Note: Descriptions are shown in the official language in which they were submitted.
" ~ 10~6~L8
i .
. me present invention relates to new tetrahydropyridine
i;, and piperidine derivatives with valuable pharmacological pro-
`;' perties, processes for the manufacture of these new compounds
and therapeutic preparations containing them.
me new tetrahydropyridine and piperidine derivatives
according to the invention correspond to the general formula I
'~
. , /CH -----CH
\ c c~
. in which Rl denotes hydrogen, an alkyl group wltn at most
4 carbon atoms or the 2-propynyl, cyclopropylmethyl or
,s,~ benzyl group,
;~
~ s ~
. ~ ~ : : :: :
1 ;
,
.
,
. ~ .
, .
., .
, .
-
-2-
. :^: ,' ' ' :' . ' . ' ' ,:
~: . . .. . ~
.'- ' ' '' ' , ' - ' ' ' " '
: ' : . :
.. ... . .
.
'``` 1076~
. ~ ..
and X and Y each denote a hydrogen atom or conjointly denote an additional bond.
The invention also relates to addition salts, especially pharmaceuti-
cally acceptable addition salts, of the compounds of the general formula I
with inorganic and organic acids and to the manufacture of these addition salts.
.:
In the compounds of the general formula 1, Rl, as an alkyl group
with at most 4 carbon atoms is, for example, an ethyl, propyl, isopropyl, butyl,
.
or isobutyl group and, above all, a methyl group.
The compounds of the general formula I and their addition salts
with inorganic and organic acids possess valuable pharmacological properties.
In the rat, they effect after oral administration a moderate inhibi-
~- tion of mono-amino oxidase, as can be seen from the results of isotopic deter-
!
mination of the enzyme activity. Especially to be mentioned is the inhibition
; of the absorption of serotonin into the mesencephalic synaptosomes of rats
, :
after oral administration of a dose of I00 mg/kg. Certain compounds of the
general formula I such as ~-(3-ben~ofuranyl)-piperidine and its pharmaceutica-
lly acceptable salts, e.g. the hydrochloride, in the same dosage also inhibit
.~:
the absorption of noradrenaline into the heart and the mesencephalic synapto-
.;~ somes of rats. After intraperitoneal administration of doses from 3 mg/kg
upwards, the compounds of the general formula I potentiate the agitation in-
duced by 5-hydroxy-tryptophan.
, : ~ ,
., : ~ :
.,
. ,:
~, . ~ .
,. . - .
... .
-. ' - :'' ,
. ~ , . . :
' ,' , ' ' , . . '~ :
. ~-
. ~ , ~ , , : : .'
. ,f `l ~ ,
: J
-3-
, .,, , , . , , ~ . . . .
: . .,. ,: . . , , , ,, . ;, :
;'` 10761~L8
,~ .
Together with a favourable therapeutic index, the abovementioned
properties characterise the compounds of the general formula I and their pharm-
-~ aceutically acceptable salts with inorganic and organic acids as anti-depress-
~ ants, which can be administered, for example, orally or parenterally for the
: treatment of states of depression.
The present invention relates in particular to compounds of the
. general formula I in which Rl above all denotes hydrogen or the methyl group
- as well as the ethyl, 2-propynyl, cyclopropylmethyl or benzyl group, and X and Y
`. have the meaning indicated under the formula I, such as l-methyl-4-(3-benizo-
furanyl)-1,2,3,6-tetrahydropyridine, 1-methyl-4-(3-benzofuranyl)-piperidine
. j .
`;~ and
' '' -
. j .
1~ ~
~, .
. ~ . .
. ,~ , - .
; ~ , . .
'~',~ ' ,, ,
. . .
. '~'' ' , .
4-
, ' - , ., . : . :
--: '. . :
. : .
... , , . ,~ .
:.. ., . :
~ . : , , - :. . . .
. ., . ,: ,, ~
.. ' ~ . . .
.
` ' - 1076~18
.
4-(3-benzofuranyl)-piperidine, as well as the pharmaceutically : .
acceptable acid addition salts of these compounds, such as the
hydrochlorides. ~:
The new tetrahydropyridine and piperidine derivatives of
the general formula I and their acid addition salts are manu- -
factured according to the invention when, in a manner which is `~.
in itself known,
;. . .
:~ a) in a compound of the general formula II
- . .
~ ~ ~ ~CH2 CH2~
~ C~ CH2 ~ (II) ~ ~
; - . ~ ~ , . . .
in which Ac denotes a radical which can be split off and
x and Y have the meaning indicated under formula I, the
~i~ radical Ac is spLit off and
b) if desired, a compound, obtained according to a) or by
other means, of the general formula Ia
, ~; :
:~;: i~
wS ~R-H
, ~ .
: . . ` , . . `
`-:~` .
~ 5-
, . ' ' ' ~ . , , , . ., ' ' '
.~ ' . ' . ' . ' . , ~ , ,' . . .
: . ; ' , . .
.' . '.'., .` "., 'i
'~'' ''' ' .',', .. , ' ', ' , ~ ' ' . ' " ' ' ',
' ' '
.
1076~
. . .
.',: .
. .
which is comprised by the formula I and in which X and Y
have the meaning indicated under the general formula I,
, is reacted with a reactive ester of a hydroxy compound
of the general formula ITI
HO - Rla (III)
in which Rla has the meaning indicated for Rl under the
. formula I, with the exception of hydrogen, or is reacted,
under reducing conditions, with an oxo compound of the
: general formula IIIa
= Rl (IIIa~
: in which Rlb denotes the geminal divalent radical which
corresponds to a monovalent radical Rla, or~
c) in a compound of the seneral formu~a IV
CH2 . CH2
O-RlC ~.
~J ,C~ 2 ~ ~IV~
: in which R denotes a radical corresponding to the
definition for Rl but reduced by a methyIene group or
:denotes a lower alkoxycarbonyI group, and X and Y have
the meaning indicated under the general formula I, the
carbonyl group or alkoxycarbonyl group is reduced or
d) a compound of the general formula V
~ ~ ~ 9
.. i~ . . . . .
: : a 1 -6-
' '' ', , ' ' ' ' ' ' ' :'"'
' ' : . ' ' ''. . . .
.
: . . ;' ' ',, , ' ' . . ~ , .:
.. ,: ~ .. . .. , :
, :,,
.'' . - . ... . , , ' ~ .. ,..... ;' ' ' , ,
~ '76~
.
