NOVEL PIPERIDIN-4-SPIRO-OXIRANES

Abstract: Novel piperidin-4-spiro-oxiranes of formula (I) are provided which have application in the synthesis of various anilidopiperidine compounds. The novel compounds can be synthesised in a one pot reaction from 4-substituted piperidones and phenyl-sulphoxide or sulphone starting materials. Use of the novel compounds allows anilidopiperidines to be produced in a significantly reduced number of stages than with previously known methods.

Description: NOVEL PIPERIDIN-4-SPIRO-OXIRANES The present invention relates to novel piperidin-4-spiro-oxirane compounds and to a method for their preparation. The invention further provides a novel method for the preparation of anilidopiperidines using said compounds or incorporating the method for their preparation. The anilidopiperidines include the highly useful fentanyl type compounds having potent analgesic and anaesthetic properties which render them useful in major surgical procedures. Particularly useful and well known examples of these compounds are the drugs Sufentanil and R.30.490 both of which have high potency yet good safety ratios as defined by the ratio ED50 D50 as determined in rats. Sufentanil Other related compounds are also known eg: 4-keto analogues where the 4-alkoxyalkyl substituent of the piperidine is replaced by keto groups as described in US 4179569. A disadvantage of all these compounds is the lengthy multistage synthesis required to prepare them from readily available starting materials. Previously reported procedure (Refs 1 and 2) for the preparation of Sufentanil involves a nine stage synthesis from 1-benzyl—4-piperidone (see Fig 1). A similar multistage process is reported in US 4179569 and Drugs Future 5_ p4l0-4H (1980) for the synthesis of R.30.490 starting from 1-benzyl piperidone. It is clear that an alternative, shorter synthetic route would reduce manufacturing costs considerably. The present invention provides such a route via novel piperidin -4-spiro-oxiranes of general formula (I). Wherein R1 is a hydrogen atom or an optionally substituted alkyl alkenyl, aryl or arylalkyl group is a hydrogen atom or an optionally substituted alkyl, alkenyl, arylalkyl, alkoxyalkyl, aryloxyalkyl or heterocyclylalkyl group R5 is an optionally substituted alkyl or hydroxy group or a halogen, sulphonic, nitro, cyano or trifluoromethyl group. Y is an optionally substituted alkyl, alkenyl, aryl, cycloalkyl, or heterocyclyl group n is 0 or an integer from 1 to 8 with R5 being independently selected for each substitution such that where n is greater than 1 each value of R5 may be different, and a is an integer 1 or 2. Preferably R-| is hydrogen or an optionally substituted Cι_8 alkyl c 2-8 alkenyl, aryl or Cγ_ιo arylalkyl group R is hydrogen or an optionally substituted C - _Q alkyl C 2 _8 alkenyl, aryl, C7..10 arylalkyl, C7..10 aryloxyalkyl, Cn_ι 0 alkoxyalkyl , thienylalkyl, furanylalkyl, pyridinylalkyl or indenylalkyl group R5 is an optionally substituted C -\ _Q alkyl or a C 2 _g alkenyl group, a halogen atom or a sulphonic or nitro group Y is an optionally substituted C- j _β alkyl or aryl group and n is 0 or an integer from 1 to 4. Most preferably 3 is an optionally substituted C^.g alkyl, phenylmethylene, phenylethylene, thienylethylene, furanylethylene, pyridinylethylene or indenylethylene group. Most advantageously R- | is hydrogen or C- | _3 alkyl, 3 is phenylmethyl (benzyl) or 2-phenylethyl, R5 is C-|_8 alkyl, n is 0, 1 or 2 and Y is optionally substituted alkyl or aryl. When intended for the preparation of anilidopiperines the values of R- ) , 3 and Rg conveniently correspond to the substituents on the piperidyl nitrogen of a desired final product eg; for R this might be carbocyclic or heterocyclic substituted alkyl groups such as 2-phenylethyl, 2-thienylethyl, 2-furanylethyl, 2-pyridinylthyl or 2-indenylethyl groups or their substituted analogues for synthesis of fentanyls of compounds described in US 4179569 eg; 2-thienylethyl in the case of sufentanil or 2-phenyl ethyl in the case of R.30. 