CA1239938A - Process for the preparation of a benzamide derivative - Google Patents
Process for the preparation of a benzamide derivativeInfo
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- CA1239938A CA1239938A CA000472445A CA472445A CA1239938A CA 1239938 A CA1239938 A CA 1239938A CA 000472445 A CA000472445 A CA 000472445A CA 472445 A CA472445 A CA 472445A CA 1239938 A CA1239938 A CA 1239938A
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- formula
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- ethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention provides a process for the preparation of 2-hydroxy-5-[1-hydroxy-2-[1-methyl-3-phenylpropyl))amino]ethyl}
benzamlde of the formula ( I ) and pharmaceutlcally acceptable acld addltion salts thereof which comprises hydrogenating 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene-3-ylldene)lmlno]ethyl}benzamlde of the formula (V) and, if desired, converting the compound of the formula I thus obtained into a pharmaceutically acceptable acid addition salt.
The present invention also provides a compound of the formula V .
The invention provides a process for the preparation of 2-hydroxy-5-[1-hydroxy-2-[1-methyl-3-phenylpropyl))amino]ethyl}
benzamlde of the formula ( I ) and pharmaceutlcally acceptable acld addltion salts thereof which comprises hydrogenating 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene-3-ylldene)lmlno]ethyl}benzamlde of the formula (V) and, if desired, converting the compound of the formula I thus obtained into a pharmaceutically acceptable acid addition salt.
The present invention also provides a compound of the formula V .
Description
~3~3~33~
Thls Inventlon relates ~o a process for the preparatlon oF a benzamlde derlvatlve. More partlcularly, It Is concerned ~ h a new and Improved process For the preparatlon of 2-hydroxy-5-~1-hydroxy-2~ methyl-3-phenylpropyl)-amlno]ethyl}benzamlde and pharmaceutlcally acceptable acld addltlon salts thereof.
It Is known that 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenylpropyl)-amlno]ethyl~benzamlde Is a,useful and wlde spread alpha- and beta-blocklng hypotenslve agent.
In the prlor art a number of procedures are dlsclosed for the preparatlon of 2-hydroxy-5-C1-hydroxy-2-[(1-methyi-3-phenylpropyl)amlno]ethyl}benzamlde. Accordlng to DOS No.
Thls Inventlon relates ~o a process for the preparatlon oF a benzamlde derlvatlve. More partlcularly, It Is concerned ~ h a new and Improved process For the preparatlon of 2-hydroxy-5-~1-hydroxy-2~ methyl-3-phenylpropyl)-amlno]ethyl}benzamlde and pharmaceutlcally acceptable acld addltlon salts thereof.
It Is known that 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenylpropyl)-amlno]ethyl~benzamlde Is a,useful and wlde spread alpha- and beta-blocklng hypotenslve agent.
In the prlor art a number of procedures are dlsclosed for the preparatlon of 2-hydroxy-5-C1-hydroxy-2-[(1-methyi-3-phenylpropyl)amlno]ethyl}benzamlde. Accordlng to DOS No.
2,032,642, 2-hydroxy-5-acetylbenzamlde Is bromlnated, the ~)-bro-moacetyl derlvatl~e thus obtalned Is reacted wlth N-b~nzyl-N-(1-methyl-3-phenylpropyl)amlne and the ~eto group of the 2-hydroxy-5-~2-~N-benzy1-N-(1-methyl-3-phenyipropyl)-amlno] acetyl}benz-amlde Is reduced by catalytlc hydrogenatlon while the protectlng N-benzyl group Is cleaved to ylelci 2-hydroxy-5-{1-hydroxy-2-r~1-methyl-3-phenylpropyl)amlnoie-thyl} benzamlde.
The drawback of thls process Is that the end-product Is obtalned by means of a synthesls comprlslng many steps and In low yields. Moreover, the N-benzyl-N~(1-methyl-3-phenylpropyl)amine component can be produced only In the multlstep synthesls In a complIcated manner, too.
Accordlng to another process dlsclosed In DOS No.
2,032,642~ 2-hydroxy-5-(bromoacetyl)benzamlde Is reacted with N,N-dlbenzylamlne and the 2-hydroxy-5-(N,N-dlbenzylglycyl)-benza--; mlde of the formula , ~
~ ~ 3~
CONrl2 / C~12 ~ (IV) llO ~ CIT, - N ~
obtalned Is reac-ted wlth 1-phenyl-3-butanone under reduclng con-dltlons. The ylelds achleved are medlum. A further dlsadvantage vF thls method resldes In the fact that 1-phenyl-3-butanone Is not avallable on Industrlal scale and In the prlor art no econom-lcal Industrlal scale rrlanu~acturlng process o~ the sald compound Is dlsclosed.
Accordlng to a further method of sald DOS 5-(2-am1no-12-hydroxyethyl)sallcylamlde Is reacted wlth 1-phenyl-3-butanone In ethanoll~ solutlon under reduclng condltlons t~ ~Ive the deslred compound 2-hydroxy-5--C~-hydroxy-2-~(1-methyl-3-phenyl-propyl)amlno]ethyl}benzam1de.
In the correspondln~ example, however, no y~eld ~s glven. A dra~back of thls method Is 9 ~S It was already mentloned aboYe, that 1-phenyl-3-butanone startlng materlal Is not avall-able on Industrlal scale.
