dioxahe, diglyme, or alkylated polyethers. An alternative preparation of cyclohexyl-(4-methoxy-phenyl)-methanol (V) may be performed by treating the compound of formula (XI): namely cyclohexanecarbaldehyde, with anisyl magnesium halide or anisyl lithium. In a quite different alternative process according to the present invention, the compound corresponding to formula (VII): namely cyclohexylidene-(4-methoxy-phenyl)-acetonitrile, is treated with an epoxidating agent, such as m-chloroperbenzoic acid (m-CPBA) to yield the desired compound of formula (I). The epoxidating agent may alternatively be selected from perbenzoic acid, peracetic acid, performic acid and other organic peracids, hydrogen peroxide, persulphuric acid, alkylhydroperoxides, and other epoxidating agents known in the literature. The solvent for the epoxidation is selected from dichloromethane, dichloroethane, carbon tetrachloride, chloroform, ethyl acetate and toluene. Preferably, the solvent used is dichloromethane. The reaction temperature may be in the range of from 0°C to the reflux temperature of the corresponding solvent but will preferably be substantially 40°C. The reaction time may be in the range of from 1 hour to 48 hours, but will preferably be in the range of from 6 to 8 hours. Preferably, the second alternative process further comprises a previous step of preparing the compound of formula (VII), by treating the compound corresponding to formula (VIII): namely (4-methoxy-phenyl)-acetonitrile, with cyclohexanone and a condensing agent such as sodium methoxide, to secure the compound of formula (VII). This'reaction is reported in United States Patent No. 2,647,122. The condensing agent may alternatively be selected from sodium ethoxide, potassium t-butoxide, quaternary ammonium hydroxide and other alkali and alkaline earth metal alkoxides, alkali and alkaline earth metal hydrides, alkali and alkaline earth metal amides. The solvent may be selected from methanol, ethanol, t-butanol and other solvents known to the art. Preferably methanol is used. The reaction time may be in the range of from 1 to 24 hours, but preferably is in the range of from 3 to 6 hours. The reaction temperature may be in the range of from 10°C to 60°C, but is preferably room temperature, that is to say substantially 25°C. A further possible alternative process for the preparation of t 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile (I), comprises subjecting the compound corresponding to formula (XII): namely chloro-(4-methoxy-phenyl)-acetonitrile, to Darzen's condensation (i.e. halohydrin formation, followed by cyclization), using cyclohexanone in the presence of a base. The compound of formula (I), when thus prepared by any of the alternative processes as described above, may desirably be used as an intermediate in the preparation of the compound corresponding to formula (IX): namely (±)-1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol. According to a further aspect of the present invention there is therefore provided a process for the preparation of the compound of structural formula (IX), which comprises the steps of: (a) hydrogenating the epoxy-nitrile of structural formula (I) in the presence of a catalyst, so as to yield 1-[2-amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol corresponding to formula (X): and (b) treating the 1-[2-amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol (X) produced by step (a) above with formaldehyde and formic acid, in the presence of water; to yield the desired (±)-1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethylj-cyclohexanol. The hydrogenation is preferably effected in the presence of Raney nickel catalyst, at a pressure in the range of from 500 to 1000 kPa. The ratio of Raney nickel to epoxy nitrile (I) may be in the range of from 5:1 to 1:5 by weight. Preferably, the ratio used is substantially 1:1. Alternatively, the hydrogenation may be carried out using a reagent selected from platinum dioxide, platinum and palladium and nickel on different inert supports, aluminium hydride, lithium aluminium hydride, sodium . borohydride, potassium borohydride, lithium borohydride in the presence of Lewis acids, or quaternary