IE45988B1 - 3-acyloctahydro-2,5-methanobenzo(g)quinoline-3-carboxylates - Google Patents

Description

This invention relates to lower-alkyl 3-aoyloctahydro-2,5-methanobenzo[g]quinoline-3-carboxylates, useful as intermediates for the preparation of ll(eq)-(2acylethyl)-2,6-methano-3-benzazocines, which in turn are useful as analgesics and analgesic antagonists and to the preparation of said benzazocines from said carboxylates.

United states Patent No. 3,932,422 describes certain 3-acyl-l, 2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo[g]quinolines useful as intermediates for the preparation of 1,2,3,4,5,6-hexahydro-11(eq)-(2-acylethyl)-2,6-methano-3bensazocines. Even under the most favorable reaction conditions, however, the prior method produces, as a slj.de product, substantial quantities of 2-substituted-l,2,3,4,4a, 5,10,10a-octahydro-3,5-ethenobenzo[gIquinolines, thus ap15 preciably diminishing the yield of the main product, the 2,6-methano-3-benzazocines.

Patent No. 45987 relates to certain lower-alkyl 1-^-3R5CO-4act-R3-5ci-R4-6-R2-7-R2-8-R2' -9-R2 ' -1,2,3,4,4a, 5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates, which are useful as intermediates for the preparation of certain hexahydro-2,6-methano-3-benzazooines. More specifically, said valuable intermediates have the formula: which can ba designated lower-alkyl l-R1-3-RsCO-4aa-R3-5a^-6-¾ -7-r2-8-r2·-9-Rj '-1,2,3,4,4a,5,10,lOa-octahydro2,5-methanobenzo[g]quinoline-3-carboxylates and, which are useful in the preparation of 3-R^-6(eq)-Η^-7-Η2-8-Η2-9R2'-10-R2 '-11(ax)-R3-H(«9)-CH2CH2COR5-2,6-methano-3benzazocines having the formula: wherein, in both Formulas I and II: R^ is hydrogen, lower-alkyl, lower-alkenyl, loweralkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-loweralkyl, 2- or 3-furylmethyl, or such 2- or 3-furylmethyl substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl-lower-alkyl, or phenyllower-alkyl, substituted in the phenyl ring by from one to two members of the group consisting of halogen (including bromine, chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms; R2, r2‘, R2 and R2’·1 are each hydrogen, or three of them are hydrogen and the fourth is halogen (including bromine, chlorine or fluorine), lower-alkyl, hydroxy, loweralkanoyloxy, lower alkoxy, lower-alky lmercapto, trifluownethyl, nitro, amino, lower-alkanoylamino, lower-alkoxyoarbonylamino -3or phenyl, or two of the adjacent such groups together are methylenedioxy; R3 is hydrogen or lower-alkyl; R^ is hydrogen, lower-alkyl, lower-alkoxy-lower5 alkyl, hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkyl-sulfinyl-lower-alkyl, phenylthio-lower-alkyl, phenyl-sulfinyl-lower-alkyl, lower-alkenyl or halo-loweralkyl, or R3 and together are divalent lower-alkylene, "(CH2^n"' wIlere n is one of the inte9ers 3 or 4; Rg is lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl, cycloaliyllower-alkyl, 2- or 3-furyl, 2- or 3-furyl-(CH2)m, where m is an integer from 2 to 4, or such 2- or 3-furyl or 2- or 3furyl-(CH0) substituted on the unsubstituted ring carbon 4 xu atoms by from one to three methyl groups, phenyl, phenyl^CH2^m' or Phenyl or phenyl-(CH2)m substituted in the phenyl ring by from one to two members of the group consisting of halogen (including bromine, chlorine and fluorine), loweralkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower20 alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms; and Aik is lower-alkyl.

The present invention deals with certain novel compounds of Formula II wherein Rg is lower-alkylthiolowar-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furyl, 2- or 3-furyl-(CH,,) , where m is an integer from 2 to 4, or such £ in 2- or 3-furyl or 2- or 3-furyl-(CH2)m substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, and R^, R2', R2, R2', R, and R4 are as defined above. Such compounds are not disclosed in said above D.S. Patent No. 3,932,422.