2~ In Belgian patent No. 840,7799 and DOS No. 2,616,403 a process For the preparatlon and separatlon of dlasteroisomers of Z-hydroxy-5-C1-hydroxy-2-~1-methyl-3-phenylpropyl)amlno] ethyl}
benzamlde Is dlsclosed. ~n the me~ho~s described hereln as a result of the formatlon of the chlral centrum the number of r-eac-tlon steps Is Increased, and the total yleld of the synthesls Is ; rather low.
Accordlng to the general formulae of ~lungarlan patent No. 165,291, 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenylproPyl) amlno]ethyl~benza~lde rnay be prepared by condenslng 2-hydroxy-5-glyoxylylbenzolc acld ester wlth 1-phenyl-3-butylamlne and sub-
The drawback of thls process Is that the end-product Is obtalned by means of a synthesls comprlslng many steps and In low yields. Moreover, the N-benzyl-N~(1-methyl-3-phenylpropyl)amine component can be produced only In the multlstep synthesls In a complIcated manner, too.
Accordlng to another process dlsclosed In DOS No.
2,032,642~ 2-hydroxy-5-(bromoacetyl)benzamlde Is reacted with N,N-dlbenzylamlne and the 2-hydroxy-5-(N,N-dlbenzylglycyl)-benza--; mlde of the formula , ~
~ ~ 3~
CONrl2 / C~12 ~ (IV) llO ~ CIT, - N ~
obtalned Is reac-ted wlth 1-phenyl-3-butanone under reduclng con-dltlons. The ylelds achleved are medlum. A further dlsadvantage vF thls method resldes In the fact that 1-phenyl-3-butanone Is not avallable on Industrlal scale and In the prlor art no econom-lcal Industrlal scale rrlanu~acturlng process o~ the sald compound Is dlsclosed.
Accordlng to a further method of sald DOS 5-(2-am1no-12-hydroxyethyl)sallcylamlde Is reacted wlth 1-phenyl-3-butanone In ethanoll~ solutlon under reduclng condltlons t~ ~Ive the deslred compound 2-hydroxy-5--C~-hydroxy-2-~(1-methyl-3-phenyl-propyl)amlno]ethyl}benzam1de.
In the correspondln~ example, however, no y~eld ~s glven. A dra~back of thls method Is 9 ~S It was already mentloned aboYe, that 1-phenyl-3-butanone startlng materlal Is not avall-able on Industrlal scale.
2~ In Belgian patent No. 840,7799 and DOS No. 2,616,403 a process For the preparatlon and separatlon of dlasteroisomers of Z-hydroxy-5-C1-hydroxy-2-~1-methyl-3-phenylpropyl)amlno] ethyl}
benzamlde Is dlsclosed. ~n the me~ho~s described hereln as a result of the formatlon of the chlral centrum the number of r-eac-tlon steps Is Increased, and the total yleld of the synthesls Is ; rather low.
Accordlng to the general formulae of ~lungarlan patent No. 165,291, 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenylproPyl) amlno]ethyl~benza~lde rnay be prepared by condenslng 2-hydroxy-5-glyoxylylbenzolc acld ester wlth 1-phenyl-3-butylamlne and sub-
3~
Jectlng the SchifF base thus obtalned to catalytic hydro~enatlon.In the patent speclflca-~lon, ho~ever, no exampJe is dlsclosed For the pr~paratlon oF 2-hydrvxy-~-C1-hydroxy-2-~(1-methyl-3-phenyl-propyl)amino~ethyl3benzamlde.
It Is the obJect of the present Inventlon to elaborate a proces~ for the preparatlon o-F 2-hydroxy-5-{1-hydro~y-2-[(1-methyl-3-phenylpropyl)amlno]ethyl}benzamlde whlch ellmlnates the above drawbacks of the Icnown methods, provldes hlgher ylelds, Is readlly feaslble on Industrlal scale pro~uctlon and uses easlly avallable startlng materlals.
It has been found that 2-hydroxy-5C1-hydroxy-2-~
methyl-3-phenylpropyl)amlno]ethyl}benzamlde of the formula ('ONII
16 \ 2 . ( r ) ElO ~ Cll- Cl[
011 Nl-l - Cll C112 - Cl12 - ~
may be prepared In a more slmple and economlcal manner from ~-hydroxy-~-[1-hydroxy-2-[(1-phenyl-but-1-ene-3-ylldene)-lmlno3 ethyl~benzamlde of the formuia CON~12 llO ~ 3 (V) Oil N = C
\ Cll = C~{
3~ ~ ~
Accordlng to the present Inventlon there 19 provlded a process for the preparatlon of 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenylpropyl)amlno]ethyl}benzamlde of the formula I and 3~ pharmaceutlcally acceptable acld addltlon salts thereo~ whlch comprlses hydrogenatlng 2-hydroxy-5-C1-hydroxy-2-~(1-phenyl-but-~ .....
3~9~3~
1-ene-3-ylldene)amlno]ethyl}benzamlde of the Formula V and, IF
deslred, convertlng the compound o~ the formula ~thus obtalned Into a pharmaceutlcally acceptable acld addi-tlon s~lt.
