United States Patent Office
`
`3,471,503
`Patented Oct. 7, 1969
`
`3,471,503
`1,2,3,5,6,7-HEXAHYDRO-4-PHENETHYL-2,6-
`METHANO-4H-4-BENZAZONN-12-OLS
`John R. Carson, Norristown, Pa., assignor to
`McNeil Laboratories, incorporated, a cor
`poration of Pennsylvania
`No Drawing. Filed May 5, 1967, Ser. No. 636,250
`Int. C. C07d 29/16, 29/24; A61k 27/00
`U.S. C. 260-294.7
`2 Claims
`
`ABSTRACT OF THE DISCLOSURE
`The compounds are of the class of 1,2,3,5,6,7-hexahy
`dro-benzazonines, useful for their pharmacological prop
`erties as hypotensive agents in certain instances and
`for their ability to produce ataxia in other instances.
`
`This invention relates to novel organic compounds and,
`more particularly, to certain benzazonine derivatives and
`to the method of preparation.
`The subject benzazonines may be structurally repre
`Sented by the following formulae:
`
`10
`
`15
`
`20
`
`25
`
`wherein R2 is a member selected from the group con
`30
`sisting of hydrogen and phenyl; and
`4.
`
`35
`
`50
`
`55
`
`III
`wherein R1 is a member selected from the group consist
`ing of hydroxyl, loweralkylcarbonylamido and lower
`alkylcarbonyloxy; R1 and R taken together is a member
`selected from the group consisting of oxo and oximino;
`R is a member selected from the group consisting of
`benzyl, g-phenethyl and methyl; and the nontoxic acid
`addition salts and the therapeutically active loweralkyl
`quaternary ammonium derivatives of compounds repre
`sented by Formula III.
`The thereapeutically active non-toxic acid addition salts
`of the basic nitrogen containing compounds are prepared
`by treatment with an appropriate acid such as an inorganic
`acid, e.g., hydrochloric, hydrobromic, hydriodic, sulfuric,
`nitric or phosphoric; an organic acid such as acetic,
`propionic, glycolic, lactic, pyruvic, malonic, succinic,
`maleic, malic, fumaric, tartaric, citric, benzoic, mandelic,
`cinnamic, methane sulfonic, benzene sulfonic, salicylic,
`2-phenoxybenzoic. Conversely, the salt form may be con
`verted in the usual manner into the free base.
`70
`The novel basic nitrogen containing compounds may be
`converted into the corresponding quaternary ammonium
`
`60
`
`65
`
`2
`compounds by reaction of the tertiary bases with alkylat
`ing agents, i.e., alkyl or aralkyl halides or esters formed
`by reacting alkanols with an oxygen-containing acid such
`as methyl iodide, ethyl bromide, propyl chloride; lower
`alkenyl halides-allyl bromide; dilower alkylsulfates-di
`methylsulfate, diethylsulfate; lower alkylarylsulfonates
`methyl p-toluenesulfonate or aralkyl halides-benzyl chlo
`ride. The quaternizing reaction may be performed in the
`presence or absence of a solvent, at room temperature or
`under cooling, at atmospheric pressure or in a closed ves
`Sel under pressure. Suitable solvents for this purpose are
`ethers such as diethylether or tetrahydrofuran, hydro
`carbons such as benzene and heptane, ketones such as ace
`tone and butanone, loweralkanols such as ethanol, pro
`panol or butanol; or organic acid amides such as forma
`mide or dimethylformamide. When lower alkyl halogen
`ides are used as quarternizing agents, diethyl ether and
`benzene are the preferred solvents.
`The compounds of Formula III wherein R is OH, R
`is methyl or hydrogen and R3 is phenethyl when admin
`istered intravenously to anesthetized dogs at doses of 1
`to 16 mg./kg. of body weight cause a lowering of blood
`pressure. The remainder of the compounds tested all cause
`ataxia when administered intraperitoneally to mice in
`doses ranging from 30 to 300 mg/kg. of body weight.
`Ataxia can be used as an indication of central nervous
`System depression. The acid addition salts of the basic
`nitrogen containing compounds have the same utility as
`the basic compounds.