~', I ; .
:.
in which Z ~ denotes a monovalent anion or the normal
- equivalent of a polyvalent anion and Rla has the meaning
;~1 indicated under the general formula III, is partially
reduced to the corresponding compound of the general
:. formula I, in which X and Y denote an additional bond, or
.~ e) 4-(3-benzofuranyl)-pyridine or a compound of the general
formula Ib, :
.,.~ ,~ . : .
/CH2~ CH2
which f~ls ~nder the general formula I and in which R
: has the meaning indicated under the general formula I, is :
hydrogenated catalytically to the corresponding piperidine
: compound, or
f) l-benzyl-4-(3-benzofuranyl)-piperidine is subjected to :
. hydrogenolysis, or
g) water is eliminated from a compound of the general ~ :
~: . . formula VI
': ~ c , . , ~
-R a (VI~
HO C~ CN ~
:'
~: in which Rla has the meaning indicated under the general :
formula III
and, if desired, a compound of the general formula I,. : .
~:. obtained according to a process indicated under a) to g). is converted into an addition salt with an inorganic or
;1: organic acid.
i'" , .
',.,, . i~i -
i~ ? . 7
. . , ~
.. -. . ~ . . - , ... . .
. .
,, .,, , ,, ,, ,.. " ,, , , .,,.,',., .' ' . . . ' , . , ~- : ':
!176118
' `
The removable radical Ac is, in particular an acyl radical. It is
split off, for example, by hydrolysis or solvolysis, hydrogenolysis or reduc-
tion. In the starting materials of the general formula II, Ac can be, for ex-
ample, any desired organic acyl group, for example a lower alkanoyl group, such
as the acetyl group, an arenecarbonyl group, such as the benzoyl group, an
alkanesulphonyl or arenesulphonyl group, such as the methanesulphonyl or p-
~i~ toluenesulphonyl group, or an inorganic acyl group such as the nitroso group
N0. However, acyl groups which ensure ready accessibility of the compounds of
the general formula II in which they are contained and/or which can be split
,~ 10 off relatively easily are preferred. From these points of view, possible acyl
`~ ~ groups Ac are, on the one hand, above all acyl groups of carbonic acid half-
esters and thiocarbonic acid half-ester, especially groups which can be split
off by hydrolysis, for example lower alkoxycarbonyl groups, such as the meth-
oxycarbonyl~ ethoxycarbonyl and tert.butoxy-carbonyl group, as well as the
~` :
phenoxycarbonyl and benzyloxycarbonyl group and also the methoxythiocarbonyl
and methylthio-thiocarbonyl group, and, on the other hand, acyl groups of other
derivatives of carbonic acid, such as the chlorocarbonyl group and especially
the cyano group.
, . ~
Hydrolysis of compounds of the new general formula II according to
process a) can be carried out in an alkaline or acid medium. For example, it
is effected by prolonged heating with an alkali metal hydroxide, especially
sodium hydroxide or potassium hydroxite, in a hydroxy compound in the presence
of a little water at temperatures between about 80 and 200C. A suitable
, ~
~ reaction medium is, for example, ethylene glycol or a lower monoalkyl ether
: thereof and also, when the hydrolysis is carried out in a closed vessel, a low-
er aikanol, such as methanol, ethanol or butanol. ~urthermore, compounds of
.~.................... .. .
'; ~ the general formula II in which Ac denotes a cyano group, that is to say the
: .; ` . . .-.
acyl radical of cyanic acid, or a chlorocarbonyl group, in particular, can
.~ , .
also be hydrolysed by heating with a mineral acid in an organic~aqueous or
. .: .~;
,^,.~ ,, ~ -
:- -- . ~,
~ 8-
:' -` - ` `. , . ,` ' , ,':: , j,, . :,'.. . .
. . . ,, - . . ,: ~ ,:, . .: : .. :
~ '~ 1076118
aqueous medium, for example by boiling for seYeral hours in a mixture of 85%
strength phosphoric acid and formic acid or by heating at about 60-100C,
preferably 60-70C, for several hours in 48% strength hydrobromic acid or in
- a mixture of hydrobromic acid and acetic acid.
A radical which can be split off by solvolysis is, for example, the
, tert.butoxycarbonyl radical, which can be split off under anhydrous conditions
by treatment with a suitable acid, such as tri1uoroacetic acid. -
Radicals Ac which can be sp]it off by reduction are, for example, ~-
aralkoxycarbonyl radicals, such as benzyloxycarbonyl radicals, which can be
, 10 spllt off in the customary manner by hydrogenolysis, especially by catalytically
activated hydrogen, such as by hydrogen in the presence of a hydrogenation
~-~ catalyst, for example platinum, palladium or Raney nickel. Other radicals
which can be split off by reduction are, for example, 2-halogeno-alkoxycarbon- ;
yl radicals, such as the 2,2,2-trichloroethoxycarbonyl radical or the 2-iodo-
ethoxycarbonyl or 2,2,2-tribromoethoxycarbonyl radical, which can be split off -~
in the customary manner, especially by metallic reduction ~so-called nascent
hydrogen). Nascent hydrogen can be obaained by the action of metal or metal
alloys, such as amalgams, on hydrogen donors, such as carboxylic acids, alco-
hols or water~ it being possible to use, in particular, zinc or zinc alloys
together with acetic acid. The reduction of 2-halogenoalkoxycarbonyl radicals
'' I` :
can also be effected by chromium-II compounds, such as chromium-II chloride
or chromium-II acetate.
A radical Ac which can be split off by reduction can
. ~ , . . ..
., .
. . .
.'`,`, ' , .
. ,. t~ ''
'.` ~_1 :.
- _9_
.,. ~ ' . ' ' ' . ~ , , .
, . ...... , . ' . , . :.. . , .. ,: ' , , ,. , .. , : . :, . ,, , . :, .
~; ~ `\
107611~3
; also be a sulphonyl group, such as a lower alkanesulphonyl group
or arylsulphonyl group, for example methanesulphonyl or p-
toluenesulphonyl, which can be split off in the customary
,
manner by reduction with nascent hydrogen, for example by an
alkali metal, such as lithium or sodium, in liquid ammonia, or
electrolytically.
The manufacture of the starting materials of the general
; formula II is explained further below.