The reduction oF the Schlff base of the formula ~may be carrled out by catalytlc hydrogenatlon. As cataiyst preferably paliadlum, platlnum, nlckel or an Adams catalyst may be used. The catalyst may also be applled on a carrler (e.g.
charcoal, barlum sulfate). Hydrogenatlon may be carrled out at a 10 temperature of about 20-30C, and under a pressure of 1-10 atm., preferably 2-4 atm. One may partlcularly advantageously work at 25C and under a pressure of 3 atm. The reductlon may be carrled out In an Inert organic soivent. As reactlon medlum preFerbly an ether (e.g. dlethyl ether, dloxane or tetrahydrofurane~ or an alcohol le.g. methanol or ethanol), partlcularly tetrahydroFurane may be used. In the course of the reactlon two equlvalents of hydrogen are consumed and both the azome-thlne bond and carbon-carbon double bond are saturated. The reactlon may be accomplIshed In the presence of a small amoun-t of an or0anlc acld (e.g. glaclai acetlc acld). The ylelds achleved are almost theore-tlc.
The reactlon mlxture may be worked up by methods known ~ se. One may preferably proceed by fllterlng off the catalyst and evaporatlng the flltrate. The hydrochlorlde may be Isolated by addlng anhydrous ethanollc hydrogen chlorlde or a mixture of concentrated hydrochlorlc acld and ethanol to the hydrogenated flltrate.
The startlng materlal of the Formula V Is a new com-pound and may be prepared by reactlng 2-hydroxy-5-(1-hydroxy-2-amlnoethyl)benzamlde of the formula 3~3~
CON~-I
2 ( II ) ~10 -- _ CH - CH2 wlth 1-phenyl-but-1-ene-3-one of the formula ~ ~ ( III), W CH = C~l - COC113 The reactlon may be carrled out In an Inert organlc solvent. As reactlon medlum preFerably ~n e-ther ~e.~. dlethyl ether, dloxane or tetrahydrofurane), alcohol (e.g. methanol or etharlol) or an aromatlc hydrocarbon (e.g. benzene, toluene or xylene), partlcu-larly tetrahydrofurane may be used. The reactlon may be accom-pllshed at a temperature between ~5-100C, preferably at a tem-perature of about 40C. The reactlon may optlonally be carrled out In the presence of a base (e.g. trlethyl amlne or morpho-llne).
The compound of the formula ~ thus obtalned may either be Isolated or subJected to catalytlc hydrogenatlon In sltu wlth-out Isolatlon.
Accordlng to a form of realIzatlon of the process ofthe present Inventlon the compound of the formula 11 prepared by catalytlc hydrogenatlon of the compound of the formula llO ~ Cll - CH2 - N ~ (VI) 0~ C~l2 -,~ .
3~3 Is used. One may wor~ preferably by subJectlng a compound of the Formul~ Vl to catnlYtlc hydrogenatlon, reactlng the compound of the formula 1~ thus formed In sltu wlth the compound of the for-__ mula 1~ and hydrogenatlng the compound of the formula V thusformed wlthout Isoia~lon.
Accordlng to a further form of reallzatlon oF -the pro-cess of the present Inventlon the compound of the formula 1~ pre-pared by ca~alytlc hydrogenatlon of the compound of the Formula IV Is used. One may proceed preFerably by subJectlng the com-pound of the iormula IV to catalytlc hydrogenatlon, reactlng the compound of the formula IV to catalytlc hydrogenatlon, reactlng the compound of the formula 1~ thus Formed In sltu wlth a corn-pound of the Formula ~ and hydrogenatlng the compound of the formula V thus formed wlthout Isolatlon.
The two Iatter forms of reallzatlon of the process of the present Inventlon may be carrled out preferably at an ele-vated temperature, preFerably at 50-70C and under a pressure between 1 and 100 atm., preferably under a pressure of about 50 atm. The reactlon may be carried out In an Inert organlc solvent. As reactlon medlum preferably an alcohol (e.g. methanol or ethanol) may be used. The reactlon mlxture may also contaln an acld (e.g. glaclal acetlc acld). As catalyst e.g. pailadium, platlnum, nlckel or Adams catalyst may be used. The catalyst may be applled onto a carrler, e.~. charcoal, barlum sulfate, etc., If deslred.
The maJor advantage of the process oF the present Inventlon Is that -the s-tartlng materlals ~sed for the preparatlon of the compound of the formula V may be prepared from materlals (e.g. benzal acetone) readlly feaslble and economlca~ on indus-trlal scale, ~oo and the yields are hlgh.
3~ Wlthout llmltlng the scope of the inventlon by theoret-lcal conslderatlons we presume that thls Is due to the Fact tha-t ~3~3~
because oF conJugatlon -the keto group oF 1-phenyl-bu-t-1-ene-3-one (benzal acetone) u~ed In the process of the present Inventlon Is more reactlYe than the keto group of 1-phenyl-butan-3-one applled In the process dlsclosed ~n DOS No. 2,03Z,642. For thls reason the compound of the formula lll reacts wlth the 2-hydroxy-5-(1-hydroxy-~-amlno-ethyl)-benzamlde of the formula ll to give the correspondlng 2-hydroxy-5-[1-hydroxy-Z-~(1-phenyl-but-1-ene-3-ylldene)Imlno~ethyl)-benzamlde much more easlly than the corre-spondlng Intermedlate Is formed In the process descrlbed In DOS
10 No. 2,032,6~Z, namely 2-hydroxy-5 r 1-hydroxy-2-[(1-phenyl-but-3-ylldene)lmldo]ethyl~benzamlde or 2-hydroxy-5-C1-keto-2-[(1-phenyi-but-3-ylldene)-Imlno]ethyl}benzamlde.
