GB2039902A - Process for stereospecific reduction of quinolizine derivatives - Google Patents
Process for stereospecific reduction of quinolizine derivatives Download PDFInfo
- Publication number
- GB2039902A GB2039902A GB7943953A GB7943953A GB2039902A GB 2039902 A GB2039902 A GB 2039902A GB 7943953 A GB7943953 A GB 7943953A GB 7943953 A GB7943953 A GB 7943953A GB 2039902 A GB2039902 A GB 2039902A
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- GB
- United Kingdom
- Prior art keywords
- general formula
- process according
- formic acid
- optically active
- compound
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
2-Carbalkoxymethyl-3-ethyl-9,10- dimethoxy 1,2,3,4,6,7-hexahydro-11bH- benzo[a]quinolizines are obtained stereospecifically by reduction of the corresponding 2-carbalkoxymethylene compound with formic acid in the presence of a palladium catalyst, preferably in an aqueous medium.
Description
SPECIFICATION
Process for stereospecific reduction of quinolizine derivatives
This invention is directed to a process for stereospecific reduction of quinolizine derivatives and more particularly concerns the preparation of optically active or racemic 2-carbalkoxymethyl-9,10-dimethoxy1 ,2,3,4,6,7-hexahydro-1 1 bH-benzo[a]-quinolizines.
In one aspect our invention provides a process for the preparation of an optically active benzoquinolizine of the general formula I or its acid addition salt
or an enantiomer thereof or mixture of enantiomers, wherein R is as defined above, with formic acid in the comprises reducing a corresponding optically active compound of the general formula li or its acid addition salt
or an enantiomer thereof or mixture of enantiomers, wherein R represents a methyl or ethyl group, which presence of a palladium catalyst.
Compounds of the formula I are useful intermediates in the synthesis of emetine or its derivatives having pharmacologically valuable amoebicidal activities. There are four asymmetric centres in the emetine molecule, but only the "natural" [-]-emetine of the formula Ill is biologically active.
Therefore a basic difficulty in synthesising emetine is that the reactions should be stereospecific. One of the known total syntheses of emetine is described in J. Chem. Soc. (1963).
One of the reaction steps of this total synthesis is the reduction of the compounds of the general formula II to the compounds of the general formula I. Naturally, this reaction step should be also stereospecific, i.e. the configuration of the substituents in the molecule should be the same as illustrated in the general formula I.
This reduction step has been described in several publications (e.g. Swiss Patent 408,816 and its patent of addition No.437,301). It is a common feature of these known processes that the compounds of the general formula II are reduced by hydrogenation in the presence of a platinum or palladium catalyst.
It is known that the hydrogenation is a complicated, expensive and rather dangerous operation, which requires special apparatus.
According to the present invention the compounds of the general formula I may be obtained under more favourable conditions by reducing the compounds of the general formula II with formic acid in the presence of a palladium catalyst. It was found that the reduction takes places stereospecifica Ily and practically only the desired 2,3-trans-axial-isomer is obtained. The optical purity of the products prepared according to our invention is the same as that of the products prepared according to the above Swiss patents.
On the other hand the product according to our process can be obtained in more than 80% yield, which is higher than that of the known processes.
According to another feature of our invention the reduction can be carried out in an aqueous reaction medium, in contrast to the known processes which employ reduction in alcoholic solution. This renders our process still more economic and straightforward. Moreover problems caused by the pyrophoric character of the catalyst are solved by the use of an aqueous reaction medium and thus our process is very safe.
According to a preferred embodiment of our invention the reduction is carried out in a diluted aqueous medium, wherein the excess of formic acid is 2-8 moles, preferably about 5 moles calculated on one mole of the compounds of the general formula II.
In addition to one mole of formic acid required for the reduction, a further mole forms the water soluble acid addition salt of the compound of the general formula II, which in the free base form is insoluble in water.
Other acids e.g. acetic acid, can also be used together with the formic acid for the salt formation. If desired, reduction can be carried out in a formic acid medium.
A further advantage of our process is that the catalyst can be reused more than once because it does not lose its activity. An excess of the palladium, calculated on the weight of the carrier or on the weight of the complete catalyst, may be used, a wide range of proportions being effective and the proportion selected is determined largely by economic considerations. Preferably 10 to 15% of the supported catalyst calculated on the weight of the substrate is used, the catalyst containing from 1 to 15% by weight palladium.
According to a preferred embodiment of our invention an optically active compound of the general formula 11 is suspended in water, then 5 mole equivalents of formic acid and 10% catalyst (palladium on charcoal, containing 9% palladium) calculated on the substrate are added. The progress of the conversion may be followed by TLC. When the reaction is complete the optically active compounds of the general formula I or their enantiomers or the mixture thereof are preferably set free from their acid addition salts.
Starting materials of the general formula II or their enantiomers or mixtures thereof can be prepared from the corresponding 2-oxo-compounds which should be reacted e.g. with methoxy-carbonylmethylenetriphenylphosphorane [J. Chem. Soc. 1461(1963)].