90. Alternatively R-|, R and R3 may be selected such that the final product may be conveniently be synthesised with respect to them ie: they may be selected as protecting groups or as intermediates. Expensive reagents such as those used to form the thienylethylene group might be advantageously used at the last stage of the synthesis rather than be wasted through yield losses while cheaper benzyl or methyl groups are used to protect the piperidinyl nitrogen in preceeding stages. A final step would for example involve removal of said benzyl group by hydrogenation and then reaction with 2-thienylethylbromide. The present invention further provides a method for the synthesis of the compounds of the formula (I) wherein:- (a) a compound of general formula (II) ,wherein 3 and R5 are as defined in formula (I), is reacted with a compound of formula (III), wherein X is a halogen atom and a, Y and R- | are as defined in formula (I) to produce a compound of formula (IV) wherein R- j , R3, R5, Y, n and a are as defined in formula (I). (IV) Y-S(0) a CHXR 1 (III) then (b) the compound of general formula (IV) is converted under basic conditions to a compound of formula (I) In practice the conversion of the compound of formula (II) to that of one of formula (I) is preferably carried out in one stage in a single reaction vessel without isolation of the formula (IV) intermediate. However, the compounds of formula (IV) may be isolated (eg. Example 11 below) and as they solidify much more readily than the oxiranes, their isolation is possible by precipitation thus giving a further purification option in the oxirane preparation. The reaction of the compound of formula (II) with that of formula (III) may be carried out under influence of a base in a dry solvent with the exclusion of air (eg; by use of a nitrogen atmosphere) and at low temperature. In the dry solvent technique the step (b) is typically instigated by use of an organometallic agent, preferably an organo-alkali metal agent, preferably N-butyllithium. The reaction is preferably worked up by pouring the reaction mixture onto water and extracting it into a water immiscible organic solvent; preferably ether, dichloromethane or chloroform. By use of such basic conditions in the reaction medium the cyclisation of the compound of formula (IV) to formula (I) occurs readily but in order to maintain purity reaction is carried out at temperatures below zero, preferably below -30°C, most preferably at temperatures below -70°C, particularly about -78°C. A second method of producing the componds of formula (I), preferred for synthesis of sulphones of formula (I) (a is 2), reacts the compounds of formulas (II) and (III) in an organic solvent in the presence of a phase transfer catalyst and an aqueous base (eg.NaOH, KOH or other strong base) solution under agitation conditions. Examples of suitable phase transfer catalysts are tricaprylmethylammonium chloride, Aάogen 464(TM) and triethylbenzylammonium chloride. This reaction technique allows use of ambient temperature and may be advantageous for industrial scale production in it's avoidance of hazardous hydride reagents. The reaction is worked up by separation and drying of the organic layer followed by purification techniques. The third embodiment of the present invention comprises a novel route to the anilidopiperidines comprising use of compounds (I) as starting products or intermediates. The compounds of general formula (I) are readily prepared as outlined above and are then converted to compounds of general formula (V) wherein the compound of formula (I) is reacted with an optionally substituted aniline; R-j, R and R5, n, a and Y are as previously defined and 4 is