IL25699A - Process for the production of methanobenzazocines - Google Patents

Description

Process for the production 24524 la a process for the tion of derivatives and their of the general formula wherein represents a halogen a yl or a hydroxyl represents a hydroxyl group or an radical having up to and including 4 carbon atoms or an radical having up to and including carbon Y represents a cycloalkylmethyl or an radical having up to and including carbon atoms and being or substituted by a phenyl or an arninophenyl and represents hydrogen or an having up to and including carbon which process comprises treating a compound having the formula wherein A represents a carbonyl group or the group one Z represents a carbonyl group and other a methylene provided that A and shall not simultaneously sents and R X and Y have the lb meanings with a agent suitable for the reduction a group to a and a substituted having the formula I represents an radical is subsequently treating a substituted obtained as the in the presentee the of as the p into a Another this hydrochloric acid tke literature also fee starting for the according the their new are produced the scheme Starting compounds of general formula II which are substituted according to the definitions of and are produced in an analogous This is also illustrated in the Another possibility for the production of starting materials of general formula II which also contain an oxo group in the is illustrated by the following scheme of The following scheme of reactions illustrates the production of compounds of general formula II wherein Z in the is a carbonyl group and Z in the is a methylene NaH Heating Other starting compounds containing substituents corresponding to the definitions of and are produced in an logous Compounds of general formula I wherein X is hydrogen and and Y have the meanings given in formula as well as their acid addition are obtained according to the invention by treating a pound of the general formula III wherein and have the meanings given with a reducing agent suitable for the reduction of a carbonyl group into a methylene group if modifying a compound of formula I wherein Rj is a low alkoxy or alkanoyloxy by ether cleavage or hydrolysis into a compound which is also embraced by formula I wherein is the hydroxyl if converting such a compound by treatment with an alkylating or alkanoylating agent depending on the meaning of into a compound of general formula I wherein 2 is a low alkoxy or alkanoyloxy if converting a compound so obtained into a salt with an inorganic or organic For this reduction the same reducing agents as those mentioned for the reduction of compounds of formula II into those of formula I are Starting materials of the general formula III which are also new are for in the following 6 In this case compounds of general formula III substituted corresponding to the meanings of the substituents and are produced in an analogous Any ether cleavage required to convert an alkoxy radical in the substituent Rj into the hydroxyl radical is performed by in particular by treatment with boiling hydrobromic Any conversion necessary of an alkanoyloxy radical in the substituent 2 into the hydroxyl group is formed by likewise by methods known per Particularly diazoalkanes are used as alkylating for the conversion of an group into a low alkoxy Also phenyl ammonium halides such as ammonium in the presence of sodium in are The main suitable alkanoylating for the conversion of the group into a low alkanoyloxy are reactive functional derivatives of low alkane oxylic acids such as the anhydrides and As examples can be acetic acid propionic acid acetyl acetyl bromide and propionoyl prepared As can be seen from formula the to the invention may be in the form of optical the presence of an asymmetric carbon atom in the methanoazocine ring will lead to the formation of and If X in formula I is an alkyl then stereoisomers are the alkyl group being cis or trans to the phenyl group in the Further isomeric forms will exist if the group represented by Y lacks a plane of In all these the geometric or stereoisomeric forms can be separated by taking advantage of differences in their by fractional crystallisation or When it is desirable to resolve enantiomorphs the standard formation of diastereoisomeric salts by the use of The separation of an optically active acid is ll these isomeric forms is within the purview of the present The compounds of general formula I form some of which have good water with inorganic and organic acids such as hydrochloric hydrobromic sulphuric phosphoric methane sulphonic ethane onic ethane sulphonic acetic propionic fumaric lactic malic tartaric citric benzoic salicylic phenylacetic acid and mandelic The following examples illustrate the present invention but in no way limit it The temperatures are given in degrees 8 Example zoclne hydrochloride acid To a solution of 1 mole of sodium prepared by the addition of 168 of diphenylmethane in ether to a solution of 1 mole of sodium amide in liquid was added an ethereal solution of of The orange color of the diphenylmethlde disappeared as the last of the acid was The ammonia was evaporated and the solid was separated by filtration and dissolved in and the aqueous solution was acidified with hydrochloric The white precipitated acid was recrystallised from aqueous ethanol to give 96 of white To 250 of polyphosphoric heated to was added 66 of 4 The mixture was stirred and heated at for 30 The solution was cooled and ice and water were The yellow precipitate was separated by stirred with dilute sodium washed with water and recrystallized from aqueous ethanol to give of pale yellow To a solution