`In preparing the compounds of this invention, dimethyl
`acetone-1,3-dicarboxylate and o-phthalaldehyde are re
`acted in a solvent such as benzene in the presence of
`piperidine and glacial acetic acid, with removal of water,
`for example, by azeotropic distillation to form dimethyl
`7-OXO-7H-benzocycloheptene-6,8-dicarboxylate. This com
`pound is reduced, for example, by hydrogenation in the
`presence of platinum oxide catalyst to form 7-oxo-5,6,8,9-
`tetrahydro-7H-benzocycloheptene-6,8-dicarboxylate. Re
`action of this compound with 6-phenethylamine in the
`presence of formaldehyde yields dimethyl 1,2,3,5,6,7-hex
`ahydro - 12 - oxo - 4 - phenethyl-2,6-methano - 4H - 4
`benzazonine-2,6-dicarboxylate. Using benzylamine or
`methylamine in place of 3-phenethylamine, the corre
`sponding 4-benzyl and 4-methyl derivatives are obtained.
`The 2,6-dicarboxylic acid derivatives are prepared by hy
`drolysis of the dicarboxylic esters, for example, with hy
`drochloric acid. Hydrolysis and decarboxylation of the
`2,6-dicarboxylic esters with phosphoric acid produces the
`corresponding 4 - substituted-1,2,3,5,6,7-hexahydro-2,6-
`methano-4H-4-benzazonin-12-ones. The 4-substituted-1,2,
`3,5,6,7 - hexahydro-12-hydroxyimino-2,6-methano-4H-4-
`benzazonines may be prepared by reacting the 1,2,3,5,6,7-
`hexahydro - 4 - substituted.-2,6-methano-4H-4-benzazonin
`12-one compounds with hydroxylamine hydrochloride in
`the presence of anhydrous sodium acetate in a suitable
`solvent such as ethanol. When the 1,2,3,5,6,7-hexahydro
`4 - substituted.-2,6-methano-4H-4-benzazonin-12-ones are
`reacted with organolithium reagents such as methyl lith
`ium or phenyl lithium in inert solvents such as ether or
`benzene, the corresponding 12-substituted-12-alcohols are
`produced. The 1,2,3,5,6,7-hexahydro-4-substituted-2,6-
`methano-4H-4-benzazonin-12-ones may be reduced cata
`lytically, for example with platinum in acetic acid, to
`give 1,2,3,5,6,7-hexahydro-4-substituted-2,6-methano-4H
`4-benzazonin-12-ols. These alcohols may be esterified by
`reaction with a lower aliphatic anhydride in the presence
`of a base such as the salt of the corresponding aliphatic
`acid to give the 12-alkanoates. The 12-lower alkyl car
`bonylamido compounds may be prepared by reducing the
`1,2,3,5,6,7-hexahydro-12-hydroxyimino-4-substituted.-2,6-
`methano-4H-4-benzazonine compounds, for example, with
`
`R5
`
`II
`40
`wherein R3 is a member selected from the group con
`sisting of benzyl, B-phenethyl and methyl and R4 and
`R5 are members selected from the group consisting of
`carboxyl and loweralkylcarbonyloxy; and
`
`45
`
`Pfizer Ex. 2002, p. 1
`
`

`

`3,471,503
`3
`4
`benzyl-1,2,3,5,6,7-hexahydro - 2,6 - methano - 4H - 4
`lithium aluminum hydride in a suitable solvent such as
`tetrahydrofuran, and reacting the resulting product with
`benzazonin-12-one, M.P. 128-130' C.
`a lower aliphatic anhydride.
`EXAMPLE VI
`The following examples are intended to illustrate, but
`A 5 gram (0.019 mole) sample of dimethyl 1,2,3,5,6,7-
`not to limit, the scope of the present invention.
`hexahydro - 12-oxo - 4 - phenethyl - 2,6-methano - 4H
`4-benzazonine-2,6-dicarboxylate hydrochloride is dissolved
`EXAMPLE I
`in 50 cc. of 85 percent phosphoric acid, diluted with 50
`The procedure described by Tarbell and Wargotz, J.