Further detalls of the process of the Inventlon are to be found In the followlng Examples wlthout llmltlng the scope of protectlon by the sald Examples.
Example 1 Preparatlon of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene-3-ylldene)amlno]ethyl~benzamlde 2.30 9 (10 milllmoles) of 2-hydroxy-5-(1-hydroxy-2-amlnoethyl)benzamld0 hydrochlorIde and 1.46 9 (10 mllllmoles) of 25 1-phenyl-~ut-1-ene-3-one are admlxed wlth 10 ml of tetrahydrofu-rane whereupon under further stlrrln~ and Ice-coolIng 1.20 ~l of trlethyl amlne are added dropwlse at a temperature of 10-15C.
The addltlon havlng been completed the reactlon mlxture Is stlrred at room temperature for further 5 hours and the preclpl-tated trlethyl amlne hydrochlorIde Is filtered of-F. From the ; flltrate the 2-hydroxy-5-{1-hydroxy-2-~ phenyl-but-1-ene-3~yll-dene)Imlno~-ethyl}benzamlde Is Isolated by column chromatography on slllca gel. Thus 1.56 g of the deslred compound are obtalned, yleld 48%, m.p.: 142-146C.
~.' Exam~le Z
Preparatlon of 2-hydroxy-5-~1-hy~roxy-2-[~l-phenyl-but-1-ene-3-ylldene)lmlno]ethyl}benzamlde 2.30 ~ ~10 mllllmoies) of 2-hydroxy-~-(1-hydroxy-2-amlnoe-thyl)benzamlde hydrochlorlde and 1.46 9 (10 mllllmoles) of 1-phenyl-but-1-ene-3-one are admlxed wlth 10 ml of tetrahydroFu~
ran, whereupon under Further stlrrlng and Ice-coollng 4 ml oF
morpholIne are added dropwlse at a temperature oF 10-15C. The reactlon mlxture Is stlrred at room temperature for a Further perlod of 5 hours, the preclpltated morphollne hydrochlorlde Is flltered o~f and the FlItrate Is heated to bolllng for 3 hours.
From the flltrate the deslred compound Is Isola-ted by column chromatography on slllca gel. Thus 2.05 9 of the deslred com-pound are obtained, yleld 63%, M.p.: 142-145C.
Example 3 Preparatlon of 2-hydroxy-5-{1-hydroxy-2-C~1-methyl-3-phenyl-pro~yl)amlnoiethyl}benzamlde hydrochlorlde 3.24 9 ~10 mlllimoles) of 2-hydroxy-5-[1-hydroxy-2-~(1-phenyl-but-l-ene-3-ylldene)lmlno~iethyl}benzamlde prepared accord-Ing to Example 1 or 2 are dlssolved In 25 ml of te-trahydro~uran, ~hereupon 0.5 ~ of a 10~ paliadlum-on-charcoal catalyst are added and the mixture Is hydrogenated at a temperature of 25C under a pressure oF 3 atm. The reductlon havlng been termlnated the cat-alyst Is Flltered ofF and to the flltrate 5 ml of ethanol con-talnln~ 20% of hy~lrochlorlc acld are added. The preclpltatedwhlte crystals are flItered off and washed wl-th ethanol. Thus 3.46 9 of the deslred compound are obtalned, yleld 95~, m.p.:
188-189C.
.
~3~
Exam~e 4 Preparatlon of 2 hydroxy-5-t1-hydroxy-2-[(1-methyl-3-phenyl-propyl)amlno]ethyl~benzamlde hydrochlorlde To a solutlon of 3.74 g (10 mllllmoles) of 2-hydroxy-5-(N7N-dlbenzylglycyl)benzamlde, 1.46 g (10 ml~llmoies) of 1-phenyl-but-1-ene-3-one and 50 ml of methanol 1.0 ml of glaclal acetlc acld, 1.0 9 of a 10% pailadlum-on-charcoal catalyst and 0.1 g of platlnum oxlde (Adams catalyst) are added. The reactlon mlxture Is hydrogenated at a temperature o-F 60C and under a pressure of 50 atm. The catalyst Is flltered off and the fll-trate Is evaporated to a small volume. T~ the resldue 3 ml of propanol saturated wlth hydrogen chlorlde and 5 ml of ethyl acetate are added. On standlng crystals preclplta-te whlch are flltered off and washed. Thus 2.62 g of the deslred compound are obtalned, yleld: 72%, m.p.: 187-190C.