As used herein, the terms lower-alkyl or lower35 alkoxy mean saturated, acyclic groups which may be straight or branched containing from one to about seven carbon atoms as exemplified by methyl, ethyl, propyl, isopropyl, butyl, -4ncn-adjacent t-fcutyl, methoxy, ethoxy, propoxy, isopropoxy, or t-butcxy.

As used herein, the terme lower-alkenyl, halolower-alkenyl and lower-alkynyl represent monovalent groups of from three to seven carbon atoms containing one double or triple bond as illustrated, for example, by 1-propenyl, 2-butenyl, 4-pentenyl, 3-methyl-2-butenyl, l-methyl-2propenyl, 2-methyl-2-propenyl, 2-propynyl, 2-butynyl, 4pentynyl, 2-hexynyl and the like. The term halo-lower-alkenyl includes, for example, 3-chloro-2-propenyl, 3-bromo-2-propenyl, 3,3-diohloro-2-propenyl, 3-bromo-2-methyl-2-propenyl and the like.

As used herein, the term cycloalkyl means saturated carbooyclic groups containing from three to seven ring carbon atoms as illustrated, for example, by cyclopropyl, cyclobutyl, cyclopentyl, oyolohexyl, 2-methylcyclobutyl, 4-etbylcyclotaexyl and the like.

As used herein, the term lower-alkanoyl means such groups derived from saturated, aliphatic monocarboxylic acids having from one to four carbon atoms, as illustrated, for example, by formyl, acetyl, propionyl, butyryl, isobutyryl and the like.

The compounds of Forumula IX can be produced by heating the novel β-keto esters of Formula I with formic acid in an inert organic solvent or with a benzyl-di-loweralkylammoniura formate or a tri-lower-alkylammonium formate, usually at a temperature in the range from 120-150°C. The reaction results in simultaneous ring opening between the 2- and 3-ring carbon atoms of the compounds of Formula I and hydrolysis and decarboxylation of the 3-carbo-loweralkoxy group, COOAlk. Suitable solvents are toluene, xylene or mesitylene. A preferred solvent medium is formic acid in mesitylene.

The compounds of Formula I used in preparing the novel compounds of Formula II are prepared by reacting a l-R1-3-R5,,CO-4a«-R3-5a-R4-6-R2-7-R2-8-R2'-9-R2 '-1,2,3,4, 4a,5,10,10a-octahydro-2,5-methanobenzo[g]guinoline of Formula lb with an alkali metal amide, for example sodamide or lithium -5diisopropylamide, in an inert organic solvent and reacting the alkali meta], salt thus formed with an appropriate acyl halide, Rg''*-CO-X(a lower-alkyl halo formate when Rg*'' is where R^, R2, R2', R2, R2''', R3' R4 and have the meanings given above Rg has the same meaning as Rg and Rg'*' is lower-alkoxy, X is halogen and M-N=B is an alkali metal (M) amide (N=B). The reaction is preferably carried out at a temperature from about -10°C. to about -70°C. Suitable solvents are tetrahydrofuran, diethyl ether or dioxane.

The starting materials of Formula lb and methods for their preparation are disclosed in United States Patent 3,932,422.

As indicated above, the sterio configurations of the 3-acyl group (CORg) in the compounds of Formula lb and of the 3-acyl (RgCO) and 3-carbo-lower-alkoxy groups (COOAlk) in the β-keto esters of Formula I are not known with absolute certainty. However, insofar as the structures of the 2,6-methano-3-benzazocines of Formula II (which are prepared from the β-keto esters of Formula I) are concerned, the question of the steric configuration at the 3-position of the compounds of Formula I is moot, because the asymmetry at the 3-position is destroyed on conversion of the compounds of Formula I to the compounds of Formula II. Compounds of 43988 -6Formula I having both possible steric configurations at the 3-position are fully operable for the preparation of the compounds of Formula II. in any event, acylation or carboxylation of the compounds of Formula lb followed by ring opening and decarboxylation gives, in each case, a single, clean product of Formula II.

The compounds of this invention can exist in stereochemically isomeric forms, that is, optical ieomers and geometric isomers. If desired, the isolation or the production of a particular stereochemical form can. be accomplished by application of general principles known in the prior art.