Reactive esters of compounds of the general formula III
~- which are suitable for the reaction with compounds of the
. ~ general formula Ia according to process b) are, for example,
hydrogen halide acid esters, especially chlorides, bromides
~- ~ and iodides, and also lower alkanesulphonic acid esters and
i~ arenesulphonic acid esters, such as the methanesulphonic acid
esters and the benzenesulphonic acid esters and p-toluene-
.; r.
sulphonic acid esters, as well as esters o~ other strong acids 9
for eXr mple sulphuric acid esters, such as dimethyl sulphate
and diethyl sulphate. The reactions with compounds of
the general formula Ia are preferably carried out in the
presence of an acid-binding agent in an organic solvent which
,` i , ~ .
- is inert under the reaction conditions Suitable acid- ~
,~, ~: . . . . .
binding agents are tertiary organic bases, such as, for example,
triethylamine, pyridine, sym -collidine and, above all, ethyl-
diisopropylamine, or inorganic basic substiances, such as, for
~ example, sodium carbonate or potassium carbonate, and suitable
``~ solvents are, for example, lower alkanols, such as methanol,
~1~ ethanol, isopropanol or butanol, ether-like compounds, such as
".,:~ ' ' . : '
lf ' 1~ _
.,. . ~. ~, - .
..
:.: ,: ... .. ~ - . ...... - - .. : . . .. . . .. . . .. ...... ..
.. :, . .,. .. , : ., . . , . ,,~
761~
.
. ~
dioxane, tetrahydrofurane or 2-methoxyethanol, lower aliphatic ~etones, such
as methyl ethyl ketone, and N-substituted acid amides, such as dimethylformam-
ide or N,N,N',N',N",N"-hexamethylphosphoric acid triamide. The reaction tem-
.~, . . .
perature is between about 0 and 200C, preferably between room temperature
and about 120C. The reaction temperatures required for reaction with reactive
, .
esters of primary hydroxy compo~mds are usually at the lower limit of the indi-
cated ranges, whilst reactions with reactive esters of non-primary hydroxy
compounds usually have to be carried out at higher temperatures and according-
ly, if necessary, in closed reaction vessels, the use of a particularly active ~-
acid-binding agent, such as ethyl-diisopropylamine, being advantageous.
Reactions of compounds of the general formula Ia with oxo compounds
. . .. .
of the general formula IIIa can be carried out, for example, in formic acid
at temperatares between about 70 and 100C or optionally also under the action
of hydrogen in the presence of a hydrogénation catalyst, such as, for example,
.~ . .
Raney aickeI, platinum oxide'or palladium-on-charcoal, at normal or moderately
elevated pressures and temperatures in a suitable organic solvent, such as,
for~example, ethanol or dioxane. Oxo compounds which can be uset are, for ex-
ample,~aliphatic aldehydes with at least 2 and at most 4 carbon atoms, acetone,
;2-butanone and benzaldehyde. However, formaldehyde is suitable above all and
20 ~ lS preferably used with formic acid as the reducing agent.
. A considerable number of reactive esters of all hydroxy compounds of
the general formula III and the oxo compounds of the general formula IIIa are
known and further compounds can be manufactured analogously to the known com-
~ ::
~ pounds. In general, the starting materials of the general formula Ia can be
,
; ~ manufactured according to the process mentioned under aj. A further advantage-
ous method for the maaufacture of those compounds in which X and Y denote hy-
drogen atoms is the hydrogenation, which is mentioned under e) and which is
- explained in more detail further below, of 4-~3-benzofuranyl)-pyridine,
The reduction of the amide group of compounds of the general formula
.:: ~ : ,
,: , -11-
; ' '"" '' ;' ' .."' ". ' " '. ''' " ,."". ," ~, , ,'~
0~6~8
IV according to c) is carried out, for example, by means of lithium aluminium
hydride or diborane in an ether-like solvent, such as diethyl ether, tetra-
hydrofurane, dibutyl ether or diethylene glycol diethyl ether or mixtures
thereof, at temperatures between about 20 and 100C or at the boiling point
of the reaction medium used if this is belo~i 100C. The diborane can either
be produced separately and passed in or can be formed in situ from sodium boro-
:
hydride and boron trifluoride-etherate. The manufacture of the starting mate-
rials of the general formula IV is explained further below.
The partial reduction of compounds of the general formula V according
~ ;
i~ 10 to d) is preferably carried out with the aid of sodium borohydride or potassium
borohydride in an organic-aqueous medium by, for example, gradually adding an
` aquèous solution of sodium borohydride to the solution, which has been initial-
ly introduced, of the starting material of the general formula V in an organic,
waeer-miscible solvent, for example in a lower alkanol, such as methanol or
ethanol, or mixtures thereof with water, and then allowing the reaction mix-
ture to react further for some timeJ a reaction temperature of between about
'`', ! ~
; ~ S and 60C, preferably from room temperature to 35C, being maintained. The
manufacture of the~tarting materials of the general formula V is explained
` further below.
~ The catalytic hydrogenation of 4-(3-bensofuranyl)-pyridine and of
compounds of the general formula Ib can be carried out using customary hydro-
genation catalysts, for example noble metal catalyst, such as palladium-on-
charcoal or platinum oxide, rhodium catalysts, SUCII as rhod1um-on-charcoal or
rhodium-on-aluminia or skeletal alloy catalysts, such as Raney nickel, in an
inert organic solvent, such as methanol, ethanol or dioxane, at room tempera- --
ture and normal pressure or at moderately elevated temperatures up to about
100C and elevated pressures up to about 100 bars. The hydrogenation of tetra-
hydropyridine derivatives of the general formula Ib generally proceeds under
milder conditions than the hydrogenation of 4-~3-benzofuranyl)-pyridine. The
~: C7 -12-
:: :
. ~ : .. .: ", . .. . . , : . , . .. , . - . . . ~ : .
'.' ' ' ' ~''';~ :''.: '' .' :'': ,`'': '": ':' `. ~ "' '` "''; ' ' '
: .. . . . - . . .. . .. . . , , . ~ . , , :. : .