Example 5 Preparation of 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenyl-propyl)amlno]ethyl~benzamlde hydrochlorlde l~o a solutlon of 3.7~ g (10 milllmoles) of 2-hydroxy-5-25 ~I-hydroxy-2-(dlbenzylamlno)ethyl]benzamlde nnd 1.~ 9 (10 mll-llmoles) of 1-phenyl-but-1-ene-3-one ln 50 ml of methanol 2.0 ml of glaclal acetlc acld, I.O g of a 10% palladlum-on-charcoal cat-alyst and 0.1 9 of platlnum oxlde (Adams catalyst) are added and the reactlon mlxture Is hydro~enated at a temperature of 60C and under a pressure of 50 atm. The reactlon mlx-ture Is worked up and the produc-t Isolated accordlng to Example ~. Thus 2.77 9 of the deslred product are obtalned, yleld 76%, m.p.: 18fl-189C.
~,:
Jectlng the SchifF base thus obtalned to catalytic hydro~enatlon.In the patent speclflca-~lon, ho~ever, no exampJe is dlsclosed For the pr~paratlon oF 2-hydrvxy-~-C1-hydroxy-2-~(1-methyl-3-phenyl-propyl)amino~ethyl3benzamlde.
It Is the obJect of the present Inventlon to elaborate a proces~ for the preparatlon o-F 2-hydroxy-5-{1-hydro~y-2-[(1-methyl-3-phenylpropyl)amlno]ethyl}benzamlde whlch ellmlnates the above drawbacks of the Icnown methods, provldes hlgher ylelds, Is readlly feaslble on Industrlal scale pro~uctlon and uses easlly avallable startlng materlals.
It has been found that 2-hydroxy-5C1-hydroxy-2-~
methyl-3-phenylpropyl)amlno]ethyl}benzamlde of the formula ('ONII
16 \ 2 . ( r ) ElO ~ Cll- Cl[
011 Nl-l - Cll C112 - Cl12 - ~
may be prepared In a more slmple and economlcal manner from ~-hydroxy-~-[1-hydroxy-2-[(1-phenyl-but-1-ene-3-ylldene)-lmlno3 ethyl~benzamlde of the formuia CON~12 llO ~ 3 (V) Oil N = C
\ Cll = C~{
3~ ~ ~
Accordlng to the present Inventlon there 19 provlded a process for the preparatlon of 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenylpropyl)amlno]ethyl}benzamlde of the formula I and 3~ pharmaceutlcally acceptable acld addltlon salts thereo~ whlch comprlses hydrogenatlng 2-hydroxy-5-C1-hydroxy-2-~(1-phenyl-but-~ .....
3~9~3~
1-ene-3-ylldene)amlno]ethyl}benzamlde of the Formula V and, IF
deslred, convertlng the compound o~ the formula ~thus obtalned Into a pharmaceutlcally acceptable acld addi-tlon s~lt.
The reduction oF the Schlff base of the formula ~may be carrled out by catalytlc hydrogenatlon. As cataiyst preferably paliadlum, platlnum, nlckel or an Adams catalyst may be used. The catalyst may also be applled on a carrler (e.g.
charcoal, barlum sulfate). Hydrogenatlon may be carrled out at a 10 temperature of about 20-30C, and under a pressure of 1-10 atm., preferably 2-4 atm. One may partlcularly advantageously work at 25C and under a pressure of 3 atm. The reductlon may be carrled out In an Inert organic soivent. As reactlon medlum preFerbly an ether (e.g. dlethyl ether, dloxane or tetrahydrofurane~ or an alcohol le.g. methanol or ethanol), partlcularly tetrahydroFurane may be used. In the course of the reactlon two equlvalents of hydrogen are consumed and both the azome-thlne bond and carbon-carbon double bond are saturated. The reactlon may be accomplIshed In the presence of a small amoun-t of an or0anlc acld (e.g. glaclai acetlc acld). The ylelds achleved are almost theore-tlc.
The reactlon mlxture may be worked up by methods known ~ se. One may preferably proceed by fllterlng off the catalyst and evaporatlng the flltrate. The hydrochlorlde may be Isolated by addlng anhydrous ethanollc hydrogen chlorlde or a mixture of concentrated hydrochlorlc acld and ethanol to the hydrogenated flltrate.
The startlng materlal of the Formula V Is a new com-pound and may be prepared by reactlng 2-hydroxy-5-(1-hydroxy-2-amlnoethyl)benzamlde of the formula 3~3~
CON~-I
2 ( II ) ~10 -- _ CH - CH2 wlth 1-phenyl-but-1-ene-3-one of the formula ~ ~ ( III), W CH = C~l - COC113 The reactlon may be carrled out In an Inert organlc solvent. As reactlon medlum preFerably ~n e-ther ~e.~. dlethyl ether, dloxane or tetrahydrofurane), alcohol (e.g. methanol or etharlol) or an aromatlc hydrocarbon (e.g. benzene, toluene or xylene), partlcu-larly tetrahydrofurane may be used. The reactlon may be accom-pllshed at a temperature between ~5-100C, preferably at a tem-perature of about 40C. The reactlon may optlonally be carrled out In the presence of a base (e.g. trlethyl amlne or morpho-llne).
The compound of the formula ~ thus obtalned may either be Isolated or subJected to catalytlc hydrogenatlon In sltu wlth-out Isolatlon.
Accordlng to a form of realIzatlon of the process ofthe present Inventlon the compound of the formula 11 prepared by catalytlc hydrogenatlon of the compound of the formula llO ~ Cll - CH2 - N ~ (VI) 0~ C~l2 -,~ .