In the nomenclature employed for the compounds of Formula II, herein, ax stands for axial and eq for equatorial, and the configurations are given with reference to the hydroaromatic ring. Thus, the 6(eq), 11(ax) compounds of Formula II are in the cis configuration, whereas the 6 (eq), 11(eq) compounds are in the tranB configuration.

In the nomenclature employed for the compounds of Formulas I and lb again configurations are given with reference to the hydroaromatio ring, and the designation β indicates the cis configuration relative to the 2,5-methano bridge of the compounds of Formula I. Conversely, the designation a indicates the trans configuration relative to the same groups.

The structures of the compounds of this invention were established by the modes of synthesis, by elementary analyses and by infrared and nuclear magnetic resonance spectra. The course of reactions and homogeneity of the products were routinely ascertained by thin layer chromatography.

The manner and process of making and using the invention, and the best mode contemplated of carrying out this invention, will now be described so as to enable any person skilled in the art to which it pertains to make and use the same. The melting points are uncorrected unless noted otherwise. -7A. Preparation of Lower-alkyl 3-R5CO-Octahydro-2,5-methanobenzo[g]quinoline-3-caroxylates of Formula I Example 1 A. To a solution of 0.0625 mole of n-butyl lithium in hexane was added a solution of 6.3 g. (0.063 mole) of diisopropylamine in 100 ml. of tetrahydrofuran while maintaining the temperature at 0°C. The mixture was then cooled to -70°C., and a solution of 20.2 g. (0.059 mole) of ethyl 7-methoxy1,4aa,5a-trimethyl-l,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzotg]quinoline-3-carboxylate in 100 ml. of tetrahydrofuran was added over a period of one hour. The solution was then treated, over a period of about one hour while cooling at -70°C., with a solution of 9.5 g. (0.625 mole) of γ-methylmercaptobutyryl chloride in 100 ml. of tetrahydrofuran, and the solution was stirred at -70°C. for an additional hour.

The solution was then poured into 400 ml. of water, the mixture was extracted two times with diethyl ether, and the ether extracts were dried and concentrated to dryness to give 30.0 g. of residue which solidified. Recrystallization of the latter from hexane afforded 12.6 g. of ethyl 3(4-methylmercapto-l-oxobutyl) -7 -methoxy-1,4act, 5ct-trimethyl1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]guinoline3-carboaylate, m.p. 117.5-119°C.

Following a procedure similar to that described in Example 1 above, the following compounds of Formula I listed in Table I are similarly prepared. The melting point and solvent used for crystallization are given in the column headed m.p. (°C.)/Solv.

Example Ri/r5 Table 1 r2/r4 Aik/ % Yield m.p.CC.)/ Solv. w r2VR2· IB CH, CH,0 H ch3c?H5 oil cyclopentyl(CH,)- H H ch3 100+(crude) 1C CH CH-0 H chC2H5 oil cyclopropyl(CH-)_ H H C,3 60 ID ch3 ch3° H ch3C2H5 142-144 2-furyl H H ch3 26 acetone 45888 -8Table 1 (cont'd) IE ch3 ch3o H ch3 C Hq 2 5 121-123 2-furyl-(CH2)2 H HCH3 54 hexane IF ch3 h H HC2H5 cyclohesqd. H HCH2CH2 och3 1G ch3 h H HC2H5 cyclohexyl-CH2 H H ch2ch2 sc6h5 IH CgH5CH2 H H CH3C2H5 cyclopropyl H ch3° ch3 IX CH3 h a HC2H5 cyclopropyl-CH2 H K ch2ch2 soc6hs 1J Η H HCH3C2H5 2-furyl-(.OljJj CHjO H ch3 IX Η H H ch3C2H5 3-furyl-(ch2)2 h ch3° ch3 IL CHjOKHj H H ch3C2H5 5-CH3-3-furyl-(CH^ 3 Η H ch3 2-By carboxylation of the corresponding 3-R^CO ketones 1 EXRMPtE i A solution of 0.055 mole of lithium diisopropylamide in 60 ml. of tetrahydrofuran was prepared from butyl lithium and diisopropylamine using the procedure described in Example 1 above. The solution thue prepared was cooled to -75°C. and treated with a solution of 17.1 g. 10.05 mole) of ethyl 7-methoxy-l,4aa,5a-trimethyl-l,2,3,4,4a,5,10,10aoctahydro-2,5-methanobenzo[g]quinoline-3-carboxylate added over a period of about thirty minutes while maintaining the temperature at -75eC. The solution was then treated dropwise over a period of one hour at -75°c. with a solution of 5.4 g. (0.05 mole) of ethyl chloroformate in 80 ml. of tetrahydrofuran. The mixture was stirred for one hour, then poured into 400 ml. of aqueous sodium bicarbonate and worked up in the same manner as described in Example 1 to give 9.7 g. of crude material which was recrystallized from pentane to give 6.3 g. (^0%) of diethyl 7-methoxy-l, 4aa,5a-trimethyl1,2,3,4,4a,5,10,lOa-octahydro-2,5-methanobanzo[g]-quinoline-93,3-dicarboxylate, m.p. 89-91°C.