halogen, hydroxy, cyano, trifluoromethyl, nitro, sulphonic, or an optionally substituted alkyl, alkenyl or alkoxy group or two R moieties may together form a carbocyclic or heterocyclic ring; Rg is hydrogen or optionally substituted alkyl; value m is selected from 0 or an integer from 1 to 5 and R1 may be independently selected at each occurance. Generally this reaction proceeds at room temperature with a trace of polar organic solvent present eg; dimethylsulphoxide. The compounds of formula (V) open the way to further conversions of known type as summarised in Fig 2. These include the following examples whereby further intermediates (VT) and (VII) are synthesised. Reduction of a compound of formula (V) eg; using sodium borohydride or lithium aluminium hydride gives a compound of formula (VI) which can be alkylated using the general methods of Janssen or by the action of diazoalkanes in the presence of silica or of halogenoalkanes in the presence of a hydride to give compounds of the general formula (VII). Examples of synthetic routes: (see Fig 2). (i) N-acylation of compounds of the formula (VI) where R6 is hydrogen with a compound R 2 C0C1 in the presence of triethylamine or with (R 2 C0) 2 0 wherein R 2 is optionally substituted Cι_g alkyl, C 2 _8 alkenyl or aryl provides novel compounds of formula (X). Where R is cyclopropyl, isobutyl or propionyl potencies comparable with that of Sufentanil may be provided. (ii) N-acylation of compounds of the formula (VII) with compounds (R 2 C0) 0 or with R 2 C0C1 in the presence of triethylamine using the same procedure as described by Janssen gives compounds of formula (IX). Where R 2 is propyl R.30. 90 results. (iii) Where compound (VII) has R value benzyl hydrogenation may be used to remove it to provide a compound of formula (VIII) allowing N-alkylation of the piperidine nitrogen with a 2-haloethyl-2-thiophene or 2-methanesulphonyl -oxyethyl-2-thiophene followed by N-propionylation as described by Janssen to provide sufentanil. The debenzylation may also be carried out, for example, by reaction with 2,2,2-trichloroethyl -orthofoπnate followed by reduction of the carbamate with zinc. Removal of a methyl protecting group may be carried out analogously using 2,2,2-trichloroethyl chloroformate. (iv) N-acylation of compounds of the general formula (V) allows preparation of keto analogues of the Janssen patents as shown by formula (XI) . SYNTHESIS EXAMPLES Example 1. 2 ' -phenylsulphinylspiro { 1 - ( 2-phenylethyl ) piperiάinyl -4, 1 ' -oxirane} . To a stirred solution of diisopropylamine (3.0g, 30mmol) in dry THF (20 ml), at -78°C under nitrogen, was added a solution of n-butyllithium (20 ml of a 1.6 M solution, 30 mmol) in hexane. After stirring for 30 rain at -78°C, a solution of chloromethyl phenyl sulphoxide (2.75 g, 15 mmol) in dry THF (15 ml) was added dropwise. The mixture was stirred for a further 30 min at -78°C, and then 1-(2-phenylethyl)-4-piperidone (3 g, 15 mmol) in THF (15 ml) added dropwise. The reaction mixture was left for a further hour at -78°C and then allowed to reach ambient temperature before pouring onto water. The aqueous mixture was extracted with ether, and the combined extracts washed, dried (over MgSOi j ) and concentrated. Chromatography of the residue on silica gel using light petroleum-acetone 7:3 as eluant afforded 2 » -phenylsulphinylspiro{1-(2-phenylethyl)piperidinyl-4, 1 » -oxirane} (2.4 g) Example 2. 4-(N-Phenylamino)-1-(2-phenylethyl)piperiάine-4-carboxaldehyάe. A mixture of 2'-phenylsulphinylspiro{1-(2-phenylethyl)piperidinyl -4 ,1'-oxirane} (2 g) , aniline (5 ml) and two drops of dimethyl sulphoxide was stirred at room temperature for 16 hours. The reaction mixture was chromatographed directly onto silica gel using ether as an eluant to separate the crude reaction product from excess aniline, and then rechromatographed on silica gel, using petrol-ether 1:1 as eluant, to afford 4-(N-phenylamino)-1- (2-phenylethyl)piperidine-4-carboxaldehyde (1.56 g), m.p. 83-84°C after recrystallisation from petrol - ether. Example 3. 