CA1076118A - Benzofuranyl derivatives of tetrahydropyridine and piperidine compounds - Google Patents
Benzofuranyl derivatives of tetrahydropyridine and piperidine compoundsInfo
- Publication number
- CA1076118A CA1076118A CA234,433A CA234433A CA1076118A CA 1076118 A CA1076118 A CA 1076118A CA 234433 A CA234433 A CA 234433A CA 1076118 A CA1076118 A CA 1076118A
- Authority
- CA
- Canada
- Prior art keywords
- general formula
- benzofuranyl
- compound
- methyl
- piperidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Abstract of the Disclosure The invention relates to processes for the production of of new tetrahydropyridine and piperidine derivatives of the general formula I
(I) in which R1 denotes hydrogen, an alkyl group with at most 4 carbon atoms or the 2-propynyl, cyclopropylmethyl or benzyl group, and X and Y each denote a hydrogen atom or conjointly denote an additional bond, and of their acid addition salts.
These new substances possess valuable pharmacological properties. In particular they have an antidepressant activity and are useful as active substances for pharmaceutical prepara-tions for the treatment of states of depression.
(I) in which R1 denotes hydrogen, an alkyl group with at most 4 carbon atoms or the 2-propynyl, cyclopropylmethyl or benzyl group, and X and Y each denote a hydrogen atom or conjointly denote an additional bond, and of their acid addition salts.
These new substances possess valuable pharmacological properties. In particular they have an antidepressant activity and are useful as active substances for pharmaceutical prepara-tions for the treatment of states of depression.
Description
" ~ 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 ;
, .
, . ~ .
, .
., .
, .
-
. 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.
, : ~ , ., : ~ :
., . ,:
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... .
-. ' - :'' , . ~ , . . :
' ,' , ' ' , . . '~ :
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~: . . .. . ~
.'- ' ' '' ' , ' - ' ' ' " ' : ' : . :
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. ~ ..
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~ ~
~, .
. ~ . .
. ,~ , - .
; ~ , . .
'~',~ ' ,, , . . .
. '~'' ' , .
: . .,. ,: . . , , , ,, . ;, :
;'` 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-, - . , . : . . ~ ,; , . : . ... . . .. . ......... .. .
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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.
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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:
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'' 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 :. . ~ '' , ' ' .. "' '. . , . , , . , : , , . .. .' ,' . .'' ., ~ , .' ~ ' '.:
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~-` 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-, , : . . . ~ ... . ., . ,:
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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 ~ _ ~2 - , '', ' , .', ~ '' . . ..
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--`i 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.
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: ~ ~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~
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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 ,: , .. , i: `". "
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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 -:~ -. ~, , ~ . , . , ;, ~ . ~ . , - -. : . , . ,-. . .: " , ., ~ , , :` :, '' " ' ' 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.
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,,:, , ~ ,. `,: -:.', , , ~ 1~761~8 .,; , :
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 .:, . ' :
!~
:~' , . ' :' . . ,, . ~ ', ' ''' ~ ' ' ' , ' ''' ''", ' ' ' , ' . , ': "' .. . .
.
' ', ', ' . ' : . ' , ' ' ' , ,;-,,~, .
:- 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.
~,.:; , .
..
;~: C
-, :, . .
.' ., ~ ~ ' " :
; ~ ~
` ~'~,' ' ' . ' ., ,:
:.. j' ' ' . f .''~ ' , . .
, ~ '~. ' '- . . ' ,:
. .~ ~ . . .
.," ~'~ .' . '.
~r?~ ~ ~ 31 ; ., .
,'~ ' ' .
.. -. , : , , : . ~ ;:
:................ : . . .
.: -- - . : :
. ' ; .' '''"' ~ '.. :'' '' . .- ', ' ' ;~ "; ' ~ . .
.~; : '' ' . ' .. . ..
, .
--: '. . :
. : .
... , , . ,~ .