- 107611~3
.
hydrogenations of the compounds of the general formula Ib, which contains, as
Rl, the benzyl group, the splitting off of which should be avoided, is advant-
ageously carried out in the presence of one equivalent of hydrogen chloride
and is discontinued after absorption of the equimolar amount of hydrogen. The
manufacture of 4-(3-benzofuranyl)-pyridine is explained further below. The
starting materials of the general formula Ib are manufactured, for example,
; according to one of the abovementioned processes for the manufacture of compounds
of the general formula I, preferably by the partial reduction of corresponding
pyridinium salts, which has been mentioned under d). ~-
The hydrogenolytic removal of the benzyl group according to f) is
carried out essentially under the reaction conditions indicated for the above-
mentioned process e) and using the catalysts indicated there. Therefore,
this hydrogenolysis can also be carried out in the same operation as the hydro-
: I
~ genation according to e) but, on the other hand, as already mentioned, the
! I
selective hydrogenation, in particular, of the cyclic double bond of the cor-
responding compound of the general formula Ib can also be carried out readily
,
whilst preserving the benzyl group.
The elimination of water according to process g) is carried out in
a manner which is in itself known by warming the compounds of the general
formula VI and advantageously the water formed is separated off and the elimin-
ation is preferably carried out in the presence of a strong acid, for example
of concentrated hydrochloric acid in glacial acetic acid or of suiphuric acid,
~ .,
~- which is used in the concentrated form but in small amounts, or of p-toluene-
sulphonic acid. Water can also be eliminated by heating in an inert organic
solvent, for example in a solvent which is immiscible with water, such as
.jl. benzéne, toluene or xylene, the water advantageously being separated off.
, Some of those starting materials for the abovementioned ~rocesses
which do not already fall under the general formula I and which have not already
, been mentioned in particular can be manufactured in one or several stages from
;'',~ ~, , ' ' '
: ~ ; - .. ; . .
~ 13-
, - . , . : . . ~ ,; , . : . ... . . .. . ......... .. .
". . : -,: , , . : ,
. . . .
7611~3
:
4~(3-benzofuranyl)-pyridine which together with its hydrochloride is described
in United States Patent Specification 3,678,062. According to the manufactur-
ing process indicated in this patent specification, 3(2H)-benzofuranone is
first reacted with 4-pyridrl-lithium in diethyl ether at -30~C and the result-
ing 2,3-dihydro-3-(4-pyridyl)-3-benzofuranol is dehydrated to the desired 4-(3-
benzofuranyl)-pyridine by heating to 190C with potassium bisulphate.
A further proccss for the manufacture of 4-(3-benzofuranyl)-pyridine
consists in first reacting 4-(o-hydroxybenzoyl)-pyridine in the presence of
an acid-binding agent, such as potassium carbonate, as well as optionally a
.~
small amount of potassium iodide, with a chloroacetic acid lower alkyl ester
or bromoacetic acid lower alkyl ester, especially the methyl ester, in an
organic solvent, such as, for example, dimethylformamide, under warm conditions?
the corresponding 3-(4-pyridyl)-2-benzofuranecarboxylic acid lower alkyl ester
. . ~ .
being obtained by etherification and subsequent cyclisation in the same opera-
tion. The corresponding free carboxylic acid is obtained from this ester by
hydrolysis, for example in the customary manner with a lower alkanolic alkali
etal hydroxlde solution, and is decarboxylated in a manner which is in itself
; - ~ known, for example by heating with powdered copper in quinoline to the boiling
.,j ~: ,
point thereof, to give the 4-(3-benzofuranyl)-pyridine. The 4-~o-hydroxy-ben-
zoyl~-pyridine required as the starting material for this reaction sequence
j ~:, :
~ is described in British Patent Specification 1,231,783. ~ ~
, ` . ~ . , .
The compounds of the general formula V, amongst which l-methyl-4-
(3-benzofuranyl~-pyridinium iodide is described in U~ited States Patent
Specification 3,678,062, are obtained from the compounds of the general formula
YI by quaternisation with reactive esters o hydroxy compounds o the general
; ~ ormula III.
- . .
''~ ' '~
,~ :
:,1 '' ' , . : ~
,1 , . .;
-14-
,, ''': ,," , ', ' '. ,'' ' ', ' ~ . .:
;:
The quaternisation can be carried out in the customary manner
in an inert organic solvent, for example in the lower alkanol
on which the reactive ester also is based, and also, for example,
' in ethyl acetate, tetrahydro~urane or dioxane, at room tempera~
~ ture or moderately elevated temperatures up to about 100.
; Starting materials of the general formula II, in ~hich
Ac is the acyl radical of a carbonic acid half-ester or of a
~; ''thiocarbonic acid half-ester or is a cyano radical or a chloro-
' carbonyl radical, can be manufactured, ~or example, from corres-
'~ ponding compounds of the general formula I, in which Rl is an
~' 'easily removable group, such as the benzyl group and
above all the methyl group, by reaction with esters or thioesters
.,
of chloroformic acid, above all with the ethyl ester, tert.
butyl ester, benzyl ester or phenyl ester of chloroformic acid
or with chlorothioformic acid S-methyl ester, or with cyanogen
bromide or phosgene in an'inert organic solvent under warm
,:
;~ conditions, ~or example in toluene at the boiling point thereof.
It is also possible, for example, to employ carboxylic
acid'halides, such as, for example, acetyl bromide or benzoyl
chloride, in place o~ the abovementioned carbonic acid deriva-
' ; tives,but the corresponding réac-tion to split o~f the group R
, usually requires more vigorous conditions and is less complete
-; than, for example,'when chloro~ormic acid ethyl ester or, in
;~ ' particular, cyanogen bromide is used. me reaction sequence
consisting of the reaction of suitable compounds oX the general
.. 1.~ . j .
~ formula I with chloro~ormic acid esters, cyanogen bromide or
,.~ i, . . . .
~ similar reagents and the subsequent hydrolysis according to a)
: . j:
6~ ' ' ' .
.
. . . ... - , . .~ .. , : :
.. . . .. ,, ~ . . . .. .
: . . ,.. - . - , . .. : :
': ' , , : , . . . . , . .. ~ . :
i . : .. -.. :. . . ,. . . ,. . , ~ . : ..
- '~ .- .' ,' ,~:.'. . ,- ': :' ''', , ',', ' :.
~,, ~'" . ' ' ' '' ,' ' ' ' ,' . ' ' ' ' " :. ~ ,:
.; . , .
'' 10~61~8
is of importance, in particular, for the mauufacture of end products of the
general formula I, in which Rl denotes a hydrogen atom and X and Y conjointly
denote an additional bond. Thus, compounds of the more restricted general
formula Ib, in which R is a methyl, or benzyl group, are used, in particular,
as the starting materials for the manufacture of such starting materials of
the general formula II.
