CA1328107C - Enantiomers of absolute configuration s and r of 3-aminoquinuclidine, and processes for preparing them - Google Patents
Enantiomers of absolute configuration s and r of 3-aminoquinuclidine, and processes for preparing themInfo
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- CA1328107C CA1328107C CA000615753A CA615753A CA1328107C CA 1328107 C CA1328107 C CA 1328107C CA 000615753 A CA000615753 A CA 000615753A CA 615753 A CA615753 A CA 615753A CA 1328107 C CA1328107 C CA 1328107C
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- aminoquinuclidine
- absolute configuration
- quinuclidinyl
- chlorobenzamide
- enantiomers
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Abstract
ABSTRACT OF THE DISCLOSURE
The enantiomers of absolute configuration S and R of 3-aminoquinuclidine and processes for their preparation. The compounds are useful as intermediates in the preparation of valuable antiemetics.
The enantiomers of absolute configuration S and R of 3-aminoquinuclidine and processes for their preparation. The compounds are useful as intermediates in the preparation of valuable antiemetics.
Description
-13~07 Enantiomers of absolute confiquration S and R of 3-aminoquinuclidine, and processes for preParing them This invention relates to enantiom~rs of absolute configuration S and R of 3-aminoquinuclidine and a process for their preparation.
The present application is divided from Application Ser.ial ~o. 558,014, filed February 3, 1988, the parent application.
Amide derivatives of 3-aminoquinuclidine, corresponding to the formula:
,. I
H Ar ( I ) N X
; in which:
`~ - X denote~ an oxygen or ~ulphur atom; and - Ar has one of the following meanings:
*) a phenyl ring substituted with one, two or three alkoxy groups containing 1 to 4 carbon atoms;
*) a phenyl ring of structure:
~ ,~ Rl .
.:
;, Where Rl denotes a halogen atom or an alkylcarbonyl 1 20 group in which the alkyl group contain~ from 1 to 4 :j carbon atoms;
~ *) a phenyl group of structure:
"I R2 ~l R3-N
.~1 OCH3 3 .~
:,, ,` .
~ . ~ .. . .
' , : ': , ' :
~: . : - ... : .
:~ . ~ ': '' ' ~ 32~07 .
where R2 denotes a halogen atom and R3 is a hydro-gen atom or an alkylcarbonyl group in which the alkyl residue contains l to 4 carbon atoms;
*) a 3-fluoro-2-~ethoxyphenyl group; ~r *) a S-pyrimidinyl group of structure:
H2N~ ~
where R4 denotes an alkyl group containing 1 to 4 carbon atoms or a phenyl ring, the addition salts of these derivatives with an organic or inorganic acid, the hydrates of these derivatives and their salts are already known from ~P-A-0,099,789.
The above derivatives of formula (It, the salts and hydrates are, however, described in EP-A-0,099,789, only in the form of their racemic mixture. In the course of studying the racemic mixture of these compounds, the applicant endeavoured to synthesize the two enantiomers corresponding ' to each racemic mixture. After overcoming the problem pre~ented by this synthesis, he studied the pharmacological properties of these enantiomers and was thus able to observe that, altogether unexpectedly, the enantiomers of absolute configuration S had a pharmacological behaviour that was very ~' different both from that of the corresponding racemic mixtures and from that of their ankipodes of absolute configuration R.
Consequently, the subject of the above parent application is the enantiomers of absolute configuration S of the above derivatives of ormula ~I), salts and hydrates.
It~ subject is, in addition, the processes for preparing these enantiomers, as well as the application of these enantiomers in therapy.
' ~', .: .: ~ , , : :, : , , . ,..... . ..
, t ~32~ ~7 The enantiomers of the parent application are valuable antiemetics as shown by clinical trials described in the parent application. The laevorotatory enantiomer of absolute configuration S of N-~3-quinuclidinyl) 4-amino-5-chloro-2-methoxybenzamide, or its addition salts with an organic orinorganic acid and the hydrates of this benzaminde and these salts is particularly preferred but the dextrorotatory enantiomer of R configuration and its derivatives was also studied.
The enantiomers according to the parent application were obtained by the resolution of racemic mixtures or by stereospecific synthesis.
The preferred stereospecific synthesis involves condensing laevorotatory 3-aminoquinuclidine of configuration S with acids defined in the parent application or with acid chlorides of a structure also defined in the parent application to produce the preferred compounds of the parent application.
Thus, the enantiomers of 3-aminoquinuclidine are useful a~ chemical intermediates in the production of pharmaceutically useful compounds, particularly compounds ~i useful as antiemetics, and the present invention provides the -' enantiomers of absolute configuration S and R of 3-aminoquinuclidine.
ii 25 3-Aminoguinuclidine has the structural formula:
~ ~ ~H~
J
N
~:.
~3 In a preferred embodiment the invention provides laevorotatory 3-aminoquinuclidine of absolute configuration S. This preferred compound may be prepared by two differen-t groups namely:
(i) the action of D-tartaric acid on N-~3-quinu-clidinyl)-3-chlorobenzamide, resolution by , ',: . : ' .: .
:: : .: :., .,. :
,:: :.: - .
3281~7 crystallization of the diastereo isomeric salts thereby formed to obtain laevorotatory N-(3-quinuclidinyl)-3-chlorobenzamide D--tartrate, and the action of a base such as an alkali metal hydroxide on -this tartrate to : S obtain (S)-(-)-N-(3-quinuclidinyl)-3-chlorobenzamide, followed by the acid hydrolysis of this S-(-) amlde, or (ii) the reaction of quinuclidinone with (R)-~-methylbenzylamine to obtain (R)-N-~a.-methylbenzyl)3-quinuclidinimine, and reduction of this imine with an alkali metal borohydride to obtain (S3-N-[ (R~a-methylbenzyl]-3-aminoquinuclidine, followed by ~ hydrogenolysis of the latter in acid medium. It will be .~ noted that dextrorotatory 3-aminoquinuclidine of absolute configuration R may be obtained by route li) above, but using L-tartaric acid in place of D-tartaric acid, or by route (ii) above, but using (S)-a-methylbenzylamine in place of (R) a-methylbenzylamine The preparations below are given by way of example :in order to illustrate the invention.
Example 1: Preparation of ~S)-t-)-3-aminoquinuclidine A/ First sYnthetic route (resolution of the . diastereoisomeric salts):
., 1st ~tage: Preparation of (S)-(-)-N-(3-qu.inuclidinyl)-3-chlorobenzamide N-(3-Quinuclidinyl)-3-chlorobenzamide (52.5 g) dissolved in methanol is added to a solution of D-tartaric .~.. , acid (29.7 g) in methanol~ ~he precipitate obtained is ~ collected by filtration and treated twice with methanol under :~ reflux. The salt thus purified (20 g) is decomposed with ;~ 30 aqueous sodium hydroxide solution and the product extracted ~ with chloroform. After the organic phase has been dried and : evaporated, the base obtained is treated in acetone with :~ ethanolic hydrogen chloride solution. The hydrochloride ;', which precipitates is collected by filtration and . 3S recrystallized in ethanol. 9.4 g of optically pure (S)~
N-(3-quinuclidinyl)-3-chlorobenzamide hydrochloride are obtained.
, .
` ` ~ . ' ~ . ~ , !
'~ ~, ' : ... ."' , ' :. ' ' ~3281~7 Melting point: 244-247C
[~1D2O = -16.8 tC = 1, CH30H) 2nd stage: Preparation of (S)-t-)-3-aminoquinuclidine dihydrochloride The hydrochloride obtained in the preceding stage tg g) is treated under reflux for 3 hours 30 minutes with concentrated hydrochloric acid. ~he reaction medium is cooled, filtered and concentrated to dryness. The residue is treated with absolute ethanol and the (S)-t-)-3-amino-;10 quinuclidine dihydrochloride which crystallizes is collected by filtration.
Melting point: > 260C
[~]20 = -24.9 (c = 1, H20)-The R antipode is obtained under the same conditions, using L-tartaric acid as resolving agent.
Melting point > 260C
[~20 = ~24.8 (c = 1, H20)~
B/ AsYmmetric synthesis:
,, 1st stage: Preparation of (R~-N-t~-methylbenzyl)3-quinuclidinimine ~ Quinuclidinone (80 g~ in 800 ml of toluene is brought to ; reflux in the presence of (R)-~-~ethylben~ylamine t77.4 g) ; for 24 h, the water formed being removed with a Dean Stark apparatus. The reaction medium is then concentrated to dryness and the imine formed tl30 g) is distilled.
Yield: 89~
Boiling point: 14o-l5ooc ~0.05 mm Hg) [~l20 = +97.2 (c = 1, CHC13~-2nd ~taqe: Preparation of ~S)-N-[tR)-~-methylbenzyl]-3-aminoquinuclidine dihydrochloride The imine tl29.5 g) , obtained in the preceding stage is dissolved in methanol and potassium borohydride (30.6 g) is added in small portions at between 10 and 200C. After one hour, the medium is evaporated to dryness under reduced pressureO
' 35 The re~idue is dissolved in a mixture of acetone and `~ isopropyl alcohol ~ 2: 1 ) . The expected amine is ~`
~', - \
13281~7 precipitated in the form of the dihydrochloride by adding ethanolic hydrogen chloride solution. The product is recrystallized twice in an ethanol/methanol (1:1) mixture to obtain optically pure (~)-N-1 tR)-a-methylbenzyll-3-aminoquinuclidine dihydrochloride (81 g) .
Yield: 47%
Melting point: > 260C
` ~a]20 = -2 (c = 2, H20).
D
3rd æta~e: Preparation of ~S)-(-)-3-aminoquinuclidine dihydrochloride The product obtained in the preceding stage ~64.4 g) is disæolved in ethanol with 2 equivalents of lN hydrochloric 15 acid solution and palladium on charcoal, 50~ H20 (12.8 g).
The reaction medium i~ stirred for 18 h under a hydrogen atmo~phere, filtered, and then evaporated to dryness under reduced pressure.
~S)-(-)-3-aminoquinuclidine dihydrochloride is crystallized 20 in an ethanol/ether ~1:1) mixture.
al2o = -24-2 ~c = 1, H20)-.',''1 The R-(~) antipode is obtained by the same sequence of reactions, starting with (s)-a-methylbenzylamine.
25 ~xam~l_ 2: Stereospecific synthe~iæ of N-(3-quinuclidinyl)-l 4-amino-5-chloro-2-methoxybenzamide hydrochloride, - S-(-) isomer [code MD 200054] and R-~+) isomer ' lcode MD 200051]
1st variant:
"!, 30 (S)-(-)-3-Aminoquinuclidine dihydrochloride (40 g;
0.2 mole) i~ dissolved in 80 ml of 2.5 N aqueous sodium hydroxide solution. 4-Amino-5-chloro-2-methoxybenzoic acid (44.5 9) dissolved in 300 ml of pyridine is added to this solution, cooled in an ice bath. Dicyclohexylcarbodiimide (85 9) is added in two portions. The mixture is stirred vigorously for 18 h at room temperature. The medium is then diluted with 150 ml of water. The insoluble material is removed by filtration and washed with water. The aqueou~
., ;} . . . - : : : , -_ 7 ~32~ ~7 phase is brought to pH 10 with 10 N sodium hydroxide solution and extracted with chloroform. After the organic phase has been dried ~over Na2S04) and evaporated, the re~idue is crystallized in isopropyl ether.
The solid obtained (56 g) is dissolved in 2~0 ml of isopropyl alcohol and the solution acidified with 5N HCl.
The hydrochloride which precipitates is collected by filtration and recrystallized in 99% pure ethanol. The desired product (MD 200054) is obtained in a 60% yield.
Melting point: 233-235C
Z~]25 = -3.90 (c = 1, ~2)-The dextrorotatory antipode (MD 200051) is obtained under the same conditions, starting with (R)-(~)-3-aminoquinu-clidine dihydrochloride.
Melting point: 232-2340C
l lal20 = +3.80 (c = 1, H20).
2nd variant:
~ 20 (S)-(-)-3-Aminoquinuclidine (1.9 g) is diæsolved in 33.5 ;' ml of lN aqueous sodium hydroxide solution. 4-Acetamido-5-chloro-2-methoxy~enzoyl chloride (3.75 9) dissolved in 70 ml ~i of dioxane is added dropwi~e to this solution. After 15 minutes' stirring, the medium is acidified, washed with i, 25 chloroform and alkalinized with concentrated aqueous sodium ;~ hydroxide solution, and the product extracted with ~ chloroform. The organic phase is dried (over Na2So4) and `~ then evaporated. The oily residue iæ dissolved in ethanol ; and ethanolic hydro~en chloride is added until an acid pH is ~l 30 obtained. The N-(3-quinuclidinyl)-4-acetamido-5-chloro-2-;' methoxybenzamide hydrochloride thereby formed precipitates tquantitative yield), and the latter is collected by -~ filtration.
The product is then deacetylated by treating it under reflux for 30 minutes in a 5% strength solution of potassium hydroxide in ethanol.
~, The reaction medium is then dissolved in water and extracted with chloroform. After the organic phase has been :`
,, - ~
-132~1~7 dried and evaporated, the hydrochloride MD 200054 is prepared and isolated a~ above.
[a]20 = -3.7 ~c = 1, H20).
As discussed in the parent application the compounds produced from the intermediate to the present invention have activity with respect to the digestive system and, in particular, are active with respect to ~astric movements and antiemetic activity. These properties are demonstrated by clinical examples in the parent application.
Thus the present invention is useful in proviaing chemical intermediates that are themselves useful in the production of valuable pharmaceutical compounds.
, ~' ,, :, . .
....
~.~
:
:. : . . . . .
~, . ' ',, - -
The present application is divided from Application Ser.ial ~o. 558,014, filed February 3, 1988, the parent application.
Amide derivatives of 3-aminoquinuclidine, corresponding to the formula:
,. I
H Ar ( I ) N X
; in which:
`~ - X denote~ an oxygen or ~ulphur atom; and - Ar has one of the following meanings:
*) a phenyl ring substituted with one, two or three alkoxy groups containing 1 to 4 carbon atoms;
*) a phenyl ring of structure:
~ ,~ Rl .
.:
;, Where Rl denotes a halogen atom or an alkylcarbonyl 1 20 group in which the alkyl group contain~ from 1 to 4 :j carbon atoms;
~ *) a phenyl group of structure:
"I R2 ~l R3-N
.~1 OCH3 3 .~
:,, ,` .
~ . ~ .. . .
' , : ': , ' :
~: . : - ... : .
:~ . ~ ': '' ' ~ 32~07 .
where R2 denotes a halogen atom and R3 is a hydro-gen atom or an alkylcarbonyl group in which the alkyl residue contains l to 4 carbon atoms;
*) a 3-fluoro-2-~ethoxyphenyl group; ~r *) a S-pyrimidinyl group of structure:
H2N~ ~
where R4 denotes an alkyl group containing 1 to 4 carbon atoms or a phenyl ring, the addition salts of these derivatives with an organic or inorganic acid, the hydrates of these derivatives and their salts are already known from ~P-A-0,099,789.
The above derivatives of formula (It, the salts and hydrates are, however, described in EP-A-0,099,789, only in the form of their racemic mixture. In the course of studying the racemic mixture of these compounds, the applicant endeavoured to synthesize the two enantiomers corresponding ' to each racemic mixture. After overcoming the problem pre~ented by this synthesis, he studied the pharmacological properties of these enantiomers and was thus able to observe that, altogether unexpectedly, the enantiomers of absolute configuration S had a pharmacological behaviour that was very ~' different both from that of the corresponding racemic mixtures and from that of their ankipodes of absolute configuration R.
Consequently, the subject of the above parent application is the enantiomers of absolute configuration S of the above derivatives of ormula ~I), salts and hydrates.
It~ subject is, in addition, the processes for preparing these enantiomers, as well as the application of these enantiomers in therapy.
' ~', .: .: ~ , , : :, : , , . ,..... . ..
, t ~32~ ~7 The enantiomers of the parent application are valuable antiemetics as shown by clinical trials described in the parent application. The laevorotatory enantiomer of absolute configuration S of N-~3-quinuclidinyl) 4-amino-5-chloro-2-methoxybenzamide, or its addition salts with an organic orinorganic acid and the hydrates of this benzaminde and these salts is particularly preferred but the dextrorotatory enantiomer of R configuration and its derivatives was also studied.
The enantiomers according to the parent application were obtained by the resolution of racemic mixtures or by stereospecific synthesis.
The preferred stereospecific synthesis involves condensing laevorotatory 3-aminoquinuclidine of configuration S with acids defined in the parent application or with acid chlorides of a structure also defined in the parent application to produce the preferred compounds of the parent application.
Thus, the enantiomers of 3-aminoquinuclidine are useful a~ chemical intermediates in the production of pharmaceutically useful compounds, particularly compounds ~i useful as antiemetics, and the present invention provides the -' enantiomers of absolute configuration S and R of 3-aminoquinuclidine.
ii 25 3-Aminoguinuclidine has the structural formula:
~ ~ ~H~
J
N
~:.
~3 In a preferred embodiment the invention provides laevorotatory 3-aminoquinuclidine of absolute configuration S. This preferred compound may be prepared by two differen-t groups namely:
(i) the action of D-tartaric acid on N-~3-quinu-clidinyl)-3-chlorobenzamide, resolution by , ',: . : ' .: .
:: : .: :., .,. :
,:: :.: - .
3281~7 crystallization of the diastereo isomeric salts thereby formed to obtain laevorotatory N-(3-quinuclidinyl)-3-chlorobenzamide D--tartrate, and the action of a base such as an alkali metal hydroxide on -this tartrate to : S obtain (S)-(-)-N-(3-quinuclidinyl)-3-chlorobenzamide, followed by the acid hydrolysis of this S-(-) amlde, or (ii) the reaction of quinuclidinone with (R)-~-methylbenzylamine to obtain (R)-N-~a.-methylbenzyl)3-quinuclidinimine, and reduction of this imine with an alkali metal borohydride to obtain (S3-N-[ (R~a-methylbenzyl]-3-aminoquinuclidine, followed by ~ hydrogenolysis of the latter in acid medium. It will be .~ noted that dextrorotatory 3-aminoquinuclidine of absolute configuration R may be obtained by route li) above, but using L-tartaric acid in place of D-tartaric acid, or by route (ii) above, but using (S)-a-methylbenzylamine in place of (R) a-methylbenzylamine The preparations below are given by way of example :in order to illustrate the invention.
Example 1: Preparation of ~S)-t-)-3-aminoquinuclidine A/ First sYnthetic route (resolution of the . diastereoisomeric salts):
., 1st ~tage: Preparation of (S)-(-)-N-(3-qu.inuclidinyl)-3-chlorobenzamide N-(3-Quinuclidinyl)-3-chlorobenzamide (52.5 g) dissolved in methanol is added to a solution of D-tartaric .~.. , acid (29.7 g) in methanol~ ~he precipitate obtained is ~ collected by filtration and treated twice with methanol under :~ reflux. The salt thus purified (20 g) is decomposed with ;~ 30 aqueous sodium hydroxide solution and the product extracted ~ with chloroform. After the organic phase has been dried and : evaporated, the base obtained is treated in acetone with :~ ethanolic hydrogen chloride solution. The hydrochloride ;', which precipitates is collected by filtration and . 3S recrystallized in ethanol. 9.4 g of optically pure (S)~
N-(3-quinuclidinyl)-3-chlorobenzamide hydrochloride are obtained.
, .
` ` ~ . ' ~ . ~ , !
'~ ~, ' : ... ."' , ' :. ' ' ~3281~7 Melting point: 244-247C
[~1D2O = -16.8 tC = 1, CH30H) 2nd stage: Preparation of (S)-t-)-3-aminoquinuclidine dihydrochloride The hydrochloride obtained in the preceding stage tg g) is treated under reflux for 3 hours 30 minutes with concentrated hydrochloric acid. ~he reaction medium is cooled, filtered and concentrated to dryness. The residue is treated with absolute ethanol and the (S)-t-)-3-amino-;10 quinuclidine dihydrochloride which crystallizes is collected by filtration.
Melting point: > 260C
[~]20 = -24.9 (c = 1, H20)-The R antipode is obtained under the same conditions, using L-tartaric acid as resolving agent.
Melting point > 260C
[~20 = ~24.8 (c = 1, H20)~
B/ AsYmmetric synthesis:
,, 1st stage: Preparation of (R~-N-t~-methylbenzyl)3-quinuclidinimine ~ Quinuclidinone (80 g~ in 800 ml of toluene is brought to ; reflux in the presence of (R)-~-~ethylben~ylamine t77.4 g) ; for 24 h, the water formed being removed with a Dean Stark apparatus. The reaction medium is then concentrated to dryness and the imine formed tl30 g) is distilled.
Yield: 89~
Boiling point: 14o-l5ooc ~0.05 mm Hg) [~l20 = +97.2 (c = 1, CHC13~-2nd ~taqe: Preparation of ~S)-N-[tR)-~-methylbenzyl]-3-aminoquinuclidine dihydrochloride The imine tl29.5 g) , obtained in the preceding stage is dissolved in methanol and potassium borohydride (30.6 g) is added in small portions at between 10 and 200C. After one hour, the medium is evaporated to dryness under reduced pressureO
' 35 The re~idue is dissolved in a mixture of acetone and `~ isopropyl alcohol ~ 2: 1 ) . The expected amine is ~`
~', - \
13281~7 precipitated in the form of the dihydrochloride by adding ethanolic hydrogen chloride solution. The product is recrystallized twice in an ethanol/methanol (1:1) mixture to obtain optically pure (~)-N-1 tR)-a-methylbenzyll-3-aminoquinuclidine dihydrochloride (81 g) .
Yield: 47%
Melting point: > 260C
` ~a]20 = -2 (c = 2, H20).
D
3rd æta~e: Preparation of ~S)-(-)-3-aminoquinuclidine dihydrochloride The product obtained in the preceding stage ~64.4 g) is disæolved in ethanol with 2 equivalents of lN hydrochloric 15 acid solution and palladium on charcoal, 50~ H20 (12.8 g).
The reaction medium i~ stirred for 18 h under a hydrogen atmo~phere, filtered, and then evaporated to dryness under reduced pressure.
~S)-(-)-3-aminoquinuclidine dihydrochloride is crystallized 20 in an ethanol/ether ~1:1) mixture.
al2o = -24-2 ~c = 1, H20)-.',''1 The R-(~) antipode is obtained by the same sequence of reactions, starting with (s)-a-methylbenzylamine.
25 ~xam~l_ 2: Stereospecific synthe~iæ of N-(3-quinuclidinyl)-l 4-amino-5-chloro-2-methoxybenzamide hydrochloride, - S-(-) isomer [code MD 200054] and R-~+) isomer ' lcode MD 200051]
1st variant:
"!, 30 (S)-(-)-3-Aminoquinuclidine dihydrochloride (40 g;
0.2 mole) i~ dissolved in 80 ml of 2.5 N aqueous sodium hydroxide solution. 4-Amino-5-chloro-2-methoxybenzoic acid (44.5 9) dissolved in 300 ml of pyridine is added to this solution, cooled in an ice bath. Dicyclohexylcarbodiimide (85 9) is added in two portions. The mixture is stirred vigorously for 18 h at room temperature. The medium is then diluted with 150 ml of water. The insoluble material is removed by filtration and washed with water. The aqueou~
., ;} . . . - : : : , -_ 7 ~32~ ~7 phase is brought to pH 10 with 10 N sodium hydroxide solution and extracted with chloroform. After the organic phase has been dried ~over Na2S04) and evaporated, the re~idue is crystallized in isopropyl ether.
The solid obtained (56 g) is dissolved in 2~0 ml of isopropyl alcohol and the solution acidified with 5N HCl.
The hydrochloride which precipitates is collected by filtration and recrystallized in 99% pure ethanol. The desired product (MD 200054) is obtained in a 60% yield.
Melting point: 233-235C
Z~]25 = -3.90 (c = 1, ~2)-The dextrorotatory antipode (MD 200051) is obtained under the same conditions, starting with (R)-(~)-3-aminoquinu-clidine dihydrochloride.
Melting point: 232-2340C
l lal20 = +3.80 (c = 1, H20).
2nd variant:
~ 20 (S)-(-)-3-Aminoquinuclidine (1.9 g) is diæsolved in 33.5 ;' ml of lN aqueous sodium hydroxide solution. 4-Acetamido-5-chloro-2-methoxy~enzoyl chloride (3.75 9) dissolved in 70 ml ~i of dioxane is added dropwi~e to this solution. After 15 minutes' stirring, the medium is acidified, washed with i, 25 chloroform and alkalinized with concentrated aqueous sodium ;~ hydroxide solution, and the product extracted with ~ chloroform. The organic phase is dried (over Na2So4) and `~ then evaporated. The oily residue iæ dissolved in ethanol ; and ethanolic hydro~en chloride is added until an acid pH is ~l 30 obtained. The N-(3-quinuclidinyl)-4-acetamido-5-chloro-2-;' methoxybenzamide hydrochloride thereby formed precipitates tquantitative yield), and the latter is collected by -~ filtration.
The product is then deacetylated by treating it under reflux for 30 minutes in a 5% strength solution of potassium hydroxide in ethanol.
~, The reaction medium is then dissolved in water and extracted with chloroform. After the organic phase has been :`
,, - ~
-132~1~7 dried and evaporated, the hydrochloride MD 200054 is prepared and isolated a~ above.
[a]20 = -3.7 ~c = 1, H20).
As discussed in the parent application the compounds produced from the intermediate to the present invention have activity with respect to the digestive system and, in particular, are active with respect to ~astric movements and antiemetic activity. These properties are demonstrated by clinical examples in the parent application.
Thus the present invention is useful in proviaing chemical intermediates that are themselves useful in the production of valuable pharmaceutical compounds.
, ~' ,, :, . .
....
~.~
:
:. : . . . . .
~, . ' ',, - -
Claims
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. The enantiomers of absolute configuration S and R
of 3-aminoquinuclidine.
2. Dextrorotatory 3-aminoquinuclidine of absolute configuration R.
3. Process for preparing dextrorotatory 3-aminoquinuclidine of absolute configuration R, the process being selected from:
(a) (i) reacting L-tartaric acid with N-(3-quinuclidinyl)-3-chlorobenzamide, (ii) resolving by crystallization the diastereo isomeric salts thereby formed to obtain dextrorotatory N-(3-quinuclidinyl)-3-chlorobenzamide L-tartrate, (iii) reacting a base with this tartrate to obtain (R-(+)-N-(3-quinuclidinyl)-3-chlorobenzamide, and then (iv) subjecting this (R)-(+) amide to an acid hydrolysis; and (b) (i) reacting quinuclidinone with (S)-.alpha.-methyl-benzylamine to obtain (S)-N-(.alpha.-methylbenzyl)-3-quinuclidinimine, (ii) reducing this imine with an alkali metal borohydride to obtain (s)-N-[(S)-.alpha.-methylbenzyl]-3-aminoquinuclidine, and then (iii) subjecting the latter to a hydrogenolysis in acid medium.
4. Laevorotatory 3-aminoquinuclidine of absolute configuration S.
5. Process for preparing laevorotatory 3-aminoquinuclidine of absolute configuration S, the process being selected from:
(a) (i) reacting D-tartaric acid with N-(3-quinuclidinyl)-3-chlorobenzamide, (ii) resolving by crystallization the diastereo isomeric salts thereby formed to obtain laevorotatory N-(3-quinuclidinyl)-3-chlorobenzamide D-tartrate, (iii) reacting a base with this tartrate to obtain (S-(-)-N-(3-quinuclidinyl)-3-chlorobenzamide, and then (iv) subjecting this (S)-(-) amide to an acid hydrolysis; and (b) (i) reacting quinuclidinone with (R)-.alpha.-methyl-benzylamine to obtain (R)-N-(.alpha.-methylbenzyl)-3-quinuclidinimine, (ii) reducing this imine with an alkali metal borohydride to obtain (R)-N-[(R)-.alpha.-methylbenzyl]-3-aminoquinuclidine, and then (iii) subjecting the latter to a hydrogenolysis in acid medium.
1. The enantiomers of absolute configuration S and R
of 3-aminoquinuclidine.
2. Dextrorotatory 3-aminoquinuclidine of absolute configuration R.
3. Process for preparing dextrorotatory 3-aminoquinuclidine of absolute configuration R, the process being selected from:
(a) (i) reacting L-tartaric acid with N-(3-quinuclidinyl)-3-chlorobenzamide, (ii) resolving by crystallization the diastereo isomeric salts thereby formed to obtain dextrorotatory N-(3-quinuclidinyl)-3-chlorobenzamide L-tartrate, (iii) reacting a base with this tartrate to obtain (R-(+)-N-(3-quinuclidinyl)-3-chlorobenzamide, and then (iv) subjecting this (R)-(+) amide to an acid hydrolysis; and (b) (i) reacting quinuclidinone with (S)-.alpha.-methyl-benzylamine to obtain (S)-N-(.alpha.-methylbenzyl)-3-quinuclidinimine, (ii) reducing this imine with an alkali metal borohydride to obtain (s)-N-[(S)-.alpha.-methylbenzyl]-3-aminoquinuclidine, and then (iii) subjecting the latter to a hydrogenolysis in acid medium.
4. Laevorotatory 3-aminoquinuclidine of absolute configuration S.
5. Process for preparing laevorotatory 3-aminoquinuclidine of absolute configuration S, the process being selected from:
(a) (i) reacting D-tartaric acid with N-(3-quinuclidinyl)-3-chlorobenzamide, (ii) resolving by crystallization the diastereo isomeric salts thereby formed to obtain laevorotatory N-(3-quinuclidinyl)-3-chlorobenzamide D-tartrate, (iii) reacting a base with this tartrate to obtain (S-(-)-N-(3-quinuclidinyl)-3-chlorobenzamide, and then (iv) subjecting this (S)-(-) amide to an acid hydrolysis; and (b) (i) reacting quinuclidinone with (R)-.alpha.-methyl-benzylamine to obtain (R)-N-(.alpha.-methylbenzyl)-3-quinuclidinimine, (ii) reducing this imine with an alkali metal borohydride to obtain (R)-N-[(R)-.alpha.-methylbenzyl]-3-aminoquinuclidine, and then (iii) subjecting the latter to a hydrogenolysis in acid medium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000615753A CA1328107C (en) | 1987-02-04 | 1990-05-28 | Enantiomers of absolute configuration s and r of 3-aminoquinuclidine, and processes for preparing them |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8701355A FR2610323B1 (en) | 1987-02-04 | 1987-02-04 | ENANTIOMERS OF ABSOLUTE CONFIGURATION OF AMINO-3 QUINUCLIDINE AMIDE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION |
| FR8701355 | 1987-02-04 | ||
| CA558014 | 1988-02-03 | ||
| CA000615753A CA1328107C (en) | 1987-02-04 | 1990-05-28 | Enantiomers of absolute configuration s and r of 3-aminoquinuclidine, and processes for preparing them |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615753A Division CA1328107C (en) | 1987-02-04 | 1990-05-28 | Enantiomers of absolute configuration s and r of 3-aminoquinuclidine, and processes for preparing them |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615753A Division CA1328107C (en) | 1987-02-04 | 1990-05-28 | Enantiomers of absolute configuration s and r of 3-aminoquinuclidine, and processes for preparing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1328107C true CA1328107C (en) | 1994-03-29 |
Family
ID=25671693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615753A Expired - Fee Related CA1328107C (en) | 1987-02-04 | 1990-05-28 | Enantiomers of absolute configuration s and r of 3-aminoquinuclidine, and processes for preparing them |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1328107C (en) |
-
1990
- 1990-05-28 CA CA000615753A patent/CA1328107C/en not_active Expired - Fee Related
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