:.. ., . :
~ . : , , - :. . . .
. ., . ,: ,, ~
.. ' ~ . . .
.
` ' - 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 , . .;
,, ''': ,," , ', ' '. ,'' ' ', ' ~ . .:
;:
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 :. . ~ '' , ' ' .. "' '. . , . , , . , : , , . .. .' ,' . .'' ., ~ , .' ~ ' '.:
: , . . . . . .
~-` 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 ... : . .. :
: ~:
. .', , .
. ~ , ..
: .: , .: "
.~
- . , .
.
. ' . . , , :
. " , . .
::
;,., , ' .
,: . ~ ,:
' : ,: ' .. . - ' ' . , , ,.'.,: , :
: .; , - . . . . . . . .. . . . .
`` 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 ~. .
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.
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 ~ _ ~2 - , '', ' , .', ~ '' . . ..
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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.
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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~
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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 ,: , .. , i: `". "
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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 -:~ -. ~, , ~ . , . , ;, ~ . ~ . , - -. : . , . ,-. . .: " , ., ~ , , :` :, '' " ' ' 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.
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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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:- 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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Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the manufacture of benzofuranyl derivatives of tetra-hydropyridine and piperidine compounds of the formula I
(I) in which R1 denotes hydrogen, an alkyl group with at most 4 carbon atoms or the 2-propynyl, cyclopropylmethyl or benzyl group and X and Y each denote a hy-drogen atom or conjointly denote an additional bond, and their addition salts with inorganic and organic acids, characterised in that a) in a compound of the general formula II
(II) in which Ac denotes a radical which can be split off and X and Y have the mean-ind indicated under formula I, the radical Ac is split off and b) if desired, a compound, obtained according to a) or by other means, of the general formula Ia (Ia) 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 III
HO - R1a (III) in which R1a has the meaning indicated for R1 under the formula I, with the exception of hydrogen, or is reacted, under reducing conditions, with an oxo compound of the general formula IIIa O = R1b (IIIa) in which R1b denotes the geminal divalent radical which corresponds to a monovalent radical R1a, or c) in a compound of the general formula IV
(IV) in which R1c denotes a radical corresponding to the definition for R1 but reduced by a methylene group or denotes a lower alkoxycarbonyl 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
(V) in which Z ? denotes a monovalent anion or the normal equivalent of a polyvalent anion and R1a has the meaning 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, (Ib) which falls under the general formula I and in which R1 has the meaning indicated under the general formula I, is hydrogenated catalytically to the corresponding piperidine compound, or f) 1-benzyl-4-(3-benzofuranyl)-piperidine is subjected to hydrogenolysis, or g) water is eliminated from a compound of the general formula VI
(VI) in which R1a 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 organic acid.
(I) in which R1 denotes hydrogen, an alkyl group with at most 4 carbon atoms or the 2-propynyl, cyclopropylmethyl or benzyl group and X and Y each denote a hy-drogen atom or conjointly denote an additional bond, and their addition salts with inorganic and organic acids, characterised in that a) in a compound of the general formula II
(II) in which Ac denotes a radical which can be split off and X and Y have the mean-ind indicated under formula I, the radical Ac is split off and b) if desired, a compound, obtained according to a) or by other means, of the general formula Ia (Ia) 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 III
HO - R1a (III) in which R1a has the meaning indicated for R1 under the formula I, with the exception of hydrogen, or is reacted, under reducing conditions, with an oxo compound of the general formula IIIa O = R1b (IIIa) in which R1b denotes the geminal divalent radical which corresponds to a monovalent radical R1a, or c) in a compound of the general formula IV
(IV) in which R1c denotes a radical corresponding to the definition for R1 but reduced by a methylene group or denotes a lower alkoxycarbonyl 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
(V) in which Z ? denotes a monovalent anion or the normal equivalent of a polyvalent anion and R1a has the meaning 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, (Ib) which falls under the general formula I and in which R1 has the meaning indicated under the general formula I, is hydrogenated catalytically to the corresponding piperidine compound, or f) 1-benzyl-4-(3-benzofuranyl)-piperidine is subjected to hydrogenolysis, or g) water is eliminated from a compound of the general formula VI
(VI) in which R1a 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 organic acid.