Starting materials of the general formula IV for the reduction
according to c), especially those which have an additional bond in place of X
. and Y, can be manufactured according to or analogously to the abovementioned
manufacture of starting materials of the general formula II, using suitable
carboxylic acid halides obtained from corresponding compounds of the general
formula IJ above all that of the more restricted formula Ib, which has a methyl
group as Rl. ~owever, it is more advantageous, especially for the manufacture
;
of compounds of the general ~ormula IV which have hydrogen atoms as X and Y,
to start from compounds of the general formula Ia, especially from the compound
of this formula which has hydrogen atoms as X and Y and which is readily ac- ;
cessible by hydrogenation according to process e), and to acylate the imino
group therein in the customary manner, for example by reaction with suitable
carboxyiic acid halides, that ~is to say carboxylic acid halides which agree
~with the definition of RlC, in the presence of acid-binding agents, such as,
for example, potassium carbonate, in an inert organic solvent, such as, for
example, dioxane, or in pyridine or in a mixture thereof with inert organic
. .
~- ; solvents, at room temperature of moderately elevated ~emperatures.
; Starting materials of the general formula VI are obtained, in parti- ~;~
cular, by reacting benzofurane, which is substituted in the 3-position by
halogen, especially 3-bromo-benzofurane with magnesium or, in particular,
. ::
with aikali metal compounds, such as butyl-lithium, and immediately thereafter
reacting the resulting metallo-organic compounds with 4-piperidones, which are
sabstituted corresponding to the definition for Rl and some of which are known
-16-
:. . ~ '' , ' ' .. "' '. . , . , , . , : , ,
. .. .' ,' . .'' ., ~ , .' ~ ' '.:
: , . . . . . .
~-` 1076118 ~ ~
and others of which can be manufactured analogously to the known compounds.
The present invention also relates to those modifications of the
processes mentioned under a) to g) in which a starting material optionally is
used in the form of a salt. Preferably, the starting materials used for carry-
ing out the reactions according to the invention are those which lead to the
groups of end substances which have initially been mentioned in particular.
Depending on the process conditions and the starting materials, the
end products are obtained in the free form or in the form of their acid addi-
tion salts, which are also included in the invention, or optionally also as
hydrates of these salts. The acid addition salts of the new compounds of the
general formula I can be converted into the free bases in a msnner which is in
itself known, for exampIe with basic agents, such 95 alkalis or ion exchangers.
On the other hand, the compounds of the general formula I obtained according
to the process of the invention can, if desired, be converted in a customary
manner into their addition salts with inorganic or organic acids. For example,
the acid desired as the salt component is added to a solution of a compound of
the general formula I in an organic solvent. Preferably, organic solvents in
~ which the resulting salt is sparingly soluble are selected for the reaction
`,'iJ~ 50 that the salt can be separated off by filtration. Such solvents are, for
; ~20 examplej ethyl acetate, methanol, ether, acetone, methyl ethyl ketone, acetone/
ether, acetone/ethanol, methanol/ether or ethanol/ether.
Instead of free bases, pharmaceutically acceptable acid addition
salts, that is to say salts with those acids which have anions which are not
toxic at the relevant dosagesj can be employed for use as medicaments. It is
. . ~ . . .
also advantageous if the salts to be used as medicaments crystallise readily
and are not hygroscopic or only slightly hygroscopic. Acids which can be used
to form salts wIth compounds of the general formula I are, for example, hydro-
~ chloric acid, hydrobromic acid, sulphuric acid, phosphoric acid i! methanesul-
; phonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, acetic acid,
' ` ¢; ~ ' ,
-' ."5 , ' - 17-
, , : . . . ~ ... . ., . ,:
'.' ' ' ': . : ~ , ' '
. ~ . .. . .
'.~ . : : '
: ~' ~ . ' ' '
~ -` 1076~8
.
lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric
acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic
acid and embonic acid.
Th~ new active compounds are administered perorally, rectally or
parenterally. The dosage depends on the mode of administration, the species>
the age and the state of the individual. The daily doses of the free bases,
:
or of pharmaceutically acceptable salts of the free bases vary between 0.1 mg/
kg and 10 mg/kg for warm-blooded animals. Suitable dosage unit forms, such as
dragees, tablets, suppositories or ampoules, preferably contain 5-100 mg of an
active compound according to the invention.
Dosage unit forms for peroral administration preferably contain, as
the actlve compound, between 5-90% of a compound
... : . .. :
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`` 1~76118
.
of the general formula I or of a pharmaceutically acceptable
salt of such a compound. To produce the dosage unit
forms, the active compound is combined, for example, with solid,
pulverulent excipients, such as lactose, sucrose, sorbitol or
mannitol; starches, such as potato starch, maize starch or
amylopectin, as well as laminaria powder or citrus pulp powder;
cellulose derivatives or gelatine, optionally with the addition
of lubricants, such as magnesium stearate or calcium stearate
or polyethylene glycols, to give tablets or dragee cores
The dragee cores are coated, for example, with concentrated
.:-
sugar solutions, which, for example, can also contain gum
arabic, talc and/or titanium dioxide, or with a lacquer, which
is dissolved in readily-volatile organic solvents or solvent
- mixtures. Colorants can be added to these ooatlngs, ~or
exampIe in order to characterise different dosages of active
compound,
Other suitable oral dosage unit forms are push-fit
capsules made of gelatine as well as soft closed capsules made
oi gelatine and a plasticiser, such as glycerol. The
push-fit capsules preferably oontain the active oompound as
granules, for examile mixed with fillers, such as maize starch,
and/or lubricants, such as talc or magnesium stearate, and
optionally stabilisers, such as sodium metabisulphite (Na2S205)
or ascorbic acid. In sof~ capsules the active compound is
preferably dissolved or suspended in suitable liquids~ such as
liquid polyethylene glycols, and stabilisers can also be added.
Dosage unit forms which can be used for rectal `
!`
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.. .
administration are, for example, suppositories which consist of
a combination of an active compound with a suppository base.
Suitable suppository bases are, for example, natural or syn-
thetic triglycerides, paraffin hydrocarbons, polyethylene
glycols or higher alkanols Gelatine rectal capsules
which consist of a combination of the active compound with a
base material are also suitable. Suitable base materials
``i are, for example, liquid triglycerides, polyethylene glycols or
paraffin hydrocarbons.