`cc. water and then refluxed for 18 hours. The reaction
`Amer. Chem. Soc., 76 5761 (1954) for the diethyl ester
`mixture is cooled and treated with ice water yielding a
`is followed. A solution of 34.7 grams (0.194 mole) of
`suspension which is extracted with ether. The aqueous
`dimethyl acetone-1,3-dicarboxylate, 26.0 grams (0.194
`solution is made definitely basic with potassium hydroxide
`mole) of o-phthalaldehyde, 2 ml. of piperidine and 8 ml.
`solution and the resulting suspension is extracted with
`of glacial acetic acid in 200 ml. of benzene is heated
`ether. The ethereal solution is dried with magnesium Sul
`under reflux with azeotropic removal of water until no
`fate and evaporated. The oil recovered is chromotographed
`more water comes off. The mixture is cooled and the
`on an alumina column using 1:1 benzene-petroleum ether
`precipitated solid is collected by filtration. The filtrate is
`to give a colorless eluate which upon evaporation yields
`concentrated in vacuo and the residue is triturated with
`an off-white solid. The solid is recrystallized from methyl
`methanol. Purification is effected by recrystallization
`cyclohexane. The product obtained is 4-phenethyl-1,2,3-
`from methanol. The product obtained is dimethyl 7
`5,6,7 - hexahydro-2,6-methano-4H-4-benzazonin-12-one,
`20
`oxo-7H-benzocycloheptene-6,8-dicarboxylate, M.P. 186
`M.P. 99-100° C.
`188 C.
`
`5
`
`10
`
`15
`
`25
`
`30
`
`35
`
`EXAMPLE II
`A suspension of 13.6 grams (0.05 mole) of dimethyl
`7-oxo-7H-benzocycloheptene-6,8-dicarboxylate and 0.68
`gram of platinum oxide in 100 ml. of glacial acetic acid
`is hydrogenated on a Parr shaker at 50 p.s.i. Heat is
`evolved during hydrogenation. The catalyst is removed by
`filtration, and the solvent is evaporated in vacuo. The
`residue is dissolved in hot hexane and is allowed to crystal
`lize. The product obtained is dimethyl 7-oxo-5,6,8,9-tetra
`hydro-7H-benzocycloheptene-6,8-dicarboxylate, M.P. 84
`88° C.
`EXAMPLE II
`A solution of 7.3 grams (0.0264 mole) of crude di
`methyl 7-oxo-5,6,8,9-tetrahydro - 7H-benzocycloheptene
`6,8-dicarboxylate, 3.96 ml. (0.053 mole) of Formalin and
`2.9 ml. (0.0264 mole) of benzylamine in 20 ml. of meth
`anol is heated under reflux for 1 hour. A Solid separates
`40
`on cooling and seeding. The mixture is stirred at room
`temperature for 18 hours. The solid is collected by filtra
`tion and recrystallized from methanol. The product ob
`tained is dimethyl-4-benzyl-1,2,3,5,6,7-hexahydro-12-oxo
`26 - methano-4H-4-benzazonine-2,6-dicarboxylate, M.P.
`142-143 C.
`
`EXAMPLE VII
`A 15 gram (0.0328 mole) sample of dimethyl 1,2,3,
`5,6,7 - hexahydro-12-oxo-4-phenethyl-2,6-methano-4H-4-
`benzazonine-2,6-dicarboxylate hydrochloride in 300 cc. of
`37 percent hydrochloric acid is heated at steam bath tem
`perature for 6 hours. The reaction mixture is cooled and
`filtered. The solid recovered is recrystallized from chloro
`form-methanol. The product obtained is 1,2,3,5,6,7-hexa
`hydro - 12 - oxo - 4 - phenethyl-2,6- methano - 4-H - 4
`benzazonine-2,6-dicarboxylic acid hydrochloride. M.P.
`199 C. decn.