4-( -phenylamino)-1-(2-phenylethyl)-4-piperiάinylmethanol. Sodium borohydride (2 g) was added portionwise to a stirred solution of 4-(N-phenylamino)-1-(2-phenylethyl)piperidine-4 -carboxaldehyde (2 g) in methanol (2 g) at room temperature for 2 hours, the mixture was diluted with water, extracted with chloroform and the combined extracts washed, dried over MgS0_ and concentrated. The residue was chroma ographed on silica gel, using chloroform-methanol 19:1 as eluant, to afford 4-(N-phenylamino)-1-(2-phenylethyl)-4-piperidinylmethanol (1.65 g), m.p. 98-99°C. Example 4. 4-Methoxymethy1-4-(N-pheπylamino)-1-(2-phenylethyl)piperidine. To a stirred mixture of 4-(N-phenylamino)-1-(2-phenylethyl)-4- piperidinylmethanol (0.100 g) and silica (0.5 g) in ether (5 ml) at room temperature was added an excess of ethereal άiazomethane, and the mixture stirred at room temperature until no more colour remained. The reaction mixture was filtered and the filtrate concentrated to give an oil. Purification on silica gel using chloroform - methanol 38:1 as eluant gave the title compound (0.052 g). Example 5. N-{ -methoxymethyl-1-(2-phenylethyl)-4-piperiάnyl}-N-phenyl- propionanamide .(R.30.490.) 4-methoxymethyl-4-(N-phenylamino)-1-(2-phenylethyl)piperidine was reacted with propionic anhydride as described by the general method of US 4179569. Example 6. 2'-Methyl-2'-phenylsulphinylspiro{1-(2-phenylethyl) iperidinyl- 4, 1 ' -oxirane} . To a stirred solution of diisopropylamine (3.0 g, 30 mmol) in dry THF (25 ml), at -78°C under nitrogen, was added n-butyllithium (20 ml of a 1.6 M solution in hexane, 30 mmol). After stirring for 15 min at -78°C a solution of 1-chloroethyl phenyl sulphoxide (2.7 g, 14mmol) in dry THF (10 ml) was added dropwise, the mixture stirred for a further 30 min at -78°C and then N-(2-phenylethyl)-4-piperidone (3 g, 15 mmol) in THF (15 ml) added dropwise. The reaction mixture was left for a further 45 min at -78°C and then allowed to reach ambient temperature before pouring onto water. The aqueous mixture was extracted with chloroform and the combined extracts washed, dried and concentrated. Chromatography of the residue on silice gel using petrol - acetone 7:3 as eluant gave 2'-methyl-2'-phenylsulphinyl -spiro{1-(2-phenylethyl)piperidinyl-4, 1 '-oxirane} (1.84 g) plus the intermediate chlorohydrin 4-{1-(1 '-chloro-1 '-phenylsulphinyl -ethyl)}-1-(2-phenylethylpiperidin-4-ol)(0.92 g), m.p.164-166°C. To a solution of the chlorohydrin intermediate (0.500 g) in dry dimethylformamide (5 ml) at 0 - 5°C was added sodium borohydride (0.60 g). The mixture was stirred for 30 minutes at 0 -5°C, allowed to regain room temperature and finally stirred for a further 30 minutes. The mixture was then diluted with water, extracted with ether, and the combined extracts washed, dried and concentrated. The reaction product was chromatographed on silica gel using chloroform - methanol 38:1 as eluant to give a further quantity of 2'-methyl-2*-phenylsulphinylspiro{1-(2-phenylethyl) -piperidinyl-4, 1 '-oxirane} (0.310 g). Example 7. - { ( 4-Phenylamino ) - 1 - ( 2-phenylethyl ) -4-piperidinyl } ethanone . A mixture of 2' -methyl-2'-phenylsulphinylspiro{ 1-(2-phenylethyl ) piperidinyl-4, 1 ' -oxirane} ( 2.5 g) in aniline ( 5 ml) was stirred at 60°C for 20 hours . The mixture was chromatographed directly on silica gel using ether as eluant to give 1-{4-phenylamino)-1- ( 2-phenylethyl)-4-piperidinyl}ethanone ( 2.03 g) , m.p. 98-99°C . Example 8. N-{ -Acetyl-1-(2-phenylethyl)-4-piperiάinyl}-N-phenylpropanamiάe. Was prepared from 1-{4-phenylamino)-1-(2-phenylethyl)-4- -piperidinyl}ethanone by the method of Janssen. Example 9. 