; Ampoules for parenteral administration, especially
intramuscular administration, preferably contain a water- -
` soluble salt of an active compound in a concentration of pre-
..
ferably 0.5-5%, optionally together with suitable stabilisers
and buffer substances, in aqueous solution
The instructions which follow are intended to illustrate ~;
the production of tablets and capsules in more detail.
a) 250 g of 1-methyl-4-(3-benzofuranyl)-1,2,~,6-tetra-
hydropyridine hydrochloride are mixed with 175.80 g of lactose
and 169.70 g Or potato starch and the mixture is moistened with -
an alcoholic solution of 10 g of stearic acid and granulated
through a sieve. A~ter drying, 160 g of potato starch,
200 g of talc, 2.50 g of magnesium stearate and 32 g of
colloidal silicon dio~ide are admixed ~nd the mixture is pressed
to give 10,000 tablets, each 100 mg in weight and each containing
, ......................................................................... .
25 mg of active compound, which, if desired~ can be provided
with breaking grooves for finer adjustment of the dosage.
b) In order to produce 1,000 capsules each containing
~. .
: ; ., :.
.
10~ 118
lO mg of active compound, 10 g of 4-(3-benzofuranyl)-piperidine
hydrochloride are mixed with 248 g of lactose and the mixture
is moistened uniformly with an aqueous solution of 2 g of
gelatine and granulated through a suitable sieve (for example
sieve III according to Ph. Helv. V). The granules are
mixed with 10.0 g of dried maize starch and 15.0 g of talc and
filled uniformly into l,OOO size 1 hard gelatine capsules.
The examples which follow explain in more detail the
manufacture of the new compounds of the general formula I and
of lntermediate products which have not hitherto been described,
but are not intended to restrict the scope of the invention in
any way-
Examle l
7.5 g of l-methyl-4-(3-benzofuranyl~-4-piperidinol are
boiled under reflux in 180 ml of glacial acetic acid and 60 ml
of 12 N hydrochloric acid for 7 hours. me solution is
cooled to~room temperature and evaporated in vacuo, the
evaporation residue lS dlssolved in 250 ml of water and the
aqueous phase is extracted with twice lOO ml of ethyl acetate.
The pH value of the aqueous solution is then adjusted to 12
by~adding 10% stre~gth sodium hydroxide solution and the mix- `
ture is extracted with 500 ml of chloroform. ~he chloro- -
form solution is dried with sodium sulphate and ~iltered and
the filtrate is evaporated. The crude product is dis-
solved in 100 ml ofchloroform andchromatcgraphed on 500 g of
aluminium oxide (neutral, activity III). On evaporation,
the first fractions eluted with a total o~ 1 litre of chloro-
.. ~ . ..
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form give pure l-methyl-4-(3-benzofuranyl)-1,2,3,6-tetrahydro-
'pyridine. me hydrochloride thereof is prepared with ''
hydrogen chloride in ethyl acetate and is recrystallised from '
I~ acetone, after which it melts at 248-250C. '~
.~' me starting material is prepared as follows: ' -
' a) 100 ml of a 2 N solution of butyl-lithium in '
. ( . . .
~ hexane (Fluka) are pre-cooled to -70 to -80C. A solution
, . ....
of 39.4 g (0.2 mol) o~ 3-bromobenzofurane in 150 ml of '
absolute diethyl ether is added dropwise to this solution at
a temperature o~ -70C in the course of 30 minutes. mere- '~
after the'solution is stirred ~or a further~2 hours at -70C. -
A solutlon of 2~.0 g (0.203 mol~ of l-methyl-4-plperidone in ~
. .
70 ml of absolute diethyl ether is then added dropwise in the '-~
course of 30 minutes, the reaction temperature belng kept at
70C~by external cooling. me reaction solution is
then stirred ~or a further 2 hours at -70C.
e~reaotLon fiolution ls then warmed to -5C and
poured onto 300 g of ice.~ The organic phase is separated
off~and the aqueous phase~is extracted twice~more using
250 ml;of ethyl acetate each time. ~ me organic phases
are combined, dried over sodium sulphate and filtered and the
filtrate ls evaporated. me residue is dlssolved in
300 ml of 2 N hydrochlorlc acid and the acid solution is ' '
washed with ether. The pH value of the acid aqueous
solution is then adjus'ted to 12 by adding 10% strength sodium ' -
. ( . .
~ hydroxide solution and the mixture is~extracted with l litre - '
,,
~ ' of chlorofor~. The chloroform solution is dried with
.. ' . ~ .i
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7~1~8
.
..
sodium sulphate and filtered and the filtrate is evaporated, crude l-methyl-
; 4-~3-benzofuranyl)-4-piperidinol being obtained. The evaporation residue is
dissolved in chloroform and chromatographed over 500 g of aluminium oxide
` ~neutral, activity III). On evaporation, the first fractions eluted with 7
. litres of chloroform give pure l-methyl-4-~3-benzofuranyl)-4-piperidinol. Af-
. ter recrystallisation from ethyl acetate/hexane, the free base melts at 149-
151~C.
~ ~: ! Example 2
. .
Analogously to Example 1, 7.5 g of 1-benzyl-4-(3-benzofuranyl)-4-
piperidinol give 1-benzyl-4-~3-benzofuranyl)-1,2,3,6-tetrahydropyridine and
the hydrochloride thereof.
The starting material is obtained analogously to Example la) using
37.9 g (0.203 mol) of 1-benzyl-4-piperidone.
Example 3
A solution of 9.5 g of sodium borohydride in 26 ml of water-is added
dropwise~to a solutlon of 9.5 g ~0.03 mol) of 1-methyl-4-~3-benzofuranyl)-py- -~
ridinium iodide in 160 ml of methanol, whilst stirring and with external cool-
; ing, n uch a~way that the re-ction t:~Deraturc does not Fise above 38C.
::.. ,.: : ,
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1076~:~8
;. The solution is then stirred for 20 hours at room temperature ~
:. ~ Thereafter ~he methanol is evaporated off in vacuo and the :-
residual aqueous phase is extracted with three times 300 ml of
. ethyl acetate. The combined organic phases are washed
with twice 500 ml of water, dried over sodium sulphate and ... :
filtered and the filtrate is evaporated. me resulting ~:
.
~ l-methyl-4-(3-benzofuranyl)-1,2,3,6-tetrahydropyridine is : .~
. fractionated in ahigh vacuum, the desired base distilling at : .
. ;~ 109-111C at 0 04 mm Hg. ~ : -
~ The starting material is prepared as fol~ows:
- a) 12 g of 4-(o-hydroxybenzoyl)-pyridine (compare British . .
~,: . Patent Specification 1,231,783), 11 g of bromoacetic acid
I ~ .
methyl ester, 70 g of potassium carbonate and 0.5 g of potassium
iodide are heated in 250 ml of dimethylformamide at 100-110C
for 4 hours, whilst stirring. me warm solutlon is then :
filtered and the filter residue is rinsed with 150 ml of warm
dimethylformamide. me combined filtrates are evaporated
in vacuo.and the residue ls dissolved in one litre of ethyl
acetate. The organic phase is washed with three times
one litre of water, dried over sodium sulphate and filtered :.:
and the filtrate is evaporated. The residuaI oil is
dissolved in a little methylene chloride and .chromatographed
! .
:over 300 g of.aluminium oxide (activity II, neutral). The ;..:~
; first fraction eluted with 2 litres of methylene chloride is
. 3-~4-pyridyl)-2-benzofuranecarboxylic acid methyl ester, which
after recrystallisation from diisopropyl ether melts at -.
117-119C.
1: ~ ' '
, 1 ~.. ..
~ _ 24 -
.. .
.. . . .
: ~ ~0761~8 :
b) 20 g of sodium hydroxide are added to a solution of 15 g of 3-~4-pyridyl)-
2-benzofuranecarboxylic acid methyl ester in 260 ml of ethanol and the solution
. . .
i~ is boiled under reflux for one hour under nitrogen. The ethanol is then
`~ ~ evaporated off in vacuo, the residue is dissolved in 300 ml of water, the solu-
tion is filtered and the pH value of the clear filtrate is adjusted to 5.5 by
adding 2 N hydrochloric acid. 3-(4-Pyridyl)-2-benzofuranecarboxylic acid pre-
cipitates; the crystals are filtered off and washed with ioo ml of water in
, portions. After recrystallisation from methanol, the resulting carboxylic
i~, acid melts at 259-260C. c) A solution of 6.0 g of 3-~4-pyridyl)-2-benzofurane-
carboxylic acid in 45 ml of quinoline is boiled under reflux with 0.7 g of
powdered copper for 30 minutes, whilst stirring and under nitrogen. The sol-
vent is then evaporated off in vacuo. The residue is fractionated in a high
vacuum. 4-t3-Benzofuranyl)-pyridine distills at 129-130C/0.06 mm Hg. d) 3 ml
of methyl iodide are added to a solution of 5.5 g of 4-~3-benzofuranyl)-pyri-
dine in 200 ml of methanol. The solution is stirred for 15 hours at a temper-
.. . .
ature of 50C. The solution is then cooled to -20C and the iodide which has
, . ,:.i ~
crystallised out is filtered off. After one recrystallisation from methanol,
methyl-4-(3-benzofuranyl)-pyridinium iodide melts at 242-245C.
Example 4
~ 5.33 g ~0.025 mol) of 1-methyl-4-~3-benzofuranyl)-1,2,3,6-tetra-
hydropyridine are dissolved in 200 ml of ethanol and hydrogenated in the pre-
sence of 0.6 g of palladium-on-charcoal catalyst (5% strength) at a temperature
between 20C and 25C under normal pressure. The hydrogenation is discontinued
~ after the theoretical amount of hydrogen has been absorbed, the catalyst is
:~ ~ filtered off and the filtrate is evaporated. The residual l-methyl-4-(3-
;~ benzofuranyl)-piperidine is dissolved in 100 ml of toluene and the solution is
., ;", . . .
extracted with twice 100 ml of 10% strength aqueous methanesulphonic acid.
- ~ The pH value of the combined acid aqueous extracts is adjusted to 12 by adding
~ .
~` 40% strength sodium hydroxide solution and the mixture is extracted with three
'f~
~ -25-
.. . . .. . .
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~07611~
times 300 ml of chloroform. The organic phases are combined, dried with ~:~
sodium sulphate and filtered and the filtrate is evaporated. The residual 1-
methyl-4-~3-benzofuranyl)-piperidine is converted into its hydrochloride using
a solution of hydrogen chloride in ethyl acetate. After recrystallisation
from methyl ethyl ketone, the hydrochloride melts at 205C.
Example 5
0.59 tO.002 mol~ of 1-benzyl-4-~3-benzofuranyl)-1,2,3,6-tetrahydro-
pyridine is dissolved in 5 ml of methanol and, after adding 3.2 ml of 2.28%
strength (weight/volume) methanolic hydrogen chloride solution ~corresponding
to one equivalent of HCl) and 0.1 g of palladium-on-charcoal (5% strength3,
(
hydrogenated at a temperature between 20 and 30C and under normal pressure.
`~ The hydrog~nation is discontinued after the equimolar amount of hydrogen has
been absorbed, the catalyst is filtered off and the filtrate is evaporated in
~ . , .
~`~ vacuo~ l-benzyl-4-~3-benzofuranyl)-piperidine remaining as a residue. This
-~¦i is purified by recrystallisation from hexane and converted into its hydro-
. ~ .
chloride using a solution of hydrogen~chloride in ethyl acetate.
Exa.mple 6
4.26 g (0.02 moI) of l-methyl 4-~3-benzofuranyl)-piperidine are
dissolved in 85 ml of toluene and~3.9 g t0.04 mol) of chloroformic acid ethyl ~;
ester are added. The solution is stirred for 15 hours at 50C. A further
3 9 g of chloroformic acid ethyl ester are then added and the mixture is
stirred for a further two hours at 50C. In order to work up the mixture, the ;
excess chloroformic acid ethyl ester is distilled off under normal pressure
and, in order to remo~e this completely, a small part of the toluene
:: 1
,: ,
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7~1~8
i
~, is distilled off. Thereafter, the solution is cooled
to 70C and then ~iltered and the residue on the filter is
rinsed with 50 ml of toluene. The combined filtrates
are washed successively with 100 ml of water, 100 ml of
a 10% strength aqueous methanesulphonic acid solution, 100 ml
of water, 100 ml of 2 N sodium hydroxide solution and lO0 ml
of water, dried over sodium sulphate and filtered and the
filtrate is evaporated. The residual crude 4-(3-
~l C benzofuranyl)-l-piperidinecarboxylic acid ethyl ester is a
.j :
single compound according to thin layer chromatography and is
~urther processed without puri~ication.