`
`EXAMPLE VIII
`A mixture of 5 grams (0.0164 mole) 1,2,3,5,6,7-hexa
`hydro-4-phenethyl-2,6-methano-4H-4-benzazonin-12
`one, 1.17 grams (0.0169 mole) hydroxylamine hydro
`chloride and 4.1 grams (0.05 mole) anhydrous sodium
`acetate is refluxed for 3 hours in 120 cc. of 95 percent
`ethanol. Upon cooling, the reaction mixture is filtered to
`remove excess sodium acetate. The resulting filtrate is
`recrystallized from 95 percent ethanol. The product ob
`tained is 1,2,3,5,6,7-hexahydro-12-hydroxyimino-4-phen
`ethyl-2,6-methano-4H-4-benzazonine, M.P. 150-151 C.
`EXAMPLE IX
`A 22.5 gram (0.046 mole) sample of 4-benzyl-1,2,3,-
`5,6,7-hexahydro-4-methyl-12-oxo-2,6-methano - 4H - 4
`benzazoninium p-toluenesulfonate in 200 ml. of absolute
`ethanol is hydrogenated at 50 p.s. i. in the presence of one
`gram of 10% palladium-on-carbon. The catalyst is re
`moved by filtration and the filtrate is evaporated to dry
`ness invacuo. The residual solid is recrystallized from ab
`Solute ethanol. The product obtained is 1,2,3,5,6,7-hexa
`hydro-4-methyl-2,6-methano-4H-4-benzazonin-12 - one p
`toluenesulfonate, M.P. 192-193 C.
`EXAMPLE X
`A 15.0 gram (0.0515 mole) sample of 1,2,3,5,6,7-
`hexahydro - 4 - benzyl-2,6-methano-4H-4-benzazonin-12
`one in 13.4 grams (0.072 mole) of methyl p-toluenesul
`fonate is heated at 80 C. for 18-hours. The mixture is
`cooled and ground thoroughly with ether. The product
`obtained is 4-benzyl-1,2,3,5,6,7-hexahydro-4-methyl-12
`oxo-2,6-methano-4H-4-benzazoninium p-toluenesulfonate.
`EXAMPLE XI
`Using the procedure of Example VIII and substituting
`4 - benzyl-1,2,3,5,6,7-hexahydro-2,6-methano-4H-4-benz
`azonin - 12 - one or 1,2,3,5,6,7-hexahydro-4-methyl-2,6-
`methano-4H-4-benzazonin-12-one for 1,2,3,5,6,7,-hexa
`hydro - 4 - phenethyl-2,6-methano-4H-4-benzazonin-12
`one, the products obtained are 4-benzyl-1,2,3,5,6,7-hexa
`hydro-12-hydroxyimino-2,6-methano-4H-4-benzazonine or
`
`EXAMPLE IV
`A 2.7 gram (0.01 mole) sample of dimethyl 6,7,8,9-
`tetrahydro - 7 - oxo - 5H - benzocycloheptene - 6,8-di
`carboxylate, 1.49 cc. (0.02 mole) of 40 percent aqueous
`formaldehyde solution and 1.21 grams (0.01 mole) of
`(3-phenethylamine in 20 cc. methanol is refluxed 1 hour
`and is then allowed to stand at room temperature for 20
`hours. The reaction mixture is evaporated to an oil which
`is dissolved in ether and treated with ethereal hydrogen
`chloride yielding a solid. After several recrystallizations
`from anhydrous ethanol, the product obtained is dimethyl
`1,2,3,5,6,7 - hexahydro-12-oxo-4-phenethyl-2,6-methano
`4H-4-benzazonine-2,6-dicarboxylate hydrochloride, M.P.
`180-183° C.
`
`50
`
`55
`
`60
`
`EXAMPLE V
`A solution of 14.0 grams (0.0344 mole) of methyl 4
`benzyl-1,2,3,5,6,7 - hexahydro-12-oxo-2,6-methano-4H-4-
`benzazonine-2,6-dicarboxylate in 500 ml. of 60 percent
`phosphoric acid is heated under reflux with stirring for 18
`hours. The reaction mixture is cooled, diluted with water
`and filtered. The filtrate is added with cooling and stirring
`to a solution containing one kilogram of potassium hy
`droxide. The resulting mixture is extracted 3 times with
`70
`ether. The ether solution is washed with brine, dried over
`magnesium sulfate and concentrated in vacuo. The crystal
`line material is recrystallized from methylcyclohexane.
`After recrystallization from 2-propanol followed by re
`crystallization from ether, the product obtained is 4
`75
`
`65
`
`Pfizer Ex. 2002, p. 2
`
`

`

`3,471,503
`6
`5
`1,2,3,5,6,7-hexahydro - 12 - hydroxyimino-4-methyl-2,6-
`form extracts, dried with magnesium sulfate and evapor
`ated to an oil which crystallizes upon cooling. The solid
`methano-4H-4-benzazonine respectively.
`is recrystallized from methylcyclohexane. The product
`EXAMPLE XII
`obtained is 4-benzyl-1,2,3,5,6,7-hexahydro-12-phenyl-2,6-
`A solution of methyl lithium prepared by treating
`methano-4H-4-benzazonin-12-ol, M.P. 150-151 C.
`0.68 gram (0.0984 mole) of freshly cut lithium wire in
`EXAMPLE XVI
`20 cc. ether with 6.95 grams (0.0492) mole) of methyl
`Using the procedure of Example XV and substituting
`iodide in 50 cc. ether is treated with 5 grams (0.0164
`1,2,3,5,6,7-hexahydro-4-phenethyl - 2,6 - methano-4H-4-
`mole) of 1,2,3,5,6,7-hexahydro-4-phenethyl-2,6-methano
`benzazonin-12-one or 1,2,3,5,6,7-hexahydro-4-methyl-2,6-
`4H-4-benzazonin-12-one in 80 cc. ether and allowed to
`stir 18 hours at room temperature. The reaction mixture
`methano-4H-4-benzazonin-12-one for 4-benzyl-1,2,3,5,6,7-
`hexahydro - 2,6 - methano-4H-4-benzazonin-12-one the
`is filtered to remove excess lithium pieces which are
`products obtained are 1,2,3,5,6,7-hexahydro-4-phenethyl
`promptly destroyed. The resulting filtrate is cooled and
`12-phenyl-2,6-methano-4H-4-benzazonin-12-ol or 1,2,3,5,-
`cautiously extracted several times with 3 N hydrochloric
`6,7-hexahydro-4-methyl-12-phenyl-2,6-methano - 4-H - 4
`acid. The extracts are combined and made definitely basic
`with 25 percent sodium hydroxide yielding a suspension
`benzazonin-12-ol respectively.
`which is extracted with ether. The ethereal solution is
`EXAMPLE XVII
`dried with magnesium sulfate and evaporated to an oil.
`The oily amine is converted to the hydrochloride salt
`A 10 gram (0.0271 mole) sample of 4-benzyl-1,2,3,5,-
`which is recrystallized from ethanol-ether. The product
`6,7-hexahydro - 12 - phenyl-2,6-methano - 4H-4-benza
`obtained is 1,2,3,5,6,7-hexahydro-12-methyl-4-phenethyl
`zonin-12-ol in 200 cc. glacial acetic acid containing 6
`drops perchloric acid is hydrogenated at room tempera
`2,6-methano-4H-4-benzazonin-12-ol, M.P., 195-197 C.
`ture using 0.5 gram of 10 percent palladium-on-carbon
`EXAMPLE X
`as the catalyst. The catalyst is removed by filtration and
`Using the procedure of Example XII and substituting
`the resulting filtrate is cautiously evaporated under re
`25
`4-benzyl-1,2,3,5,6,7-hexahydro - 2,6 - methano-4H4-benz
`duced pressure to an oil. The oil is treated with ice and
`azonin - 12 - one or 1,2,3,5,6,7- hexahydro-4-methyl-2,6-
`sodium bicarbonate giving a solid which is dissolved in
`chloroform. The chloroform solution is dried with mag
`methano-4H-4-benzazonin-12-one for 1,2,3,5,6,7-hexa
`hydro - 4 - phenethyl-2,6-methano-4H-4-benzazonin - 12
`nesium sulfate and evaporated to an amorphous solid.