4-(1-hyάroxyethyl)-4-(N-phenylamino)-1-( -phenylethyl) -piperidine. Sodium borohydride (0.500 g) was added portionwise to a stirred solution of 1-{(4-phenylamino)-1-(2-phenylethyl)-4-piperidinyl} -ethanone (500 mg) in methanol (10 ml), keeping the temperature below 20°C. After stirring for 2 hours the reaction mixture was carefully diluted with water and extracted with ether. The combined extracts were washed, and concentrated and the residue was purified on silica gel using chloroform - methanol 19:1 as eluant to give the title compound (O.368 g). Example 10. N-{4-( 1-hyάroxyethyl)-1-(2-phenylethyl)-4-piperidinyl}-N -phenyl-cyclopropylcarboxamide. A solution of 4-(1-hydroxyethyl)-4-(N-phenylamino)-1-(2-phenyl -ethyl)-piperidine (0.200g), cyclopropylcarboxylic acid chloride (1 g) and triethylamine (2.2 g) in dry benzene (30 ml) was stirred for 2.5 hours at 60-65°C. After cooling the mixture was washed with dilute sodium carbonate solution, dried over MgSOi j and then concentrated. The residue was chromatographed on silica gel using chloroform - methanol 76:1 as eluant to give the title compound (0.160 g), which with oxalic acid gave an oxalate salt, m.p. 158-159°C. Example 11. 2'-Phenylsulphinylspiro{1-phenylmethyl-piperiάiny1-4, 1 '-oxirane} n-Butyllithium (14 ml of a 1.1 M solution) in hexane was added dropwise to a solution of diisopropylamine (3.2 g) in dry tetrahydrofuran at -78°C under nitrogen. After stirring for 30 min at -78°C, chloromethyl phenylsulphoxide (2.5 g) in tetrahydrofuran (10 ml) was added dropwise, the mixture stirred for a further 30 min at -78°C and then a solution of 1-benzyl-4-piperidone (3 g) in dry tetrahydrofuran (10 ml) added dropwise. after stirring for a further 2 hours, the mixture was allowed to regain room temperature and, after stirring for a further hour, poured into water. The precipitate was filtered and recrystallised from methanol to yield the intermediate 4-{1 '-chloro-1 '-(phenylsulphinyl)methyl-l-phenylmethyl-piperidin- 4-ol (1.9 g), m.p. 212°C. Sodium hydride (80$ dispersion in oil, 1 g) was added portionwise to a stirred solution of the intermediate piperidinol (1.9 g) in dry dimethylformamide (10 ml) at 0 to 5°C. The solution was stirred for a further hour with ice bath cooling, then for 1 hour at room temperature and then poured into water. The mixture was then extracted with ether and the combined extracts washed with water and dried over MgSOi j . Concentration under reduced pressure and followed by chromatography of the residue on silica gel, using chloroform /methanol (38:1) as eluant gave the title compound (1.42 g) as a colourless oil. Example 12. 4-(N-phenylamino)-1-phenylmethyl-piperidine-4-carboxalάehyde. A mixture of the oxirane of Example 11 (0.6 g), aniline (0.6 g) and dimethyl sulphoxide (50 mg) was stirred at 45-50°C for 14 hours. The reaction mixture was separated by chromatography on silica gel, using chloroform/methanol (75:1) as eluant, and the crude product recrystallised from petroleum ether (b.p. 60-80°C) to give the title compound (0.416 g) m.p. 118-119°C. Example 13. 2'-Phenylsulphinylspiro{1-methylpiperiάiny1-4, 1 '-oxirane} . To a stirred solution of diisopropylamine (3 g) in dry tetrahydrofuran (20 ml) at -78°C was slowly added n-butyllithium (20 ml of a 1.6 M solution) in hexane, and the mixture stirred for an additional 30 min. a solution of chloromethyl methyl sulphoxide (2.5 g) in tetrahydrofuran (10 ml) was then added dropwise, and, after stirring for 30 min, N-methyl-4-piperidone (3.25 g) in tetrahydrofuran (10 ml) was added. After stirring for 1 hour at -78°C, the mixture was allowed to regain ambient temperature and stood overnight. The mixture was poured into water, extracted with ether and the combined extracts washed and dried. After removal of the solvent, the crude product was chromatographed on silica gel, using chloroform/methanol (38:1) as eluant, to give the title compound (1.7 g) as a colourless oil. Example 14. 