ammonium borohydrides, neat or in the presence of a phase transfer catalyst. The hydrogenation reaction may be carried out at a temperature in the range of from 0°C to W0°C, but is preferably carried out at room temperature. The solvent may be selected from tetrahydrofuran (THF), dioxane, glyme dialkylethers polyethers and elthyl acelate. Alternatively, the epoxynitrile (I) can be reduced to the desired amino compound (X) by treating it with ammonium formate and hydrogen, in the presence of a catalyst selected from noble metal or supported noble metal catalysts. The treatment of compound (X) with formaldehyde and formic acid in step (b) is best performed at a temperature of substantially 100°C for a time of substantially 6 hours, so as to yield 1-[2-dimethy!amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol of formula (IX), or Venlafaxine. Alternatively, the epoxynitrile of structural formula (I) may be reduced to a hydroxynitrile intermediate of structural formula (XIII): namely (1-hydroxy-cyclohexyl)-(4-methoxy-phenyl)-acetonitrile, using ammonium formate and a noble metal or supported noble metal catalyst. This hydroxynitrile compound (XIII) is then further reduced to the corresponding amino compound of formula (X) by treatment with Raney nickel, platinum dioxide, palladium, cobalt boride, nickel boride, or other suitable catalysts known from the literature. In order that the invention shall be well understood it will now be further described, but only for purposes of illustration with reference to the accompanying drawings, in which:- Figure 1 is a reaction diagram showing the synthesis of (±)-1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol, Venlafaxine, via 2-(4-methoxy-phenyl)-1-oxa-spiro-[2.5]octane-2-carbonitrile of structural formula (I), from methoxy-benzene; Figure 2 is a reaction diagram showing the synthesis of (±)-1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol, Venlafaxine, via 2-(4-m'ethoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile of structural formula (I), from 4-methoxy-benzaldehyde; and Figure 3 is a reaction diagram showing the synthesis of (±)-1-[2-dimethyl-amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol, Venlafaxine, via 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile of structural formula (I), from (4-methoxy-phenyl)-acetonitrile. Referring first to Figure 1, it will be seen that this synthesis starts from methoxy-benzene of structural formula (IV), which is a readily-available starting material. This is subjected to Friedel-Crafts acylation, to yield cyclohexyl-(4-methoxy-phenyl)-methanone of structural formula (III). That in turn is subjected to a-keto-halogenation with a bromination reagent, to yield the corresponding (1-bromo-cyclohexyl)-(4-methoxy-phenyl)-methanone of structural formula (II). The resultant product is then subjected to cyanation, yielding the desired intermediate 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbo-nitrile (I). Referring now to Figure 2, this alternative synthesis starts from 4-—-methoxy-benzaldehyde (VI) which-is-subjected-to ^treatment with cyclohexyl - -- magnesium bromide to yield cyclohexyl-(4-methoxy-phenyl)-methanol (V). This in turn is then oxidised so as to yield cyclohexyl-(4-methoxy-pheny!)-methanone (III). The subsequent reaction steps for the conversion of this compound to the desired intermediate, 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile (I), are the same as those described above with reference to Figure 1 for the corresponding conversion. Referring now to Figure 3, it will be seen that this further alternative synthetic route starts from (4-methoxy-phenyl)-acetonitrile (VIII), which is treated with a condensing agent, such as sodium methoxide, so as to yield cyclohexylidene-(4-methoxy-phenyl)-acetonitrile (VII). This in turn is then treated with an epoxidating agent, such as rn-CPBA, so as to yield the desired intermediate, 2-(4-methoxy-phenyl)-1-oxa-spiro[2..5]octane-2-carbonitrile (I). Having obtained the desired intermediate, 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile (I), by any of the synthetic routes described above with reference to Figures 1 to 3, it is then hydrogenated in the presence of Raney nickel so as to yield 1-[2-amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol (X). This in turn is then treated with formaldehyde and formic acid, in the presence of water, to yield (±)-1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol (IX). In order that the invention shall be still better understood it will now be . described in more detail;, though only by way of illustration, with reference to the following Examples. Example 1: Preparation of 2-(4-methoxv-phenyl)-1-oxaspiro[2.5loctane-2-carbonitrile (0 from 4-methoxv-benzaldehyde (VI) Stage 1: Preparation of cvclohexyl-(4-methoxv-phenvl)-methanol (V) A reaction vessel was charged with 1.6g Mg turnings in 50.0 ml tetrahydrofuran (THF). Cyclohexyl bromide was added thereto in small increments to initiate a reaction generating cyclohexyl magnesium bromide in situ, and thereafter the balance of 9.0g thereof was added at reflux temperature. After completion of the addition, reflux was continued for 1 hour, and then the reaction mixture was cooled to 5 to 10 °C. 5.0g 4-methoxy-benzaldehyde was then slowly added while still maintaining the temperature between 5 and 15 °C. The reaction mixture was allowed to warm up to 25°C, and stirred at that temperature for 6 hours. The mixture was dumped into a solution of 5.0g ammonium chloride, and the organic layer was separated therefrom. The aqueous layer was extracted twice, each time with 25ml ethyl acetate, and these extracts were combined with the organic layer and washed with brine solution. They were then dried over sodium sulphate, and the solvent was distilled off under vacuum. 6.5g (dry product) of the desired cyclohexyl-(4-methoxy-phenyl)- methanol was thus obtained. After purification by column chromatography, eluting with Benzene:Ethyl acetate (90:10), it has the following characteristics: M. P: 87 to 89 °C. NMR: 1H NMR ( CDCI3 ) 5 7.2 , 6.86 ( q, 4H ), 5 4.28 ( d, 1H ), § 3.79 (s, 3H ), 5 1.98 ( d, 1H ), 5 1.35 ( m, 10H ) IR: (cm"1) 3630, 3459, 2942, 2855, 2623, 2527, 2446, 1253, 1034, 822. Optical rotation: Racemic Solubility: Soluble in methanol, ethanol, chloroform, dichloromethane, acetone, ethyl acetate etc. The same preparation has been carried out using cyclohexyl chloride or cyclohexyl iodide, and using THF as the solvent. Stage 2: Preparation of cvclohexyl-(4-methoxv-phenvl)-methanone (111) 5g of the product from Stage 1 and 5ml water were charged into a reaction vessel. Separately a solution of chromic acid was prepared by dissolving 7.1g sodium dichromate dihydrate in demineralized water, adding cone, sulphuric acid and cooling to room temperature. This chromic acid solution was then added to the reaction mixture while maintaining the temperature between 20 to 30 °C, and then stirred therewith for 3 hours at room temperature. The mixture was extracted first with 15ml and thereafter twice more with 5ml each time of dichloromethane, and the combined dichloromethane layers were washed three time.s, each with 25ml demineralized water. Then the organic layer was dried over sodium sulphate, and distilled to dryness under vacuum. 3.75g of the desired cyclohexyl-(4-methoxy-phenyl)-methanone was thus obtained. After purification by column chromatography, eluting with Benzene:Ethyl acetate (80:20) it has the following characteristics: M. P: ' 61 to 63 °C NMR: 1H NMR ( CDCI3 ) 5 7.93 , 6.93 ( q, 4H ), 5 3.86 ( s,3H ), 5 1.47 ( m, 1.1H ) IR: ( cm"1 ) 2926, 2855, 1660, 1602, 1509, 1260, 1176, 834. Solubility: Soluble in Methanol, ethanol, chloroform, dichloromethane, acetone, ethyl acetate, benzene, toluene and isopropyl alcohol. Stage 3: Preparation of (1-bromo-cvclohexvl)-(4-methoxy-phenvl)-methanone (III 5g of the product from Stage 2 was charged at room temperature into a reaction vessel. with 50ml THF and 8.56g phenyl-trimethyl-ammonium perbromide and the resultant reaction mixture was refluxed for 2-3 hours. The reaction mixture was then dumped into water, and the resultant • precipitate was filtered and washed with water. The desired (1-bromo-cyclohexyl)-(4-methoxy-phenyl)-methanone was thus obtained, dry weight 5.6g. After purification by column chromatography, eluting with Hexane:Benzene (30:40), it has the following characteristics: M. P: 55 to 57 °C NMR: 1H NMR ( CDCI3 ) 5 8.14, 6.9 ( q, 4H ), 5 3.86 (s, 3H ), 5 IR: ( cm"1 ) 2934, 2855.9, 1659.9, 1596.8, 1508, 1443, 1251, 1173, 846 Solubility: Soluble in methanol, ethanol, chloroform, dichloromethane, acetone, ethyl acetate, benzene, toluene and isopropyl alcohol. Stage 4: Preparation of 2-(4-methoxv-phenvl)-1-oxa-spiro[2,5loctane-2-carbonitrile (I) 1g of sodium cyanide was dissolved in 25ml methanol at room temperature. 