3.0 g of -the above 4-(3-benzofuranyl-1-piperidine-
carboxylic acid ethyl ester are dissolved in 35 ml of ethylene
glycol. After adding 6.5 g of solid sodium hydroxide,
the resulting turbid~solution is heated at~100C for 15 hours,
whilst stirring vigorously and under nitrogen. ~ me re-
action solution is then cooled to 20C and extracted with twice
150 ml of toluene. me combined organic phases are
extràcted with three times 150 ml of a 10~ strength aqueous
methanesulphonic acid solution. ~ The pH value of the
aqueous solution is then adjusted to 12 by adding 40% strength
sodium hydraxide solution and the mixture is extracted with
500 ml of chloroform. The chloroform solution is dried
with sodium sulphate and fiitered and the filtrate lS evapora-
ted. The evaporation residue is distilled in a high
vacuum (molecular distillation), 4-(3-benzo~uranyl)-piperldine
distilling at l40C under 0.4 mm Hg. ~he hydrochloride is
,~ - . . .
~ - 27 -
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1076118
prepared from the base using hydrogen chloride in ethyl acetate and is re-
crystallised from ethyl methyl ketone.
ExamplP 7
2.0 g of 4-(3-benzofuranyl)-piperidine and 1.2 g of 3-bromop~opyne are
dissolved in 50 ml of methanol and, after adding 10 g of potassium carbonate, -
the mixture is stirred at room temperature for 30 hours. The reaction mixture
is then filtered, the material on the filter is washed with 100 ml of chloro-
form and the combined filtrates are evaporated in vacuo. The residue is
, . . .
dissolved in a little methylene chloride and chromatographed on 60 g of
~ 10 aluminium oxide ~activity II, neutral?. The first fractions, eluted with a
`~ total of 250 ml of methylene chloride, contain 1-t2-propynyl)~4-(3-benzofuranyl)-
; piperidine. The base can be recrystallised from hexane and, if desired, con-
verted into its hydrochloride using a solution of hydrogen chloride in ethyl
acetate; the hydrochloride is recrystallised from the same solvent.
` ~ ~ Analogously, l-ethyl-4-(3-benzofuranyl~-piperidine and the hydrochor-
:. ,. : :
ide thereof are obtained using 7.8 g of ethyl iodide, l-(cyclopropylmethyl)-
4-~3-benzofuraDyl)-piperidine and the hydrochloride thereof are obtained using
. ., , ~ , : : . .
~ 6.8 g of cyclopropylmethyl bromide and 1-benzyl-4-~3-benzofuranyl)-
.,~
.
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,~., .
piperidine and the hydrochloride thereof are obtained using
8.6 g of benzyl bromide.
Exam~le 8
2.5 g of 4-(3-benzofuranyl)-piperidine are dissolved
in 15 ml of formic acid. 1.5 ml of a 4~/o strength
aqueous formaldehyde solution are added dropwise to this solu-
tion, whilst stirring. The reaction mixture is heated
at 95-100C for 5 hours and then stirred for 15 hours at room
temperature. Thereafter, the solution is rendered
strongly acid by adding 2.5 ml of concentrated hydrochloric
~. . .
acid and the solvent is evaporated off in vacuo. The
evaporatlon residue is dissolved in 2.5 ml of water, the non-
basic substances are extracted with toluene, the pH of the
aqueous phase is adjusted to 12 by adding 10% strength aqueous
., . :
sodium hydroxide solution and the mixture is extracted with
three timeS 75 ml of chloroform. The organic phases are
combined, dried over sodium sulphate and filtered and the
.;4.`~
filtrate is evaporated. The residual crude l-methyl-4-
(3-benzofuranyl)-piperidine is dissolved in ethyl acetate and
, . :
converted into its hydrochloride using a solution of hydrogen
chloride in ethyl acetate and the hydrochloride is purified by
, ~
recrystallisation from methyl ethyl ketone.
Examle 9
A solution of 2.9 g of 1-(cyclopropylcarbonyl)-4-(3-
benzofuraryl)-piperidine in 25 ml of tetrahydrofurane is added
dropwise to a solution of 2.7 g of lithium aluminium hydride
in 50 ml of tetrahydrofurane, which is ~oiling under re~lux.
C ~ - 29 ~
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After boiling under reflux for 15 hours, the reaction mixture
is cooled and the excess lithium aluminium hydride is destroyed
at -10C by means of 5 ml of water, 3 ml of 10% strength sodium
hydroxide solution and 10 ml of water. The reaction solu-
tion is filtered, the material on the filter is rinsed with
one litre of chloroform and the combined filtrates are evapora-
ted in vacuo. The residue is dissolved in 100 ml of
2 N hydrochloric acid and the acid solution is washed with
, . . ---- . .
, ether. Thereafter, the pH of the aqueous solution is
adjusted to 12 by adding 10% strength sodium hydroxide solutior.
and the mixture is extracted with one litre of chloroform.
;~! . ~ .
e chloroform solution is dried with sodium sulphate and
filtered and the filtrate is evaporated, crude l-tcyclopropyl-
methyl)-4-(2-benzofuranyl)-piperidine being obtained. This
is purified by recrystallisation from hexane. The hydro-
chIoride of this base is prepared using hydrogen chloride in
ethyl acetate and recrystallised from ethyl acetate
` l-(Cyclopropylcarbonyl)-4-(3-benzofuranyl~-piperidine,
E~ '` : .
which is used as the starting material, can be prepared in the
following manner:
2.42 g~of 4-(3-benzofuranyl)-piperidine are dissolved
-~ in 50 ml of dioxane and 1.47 g of cyclopropanecarbonyl chloride
and 10 g of potassium carbonate are added to the solution.
é reaction solution is stirred for 15 hours at room tempera-
ture. me reaction solution is then filtered, the residue
on the ~ilter is rinsed with 200 ml of chloroform and the
combined filtr~tes are evaporated in vacuo. m e residue
.:, . ' :
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:' . . ,, . ~ ', ' ''' ~ ' ' ' , ' ''' ''", ' ' ' , ' . , ': "'
.. . .
.
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76
,;-,,~, .
:- is dissolved in 50 ml of ethyl acetate and the solution is
~-. washed successively with 2 N hydrochloric acid, water, 2 N
:.: ammonium hydroxide and water9 dried over sodium
sulphate and filtered and the filtrate is evaporated.
Crude l-(cyclopropylcarbonyl)-4-(3-benzofuranyl)-piperidine
is obtained as the evaporation residue and can be used direct
for the reduction with lithium aluminium hydride.
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