`one, the products obtained are 4-benzyl-1,2,3,5,6,7-hexa
`The solid is recrystallized from anhydrous ethanol. The
`30
`hydro - 12 - methyl-2,6-methano-4H-4-benzazonin-12-ol
`product obtained is 1,2,3,5,6,7-hexahydro-12-phenyl-2,6-
`or 4,12-dimethyl-1,2,3,5,6,7-hexahydro-2,6-methano-4H
`methano-4H-4-benzazonin-12-ol, M.P. 227-228 C.
`4-benzazonin-12-ol.
`EXAMPLE XVII
`Using the procedure of Example XVII and substituting
`4-benzyl - 1,2,3,5,6,7-hexahydro-2,6-methano-4H-4-benza
`Zonin-12-one for 4-benzyl-1,2,3,5,6,7-hexahydro-12-phen
`yl-2,6-methano-4H-4-benzazonin-12-ol, the product ob
`tained is 1,2,3,5,6,7-hexahydro-2,6-methano-4H-4-benza
`zonin-12-ol.
`
`35
`
`O
`
`5
`
`20
`
`EXAMPLE XIX
`A 2 gram (0.00655 mole) sample of 1,2,3,5,6,7-hexahy
`dro-4-phenethyl-2,6-methano-4H-4-benzazonin-12-one in
`75 cc. glacial acetic acid is hydrogenated at room temper
`ature using 0.17 gram of platinum oxide as the catalyst.
`After removal of the catalyst by filtration, the resulting
`solution is evaporated under reduced pressure to an oil.
`The oil is dissolved in water and the aqueous solution is
`made definitely basic with 25 percent sodium hydroxide,
`giving an oily suspension. The suspension is extracted
`with ether and the ethereal extract is dried with magne
`sium sulfate and evaporated to an oil. The oil is dissolved
`in ether and treated with ethereal hydrogen chloride. On
`recrystallization from anhydrous ethanol-ether the prod
`uct obtained is 1,2,3,5,6,7 - hexahydro-4-phenethyl-2,6-
`methano-4H-4-benzazonin-12-ol hydrochloride (% mole
`water), M.P. 186.5-188.5 C.
`EXAMPLE XX
`Using the procedure of Example XIX and substituting
`1,2,3,5,6,7 - hexahydro-4-methyl-2,6-methano-4H-4-ben
`Zazonin-12-one for 1,2,3,5,6,7-hexahydro-4-phenethyl-2,6-
`methano-4H-4-benzazonin-12-one, the product obtained
`is 1,2,3,5,6,7-hexahydro-4-methyl-2,6-methano-4H-4-ben
`zazonin-12-ol.
`
`EXAMPLE XXI
`A 7 gram (0.023 mole) sample of 1,2,3,5,6,7-hexahy
`dro-4-phenethyl-2,6-methano-4H-4-benzazonin-12-one in
`120 cc. glacial acetic acid is hydrogenated at room tem
`perature using 0.6 gram of platinum oxide as the catalyst
`until the theoretical quantity of hydrogen is taken up.
`The catalyst is removed by filtration and the resulting
`solution is evaporated to an oil. The oil is treated with
`cold 25 percent sodium hydroxide solution causing crystal
`
`70
`
`75
`
`EXAMPLE XIV
`To a stirring suspension of 3.48 grams (0.0918 mole)
`lithium aluminum hydride in 300 cc. dry tetrahydrofuran,
`a 9.8 gram (0.0306 mole) sample of 1,2,3,5,6,7-hexa
`hydro - 12 - hydroxyimino-4-phenethyl-2,6-methano-4H
`4-benzazonine dissolved in 100 cc. tetrahydrofuran is
`40
`added. The reaction mixture is refluxed 6/2 hours and
`then stirred at room temperature for 16/2 hours. Cau
`tiously 10 cc. of water and 3 cc. of 25 percent sodium
`hydroxide are added and the resulting mixture after
`addition of ether is stirred at room temperature for one
`hour. The reaction mixture is filtered to give the filtrate
`which is evaporated to an oil. The oil is dissolved in
`ether, dried with magnesium sulfate and evaporated. The
`oily amine obtained is dissolved in ether and treated with
`5 grams (0.0384 mole) of propionic anhydride. The
`50
`reaction mixture is warmed on a steam bath for /2 hour,
`cooled and filtered. The precipitate is recrystallized from
`aqueous ethanol. The product obtained is 1,2,3,5,6,7-hexa
`hydro - 12 - propionamido-4-phenethyl-2,6-methano-4H
`4-benzazonine, M.P. 150-151 C.