2. Process according to claim 1, characterised in that 1-methyl-4-(3-benzofuranyl)-1,2,3,6-tetrahydropyridine is prepared by eliminating water from 1-methyl-4-(3-benzo-furanyl)-4-piperidinol, and if desired, is converted into a pharmaceutically acceptable acid addition salt.
3. Process according to claim 1, characterised in that 1-methyl-4-(3-benzofuranyl)-1,2,3,6-tetrahydropyridine is prepared by partially reducing a compound of the general formula V, wherein R1a represents the methyl group, and, if desired, is converted into a pharmaceutically acceptable acid addition salt.
4. Process according to claim 1, characterised in that 1-methyl-4-(3-benzofuranyl)-piperidine is prepared by catalytically hydrogenating 1-methyl-4-(3-benzofuranyl)--1,2,3,6-tetrahydropyridine, and, if desired, is converted into a pharmaceutically acceptable acid addition salt.
5. Process according to claim 1, characterised in that 1-methyl-4-(3-benzofuranyl)-piperidine is prepared by reacting, under reducing conditions 4-(3-benzofuranyl)-piperidine with formaldehyde, and, if desired, is converted into a pharma-ceutically acceptable acid addition salt.
6. Process according to claim 1, characterised in that 4-(3-benzofuranyl)-piperidine is prepared by splitting off the radical Ac in a compound of the formula II wherein Ac has the meaning given in claim 1 and X and Y each denote hydrogen, and, if desired, is converted into a pharmaceutically acceptable acid additon salt.
7. Benzofurane derivatives of tetrahydropyridine and piperidine compounds of the general formula I indicated in claim 1, in which R1 has the meaning de-fined in claim 1, and their addition salts with inorganic and organic acids, whenever prepared by a process as claimed in claim 1, or by an obvious chemical equivalent thereof.
8. 1-Methyl-4-(3-benzofuranyl)-1,2,3,6-tetrahydropyridine and its pharm-aceutically acceptable acid addition salts whenever prepared by a process as claimed in claim 2, or by an obvious chemical equivalent thereof.
9. 1-Methyl-4-(3-benzofuranyl)-1,2,3,6-tetrahydropyridine and its pharm-aceutically acceptable acid addition salts whenever prepared by a process as claimed in claim 3, or by an obvious chemical equivalent thereof.
10. 1-Methyl-4-(3-benzofuranyl)-piperidine and its pharmaceutically ac-ceptable acid addition salts whenever prepared by a process as claimed in claim 4, or by an obvious chemical equivalent thereof.
11. 1-methyl-4-(3-benzofuranyl)-piperidine and its pharmaceutically ac-ceptable acid addition salts whenever prepared by a process as claimed in claim 5, or by an obvious chemical equivalent thereof.