5g of the product of Stage 3 was added thereto, and stirred at 25°C for 2 hours. The reaction mixture was then dumped into 100ml water and extracted first with 15ml and thereafter twice more each time with 5ml dichloromethane. The organic layers were separated, and washed three times, each with 25ml demineralized water, and thereafter dried over sodium sulphate and distilled under vacuum. The desired 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile-was thus obtained, in a yield of 3.9g of a viscous oil. After purification by column chromatography, eluting with Hexane:Benzene (30:40), it has the following characteristics: NMR: 1H NMR (CDCI3), 5 7.3, 6.85 (q, 4H ), 5 3.75 ( s, 3H ), 5 1.52 ( m, 10 H ). IR: ( cm"1 ) 2935, 2856, 2238, 1611, 1514, 1448, 1252, 1174, 1034. Optical rotation: Racemic Solubility: Soluble in methanol, ethanol, chloroform, dichloromethane, acetone, ethyl acetate, benzene, toluene and isopropyl alcohol. The same reaction has also been successfully performed using potassium cyanide, in methanol at room temperature. Example 2: Preparation of 2-(4-methoxy-phenvl)-1-oxaspiro[2.5loctane-2-carbonitrile (I) by an alternative route from methoxy-benzene (IV) Stage 1: Preparation of cyclohexyl-(4-methoxy-phenvl)-methanone (HI) from methoxy-benzene (IV) The same product as in Example 1, Stage 2 can also be synthesized by Friedel-Crafts reaction between cyclohexanecarbonyl chloride and methoxy-benzene as reported in the following journal: Izv.Akad.Nauk Turkm.SSR.Ser.Fiz-Tekhn.,Khim.i Geol.Nauk 1963, No.1,115-6 Example 3: Preparation of 2-(4-methoxy-phenyl)-1-oxa-spiro[2.51octane-2-carbonitrile (I) via an alternative route from (4-methoxy-phenvl)-acetonitrile (VIII) Stage 1: Preparation of cvclohexvlidene-(4-methoxy-phenyl)-acetonitrile (VII) The reaction was carried out in methanol, using sodium methoxide or t-butanol and potassium t-butoxide at room temperature, and a reaction time of about 6 hours. Stage 2: Preparation of 2-(4-methoxv-phenyh-1-oxa-spiro[2.51octane-2-carbonitrile (I) 2.0g of the product from Stage 1 was refluxed for 8 hours with 2.0g of m-chloro-perbenzoic acid, in dichloromethane. The reaction mixture was cooled to room temperature and filtered to remove precipitated m-chloro-perbenzoic acid. The filtrate was washed with saturated sodium bicarbonate solution, and the dichloromethane layer was then dried over sodium sulphate. The solvent was distilled under reduced pressure, and the residue purified by column chloromatography using a hexane:benzene (8:2) mixture as the mobile phase. The epoxidation has been carried out in various other solvents, namely chloroform, dichloroethane, acetonitrile and carbon tetrachloride, and at temperatures ranging from room temperature to reflux temperature. Example 4: Preparation of (±)-1-[2-dimethvlamino-1-(4-methoxv-phenyl)-ethvll-cvclohexanol (IX) Stage 1: Preparation of 142-amino-1-(4-methoxv-phenv0-ethyll-cvclohexanol (20 5g of the product obtained from Example 1 was added to a pressure vessel previously charged with 1g of Raney Nickel suspended in ammoniacal ethanol, and the mixture was hydrogenated at 500 kPa pressure for 7 hours at room temperature. After checking completion of the reaction by TLC, the catalyst was filtered off through a hyflo bed, and ethanol was completely distilled off. The residue was taken up in isopropanolic HCI, cooled and the resultant solid filtered off. Demineralized water was added.to the filtrate, and then extracted 3 times with 15ml dichloromethane. The aqueous layer was rendered basic with caustic lye, extracted with ethyl acetate, and the ethyl acetate then distilled off under vacuum. Dry HCI gas was passed into the solution under cooling, yielding a solid precipitate, which was triturated in ether and filtered, yielding 4g of the desired solid product, having the following characteristics: M. P: 168 to 172 °C NMR: 1H NMR ( DMSO d6 ) 5 7.85 ( s, 3H ), 5 3.75 ( s, 3H ) , 5 3.12(m, 3H ), 5 1.35 ( m, 10H ) IR: (cm"1) 3403,2930,2850,1609,1511,1245 Optical rotation: Racemic --;Solub[lity:----------Soluble;in.;methanor, chloroform;and water o Mass Spectra: m/e = 250 This reduction has also been carried out using Raney nickel suspended in various solvents, e.g. methanol and ethanol, at room temperature and at a •pressure in the range of from 500 to 1000 kPa. Stage 2: Preparation of (±)-1-[2-dimethvlamino-1-(4-methoxv-phenvl)-ethvll-cvclohexanol (IX) 12g of the product from Stage 1 above was added to a vessel containing 12.5ml of 33% aqueous formaldehyde and 16.5m! of 88% formic acid in 115ml water, and the reaction mixture was heated to reflux for 6 hours. The solvent was then distilled off, and water was added to the residue and adjusted to pH 2 with cone, hydrochloric acid, and extracted with 100ml ethyl acetate. The aqueous layer was rendered basic with 50% sodium hydroxide, and again extracted with ethyl acetate. The extract was washed with brine, dried, filtered and evaporated to a dry residue. This residue was dissolved in ethyi acetate, and treated with isopropanolic HCI, filtered and washed with chilled isopropyl alcohol. 10.Og of the desired product were thus obtained, having the following characteristics: M. P: 215 to 217 °C NMR: 1H NMR, 5 7.32, 6.98 ( q, 4H ), 5 3.78 ( s, 3H, ), 3.64 ( m, 2H ), 3.06 ( m,1H ), 2.7,4 ( s, 6H ), 1.38 ( broad m, 10H ) Optioal rptation: _ Racemic Solubility: Soluble in methanol, chloroform and water The same reaction has also been carried out for periods of up to 12 hours. WE CLAIM: 1. A process for the preparation of the compound of formula (I), namely 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile in which the compound corresponding to formula (II), namely (1-bromo-cyclohexyl)-(4-methoxy-phenyl)-methanone, is subjected to treatment with a cyanation agent. 2. A process as claimed in claim 1, wherein said cyanation agent is selected from sodium cyanide or potassium cyanide. 3. A process as claimed in claim 2, wherein said the cyanation agent is sodium cyanide. 4. A process as claimed in claim 1, wherein the reaction is performed in solution, the solvent being selected from methanol, ethanol, isopropyl alcohol, acetonitrile, dimethyl formamide, dimethyl sulphoxide, dimethyl acetamide, hexamethylene phosphoric triamide (HMPT), ethyl acetate or sulfolane; or benzene, toluene, cyclohexane dichloromethane, or chloroform in the presence of a phase transfer catalyst. 5. A process as claimed in claim 4, wherein said the solvent is methanol. 6. A process as claimed in any preceding claim, wherein the ratio of solvent to (1-bromo-cyclohexyl)-(4-methoxy-phenyl)-methanone (II) is in the range of from 1:1 to 100:1. 7. A process as claimed in claim 6, wherein said ratio of solvent to the compound of formula (II) is 25:1. 8. A process as claimed in claim 1, wherein the reaction is carried out at a temperature in the range of -10 to 60 °C. 9. A process as claimed in claim 8, wherein the reaction temperature is in the range of 20 to 25 °C. 10. A process as claimed in claim 1, wherein the reaction is carried out for a time in the range of 2 to 48 hours. 11. A process as claimed in claim 10, wherein the reaction time is in the range of 6 to 8 hours. Dated this 10th day of April, 2002

Documents:

337-mum-2002-cancelled pages(10-1-2005).pdf

337-mum-2002-claims(granted)-(10-1-2005).doc

337-mum-2002-claims(granted)-(10-1-2005).pdf

337-mum-2002-correspondence(ipo)-(25-7-2007).pdf

337-mum-2002-correspondence1(16-2-2004).pdf

337-mum-2002-correspondence2(5-3-2007).pdf

337-mum-2002-drawing(10-1-2005).pdf

337-mum-2002-form 1(10-4-2002).pdf

337-mum-2002-form 13(10-1-2005).pdf

337-mum-2002-form 19(3-11-2003).pdf

337-mum-2002-form 2(granted)-(10-1-2005).doc

337-mum-2002-form 2(granted)-(10-1-2005).pdf

337-mum-2002-form 3(10-4-2002).pdf

337-mum-2002-form 3(16-2-2004).pdf

337-mum-2002-power of attorney(4-2-2005).pdf

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