1-Methyl-4-( -phenylamino)-piperidine-4-carboxaldehyde. A mixture of 2'-phenylsulphinylspiro-{1-methylpiperidinyl -4, 1 '-oxirane} (0.55 g), aniline (0.6 g) and dimethyl sulphoxide (0.05 g) was stirred at room temperature for 12 hours. The mixture was separated by chromatography on silica gel, using chloroform/methanol (38:1) as eluant, to give the title product as an oil (0.41 g). Example 15. 4-(N-phenylamino)-1-phenylmethyl-4-piperidinylmethanol. Sodium borohydride (2 g) was added portionwise to a stirred solution of 4-(N-phenylamino)-1-phenylmethyl-piperidine -4-carboxaldehyde (2 g) in methanol at room temperature. After stirring at room temperature for 2 hours the mixture was diluted with water, extracted with chloroform and the combined extracts washed and dried. After removal of the solvent, the crude product was purified by chromatography on silica gel, using chloroform/methanol (38:1) as eluant, to give the title compound (1.53 g) 4-(N-phenylamino)-1-phenylmethyl)-4-piperidinylmethanol is then converted to sufentanil following the method described in US 4179469 and as illustrated by Figure 2. Example 16. '-Methyl-2'-phenylsulphonyl-{1-(2-phenylethyl)-piperiάinyl- , 1 ' -oxirane}: Phase-transfer synthesis of compound of formula I. N-(2-phenylethyl)-4-piperidone (500 mg) and Aliquat 336 (tricaprylmethylammonium chloride) (100 mg) were added to a stirred solution of 1-chloroethyl phenyl sulphone (500 mg) in dichloromethane (20 ml) and the organic solution then stirred vigorously with 50% aqueous NaOH (5 ml) at ambient temperature for 8 hours. The organic layer was dried (MgS0_ j ), concentrated and purified over silica gel using light petroleum:acetone 8:2. The title compound was afforded as 385 mg of oil. Example 17. 1-{(4-phenylamino)-1-(2-phenylethyl)-4-piperiάinyl}-ethanone. 2'-methyl-2'-phenylsulphonyl{1-(2-phenylethyl)piperidinyl-4, 1 ' -oxirane} (100 mg) was strirred with aniline (400 mg) and a drop of dry dimethyl sulphoxide under nitrogen at 80-85°C for 20 hours. Chromatography over silica gel using light petroleum - acetone 7:3 as eluant afforded the title compound (66 mg). References. 1. NIEMEGERS et al; ARZNEIM FORSCH 26 (1976), pp1548. 2.ZHIJIE et al; PHARMACEUTICAL INDUSTRY 16 (1985), pp241.

Claims: CLAIMS 1. A compound of the general formula (I), R wherein R- ) is a hydrogen atom or an optionally substituted alkyl, alkenyl, aryl or arylalkyl group; is a hydrogen atom, or an optionally substituted alkyl alkenyl, arylalkyl, alkoxyalkyl, aryloxyalkyl or heterocyclylaikyl group; R5 is an optionally substituted alkyl or hydroxy group or a halogen, sulphonic, nitro, cyano or trifluoromethyl group; Y is an optionally substituted alkyl, alkenyl, aryl, cycloalkyl or heterocyclyl group; n is 0 or an integer from 1 to 8 with R5 being independently selected for each substitution such that when n is greater than one each value of R5 may be different; and a is an integer 1 or 2. 2. A compound of general formula (I) as claimed in Claim 1 wherein R- | is hydrogen or an optionally substituted C- | _g alkyl, C 2 _8 alkenyl, aryl or Cγ_ιo arylalkyl group. R is a hydrogen atom or an optionally substituted Cι_8 alkyl, C 2 _8 alkenyl, aryl, Cγ_ι 0 arylalkyl, Cγ_ιo aryloxyalkyl, C4..10 alkoxyalkyl, thienylalkyl, furanylalkyl, pyridinylalkyl or indenylalkyl group; 5 is an optionally substituted C-|_8 alkyl or a C 2 _8 alkenyl group, a halogen atom or a sulphonic or nitro group. Y is an optionally substituted C-|_8 alkyl or aryl group and n is an integer from 1 to 4. 3. A compound of general formula (I) as claimed in Claim 1 or 2 wherein is an optionally substituted C- | _8 alkyl group, phenylmethylene, phenylethylene, thienylethylene, furanylethylene, pyridinylethylene or indenylethylene group. 