of mole of potassium amide in liquid ammonia was added an ethereal solution of of The dark red solution was stirred for 15 minutes and an ethereal solution of dimethylaminomethyl chloride by shaking 5 of the hydrochloride with base and and drying the ethereal extract over potassium was added until the red color was The resulting solution was stirred for 20 minutes and excess ammonium chloride was The ammonia was evaporated and the residue was stirred with ether and The ethereal layer was combined with an ethereal extract of the aqueous layer and extracted with IN hydrochloric The acidic solution was neutralized with IN sodium hydroxide and extracted with The ethereal extract was dried over sodium sulfate and affording of a pale yellow The oil was dissolved in 30 of ether and hydrogen chloride was bubbled into the solution until precipitation was The white solid was recrystallized from ether to give of a white solid which did not melt at hydrobromide To a hot solution of 40 of in 100 of acetic acid was added slowly a solution of 7 of bromine in 20 of acetic The solution was stirred and heated just below the boiling point for 35 and allowed to cool to room dark yellow solid The solid was separated by filtration and washed with The sulting pale yellow solid weighed 30 A mixture of 30 of hydrobromide 200 of 50 of methanol and 5 ml of concentrated ammonium hydroxide was stirred at room After three hours a further three of ammonium hydroxide was and enough methanol to dissolve most of the Stirring was continued The resulting clear solution was porated to give 28 of pale yellow To the solid was added 200 of and the mixture was refluxed until all the solid and for 30 minutes There was collected 8 of water with a Dean stark this is presumed to have been present in the quaternary The solution was diluted with and the mixture was tracted with The organic solution was extracted three times with hydrochloric and the acidic solution was extracted twice with ether and neutralized with 6N sodium The basic solution was extracted twice with and the ethereal solution was dried over sodium sulfate and to give corrected for ammonium bromide and of pale yellow After tallization from the solid melted at 11 hydrochloride A mixture of of the above of hydrazine hydrate and 1 of powdered potassium hydroxide in 10 of diethylene glycol was kept for 2 hours in an oil bath heated to The mixture was poured into ice and extracted with The ethereal solution was extracted with dilute hydrochloric The acidic solution was made basic and extracted with and the ethereal solution dried over sodium sulfate and The resulting yellow oil lized on The oil was dissolved in ether and hydrogen chloride was passed into the solution until itation was The yellow solid was recrystallized from to give of white needles melting at The same compound is obtained by reducing in an analogous manner the 2 3 4 5 In a similar on using 3 one from the product 3 benzazocine is of the hydrochloride of the On using 12 the 3 is On the 2 is Hydrochloride On using phenyl 2 the is Using the procedure described section there is obtained from or 2 3 4 5 the compound 225 229 346 349 from the hydrobromide 329 330 from 2 one the compound 5 225 229 264 269 The reduction can also be performed the ditions of the Clemmensen reduction with amalgamated zinc in the presence of hydrochloric Example 2 hydrochloride acid To a solution of mole of potassium methide in liquid prepared from mole of potassium amide and of was added an ethereal solution of of The solution was stirred until the color was discharged and the ammonia was The residue was stirred with ether and water and the layers were The aqueous solution was washed once with ether and The resulting solid acid melted at and weighed 3 To 250 of polyphosphoric heated to was added of the above The brown ture was stirred and heated for 1 cooled to room temperature and poured into The mixture was extracted with ether and the ethereal solution was with saturated sodium The ethereal solution was dried sodium sulfate and evaporated to give of tan which was recrystallized from aqueous ethanol to give pale yellow needles melting at 1 To a solution of mole of potassium amide in liquid ammonia was added of the above An ethereal solution of dimethylaminoethyl prepared ammonium chloride was and the ammonia was The residue was stirred wit ether and and the ethereal solution was separated and extracted with hydrochloric The acidic solution was neutralized with sodium hydroxide tracted with The ethereal solution was dried over sodium sulfate and evaporated to give of basic 3 2 The above ketone was brominated in acetic acid in the same manner as in the Example The hydrobromide was cyclized in as before and the quaternary salt was heated in monanol to effect The ketone was isolated as a pale yellow 3 hydrochloride The above mentioned ketone was reduced with hydrazine and potassium hydroxide as decribed in Example 1 The oil was converted to the hydrochloride salt by treatment with alcoholic hydrogen chloride to yield the crystalline 15 Example 3 2 4 hydrochloride be zoate of are in 150 of The solution is cooled to and acid dissolved in chloroform is added within mixture is stirred and cooled keep the temperature between tional chloroform is added to bring the volume to 2000 and the mixture is allowed to react for 5 hours at room The solution is washed with concentrated sodium bicarbonate solution and dried over sodium After removing the solvent an oily solid is obtained After washing with petroleum ether a white product is obtained crystallization1 from cyclohexane gives The NMR Spectrum shows a methine signal ppm which indicated that the