Example 3 A. To a solution of 30 ml. of trimethylammonium formate (prepared by addition of two parts of trimethylamine to five parts of 97% formic acid) heated to 100°C. was added 8.3 g. (0.02 mole) of diethyl 7-methoxy-l,4aa,5atrimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g]quinoline-3,3-dicarboxylate (described above in Example 2), and the mixture was heated to boiling for fifteen minutes. The mixture was then poured onto ice, basified with excess sodium hydroxide and extracted with ether. The ether extracts were washed once with brine, dried over magnesium sulfate and taken to dryness to give 6.5 g. of a colorless oil which was recrystallized from hexane to give 3.8 g. (55%) of ethyl 3-[8-methoxy-3,6(eq),11(ax)-trimethyl1, 2 , 3 , 4 , 5 , 6-hexahydro-2,6-methano-3-benzazocin-ll(eg)-yl] propionate, m.p. 91-93°C.

Following a procedure similar to the described in Example 3A above, using an appropriate lower-alkyl 3-RgCOl,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo [g] quinoline-3carboxylate of Formula I in trimethylammonium formate, the following 1,2,3,4,5,6-hexahydro-ll(eq)-CH2CH2COR,.-2,6methano-3-benzazocines of Formula II were similarly prepared. B„ 8-Methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydroll (eq)-[3-OXO-3-(2-furyl)propyl]-2,6-methano-3-benzazocine (1.5 g., 10%, m.p. 119-122eC. from acetone)prepared by heating 20,5 g. (0.04 mole) of ethyl 7-methoxy-l,4aa,5otrimethyl-3-(2-furoyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5methanobenzo[g]-quinoline-3-carboxylate in 60 ml. of a solution of trimethylammonium formate to boiling for twelve minutes and isolating the product in the form of the free base.

C. 8-Methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydroll (eq)-[3-ΟΧΟ-5-(2-furyl)pentyl]-2,6-methano-3-benzazocine (0.600 g., 71%, m.p. 144-149"C. from acetone/ether prepared by heating 1.0 g. (0.0022 mole) of ethyl 7-methoxy-l,4ad,5atrimethyl-3-[3-(2-furyl)-1-oxopropyl]-1,2,3,4,4a,5,10,10a45888 -10octahydro-2,5-methanobenzo[glquinoline-3-carboxylate in 10 ml. of a solution of trimethylammonium formate to boiling for ten minutes and isolating the product in the form of the free base.

D. 8-Methoxy-3,6(eg),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro11(eg)-3(oxo-6-methylmercaptohexyl)-2,6-methano-3-benzazrclne methanesulfonate (1.1 g., 70%, m.p. 140-143’C. from acetone/ ether) prepared by heating 1.5 g. (0.0033 mole) of ethyl 7-methoxy-l,4act,5a-trimethyl-3-(methylmercapto-l-oxobutyl)1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline3-carboxylate in 10 ml. of a solution of trimethylammonium formate to boiling for fifteen minutes and isolating the product in the form of the methanesulfonate salt.