4. A compound of general formula (I) as claimed in Claim 1 wherein R-] is hydrogen or Cι_3 alkyl, R3 is phenylmethyl or 2-phenylethyl, R5 is C-|_8 alkyl and n is 0, 1 or 2. and Y is an optionally substituted C- | _8 alkyl or aryl group. 5. A method for the synthesis of compounds of the general formula (I) as claimed in Claims 1 to 4 wherein:- (a) a compound of general formula (II) , herein R3 and R5 are as defined in formula (I), is reacted with a compound of formula (III) wherein X is a halogen atom and Y, a and R- ) are as defined in formula (I) to produce a compound of general formula (IV), wherein R- j , R3, R5, Y and n are as defined in formula (I). Y-S(0) a -CHXR 1 (III) Y then (b) the compound of general formula (IV) is converted under basic conditions to a compound of formula (I) 05 10 6. A method as claimed in Claim 5 wherein the conversion of compounds of formula (II) and (III) to compounds of formula (I) is carried out without isolation of the compounds of formula (IV) 157. A method as claimed in Claim 5 or 6 wherein the step (b) is initiated by use of an organometallic agent. 8. A method as claimed in Claim 7 wherein the organometallic agent is N-butyllithium. 0 9. A method as claimed in Claims 5, 6 or 7 wherein the conversion is carried out in a dry solvent. 10. A method as claimed in Claim 9 wherein the conversion is 5 carried out with the exclusion of air. 11. A method as claimed in Claim 9 or 10 wherein the conversion is carried out under nitrogen gas. 12. A method as claimed in any one of Claims 5 to 11 wherein the 5 conversion is carried out at a temperature of 0°C or below. 13. A method as claimed in Claim 12 wherein the conversion is carried out at a temperature of -30°C or below. 10 14. A method as claimed in Claim 12 wherein the conversion is carried out at a temperature of -70°C or below. 15. A method as claimed in Claim 12 wherein the conversion is carried out at a temperature of about -78°C. 15 16. A method as claimed in Claim 5 or 6 wherein the compounds of formulas (II) and (III) are reacted together in an organic solvent in the presence of a phase transfer catalyst and an aqueous base. 20 17. A method as claimed in Claim 16 wherein the reaction is mixture is agitated. 18. A method as claimed in Claim 16 or 17 wherein the reaction 25 is carried out at a temperature above 0°C. 19. A method for the synthesis of an anilidopiperidine wherein a compound of the formula (I) is reacted with an optionally substituted aniline to provide a compound of the general formula (V): 05 wherein R- j , R3, R5, Y, n and a are as defined in Claim 1; R_ j is independently selected at each occurance and is an optionally substituted alkyl, alkenyl or alkoxy group or a cyano, 15 halogen, hydroxy, trifluoromethyl, nitro or sulphonic group and two such R4 groups may comprise a carbocyclic or heterocyclic ring; Rg is hydrogen or optionally substituted alkyl ; the value m is selected from 0 or an integer from 1 to 5. 20 20. A method as claimed in Claim 19 wherein the reaction is carried out at room temperature. 21. A method as claimed in Claim 19 or 20 wherein a trace of polar organic solvent is included in the reaction mixture. 25 22. A method as claimed in Claim 21 wherein the polar organic solvent is άimethylsulphoxide. 23. A method for the synthesis of an anilidopiperidine as claimed in any one of Claims 19 to 22. wherein a compound of the general formula (VI): wherein R- j , R3, R5 and n are as defined in Claim 1 and R^, Rg and 10 m are as defined in Claim 19 and Rg is hydrogen, is produced wherein a compound of the formula (V) is reduced by a reducing agent. 24. A method as claimed in Claim 23 wherein the reducing agent 15 is a hydride. 25. A method as claimed in Claim 23 wherein the reducing agent is sodium borohydride or lithium aluminium hydride. 