`EXAMPLE XV
`To 1.43 grams (0.206 mole) of freshly cut lithium
`wire in 10 cc. ether, 16.2 grams (0.103 mole) of bromo
`60
`benzene in 25 cc. ether is added at a rate so as to con
`trol refluxing. Upon complete addition the suspension is
`allowed to stir at room temperature one hour and then
`the mixture is treated with 50 cc. benzene. The ether in
`the reaction mixture is removed by distillation. To the
`resulting reaction mixture, 10 grams (0.0344 mole) of
`1,2,3,5,6,7-hexahydro-4-benzyl-2,6-methano-4H-4-benza
`zonin-12-one in 20 cc. benzene is added and allowed to
`reflux 14 hours and then allowed to stand at room tem
`perature for 18 hours. After the large unused pieces of
`lithium are removed and destroyed, the reaction is treated
`with a saturated ammonium chloride solution. Chloro
`form is added and the resulting mixture is stirred at room
`temperature for 2 hour. The layers are separated and
`the aqueous layer is extracted several times with chloro
`form. The organic layer is combined with the chloro
`
`45
`
`55
`
`65
`
`Pfizer Ex. 2002, p. 3
`
`

`

`3,471,503
`8
`lization to occur. A 6.7 gram (0.0219 mole) sample of
`tion in 30 ml. of ethanol is stirred at room temperature
`the resulting alcohol mixed with 6.32 grams (0.0657
`for 18 hours. Crystals separate from the mixture and are
`mole) of sodium propionate and 14.3 grams (0.109 mole)
`collected by filtration and recrystallized from ethanol.
`The product is diethyl 4-methyl-1,2,3,5,6,7-hexahydro-12
`propionic anhydride is heated on a steam bath 2 hours
`and then poured into ice water. After standing for 2
`oxo-2,6-methano-4H-4-benzazonine - 2,6 - dicarboxylate,
`hour the aqueous mixture is made neutral with sodium
`M.P. 113-114 C.
`bicarbonate and allowed to stir for 2 hour at room tem
`What is claimed is:
`1. 1,2,3,5,6,7-hexahydro - 12 - methyl - 4 - phenethyl
`perature yielding an oil which slowly crystallizes to a
`solid. The solid is dissolved in methanol at 37° C. and
`2,6-methano-4H-4-benzazonin-12-ol.
`the resulting solution is cooled on Dry Ice. The crystals
`2. 1,2,3,5,6,7-hexahydro - 4 - phenethyl - 2,6-methano
`4H-benzazonin-12-ol hydrochloride.
`recovered are dissolved in ether and a solution of per
`chloric acid in ethanol is added. The precipitate that forms
`is collected and recrystallized from an anhydrous etha
`References Cited
`noi. The product obtained is (1,2,3,5,6,7-hexahydro-4-
`Cremical Abstracts, vol. 65, August 1966, pp. 3829-30,
`phenethyl-2,6-methano - 4H - 4 - benzazonin - 12-yl)pro
`Hahn et al.
`pionate perchloride, M.P. 200-202 C.
`HENRY R. JILES, Primary Examiner
`EXAMPLE XXI
`S. D. WINTERS, Assistant Examiner
`A solution of 11.2 grams (0.0369 mole) of diethyl
`7 - oxo - 5,6,8,9-tetrahydro-7H-benzocycloheptene-6,8-di
`20
`U.S. Cl. X.R.
`carboxylate, 5.54 ml. of Formalin (0.0738 mole) and
`260-293.4, 294, 294.3, 999
`3.81 ml. (0.0369 mole) of 30 percent methylamine solu
`
`O
`
`5
`
`Pfizer Ex. 2002, p. 4
`
`