To summarize, according to our invention the benzoquinolizines of the formula I and their enantiomers and mixtures thereof can be prepared with absolute safety and more simply and economically than by known methods.
Further details of the present invention may be found in the following Examples, which are illustrative only.
Example 1
10 g of [-]-2-carbethoxymethylene-3-ethyl-9,1 0-dimethoxy-1 ,2,3,4,6,7-hexahydro-1 1 bHbenzo[a]quinolizine is suspended in 50 ml of water in a four-necked flask. The suspension is stirred and formic acid is added until the solution becomes clear (about 6 ml). Then 1.2 g of wet catalyst (containing 9% palladium on charcoal carrier) is washed into the solution by 14 ml of water. Gas formation is observed. The reaction mixture is stirred under reflux on an oil-bath tempered to 1 10'C for 2 hours. Progress of the reaction is monitored by thin layer chromatography. Then the reaction mixture is cooled, the catalyst is filtered, and 34 ml of isopropanol is added. Then the pH is adjusted to 8-8.5 with concentrated ammonium hydroxide and the solution is allowed to stand overnight.The precipitate is filtered off under suction, washed with water and dried. Thus 8.5 g (82%) 2-ca rbethoxy-methyl-3-ethyl-9, 1 0-di methoxy-1 ,2,3,4,6,7-hexahydro-1 1 bHbenzo[a]quinolizine are obtained. Mp.: 88-89"C., [a]0: -40 (c = 1, ethanol).
Example 2
0.5 g (1.4 mmole) of racemic 2-carbethoxymethylene-3-ethyl-9,1 O-dimethoxy-l ,2,3,4,6,7-hexahydro-1 1 bH benzo[aiquinolizine is dissolved in 5 ml of 98% formic acid. Then the solution is dropped onto a suspension of 0.1 dry catalyst (containing 12.7% palladium on charcoal carrier) in 2 ml of formic acid, and the reaction mixture is stirred under reflux on oil-bath tempered to 110 C for 2 hours. Then the mixture is allowed to cool to room temperature. The solution is filtered off the catalyst, and formic acid is evaporated in vacuo. The residue is dissolved in 10 ml of water, basified with 2 ml of concentrated ammonium hydroxide, and then extracted with 3 x 20 ml portions of diethyl ether. The combined diethyl ether phases are dried with magnesium sulphate, filtered, and the diethyl ether is evaporated. 0.45 g of oily substance is obtained, which is recrystallized from 2 ml of petrolether. 0.4 g (80%) of racemic 2-carbethoxymethyl-3-ethyl-9,10-dimethoxy1 ,2,3,4,6,7-hexahydro-1 1 bH-benzo[a]quinolizine are obtained. Mp.: 77-78"C.
Claims (7)
1. A process for the preparation of an optically active benzoquinolizine of the general formula I or its acid addition salt
or an enantiomer thereof or mixture of enantiomers, wherein R represents a methyl or ethyl group, which comprises reducing a corresponding optically active compound of the general formula II or its acid addition salt
or an enantiomer thereof or mixture of enantiomers, wherein R is as defined above, with formic acid in the
presence of a palladium catalyst.
2. A process according to claim 1 wherein the reaction is carried out in an aqueous medium.
3. A process according to claim 1 or 2 wherein 3-8 moles of formic acid are used per mole of the compound of general formula II.
4. A process according to claim 3 wherein about 5 moles of formic acid are used per mole of the compound of general formula II.
5. A process according to any of the preceding claims wherein from 10 to 15% by weight of a supported catalyst is used based on the compound of general formula II, said supported catalyst comprising from 1 to
15% by weight palladium.
6. A process according to any of the preceding claims wherein an optically active compound of the general formula II is converted into an optically active compound of the general formula I.
7. A process according to claim 1, substantially as illustrated herein with reference to Examples 1 or 2.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HUCI001881 HU180440B (en) | 1978-12-21 | 1978-12-21 | New process for producing 2-carbalkoxy-methyl-3-ethyl-9,10-dimethoxy-1,2,3,6,7-hexahydro-11ah-benzo-bracket-a-bracket closed-quinolisine derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2039902A true GB2039902A (en) | 1980-08-20 |
GB2039902B GB2039902B (en) | 1983-03-23 |
Family
ID=10994724
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB7943953A Expired GB2039902B (en) | 1978-12-21 | 1979-12-20 | Process for stereospecific reduction of quinolizine derivatives |
Country Status (3)
Country | Link |
---|---|
CH (1) | CH644119A5 (en) |
GB (1) | GB2039902B (en) |
HU (1) | HU180440B (en) |
-
1978
- 1978-12-21 HU HUCI001881 patent/HU180440B/en unknown
-
1979
- 1979-12-20 CH CH1133879A patent/CH644119A5/en not_active IP Right Cessation
- 1979-12-20 GB GB7943953A patent/GB2039902B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
HU180440B (en) | 1983-03-28 |
CH644119A5 (en) | 1984-07-13 |
GB2039902B (en) | 1983-03-23 |
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Legal Events
Date | Code | Title | Description |
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PCNP | Patent ceased through non-payment of renewal fee |