12. 4-(3-benzofuranyl)-piperidine and its pharmaceutically accetpable acid addition salts whenever prepared by a process as claimed in claim 6, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1511677A CH609980A5 (en) | 1974-08-30 | 1974-08-30 | Process for the preparation of novel piperidine derivatives |
| CH1183774A CH605925A5 (en) | 1974-08-30 | 1974-08-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1076118A true CA1076118A (en) | 1980-04-22 |
Family
ID=25709012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA234,433A Expired CA1076118A (en) | 1974-08-30 | 1975-08-28 | Benzofuranyl derivatives of tetrahydropyridine and piperidine compounds |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5148673A (en) |
| AT (1) | AT348523B (en) |
| AU (1) | AU499372B2 (en) |
| BE (1) | BE832885A (en) |
| CA (1) | CA1076118A (en) |
| CH (2) | CH609980A5 (en) |
| DE (1) | DE2537837A1 (en) |
| FR (1) | FR2282887A1 (en) |
| GB (1) | GB1510977A (en) |
| NL (1) | NL7510142A (en) |
| SE (1) | SE7508897L (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0006524A1 (en) * | 1978-06-22 | 1980-01-09 | Ciba-Geigy Ag | Tetrahydropyridine and tetrahydropiperidine derivatives, their acid addition salts, processes for their preparation and pharmaceutical compositions containing them |
| US4455427A (en) * | 1981-07-01 | 1984-06-19 | The Upjohn Company | Pyridyl-substituted-benzofurans |
| US4490531A (en) * | 1981-07-01 | 1984-12-25 | The Upjohn Company | Pyridyl-substituted-benzofurans |
| US4495357A (en) * | 1981-07-01 | 1985-01-22 | The Upjohn Company | Pyridyl-substituted-benzofurans |
| US4447620A (en) * | 1982-06-08 | 1984-05-08 | The Upjohn Company | Imidazolyl-substituted benzothiophenes |
| US4452986A (en) * | 1982-06-08 | 1984-06-05 | The Upjohn Company | Imidazolyl-substituted benzofurans |
| US4611059A (en) * | 1982-10-12 | 1986-09-09 | The Upjohn Company | Pyridyl-substituted benzothiophenes |
| US4855435A (en) * | 1982-10-12 | 1989-08-08 | The Upjohn Company | Pyridyl-substituted benzothiophenes |
| AU579647B2 (en) * | 1985-02-21 | 1988-12-01 | Asahi Kasei Kogyo Kabushiki Kaisha | Process for adsorption treatment of dissolved fluorine |
| TW266206B (en) * | 1993-04-28 | 1995-12-21 | Takeda Pharm Industry Co Ltd | |
| US5891895A (en) * | 1996-04-15 | 1999-04-06 | Takeda Chemical Industries, Ltd. | Hydroxypyridine derivatives their production and use |
-
1974
- 1974-08-30 CH CH1511677A patent/CH609980A5/en not_active IP Right Cessation
- 1974-08-30 CH CH1183774A patent/CH605925A5/xx not_active IP Right Cessation
-
1975
- 1975-08-07 SE SE7508897A patent/SE7508897L/en unknown
- 1975-08-26 DE DE19752537837 patent/DE2537837A1/en active Pending
- 1975-08-27 NL NL7510142A patent/NL7510142A/en not_active Application Discontinuation
- 1975-08-28 GB GB35529/75A patent/GB1510977A/en not_active Expired
- 1975-08-28 CA CA234,433A patent/CA1076118A/en not_active Expired
- 1975-08-28 AU AU84356/75A patent/AU499372B2/en not_active Expired
- 1975-08-28 FR FR7526509A patent/FR2282887A1/en active Granted
- 1975-08-29 BE BE159579A patent/BE832885A/en unknown
- 1975-08-29 AT AT667875A patent/AT348523B/en not_active IP Right Cessation
- 1975-08-30 JP JP50105554A patent/JPS5148673A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CH605925A5 (en) | 1978-10-13 |
| AT348523B (en) | 1979-02-26 |
| FR2282887A1 (en) | 1976-03-26 |
| NL7510142A (en) | 1976-03-02 |
| SE7508897L (en) | 1976-03-01 |
| CH609980A5 (en) | 1979-03-30 |
| ATA667875A (en) | 1978-07-15 |
| AU499372B2 (en) | 1979-04-12 |
| BE832885A (en) | 1976-03-01 |
| JPS5148673A (en) | 1976-04-26 |
| FR2282887B1 (en) | 1980-04-18 |
| GB1510977A (en) | 1978-05-17 |
| DE2537837A1 (en) | 1976-03-18 |
| AU8435675A (en) | 1977-03-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |