CA1068289A - Process for the preparation of 2-aminoindane derivatives - Google Patents
Process for the preparation of 2-aminoindane derivativesInfo
- Publication number
- CA1068289A CA1068289A CA267,951A CA267951A CA1068289A CA 1068289 A CA1068289 A CA 1068289A CA 267951 A CA267951 A CA 267951A CA 1068289 A CA1068289 A CA 1068289A
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- Canada
- Prior art keywords
- formula
- aminoindane
- phenyl
- hydrochloride
- iii
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Preparing derivatives of 2-aminoindane of formula:
(I) in which n = 2, 3 or 4, the (CH2)n group having a straight or branched chain, R1 represents a hydrogen atom, an alkyl or hydroxy-alkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, whereby R1 and R2 may be identical or different and may form together with the contiguous nitrogen atom a nitrogenous heterocyclic group, R3 represents a hydrogen atom or a substituent, such as a hydroxy, chloro, tri-fluormethyl or lower alkyl radical, which may be in the ortho, meta or para position of the phenyl group and R4 represents a hydrogen atom, an alkoxy radical having 1 to 3 carbon atoms or a dialkylamino group, as well as the acid addition salts of the 2-aminoindane derivatives of formula (I). ??is is made possible by reacting a N-phenyl-2-aminoindane of formula:
(II) in which R3 and R4 have the meanings given above, with sodamide (NaNH2) and an halogenated amine of formula:
Preparing derivatives of 2-aminoindane of formula:
(I) in which n = 2, 3 or 4, the (CH2)n group having a straight or branched chain, R1 represents a hydrogen atom, an alkyl or hydroxy-alkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, whereby R1 and R2 may be identical or different and may form together with the contiguous nitrogen atom a nitrogenous heterocyclic group, R3 represents a hydrogen atom or a substituent, such as a hydroxy, chloro, tri-fluormethyl or lower alkyl radical, which may be in the ortho, meta or para position of the phenyl group and R4 represents a hydrogen atom, an alkoxy radical having 1 to 3 carbon atoms or a dialkylamino group, as well as the acid addition salts of the 2-aminoindane derivatives of formula (I). ??is is made possible by reacting a N-phenyl-2-aminoindane of formula:
(II) in which R3 and R4 have the meanings given above, with sodamide (NaNH2) and an halogenated amine of formula:
Description
1068Z~9 The present invention relates to a process for pre-paring derivatives of 2-aminoindane of the following general formula:
R~
-N 2 n ~ R
~ ~ ~ - R
in which n = 2, 3 or 4, the (CH2)n group having a straight or branched chain, Rl represents a hydrogen atom, an alkyl or hy-droxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, whereby Rl and R2 may be identical or different and may form together with the con-tiguous nitrogen atom a nitrogenous heterocyclic group, R3 rep-resents a hydrogen atom or a substituent, such as a hydroxy, chloro, trifluormethyl or lower alkyl radical, which may be in the ortho, meta or para position of the phenyl group and R4 re-~ presents a hydrogen atom, an alkoxy radical having 1 to 3 carbon ; atoms or a dialkylamino group, as well as the acid addition salt~
of the 2-aminoindane derivatives of formula (I).
More specifically, the invention relates to a process 20~ for preparing derivatives of 2-aminoindane of formula ,~ :
R4 ( ) / 1 N~ R2~
~ ~ l ~ R3 (I) , C
. J ~
in which n = 2, 3 or 4, the (CH2)n group having a straight or branched chain, Rl represents a hydrogen atom, an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an al~enyl or alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, whereby Rl and R2 may be identical or different and ma~ form together with the contiguous nitrogen atom a six-membered nitrogenous heterocyclic group, R3 represents a hydrogen atom, a hydroxy, chloro, tri-fluormethyl or lower alkyl radical, which may be in the ortho,meta or para position of the phenyl group and R4 represents a hydrogen atom, an alkoxy radical having 1 to 3 carbon atoms or a dialkylamino group, as well as the acid addition salts of the 2-.
aminoindane derivatives of formula (I), in which process a N-phenyl-2-aminoindane of formula ., ~ _N / (II) , ~ .
~ in which R3 and R4 have the meanings given above, is reacted .~ w~h sodamide (NaNH2) and a halogenated amine of formula ~,` ~1 " .
Hal - (CH2)n _ R2 ~' (III) ~ 20 in which n, Rl and R2 have the meanings given above, by heating the reactive mass to boiling temperature in a medium consisting of an inert organic solvent, characterized in that for the purpose of simplifying the procedure, a mixture of soda-~ mide and an organic solvent is heated to reflux temperature, :. the mixture is reached with N-p~enyl-2-aminoindane of formula ~ (II) which is used in its free form, or in the form of its hydro-.i' chloride, and after the emission of ammonia, always keeping the . mixture at reflux temperature, a halogenated amine of formula - la -(III1 is added in the form of its hydrochloride, with a molar amount of sodamide equal to the sum of the molar amount of hydro-chloride of halogenated amine of formula (III) and of the molar amount of the N-phenyl-2-aminoindane of formula (III), in its free form, or with a double molar amount of the hydrochloride of the N-phenyl-2-aminoindane of formula (II), followed by separa-tion of the entire product of formula I, in its free form or as an acid salt thereof.
It i`Q known that the compounds of formula I have inter-esting cardiac anti-arrhythmic properties.
There is known a process for preparing the compounds of formula (I), in which process a N-phenyl-2-aminoindane of formula:
, , . . .
,~
:j:
., .
, ~
:
. .
'R
':;
..
, J-~23~ - lb -1068Z~9 ~b-~
~ 3 (II) ; in which R3 and R4 have the meanings given abo~e, is reacted with sodamide (NaNM2) and an halogenated amine of formula:
R
Hal - (CH2)n - N \
R2 ~ (III) in which n, Rl and R2 have the meaning~ given above.
`~ In this known process it is necessary, before reac~
.i~ ting the N-phenyl-2-aminoindane of formula (II) with sodamide ,,~ . , ~.
and the halogenated amine of formula (III), to effect at least ~-~15 one preliminary reaction which consists in releasing the free .base of the hydrochloride of the halogenated amine of formula . :~
while this halogenated amine of formula (III) must be in .
the form of a hydrochloride because it is unstable in its free -base form.
20~ In the same manner the N-phenyl-2-aminoindane of for-mula (II? is initially al~o in the hydrochlorlde form, so that in the:known process this compound is also first converted into i:ts free~base berore it is reacted with sodamide and the haloge-nated~a~ne~of formula (III~. ~
:It ~haa now been found that the known process may con-siderably~be;simpli~ied, on an industrial scale~ when the pre-;l^~minary can~ersi:on o~anyone of the hydrochlorides of the reagents~of~fQrmulae~ and (III) is omitted~ provided that . ~ an exces~s~of~sodamide is us~ ~ith respect to the amount of sod-. ~ 30~ :amide which~iæ~necessary for the conversion of the reagent of . ~ formula~ into its~;`sodium~salt.
In~accordance wîth the present invention, a mixture ` 106~2l~9 of sodamide and an organic solvent~ such as benzene or toluene, heated to reflux tempera~ure, is reacted with N-phenyl-2-ami-noindane of formula (II), p~ sibly in the form of its hydro-chloride, and, after the emission of ammoniac has ended, al-ways keeping the mixture at reflux temperature, ~he halogenated amine of formula. (III) is added in the form of its hydrochlo-ride, the amount of sodamide (NaNH2) being sufficient not only for the formation of the sodium salt of the N-phenyl-2-aminoin-dane of formula (II), as an intermediate compound but also to - 10 release the free base from the hydrochloride of the N-phenyl-2- :
aminoindane of formula (II) and/or the hydrochloride of the ha-logenated amine of formula (III).
In a first embodiment of the process according to the invention, the reactions represented schematically hereafter 15 are involved:
'. Schemes 1 ' `
:
. 1) AH + NaNH2 ~ ANa + NH3 ... li.~ 2) ANa + BCl.HCl ~ AH + NaCl ~ BCl ~- 3) AH + NaNH2 ~~~~~~~ ANa + NH3 ~, 20 ~3 ANa + BCl -~ I + NaC1 . 1 _ . .
.. Balance: AH + BCl.HCl+2 NaNH2 ~ I+2NaC1~2 NH3 ll: In these reaction schemes:
A = ~ -N /
BCl ~ chlorinated amine of formula (III ) . I _ compound of formula (I) ,.
As can be observed from the reaction schemes 1, in , ~
_ J _ which are used as starting materials a N-ph~nyl-~-a~inoindane of formula (II) represented by AH, a h-rdrochloride of a chlori-nated amine of formula (III) represented by BCl.HCl and sodamide (NaMH2), the amount of sodamide used is equal to at least two moles for one mole of AH and one mole of BCl.HCl~ This sodamide ~erves not onl~ for the formation of the sodium salt of the N-phenyl-2-aminoindane Or formula (II) (ANa), but also to release the chlorinated amine of formula (III~ ~rom its hydrochloride.
In a second embodiment of the procèss according to the invention, one also uses the N-phenyl-2-aminoindane of formula (III) in its hydrochloride form.
In this case~ the reactions represented schematically hereafter are involved:
Schemes 2:
1) AH.HCl + NaNH2 ~~~~~ AH ~ NaCl + NH
~ 3
R~
-N 2 n ~ R
~ ~ ~ - R
in which n = 2, 3 or 4, the (CH2)n group having a straight or branched chain, Rl represents a hydrogen atom, an alkyl or hy-droxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, whereby Rl and R2 may be identical or different and may form together with the con-tiguous nitrogen atom a nitrogenous heterocyclic group, R3 rep-resents a hydrogen atom or a substituent, such as a hydroxy, chloro, trifluormethyl or lower alkyl radical, which may be in the ortho, meta or para position of the phenyl group and R4 re-~ presents a hydrogen atom, an alkoxy radical having 1 to 3 carbon ; atoms or a dialkylamino group, as well as the acid addition salt~
of the 2-aminoindane derivatives of formula (I).
More specifically, the invention relates to a process 20~ for preparing derivatives of 2-aminoindane of formula ,~ :
R4 ( ) / 1 N~ R2~
~ ~ l ~ R3 (I) , C
. J ~
in which n = 2, 3 or 4, the (CH2)n group having a straight or branched chain, Rl represents a hydrogen atom, an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an al~enyl or alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, whereby Rl and R2 may be identical or different and ma~ form together with the contiguous nitrogen atom a six-membered nitrogenous heterocyclic group, R3 represents a hydrogen atom, a hydroxy, chloro, tri-fluormethyl or lower alkyl radical, which may be in the ortho,meta or para position of the phenyl group and R4 represents a hydrogen atom, an alkoxy radical having 1 to 3 carbon atoms or a dialkylamino group, as well as the acid addition salts of the 2-.
aminoindane derivatives of formula (I), in which process a N-phenyl-2-aminoindane of formula ., ~ _N / (II) , ~ .
~ in which R3 and R4 have the meanings given above, is reacted .~ w~h sodamide (NaNH2) and a halogenated amine of formula ~,` ~1 " .
Hal - (CH2)n _ R2 ~' (III) ~ 20 in which n, Rl and R2 have the meanings given above, by heating the reactive mass to boiling temperature in a medium consisting of an inert organic solvent, characterized in that for the purpose of simplifying the procedure, a mixture of soda-~ mide and an organic solvent is heated to reflux temperature, :. the mixture is reached with N-p~enyl-2-aminoindane of formula ~ (II) which is used in its free form, or in the form of its hydro-.i' chloride, and after the emission of ammonia, always keeping the . mixture at reflux temperature, a halogenated amine of formula - la -(III1 is added in the form of its hydrochloride, with a molar amount of sodamide equal to the sum of the molar amount of hydro-chloride of halogenated amine of formula (III) and of the molar amount of the N-phenyl-2-aminoindane of formula (III), in its free form, or with a double molar amount of the hydrochloride of the N-phenyl-2-aminoindane of formula (II), followed by separa-tion of the entire product of formula I, in its free form or as an acid salt thereof.
It i`Q known that the compounds of formula I have inter-esting cardiac anti-arrhythmic properties.
There is known a process for preparing the compounds of formula (I), in which process a N-phenyl-2-aminoindane of formula:
, , . . .
,~
:j:
., .
, ~
:
. .
'R
':;
..
, J-~23~ - lb -1068Z~9 ~b-~
~ 3 (II) ; in which R3 and R4 have the meanings given abo~e, is reacted with sodamide (NaNM2) and an halogenated amine of formula:
R
Hal - (CH2)n - N \
R2 ~ (III) in which n, Rl and R2 have the meaning~ given above.
`~ In this known process it is necessary, before reac~
.i~ ting the N-phenyl-2-aminoindane of formula (II) with sodamide ,,~ . , ~.
and the halogenated amine of formula (III), to effect at least ~-~15 one preliminary reaction which consists in releasing the free .base of the hydrochloride of the halogenated amine of formula . :~
while this halogenated amine of formula (III) must be in .
the form of a hydrochloride because it is unstable in its free -base form.
20~ In the same manner the N-phenyl-2-aminoindane of for-mula (II? is initially al~o in the hydrochlorlde form, so that in the:known process this compound is also first converted into i:ts free~base berore it is reacted with sodamide and the haloge-nated~a~ne~of formula (III~. ~
:It ~haa now been found that the known process may con-siderably~be;simpli~ied, on an industrial scale~ when the pre-;l^~minary can~ersi:on o~anyone of the hydrochlorides of the reagents~of~fQrmulae~ and (III) is omitted~ provided that . ~ an exces~s~of~sodamide is us~ ~ith respect to the amount of sod-. ~ 30~ :amide which~iæ~necessary for the conversion of the reagent of . ~ formula~ into its~;`sodium~salt.
In~accordance wîth the present invention, a mixture ` 106~2l~9 of sodamide and an organic solvent~ such as benzene or toluene, heated to reflux tempera~ure, is reacted with N-phenyl-2-ami-noindane of formula (II), p~ sibly in the form of its hydro-chloride, and, after the emission of ammoniac has ended, al-ways keeping the mixture at reflux temperature, ~he halogenated amine of formula. (III) is added in the form of its hydrochlo-ride, the amount of sodamide (NaNH2) being sufficient not only for the formation of the sodium salt of the N-phenyl-2-aminoin-dane of formula (II), as an intermediate compound but also to - 10 release the free base from the hydrochloride of the N-phenyl-2- :
aminoindane of formula (II) and/or the hydrochloride of the ha-logenated amine of formula (III).
In a first embodiment of the process according to the invention, the reactions represented schematically hereafter 15 are involved:
'. Schemes 1 ' `
:
. 1) AH + NaNH2 ~ ANa + NH3 ... li.~ 2) ANa + BCl.HCl ~ AH + NaCl ~ BCl ~- 3) AH + NaNH2 ~~~~~~~ ANa + NH3 ~, 20 ~3 ANa + BCl -~ I + NaC1 . 1 _ . .
.. Balance: AH + BCl.HCl+2 NaNH2 ~ I+2NaC1~2 NH3 ll: In these reaction schemes:
A = ~ -N /
BCl ~ chlorinated amine of formula (III ) . I _ compound of formula (I) ,.
As can be observed from the reaction schemes 1, in , ~
_ J _ which are used as starting materials a N-ph~nyl-~-a~inoindane of formula (II) represented by AH, a h-rdrochloride of a chlori-nated amine of formula (III) represented by BCl.HCl and sodamide (NaMH2), the amount of sodamide used is equal to at least two moles for one mole of AH and one mole of BCl.HCl~ This sodamide ~erves not onl~ for the formation of the sodium salt of the N-phenyl-2-aminoindane Or formula (II) (ANa), but also to release the chlorinated amine of formula (III~ ~rom its hydrochloride.
In a second embodiment of the procèss according to the invention, one also uses the N-phenyl-2-aminoindane of formula (III) in its hydrochloride form.
In this case~ the reactions represented schematically hereafter are involved:
Schemes 2:
1) AH.HCl + NaNH2 ~~~~~ AH ~ NaCl + NH
~ 3
2) AH + NaNH2 ~ ANa + NH3
- 3) ANa + BCl.HCl ~ AH + NaCl I BCl
4) AH + NaNH2 ~~~~~ A.Na ~ NH3
5) ANa + BCl ~ I + NaCl ~, . . . .. . . _ ; 20 Balance: AH.HCl + BCl~HCl + 3NaNH2 ~ I + 3NaCl + 3NH3 As can be observed from the reaction schemes 2, in `~ which are used, as starting materials, the hydrochloride of a N-phenyl-2-aminoindane of formula (II) represented by AH.HCl, the hydrochloride of a halogenated amine of formula (III) re-~25 presented by BCl.HCl and sodamide (NaNH2), the amount of soda-mide u~ed is equal to at least three moles for one mole of AH.HCl and one mole of BCl.HCl.
This sodamide serves no~ only for the formation of ii the sodium salt of N-phenyl-2-aminoindane of formula II tANa), ~ut also to relea~e the N-phenyl-2-aminoindane of formula II
(AH) from its hydrochloride and the chlorinated amine of formula III (BCl) from its hydroc~loride (3Cl.HCl)~
-` ~06~289 When the reagents of formula II and of formula III
are used in their hydrochloride form, they are added ~o the reaction medium containing the sodamine as solutions in an orga-nic solvent such as benzene or toluene.
The reactions take place at reflux temperature under a nitrogen blanket and when the reactions are ended, the reac-tion mixture is cooled and treated with water to extract the sodium chloride, whereafter an acid addition salt, such as hy-drochloride, is prepared from the obtained compound of formula I.
Accordin~ to a particular feature of the invention, an exces-q of about 15/~o of the hydrochloride of the halogenated amine of formula III is used with respect to the amount of N- f ; phenyl-2-aminoindane. ~ -Other characteristics and details of the in~ention will appear from the following illustrative examples:
; EX~PLE 1 ,."~ . ........................................ I
~l~ Preparation of the hydrochloride of N-phenyl-N-diethylamino-'d ' ' ' 1:
propyl-2-amino1ndane (formula I: n - 3; R1 = R2 = -C2H5 ; R3 =
H; R4 = H ) In a reaction tank are charged i~s2~5 kilograms (~36 ;i~ mo~es) of hydrochloride of N-phenyl-2-a~inoindane, 75 liters of concentrated ammonia, 75 liters of water and 120 liters of toluene. The mixture is stirred and one observes that the N- `
phenyl-2-aminoindane gradually passes to the toluene phase. Af-~2~5 ~ ter extraction by means of two fractions of 50 liters of toluene, the toluene fractions are joined together, dried over magnesium sulph~and fiItered. Thus a toluene solution of the free base (N-phenyl-2-aminoindane) is obtained.
Further, an enamelled steel reaction tank is charged $ ~
~ 30 with 39 kilograms (100~ moles) of powdered sodamide and this .,,s ~ .
j load is covered with 100 liters of toluene.
,i~
~ 5 -,, .
The content of the tank is stirred by means of a mechanic stirrer and heated to reflux temperature under a ni-trogen stream and secured from moisture. Then the toluene solu-tion of N-phenyl-Naminoindane is slowl7 poured into the tank.
~ith each addition of a fraction of this latter solution an emission of ammonia takes place which can be easily controlled by using, for instance, a paraffin bu~bler.
When the whole solution of N-phenyl-2-aminoindane ~las been introduced into the tank, 72 kilograms t3~6.~ mole ;
- 10 excess of 15~o) of hydrochloride of y-chloroprop~ldiethylamine (formula III, n = 3; R1 = R2 = C2H5) are poured by portions into said tank, thereby securing the reagent from moisture.
The reaction mixture is further refluxed during 3 to 4 hours, and the reactions are followed on thin layers to determine the exact duration of the reactions.
; When the reactions are ended, the reac~ion mixture ,;, i5 cooled and 200 liters of water are added. After stirring the aqueous wa~hing fraction is removed and 125 liters of concentra_ ted hydrochloric acid and 275 liters of water are added.
` 20 The reaction mixture is extracted twice again with 50 liters of 1N hydrochloric acid, and then the toluene phase is removed. When the pH value is zero, th9 acidic aqueous phase is extracted by means of small fractions of dichloromethans until n ~ oloration of this solvent, which removes many impuri- ;
.~!
ties, is observed an~more.
The pH is then adjusted to a value of exactly 6, by adding a concentrated sodium hydroxide solution. ~hen the pH is stabilized at this value the aqueous phase is extracted by means ~;~ of chloroform ( 1 fraction of 250 liters and 2 fractions of 100 liters). The joined chloroformic solutions are then washed with ~ater, dried, filtered and evaporated to dryness.
The residue is taken up with ace~one (using about 10
This sodamide serves no~ only for the formation of ii the sodium salt of N-phenyl-2-aminoindane of formula II tANa), ~ut also to relea~e the N-phenyl-2-aminoindane of formula II
(AH) from its hydrochloride and the chlorinated amine of formula III (BCl) from its hydroc~loride (3Cl.HCl)~
-` ~06~289 When the reagents of formula II and of formula III
are used in their hydrochloride form, they are added ~o the reaction medium containing the sodamine as solutions in an orga-nic solvent such as benzene or toluene.
The reactions take place at reflux temperature under a nitrogen blanket and when the reactions are ended, the reac-tion mixture is cooled and treated with water to extract the sodium chloride, whereafter an acid addition salt, such as hy-drochloride, is prepared from the obtained compound of formula I.
Accordin~ to a particular feature of the invention, an exces-q of about 15/~o of the hydrochloride of the halogenated amine of formula III is used with respect to the amount of N- f ; phenyl-2-aminoindane. ~ -Other characteristics and details of the in~ention will appear from the following illustrative examples:
; EX~PLE 1 ,."~ . ........................................ I
~l~ Preparation of the hydrochloride of N-phenyl-N-diethylamino-'d ' ' ' 1:
propyl-2-amino1ndane (formula I: n - 3; R1 = R2 = -C2H5 ; R3 =
H; R4 = H ) In a reaction tank are charged i~s2~5 kilograms (~36 ;i~ mo~es) of hydrochloride of N-phenyl-2-a~inoindane, 75 liters of concentrated ammonia, 75 liters of water and 120 liters of toluene. The mixture is stirred and one observes that the N- `
phenyl-2-aminoindane gradually passes to the toluene phase. Af-~2~5 ~ ter extraction by means of two fractions of 50 liters of toluene, the toluene fractions are joined together, dried over magnesium sulph~and fiItered. Thus a toluene solution of the free base (N-phenyl-2-aminoindane) is obtained.
Further, an enamelled steel reaction tank is charged $ ~
~ 30 with 39 kilograms (100~ moles) of powdered sodamide and this .,,s ~ .
j load is covered with 100 liters of toluene.
,i~
~ 5 -,, .
The content of the tank is stirred by means of a mechanic stirrer and heated to reflux temperature under a ni-trogen stream and secured from moisture. Then the toluene solu-tion of N-phenyl-Naminoindane is slowl7 poured into the tank.
~ith each addition of a fraction of this latter solution an emission of ammonia takes place which can be easily controlled by using, for instance, a paraffin bu~bler.
When the whole solution of N-phenyl-2-aminoindane ~las been introduced into the tank, 72 kilograms t3~6.~ mole ;
- 10 excess of 15~o) of hydrochloride of y-chloroprop~ldiethylamine (formula III, n = 3; R1 = R2 = C2H5) are poured by portions into said tank, thereby securing the reagent from moisture.
The reaction mixture is further refluxed during 3 to 4 hours, and the reactions are followed on thin layers to determine the exact duration of the reactions.
; When the reactions are ended, the reac~ion mixture ,;, i5 cooled and 200 liters of water are added. After stirring the aqueous wa~hing fraction is removed and 125 liters of concentra_ ted hydrochloric acid and 275 liters of water are added.
` 20 The reaction mixture is extracted twice again with 50 liters of 1N hydrochloric acid, and then the toluene phase is removed. When the pH value is zero, th9 acidic aqueous phase is extracted by means of small fractions of dichloromethans until n ~ oloration of this solvent, which removes many impuri- ;
.~!
ties, is observed an~more.
The pH is then adjusted to a value of exactly 6, by adding a concentrated sodium hydroxide solution. ~hen the pH is stabilized at this value the aqueous phase is extracted by means ~;~ of chloroform ( 1 fraction of 250 liters and 2 fractions of 100 liters). The joined chloroformic solutions are then washed with ~ater, dried, filtered and evaporated to dryness.
The residue is taken up with ace~one (using about 10
6 -, `-` 10682~9 liters of this solvent per kilogram of compound to be obtained).
The acetonic phase is then heated to re~lux tempera-ture until dissolution of the solid matter, treated with carbon black (5%), filtered and concentrated to about half its volume.
Upon cooling by means of brine, the monohydrochloride of the desired N-phenyl-N-diethylaminopropyl-2-aminoindane crys-tallizes.
The obtained crystals are separated in a centrifugal dryer or on a buchner filter and recrystallized from acetone (without carbon black).
One thus obtains, with a yield of about 70~0, ~hite -~
crystals melting at 127 - 130C (i~Iettler).
EX~PLE_2 Preparation of the hydrochloride of N-phenyl-N-diethylamino-proP~ 2-aminoindane (Pormula I: n = 3; Rl = R2 = -C2H5; R~ _ H; R4 = H).
?i Into a dry enamelled steel tank, 52 kilograms (1.344 moles) of powdered sodamide are charged and this load is covered with 575 liters of dry toluene.
To the stirred mixture, heated to reflux temperature under nitrogen, ~2.5 kilograms (336 moles) of dry hydrochloride of N-phenyl-2 aminoindane are added by portions. ~lith each addi-tion of this reagent an emission of ammonia takes place which can easily be controlled.
~25 Then 72 kilograms (3~6.~, moles) of hydrochloride of y-chloropropyl diethylamine are added by portions whereby the stirring is maintained and the reaction mixture is kept at re-flux temperature under nitrogen.
Aftér 3 to 4 hours the reactions are ended and one ~, proceeds in the manner described in example 1.
,~
c`l One obtains white crystals of N-phenyl-N-diethyl-aminopropyl-2-aminoindane melting at 127 - 130C.
'
The acetonic phase is then heated to re~lux tempera-ture until dissolution of the solid matter, treated with carbon black (5%), filtered and concentrated to about half its volume.
Upon cooling by means of brine, the monohydrochloride of the desired N-phenyl-N-diethylaminopropyl-2-aminoindane crys-tallizes.
The obtained crystals are separated in a centrifugal dryer or on a buchner filter and recrystallized from acetone (without carbon black).
One thus obtains, with a yield of about 70~0, ~hite -~
crystals melting at 127 - 130C (i~Iettler).
EX~PLE_2 Preparation of the hydrochloride of N-phenyl-N-diethylamino-proP~ 2-aminoindane (Pormula I: n = 3; Rl = R2 = -C2H5; R~ _ H; R4 = H).
?i Into a dry enamelled steel tank, 52 kilograms (1.344 moles) of powdered sodamide are charged and this load is covered with 575 liters of dry toluene.
To the stirred mixture, heated to reflux temperature under nitrogen, ~2.5 kilograms (336 moles) of dry hydrochloride of N-phenyl-2 aminoindane are added by portions. ~lith each addi-tion of this reagent an emission of ammonia takes place which can easily be controlled.
~25 Then 72 kilograms (3~6.~, moles) of hydrochloride of y-chloropropyl diethylamine are added by portions whereby the stirring is maintained and the reaction mixture is kept at re-flux temperature under nitrogen.
Aftér 3 to 4 hours the reactions are ended and one ~, proceeds in the manner described in example 1.
,~
c`l One obtains white crystals of N-phenyl-N-diethyl-aminopropyl-2-aminoindane melting at 127 - 130C.
'
- 7 -~ . ' . . . . . . ' -` 1068Z89 EX~iPLES 3_to ~2, Proceeding in the manner described in example 1 or example 2, one can prepare by using the compounds of formula II
and formula III in the form of their hydrochlorides, the com-polmds Or rormula I indicated in the following table I:
" ,, ... .
", . .
~`i i ','~'t ` ' ~,..;, ;;' '.~
.~i, . .
i~
.'. 1 .~, ,t - ~ _ :, _ . . . . . .
` :1068Z89 : :
U~ ~ ~ ~ o ~ ~ ~ ~o o ~ ;~ U~
: ~ ~ ~~ ~ ~ , -' ~ ~ ~ ~ ~ ~ ~ o O tr~ ~ ~ o~ ~y ~ t~ o~ ~ u~
U~ ~ ~ ~ ~ ~ U~ ~ ~ o ~ .~ t.~
.. .
a~
O ~h ~ ~ ~) ~ ~ ~ ~ h ~C) ~ h ~ h ~1 OS O O O O O O O S O O O O
., . ~ ~ 5~ ~ S 5: ~ h .S S~ ,S' ,s: ~
o~ o o o o o o o h ~n o O O O h V~ h ,s: ~c~ ~ ~5 ~ h h h g ~ h h ~h h 1 h h ~ h ~ ~ -. ¢ S~ S ~ .s:: S S ~ S C t ~ .~: S ,s:: .C ~ ` ' ,',., . ., ~1 ' . ', ......
. . .
C~ N
O
o O : .
O ~ ~ X ~ S h ~: N
~ ' 0 0 0 ~ V C~ O
~' ~: ~ h 5~
, ~ ~ ~ ~ h ~ S h.
:~ ~ ~ : :
~068289 t` o ~ ~ ~ CO ~ C~ U~ ~ o ~o ~ o ~ ~ ~ ~ ~ ~ o ~ o ~ ~ ~ o .~ ~o ', . ~ ~ O ~ ~ ~ ~ ~ ~ O ~ C~
~, rl ~ ~ h O O o o .~: o o o o o~ ~ S S J~ ~ o 5~ C ~ s S: O O O S~ ~ 0 0 ~d ~ O a O ~ O
~,1 o h S~ h ~ H h H ,1 :~ h h ~ -1 h Cl ~ P~ X ~ X ~ X P~
,'~',' S 5:: S ~ O S O ~ S S S O S
,,~
~, :2 æ æ
U~
' :! ~ ::C ~ t~ ~ ~ ~
~ ~ a ~:~ ~ ¢ O o o " " " ~ ~ o ~: I
H
i . I -1~ ~ C 1 W ~
o .' ,~ ' ~1 0 ~
and formula III in the form of their hydrochlorides, the com-polmds Or rormula I indicated in the following table I:
" ,, ... .
", . .
~`i i ','~'t ` ' ~,..;, ;;' '.~
.~i, . .
i~
.'. 1 .~, ,t - ~ _ :, _ . . . . . .
` :1068Z89 : :
U~ ~ ~ ~ o ~ ~ ~ ~o o ~ ;~ U~
: ~ ~ ~~ ~ ~ , -' ~ ~ ~ ~ ~ ~ ~ o O tr~ ~ ~ o~ ~y ~ t~ o~ ~ u~
U~ ~ ~ ~ ~ ~ U~ ~ ~ o ~ .~ t.~
.. .
a~
O ~h ~ ~ ~) ~ ~ ~ ~ h ~C) ~ h ~ h ~1 OS O O O O O O O S O O O O
., . ~ ~ 5~ ~ S 5: ~ h .S S~ ,S' ,s: ~
o~ o o o o o o o h ~n o O O O h V~ h ,s: ~c~ ~ ~5 ~ h h h g ~ h h ~h h 1 h h ~ h ~ ~ -. ¢ S~ S ~ .s:: S S ~ S C t ~ .~: S ,s:: .C ~ ` ' ,',., . ., ~1 ' . ', ......
. . .
C~ N
O
o O : .
O ~ ~ X ~ S h ~: N
~ ' 0 0 0 ~ V C~ O
~' ~: ~ h 5~
, ~ ~ ~ ~ h ~ S h.
:~ ~ ~ : :
~068289 t` o ~ ~ ~ CO ~ C~ U~ ~ o ~o ~ o ~ ~ ~ ~ ~ ~ o ~ o ~ ~ ~ o .~ ~o ', . ~ ~ O ~ ~ ~ ~ ~ ~ O ~ C~
~, rl ~ ~ h O O o o .~: o o o o o~ ~ S S J~ ~ o 5~ C ~ s S: O O O S~ ~ 0 0 ~d ~ O a O ~ O
~,1 o h S~ h ~ H h H ,1 :~ h h ~ -1 h Cl ~ P~ X ~ X ~ X P~
,'~',' S 5:: S ~ O S O ~ S S S O S
,,~
~, :2 æ æ
U~
' :! ~ ::C ~ t~ ~ ~ ~
~ ~ a ~:~ ~ ¢ O o o " " " ~ ~ o ~: I
H
i . I -1~ ~ C 1 W ~
o .' ,~ ' ~1 0 ~
8 ~ ~ C~ u~ u~ ~ ~ ~ ~ ~ ~ ~ W
0 ,1 ::C ~ C O ~ C X a V
~ C:~ ~ H ~ t~ 1 N S~
.`~ ~ ~ V C~ V C~ C~ V V C~
. ;
~ Q~ `
N N CN X
` ~:::
`~ ~ ;~
. ~ ~: ~ ~ ~ t~ ~ N
~:
:
X ,~: O~ O ~ N ~ ~ ~ ~ O ~~
,~ ~ N N t~l t~ ~ (~I
'1 ~d i ` .. .- ` ` .. . . . :
0 ,1 ::C ~ C O ~ C X a V
~ C:~ ~ H ~ t~ 1 N S~
.`~ ~ ~ V C~ V C~ C~ V V C~
. ;
~ Q~ `
N N CN X
` ~:::
`~ ~ ;~
. ~ ~: ~ ~ ~ t~ ~ N
~:
:
X ,~: O~ O ~ N ~ ~ ~ ~ O ~~
,~ ~ N N t~l t~ ~ (~I
'1 ~d i ` .. .- ` ` .. . . . :
Claims (4)
1. Process for preparing derivatives of 2-aminoindane of formula (I) in which n = 2, 3 or 4, the (CH2)n group having a straight or branched chain, R1 represents a hydrogen atom, an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, R2 represents an alkyl or hydroxyalkyl group having 1 to 3 carbon atoms or an alkenyl or alkynyl group having 2 or 3 carbon atoms, whereby R1 and R2 may be identical or different and may form together with the contiguous nitrogen atom a six-membered nitrogenous heterocyclic group, R3 represents a hydrogen atom, a hydroxy, chloro, tri-fluormethyl or lower alkyl radical, which may be in the ortho, meta or para position of the phenyl group and R4 represents a hydrogen atom, an alkoxy radical having 1 to 3 carbon atoms or a dialkylamino group, as well as the acid addition salts of the 2-aminoindane derivatives of formula (I), in which process a N-phenyl-2-aminoindane of formula (II) in which R3 and R4 have the meanings given above, is reacted with sodamide (NaNH2) and a halogenated amine of formula (III) in which n, R1 and R2 have the meanings given above, by heating the reactive mass to boiling temperature in a medium consisting of an inert organic solvent, characterized in that for the pur-pose of simplifying the procedure, a mixture of sodamide and an organic solvent is heated to reflux temperature, the mixture is reached with N-phenyl-2-aminoindane of formula (II) which is used in its free form, or in the form of its hydrochloride, and after the emission of ammonia, always keeping the mixture at reflux temperature, a halogenated amine of formula (III) is added in the form of its hydrochloride, with a molar amount of sodamide equal to the sum of the molar amount of hydrochlor-ide of halogenated amine of formula (III) and of the molar amount of the N-phenyl-2-aminoindane of formula (III), in its free form, or with a double molar amount of the hydrochloride of the N-phenyl-2-aminoindane of formula (II), followed by separation of the entire product of formula I, in its free form or as an acid salt thereof.
2. Process according to claim 1, characterized in that the N-phenyl-2-aminoindane of formula II is used in its free base form and the halogenated amine of formula III is used in its hydrochloride form, the sodamide being used in an amount which is equal to the sum of the molar amount of N-phenyl-2-amino-indane of formula (II) and the molar amount of hydrochloride of halogenated amine of formula III.
3. Process according to claim 1, characterized in that N-phenyl-2-aminoindane of formula II is used in its hydrochloride form and the halogenated amine of formula III is used in its hydrochloride form, the sodamide being used in an amount which is equal to the sum of the double molar amount of hydrochloride of N-phenyl-2-aminoindane of formula II and of the molar amount of hydrochloride of halogenated amine of formula (III).
4. Process according to claims 1, 2 and 3, characterized in that a stoichiometric excess of about 15% of the hydrochlor-ide of halogenated amine of formula (III) is used.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU74197A LU74197A1 (en) | 1976-01-16 | 1976-01-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1068289A true CA1068289A (en) | 1979-12-18 |
Family
ID=19728141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA267,951A Expired CA1068289A (en) | 1976-01-16 | 1976-12-15 | Process for the preparation of 2-aminoindane derivatives |
Country Status (21)
| Country | Link |
|---|---|
| AR (1) | AR211042A1 (en) |
| AT (1) | AT347444B (en) |
| AU (1) | AU503658B2 (en) |
| CA (1) | CA1068289A (en) |
| CH (1) | CH617663A5 (en) |
| CS (1) | CS193538B2 (en) |
| DD (1) | DD123598A5 (en) |
| DK (1) | DK4677A (en) |
| ES (1) | ES454939A1 (en) |
| FI (1) | FI770039A (en) |
| HU (1) | HU174694B (en) |
| IL (1) | IL51125A (en) |
| LU (1) | LU74197A1 (en) |
| MX (1) | MX4651E (en) |
| NO (1) | NO143217C (en) |
| NZ (1) | NZ182904A (en) |
| PL (1) | PL104367B1 (en) |
| PT (1) | PT66020B (en) |
| SE (1) | SE7700321L (en) |
| SU (1) | SU640658A3 (en) |
| ZA (1) | ZA767468B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7592458B2 (en) | 2006-07-21 | 2009-09-22 | Wright George E | Dermal anesthetic compounds and pharmaceutical compositions for inducing local anesthesia and mitigating neuropathic pain |
| US7718674B2 (en) | 2004-09-27 | 2010-05-18 | Bridge Pharma, Inc. | Methods of relieving neuropathic pain with the S-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine |
-
1976
- 1976-01-16 LU LU74197A patent/LU74197A1/xx unknown
- 1976-03-01 DD DD191667A patent/DD123598A5/xx unknown
- 1976-03-04 HU HU76CI1646A patent/HU174694B/en unknown
- 1976-03-11 CS CS761606A patent/CS193538B2/en unknown
- 1976-03-12 PL PL1976187911A patent/PL104367B1/en unknown
- 1976-03-16 SU SU762333209A patent/SU640658A3/en active
- 1976-12-15 ZA ZA767468A patent/ZA767468B/en unknown
- 1976-12-15 CA CA267,951A patent/CA1068289A/en not_active Expired
- 1976-12-16 NZ NZ182904A patent/NZ182904A/en unknown
- 1976-12-17 IL IL51125A patent/IL51125A/en unknown
- 1976-12-17 AU AU20677/76A patent/AU503658B2/en not_active Expired
- 1976-12-27 AT AT966976A patent/AT347444B/en not_active IP Right Cessation
- 1976-12-28 PT PT66020A patent/PT66020B/en unknown
-
1977
- 1977-01-05 MX MX775301U patent/MX4651E/en unknown
- 1977-01-05 AR AR266112A patent/AR211042A1/en active
- 1977-01-06 DK DK4677A patent/DK4677A/en unknown
- 1977-01-06 FI FI770039A patent/FI770039A/fi not_active Application Discontinuation
- 1977-01-11 ES ES454939A patent/ES454939A1/en not_active Expired
- 1977-01-13 SE SE7700321A patent/SE7700321L/en unknown
- 1977-01-14 NO NO770126A patent/NO143217C/en unknown
- 1977-01-14 CH CH49977A patent/CH617663A5/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7718674B2 (en) | 2004-09-27 | 2010-05-18 | Bridge Pharma, Inc. | Methods of relieving neuropathic pain with the S-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine |
| US7592458B2 (en) | 2006-07-21 | 2009-09-22 | Wright George E | Dermal anesthetic compounds and pharmaceutical compositions for inducing local anesthesia and mitigating neuropathic pain |
Also Published As
| Publication number | Publication date |
|---|---|
| HU174694B (en) | 1980-03-28 |
| CS193538B2 (en) | 1979-10-31 |
| MX4651E (en) | 1982-07-16 |
| ATA966976A (en) | 1978-05-15 |
| NZ182904A (en) | 1979-01-11 |
| NO770126L (en) | 1977-07-19 |
| NO143217B (en) | 1980-09-22 |
| SU640658A3 (en) | 1978-12-30 |
| IL51125A0 (en) | 1977-02-28 |
| LU74197A1 (en) | 1977-07-22 |
| DK4677A (en) | 1977-07-17 |
| ZA767468B (en) | 1977-11-30 |
| PL104367B1 (en) | 1979-08-31 |
| PT66020A (en) | 1977-01-01 |
| DD123598A5 (en) | 1977-01-05 |
| IL51125A (en) | 1980-06-30 |
| AU503658B2 (en) | 1979-09-13 |
| ES454939A1 (en) | 1977-12-01 |
| AT347444B (en) | 1978-12-27 |
| NO143217C (en) | 1981-01-07 |
| SE7700321L (en) | 1977-07-17 |
| FI770039A (en) | 1977-07-17 |
| AR211042A1 (en) | 1977-10-14 |
| CH617663A5 (en) | 1980-06-13 |
| AU2067776A (en) | 1978-06-22 |
| PT66020B (en) | 1978-06-19 |
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