3~3 Is used. One may wor~ preferably by subJectlng a compound of the Formul~ Vl to catnlYtlc hydrogenatlon, reactlng the compound of the formula 1~ thus formed In sltu wlth the compound of the for-__ mula 1~ and hydrogenatlng the compound of the formula V thusformed wlthout Isoia~lon.
Accordlng to a further form of reallzatlon oF -the pro-cess of the present Inventlon the compound of the formula 1~ pre-pared by ca~alytlc hydrogenatlon of the compound of the Formula IV Is used. One may proceed preFerably by subJectlng the com-pound of the iormula IV to catalytlc hydrogenatlon, reactlng the compound of the formula IV to catalytlc hydrogenatlon, reactlng the compound of the formula 1~ thus Formed In sltu wlth a corn-pound of the Formula ~ and hydrogenatlng the compound of the formula V thus formed wlthout Isolatlon.
The two Iatter forms of reallzatlon of the process of the present Inventlon may be carrled out preferably at an ele-vated temperature, preFerably at 50-70C and under a pressure between 1 and 100 atm., preferably under a pressure of about 50 atm. The reactlon may be carried out In an Inert organlc solvent. As reactlon medlum preferably an alcohol (e.g. methanol or ethanol) may be used. The reactlon mlxture may also contaln an acld (e.g. glaclal acetlc acld). As catalyst e.g. pailadium, platlnum, nlckel or Adams catalyst may be used. The catalyst may be applled onto a carrler, e.~. charcoal, barlum sulfate, etc., If deslred.
The maJor advantage of the process oF the present Inventlon Is that -the s-tartlng materlals ~sed for the preparatlon of the compound of the formula V may be prepared from materlals (e.g. benzal acetone) readlly feaslble and economlca~ on indus-trlal scale, ~oo and the yields are hlgh.
3~ Wlthout llmltlng the scope of the inventlon by theoret-lcal conslderatlons we presume that thls Is due to the Fact tha-t ~3~3~
because oF conJugatlon -the keto group oF 1-phenyl-bu-t-1-ene-3-one (benzal acetone) u~ed In the process of the present Inventlon Is more reactlYe than the keto group of 1-phenyl-butan-3-one applled In the process dlsclosed ~n DOS No. 2,03Z,642. For thls reason the compound of the formula lll reacts wlth the 2-hydroxy-5-(1-hydroxy-~-amlno-ethyl)-benzamlde of the formula ll to give the correspondlng 2-hydroxy-5-[1-hydroxy-Z-~(1-phenyl-but-1-ene-3-ylldene)Imlno~ethyl)-benzamlde much more easlly than the corre-spondlng Intermedlate Is formed In the process descrlbed In DOS
10 No. 2,032,6~Z, namely 2-hydroxy-5 r 1-hydroxy-2-[(1-phenyl-but-3-ylldene)lmldo]ethyl~benzamlde or 2-hydroxy-5-C1-keto-2-[(1-phenyi-but-3-ylldene)-Imlno]ethyl}benzamlde.
Further detalls of the process of the Inventlon are to be found In the followlng Examples wlthout llmltlng the scope of protectlon by the sald Examples.
Example 1 Preparatlon of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene-3-ylldene)amlno]ethyl~benzamlde 2.30 9 (10 milllmoles) of 2-hydroxy-5-(1-hydroxy-2-amlnoethyl)benzamld0 hydrochlorIde and 1.46 9 (10 mllllmoles) of 25 1-phenyl-~ut-1-ene-3-one are admlxed wlth 10 ml of tetrahydrofu-rane whereupon under further stlrrln~ and Ice-coolIng 1.20 ~l of trlethyl amlne are added dropwlse at a temperature of 10-15C.
The addltlon havlng been completed the reactlon mlxture Is stlrred at room temperature for further 5 hours and the preclpl-tated trlethyl amlne hydrochlorIde Is filtered of-F. From the ; flltrate the 2-hydroxy-5-{1-hydroxy-2-~ phenyl-but-1-ene-3~yll-dene)Imlno~-ethyl}benzamlde Is Isolated by column chromatography on slllca gel. Thus 1.56 g of the deslred compound are obtalned, yleld 48%, m.p.: 142-146C.
~.' Exam~le Z
Preparatlon of 2-hydroxy-5-~1-hy~roxy-2-[~l-phenyl-but-1-ene-3-ylldene)lmlno]ethyl}benzamlde 2.30 ~ ~10 mllllmoies) of 2-hydroxy-~-(1-hydroxy-2-amlnoe-thyl)benzamlde hydrochlorlde and 1.46 9 (10 mllllmoles) of 1-phenyl-but-1-ene-3-one are admlxed wlth 10 ml of tetrahydroFu~
ran, whereupon under Further stlrrlng and Ice-coollng 4 ml oF
morpholIne are added dropwlse at a temperature oF 10-15C. The reactlon mlxture Is stlrred at room temperature for a Further perlod of 5 hours, the preclpltated morphollne hydrochlorlde Is flltered o~f and the FlItrate Is heated to bolllng for 3 hours.
From the flltrate the deslred compound Is Isola-ted by column chromatography on slllca gel. Thus 2.05 9 of the deslred com-pound are obtained, yleld 63%, M.p.: 142-145C.