proton is rather neighboring to the Also a singlet for the at ppm indicates the tertiary doublet would be expected for the and g of pyridine are jsolved in ml of dry Thionylchloride is slowly added to the stirred solution and the is no allowed to rise over The mixture ί refluxed for 5 hours and set aside for 3 Chloroform is added and the mixture is with water and sodium bicarbonate solution and jdried over sodium The solvent is removed in vacuo and the residue A fraction boiling between is of lis tetralorie dissolved in dimethyl formamide potassium is added to sodium hydride 54 oil The mixture is stirred with exclusion of moisture and oxygen for one hour hydrochloride The product of Example 3 is reduced in an analogous manner as described in Example 1 to yield in form of the 158 Example 4 3 2 g of are heated at with 15 ml of 48 acid for 12 The solution is rendered alkaline with aqueous ammonium hydroxide and extracted with The extracts are dried and concentrated and the residue is recrystallized from isopropanol to yield the Example 5 of hydrochloride was treated with ammonium hydroxide to liberate the free This base after drying in a vacuum oven and recrystallization from ether was heated with of acetic anhydride at the boiling point of the solution for one The reaction mixture was then concentrated to dryness in vacuo to leave a The residue was dissolved in chloroform and washed with saturated sodium bicarbonate 19 20 solution washing became Chloroform layer was then washed with dried over anhydrous sodium treated with charcoal and evaporated to dryness to leave of stalline The residue was recrystallized from isopropanol to obtain the crystalline In analogous manner on the corresponding anhydride are obtained o 2 in and in 20a Resolution of A solution of racemic zocine and of L acid in 1250 of methanol and 500 of isopropanol is concentrated to a volume of 700 During the process the diastereoisomeric levorotatory acid addition precipitates as a cooling the the salt is collected by filtration to afford of of The optically active levorotatory free base is by partially dissolving the salt in 250 of boiling water and adding 75 of aqueous Upon the product is collected to give g of white One recrystallization gives 23 Example d 729 mg of was dissolved in a mixture of 5 ml of concentrated hydrochloric acid and 2 ml of This solution was added to a stirred mixture of 10 g of zincamalgam in 20 ml of concentrated hydrochloric acid and 3 ml of After addition was the mixture was stirred for five hours at room then for minutes and 10 ml of ethanol A slow stream of hydrogen chloride was passed through the stirred mixture for two hours without then one hour with heating at a temperature of 90 After this the inflow of hydrochloric gas was stopped and the mixture stirred and heated for 12 After this all had The reaction mixture was transferred to a separatory funnel and carefully tracted with 500 ml of chloroform and 300 ml of concentrated ous ammonium The chloroform layer was separated and the aqueous phase was with 500 ml of The 23a bined chloroform extracts were dried filtered and the solvent removed in vacuo to yield 500 of as a solid Recrystallisation from ether afforded the crystalline 116 121 The mother liquors contained d 2 3 5 as could be strated by thin chromatography thereof and comparison with an authentic sample run concurrently on the same chromatoplate In a similar employing and hydrochloric there was from 2 3 5 the compound dihydrochloride 310 Example 10 Hydrochloride To 4 g of amalgamated zinc is added 10 ml concentrated HC1 and 3 ml water followed by 2 g of 2 3 4 5 hydrobromide 270 The refluxing mixture was rapidly stirred while slowly adding a stream of HC1 gas over a period of 4 Cooled to room temperature and let stir the mixture was filtered and the filtrate made basic with dilute Extract aqueous phase with ether The ether extract was concentrated in vacuo yield an The residue was taken up in ethanol and treated with ethanolic HC1 to yield the Material was crystallized from 255 256 insufficientOCRQuality

Claims (1)

1. Proc zocines havin represents halogen a trifluoromethyl or a hydroxy1 represents a hydroxyl group or a alkoxy radical having to and including 4 carbon atoms or alkanoylo y radical having up to and including 6 carbon Y represents a cycloalkylmethyl or an radical having up to and including 5 carbon atoms unsubstituted or by a phenyl o aminophenyi radical and represents hydrogen or an alkyl radical having to and carbon atoms which process a compound having the formula wherein A represents a carbonyl group or the group one Z represents a carbonyl group and the other a methylene provided that A and Z shall not simultaneously represent and X and Y have the meanings given with a reducing suitable for the reduction of a carbonyl group to a and a substituted methanobenzazocine aving the formula I wherein represents an alkanoyloxy cal is subsequently treating a substituted benzazocine obtained as above wherein represents a hydroxyl with an alkanoyla ing Process as claimed in claim wherein a substituted methanobenzazocine is obtained having an radical as wherein that alkoxy radical is subsequently by into a hydroxyl Process as claimed in claim wherein a substituted methanobenzazocine is obtained having a hydroxyl group as and wherein chat hydroxyl group is subsequently by treatment with an alkylating into an alkoxy Process as claimed in claim in which a of the formula II is wherein A is and Z is and and Y have the meanings Process as claimed in claim in which a compound of the formula is wherein A is the group one Z is carbonyl and the other is methylene and R X and insufficientOCRQuality