20 26. A method as claimed in any one of Claims 23 to 25 wherein the compound of formula (VI), where Rg is hydrogen, is N-acylated with a compound R 2 C0C1 or (R 2 C0) 0 to produce compounds of the general formula (X) 25 (X) wherein R 2 is optionally substituted C-]_8 alkyl, C 2 _8 alkenyl or aryl; and R-|, R3, R , R5, n and m are as defined in Claims 1 and 15 05 27. A method as claimed in Claim 26 wherein the reaction is carried out using R 2 C0C1 in the presence of triethylamine. 28. A method as claimed in Claim 26 or 27 wherein the compound R 2 C0C1 is cyclopropionylchloride and the group R 2 in the 10 compound of formula (X) is cyclopropyl. 29. A method for the synthesis of an anilidopiperidine as claimed in any one of Claims 23 to 25 wherein a compound of the general formula (VII) is produced 20 wherein R- j , R3, R , R5, Rg, n and m are as defined in Claims 1 and 19 wherein a compound of general formula (VI) is alkylated with a compound R7X or Rγ 2 wherein Rγ is Cι_8 alkyl or C 2 _8 alkenyl and X is a halogen atom. 25 30. A method as claimed in Claim 29 wherein the alkylation is carried out using the compound RγX in the presence of a hydride. 31. A method as claimed in Claim 29 wherein the alkylation is carried out using the compound RγN 2 on silica. 32. A method for the synthesis of an anildopiperidine as claimed in any one of Claims 19 to 2Z wherein a compound of general formula (IX) is produced wherein R , R3, R4, R5, Rγ, n and m are as defined in Claims 1, 19 and 29 wherein a compound of formula (VII) wherein Ri and Rg are hydrogen is reacted with a compound of formula ((R 2 ) 2 C0) 2 or R C0C1. 33. A method as claimed in Claim 32 wherein the compound of formula (VII) has R3 value of 2-phenylethyl, Rγ is methyl, and n and m are 0 is reacted with propionic anhydride and the compound (IX) produced is R.30.490. 34. A method as claimed in Claim 32 wherein the compound of formula (VII) has R3 group benzyl and is hydrogenated to remove said group and then reacted with (i) a 2-thienyl-1-halo-ethane compound followed by (ii) acetic anhydride to provide a compound (IX) sufentanil wherein the values n and m are 0 and Rγ is methyl in the compound of formula (VII). 35. A method for the synthesis of an anilidopiperidine as claimed in any one of Claims 19 to 22 wherein a compound 05 of the general formula (XI) is produced wherein R-|, R3, Rj j , R5 and n and m are as previously defined and R is Cι_8 alkyl, or C 2 _8 alkenyl or aryl wherein a compound of 15 formula (V) is reacted with a compound R 2 C0C1 or (R 2 C0) 2 0. 36. A method as claimed in Claim 35 wherein the reaction is carried out using R 2 C0C1 in the presence of triethylamine. 20 37. A method for the synthesis of a compound of formula (I), (V), (VI) or (VII) as herein before described in the Examples and/or Figure 2. 38. A method for the synthesis of an anilidopiperidine as 25 described in the Examples and/or Figure 2. 39- A method for the synthesis of Sufentanil or R30,490 as herein described in the Examples and/or Figure 2. 40. A method for the synthesis of N-{4-(1-hydroxyethyl) 5 -1-(2-phenylethyl)-4-piperidinyl}-N-phenyl-cyclopropylcarboxamide as herein described with reference to the Examples. 41. 2'-phenylsulphinylspiro-{1-(2-phenylethyl)piperidinyl-4,1 ' -oxirane}. 10 42. 2' -phenylsulphinylspiro { 1-phenylmethylpiperidiny 1-4 , 1 ' -oxirane} . 43. 2' -methyl -2' -phenylsulphinylspiro { 1 -( 2-phenylethyl) 15 -piperidinyl-4, 1 '-oxirane} 44. 4-{ 1-( 1 ' -chloro-1 ' -phenylsulphinyl) ethyl }-1-( 2-phenylethyl -piperidinol) 20 45. 4-{ 1 ' -chloro-l '-(phenylsulphinyl) methyl} -1-phenylmethyl -piper idi-4-ol 46. 2' -phenylsulphinylspiro-{ 1-methylpiperidinyl) -4 , 1 ' -oxirane} 25 47. N-{4-(1-hydroxyethyl)-1-(2-phenylethyl)-4-piperidinyl}-N- -phenyl-cyclopropylcarboxamide.

Inventors: BLACK ROBIN MICHAEL, BREWSTER KEITH, BLACK, ROBIN, MICHAEL, BREWSTER, KEITH
Applicants: SECR DEFENCE BRIT, THE SECRETARY OF STATE FOR DEFENCE IN HER BRITANNI
Application year: 1991
Main classification: C07D211
IPC codes: C07D211, C07D491, C07D493