Example 3 Preparatlon of 2-hydroxy-5-{1-hydroxy-2-C~1-methyl-3-phenyl-pro~yl)amlnoiethyl}benzamlde hydrochlorlde 3.24 9 ~10 mlllimoles) of 2-hydroxy-5-[1-hydroxy-2-~(1-phenyl-but-l-ene-3-ylldene)lmlno~iethyl}benzamlde prepared accord-Ing to Example 1 or 2 are dlssolved In 25 ml of te-trahydro~uran, ~hereupon 0.5 ~ of a 10~ paliadlum-on-charcoal catalyst are added and the mixture Is hydrogenated at a temperature of 25C under a pressure oF 3 atm. The reductlon havlng been termlnated the cat-alyst Is Flltered ofF and to the flltrate 5 ml of ethanol con-talnln~ 20% of hy~lrochlorlc acld are added. The preclpltatedwhlte crystals are flItered off and washed wl-th ethanol. Thus 3.46 9 of the deslred compound are obtalned, yleld 95~, m.p.:
188-189C.
.
~3~
Exam~e 4 Preparatlon of 2 hydroxy-5-t1-hydroxy-2-[(1-methyl-3-phenyl-propyl)amlno]ethyl~benzamlde hydrochlorlde To a solutlon of 3.74 g (10 mllllmoles) of 2-hydroxy-5-(N7N-dlbenzylglycyl)benzamlde, 1.46 g (10 ml~llmoies) of 1-phenyl-but-1-ene-3-one and 50 ml of methanol 1.0 ml of glaclal acetlc acld, 1.0 9 of a 10% pailadlum-on-charcoal catalyst and 0.1 g of platlnum oxlde (Adams catalyst) are added. The reactlon mlxture Is hydrogenated at a temperature o-F 60C and under a pressure of 50 atm. The catalyst Is flltered off and the fll-trate Is evaporated to a small volume. T~ the resldue 3 ml of propanol saturated wlth hydrogen chlorlde and 5 ml of ethyl acetate are added. On standlng crystals preclplta-te whlch are flltered off and washed. Thus 2.62 g of the deslred compound are obtalned, yleld: 72%, m.p.: 187-190C.
Example 5 Preparation of 2-hydroxy-5-{1-hydroxy-2-~(1-methyl-3-phenyl-propyl)amlno]ethyl~benzamlde hydrochlorlde l~o a solutlon of 3.7~ g (10 milllmoles) of 2-hydroxy-5-25 ~I-hydroxy-2-(dlbenzylamlno)ethyl]benzamlde nnd 1.~ 9 (10 mll-llmoles) of 1-phenyl-but-1-ene-3-one ln 50 ml of methanol 2.0 ml of glaclal acetlc acld, I.O g of a 10% palladlum-on-charcoal cat-alyst and 0.1 9 of platlnum oxlde (Adams catalyst) are added and the reactlon mlxture Is hydro~enated at a temperature of 60C and under a pressure of 50 atm. The reactlon mlx-ture Is worked up and the produc-t Isolated accordlng to Example ~. Thus 2.77 9 of the deslred product are obtalned, yleld 76%, m.p.: 18fl-189C.
~,:
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of 2-hydroxy-5-(1-hydroxy-2-[(1-methyl-3-phenylpropyl)amlno]ethyl)beenzamlde of the formula ( I ) and pharmaceutlcally acceptable acid addition salts thereof which comprises hydrogenating 2-hydroxy-5[1-hydroxy-2-[1-phenyl-but-1-ene-3-ylldene)lmlno]ethyl)benzamlde of the formula ( V ) and if desired converting the compound of the formula I thus obtained into a pharmaceutlcaily acceptable acid addition salt.
2. A process according to claim 1 which comprises carrying out the hydrogenation in the presence of a catalyst.
3. A process according to claim 2 which comprises using a palladlum platinum or nlicke I catalyst or a mixture thereof.
4. A process according to claim 1, which comprises carrying out the reaction in the presence of an inert organic solvent.
5. A process according to claim 4, which comprises using an ether or alcohol as solvent.
6. A process according to claim 1, 2 or 3, which com-prises carrying out the reaction at a temperature between 10°C
and 40°C and under a pressure of 1 to 10 atm.
and 40°C and under a pressure of 1 to 10 atm.
7 A process according to claim 1, which comprises using as starting material a compound of the formula V prepared by reacting 2-hydroxy-5-(1-hydroxy-2-amlnoethyl)benzamide of the formula ( I I ) with 1-phenyl but-1-ene-3-one of the formula (III)
8. A process according to claim 7, which comprises carrying out the reaction in an inert organie solvent.
9. A process according to claim 8, which comprises using an ether, alcohol or aromatie hydroearbon as solvent.
10. A process according to claim 7, which comprises using 2-hydroxy-5-(1-hydroxy-2-amlnoethyl)benzamide of the for-mula 11 prepared in situ by catalytic hydrogenation of 2-hydroxy-5-[1-hydroxy-2-(N,N-dibenylamino)ethyl]benzamide of the formula (VI) , reacting the compound of the formula II without isolation in situ with the compound of the formula III and subjecting the compound of the formula V thus obtained without isolation in situ, to hydrogenation.