E. 8-Methoxy-3,6(eg),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro11 (eg) - (3-oxo-5-cyclopentylpentyl) -2,6-iiiethano-3-benzazocine hydrochloride (19.5 g., 48%, m.p. 220-222°C. from ethanol/ ether) prepared by heating 43.7 g. (0,094 mole of ethyl 7-methoxy~l,4aa,5a-trimethyl-3-(3-cyclopentyl-l-oxopropyl)1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline3-carboxylate in a solution of 437 ml. of mesitylene and 35,3 ml. of formic acid under reflux for fifteen hours and isolating the product ln the form of the hydrochloride salt.

F. 8-Methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro11(eg)-(3-oxo-5-cyclopropylpentyl)-2,6-methano-3-benzazoclne hydrochloride (4.6 g., 20%, m.p. 224-225’C. from ethanol/ ether) prepared by heating 24.5 g. (0.056 mole) of ethyl 7-methoxy-l,4aa,5a-trimethyl-3-(3-cyclopropyl-l-oxopropyl)1,2,3,4,4a,5,10,10a-ootahydro-2,5-methanobenzo[gIquinoline3-carboxylate in a solution of 1120 ml. of mesitylene and 42 ml. of formic acid under reflux for twenty-four houre and isolating the product in the form of the free base.

Example 4A-4G Following a procedure similar to that described in Example 2 using an appropriate lower-alkyl 3-RgCO-octahydro2,5-methanobenzo[g]quinoline-3-carboxylate of Formula X, the following 11(eq)-CH2CH2COR5-2,6-methano-3-benzazocines of Formula II are prepared. -11Table 5 ExampleRl/R5 w r2’/r2"· R3/R4 4A gh3 H H H cyclohexyl H H αί2αϊ2αΗ3 5 4B ch3 H H H cyclohexyl-CH2 H H 4CC6H5CH2 H H CH cyclopropyl H ch3° CH3 4D ch3 H H H 10 cyclopropyl-CH2 H H CH^BOCgHg 4E_ H H H ch3 2-furyl-(CH2)2 ch3° H ch3 4P H H H ch3 3-furyl-(CH2)2 H ch30 ch3 15 4G ch2ch=ch2 H H CH 5'-ch3 -3 -furyl- (ch2)3 h H ch3

Claims (5)

1. CLAIMS i

1. A compound of Formula II (herein) wherein R 5 ie lower-alkyl-thia-lower-alkyl, lower-alkoxy-lower-alkyl, lower-alkoxy, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3furyl, 2- or 3-furyl-(CH 2 )m, where m is an integer from 2 to 4, or such 2- or 3-furyl or 2- or 3-furyl-(CH 2 )m substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, and R^ is hydrogen, lower-alkyl, loweralkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furylmethyl; or such 2- or 3-furylmethyl substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkyl substituted in the phenyl ring by from one to two members of the group consisting of halogen, loweralkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-·- alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms; r 2 , R 2 ', R 2 and R 2 ' are each hydrogen, or three of them are hydrogen and the fourth is halogen, lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, Iower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoylamino, loweralkoxycarbonyl -amino or phenyl, or two of the adjacent such groups together are methylenedioxy? R 3 is hydrogen or lower-alkyl; and R 4 is hydrogen, lower-alkyl, lower-alkoxy-lower alkyl, hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkyl-sulfinyl-lower-alkyl, phenylthio-lower-alkyl, phenyl- sulfinyl-lower-alkyl, lower-alkenyl or halo-loweralkyl, or r 3 and R 4 together are divalent lower-alkylene, -(CH 2 )n~, where n is one of the integers 3 or 4.

2. A compound according to claim 1, wherein R^ is lower-alkyl or cycloalkyl-lower-alkyl; R 2 is lower-alkoxy; Rj', and r 2 and R 2 ' are each hydrogen; and R^ is loweralkyl.

3. A compound according to claim 1, wherein R g is not CASE 7242-C 2- or 3-furyl or substituted 2- or 3-furyl.

4. A compound according to claim 1, substantially as herein described with reference to any one of Examples 3A, 4A to 4D.

5. A compound according to claim 1, substantially as herein described with reference to any one of Examples 3B and 3C and 4E to 4G.