11. A process according to claim 7, which comprises using 2-hydroxy-5-(1-hydroxy-2-aminoethyl)benzamide of the for-mula 11 prepared in situ by catalytic hydrogenation of 2-hydroxy-5-(N,N-dibenzylglycyl)benzamide of the formula reacting the compound of the formula II without isolation in situ, with the compound of the formula III and subjecting the compound of the formula V thus formed without isolation In situ, to hydrogenation.
12. 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene-32-ylidene)imino]ethyl}benzamide of the formula (V).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU23484A HU190867B (en) | 1984-01-20 | 1984-01-20 | Process for preparing 2-hydroxy-5-/1-hydroxy-2-/1-methyl-3-phenyl-propyl/-amino/ethyl/-benzamide and pharmaceutically acceptable salts thereof |
| HU234/84 | 1984-01-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1239938A true CA1239938A (en) | 1988-08-02 |
Family
ID=10948617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000472445A Expired CA1239938A (en) | 1984-01-20 | 1985-01-18 | Process for the preparation of a benzamide derivative |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS60231639A (en) |
| AT (1) | AT390612B (en) |
| CA (1) | CA1239938A (en) |
| CH (1) | CH662810A5 (en) |
| CS (1) | CS249536B2 (en) |
| DD (1) | DD228245A5 (en) |
| DE (1) | DE3501582A1 (en) |
| DK (1) | DK26185A (en) |
| ES (1) | ES8608481A1 (en) |
| FI (1) | FI83635C (en) |
| FR (1) | FR2558465B1 (en) |
| GB (1) | GB2152931B (en) |
| HU (1) | HU190867B (en) |
| NL (1) | NL8500119A (en) |
| NO (1) | NO165918C (en) |
| PT (1) | PT79844B (en) |
| SE (1) | SE8500236L (en) |
| SU (1) | SU1521281A3 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1247370A (en) * | 1968-12-31 | 1971-09-22 | Allen & Hanburys Ltd | Glyoxals and production thereof |
| ZA794872B (en) * | 1978-09-20 | 1980-11-26 | Schering Corp | A phenylalkylaminoethylsalicylamide,its preparation and pharmaceutical compositions containing it |
-
1984
- 1984-01-20 HU HU23484A patent/HU190867B/en not_active IP Right Cessation
- 1984-12-17 CH CH598584A patent/CH662810A5/en not_active IP Right Cessation
-
1985
- 1985-01-18 JP JP597885A patent/JPS60231639A/en active Pending
- 1985-01-18 FR FR8500702A patent/FR2558465B1/en not_active Expired
- 1985-01-18 ES ES540121A patent/ES8608481A1/en not_active Expired
- 1985-01-18 GB GB08501246A patent/GB2152931B/en not_active Expired
- 1985-01-18 DE DE19853501582 patent/DE3501582A1/en not_active Withdrawn
- 1985-01-18 SU SU853837675A patent/SU1521281A3/en active
- 1985-01-18 DK DK26185A patent/DK26185A/en not_active Application Discontinuation
- 1985-01-18 CS CS37785A patent/CS249536B2/en unknown
- 1985-01-18 AT AT11685A patent/AT390612B/en not_active IP Right Cessation
- 1985-01-18 PT PT7984485A patent/PT79844B/en unknown
- 1985-01-18 FI FI850229A patent/FI83635C/en not_active IP Right Cessation
- 1985-01-18 NL NL8500119A patent/NL8500119A/en not_active Application Discontinuation
- 1985-01-18 NO NO850225A patent/NO165918C/en unknown
- 1985-01-18 DD DD27264985A patent/DD228245A5/en not_active IP Right Cessation
- 1985-01-18 CA CA000472445A patent/CA1239938A/en not_active Expired
- 1985-06-06 SE SE8500236A patent/SE8500236L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO850225L (en) | 1985-07-22 |
| ATA11685A (en) | 1989-11-15 |
| HU190867B (en) | 1986-11-28 |
| FR2558465A1 (en) | 1985-07-26 |
| FI850229L (en) | 1985-07-21 |
| SU1521281A3 (en) | 1989-11-07 |
| NO165918C (en) | 1991-05-02 |
| NO165918B (en) | 1991-01-21 |
| GB2152931A (en) | 1985-08-14 |
| ES540121A0 (en) | 1986-07-16 |
| HUT36779A (en) | 1985-10-28 |
| GB8501246D0 (en) | 1985-02-20 |
| CS249536B2 (en) | 1987-03-12 |
| SE8500236D0 (en) | 1985-01-18 |
| PT79844B (en) | 1986-10-23 |
| CH662810A5 (en) | 1987-10-30 |
| FI83635C (en) | 1991-08-12 |
| FR2558465B1 (en) | 1988-08-26 |
| ES8608481A1 (en) | 1986-07-16 |
| AT390612B (en) | 1990-06-11 |
| JPS60231639A (en) | 1985-11-18 |
| DK26185A (en) | 1985-07-21 |
| FI83635B (en) | 1991-04-30 |
| DD228245A5 (en) | 1985-10-09 |
| PT79844A (en) | 1985-02-01 |
| DE3501582A1 (en) | 1985-08-01 |
| DK26185D0 (en) | 1985-01-18 |
| NL8500119A (en) | 1985-08-16 |
| GB2152931B (en) | 1987-03-18 |
| FI850229A0 (en) | 1985-01-18 |
| SE8500236L (en) | 1985-07-21 |
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