Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-14
2002-11-12
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S312000
Reexamination Certificate
active
06479660
ABSTRACT:
This application is a 371 of PCT/EP96/04433, filed Oct. 11, 1996.
The present invention relates to novel processes for the preparation of compounds useful as anti-malarial drugs and novel intermediates useful in the process.
U.S. Pat. No. 4,617,394 discloses various compounds, including 8-(4-amino-1-methylbutylamino)-2,6-dimethoxy4-methyl-5-(3-trifluoromethylphenoxy)quinoline which are said to be useful as anti-malarial agents.
Key intermediates in the synthesis of the compounds of U.S. Pat. No. 4,617,394 are compounds of formula (I):
in which:
R
1
is C
1-6
alkyl;
R
2
and R
3
are independently hydrogen, halogen, trifluoromethyl or C
1-6
alkoxy;
R
4
is C
1-6
alkyl; and
R
5
is hydrogen or C
1-6
alkyl.
However the process disclosed in U.S. Pat. No. 4,617,394 for the preparation of this type of compound is a multi stage synthesis in which many steps proceed in low yield. A further disadvantage is that certain process steps use reagents which are not ideally suited to large scale synthesis. There is therefore a need for an improved procedure for the preparation of these intermediates and final anti-malarial compounds.
In a first aspect the present invention therefore provides a novel process for the preparation of a compound of formula (I)
in which:
R
1
is C
1-6
alkyl;
R
2
and R
3
are independently hydrogen, halogen, trifluoromethyl or C
1-6
alkoxy;
R
4
is C
1-6
alkyl;
R
5
is hydrogen or C
1-6
alkyl; and
R
6
is nitro or amino which comprises reacting a compound of formula (II):
in which R
1
, R
4
and R
5
are as defined in formula (I) and X is a leaving group with a compound of formula (III):
in which R
2
and R
3
are as defined in formula (I) and optionally thereafter:
converting the compound of formula (I) into another compound of formula (I)
Suitably X is a halogen, for example chloro. Preferably the reaction is carried out in the presence of base such as an alkali metal hydroxide at elevated temperature in a suitably inert solvent. Preferably the reaction is carried out using potassium hydroxide in DMSO at a temperature of about 105° C. to about 110° C.
A compound of formula (I) can be converted into another compound of formula (I) using standard procedures. For example compounds of formula (I) where R
6
is nitro can be converted to compounds of formula (I) where R
6
is amino by hydrogenation using gaseous hydrogen or a hydrogen donor in the presence of a metal catalyst. Preferably the reduction is carried out in the presence of a hydrogen donor and metal catalyst. Preferably the hydrogen donor is hydrazine hydrazine hydrate and the catalyst is Palladium on carbon. Preferably the reduction is carried out in an organic solvent such as ethanol, THF, toluene or mixtures thereof Most preferably the reaction is carried out in ethanol at elevated temperature, for example at reflux temperature.
Another example is where R
5
is hydrogen when compounds of formula (I) can be converted to compounds of formula (I) where R
5
is methoxy by chlorination followed by treatment with sodium methoxide.
Preferably the reaction is used to prepare the compound 8-nitro-2,6-dimethoxy-5-(3-trifluoromethyl)phenoxy-4-methylquinoline.
Certain compounds of formula (I) are believed to be novel. In a further aspect the invention therefore provides a compound of formula (IA):
in which:
R
1
is C
1-6
alkyl;
R
2
and R
3
are independently hydrogen, halogen, trifluoromethyl or C
1-6
alkoxy;
R
4
is C
1-6
alkyl; and
R
5
is hydrogen or C
1-6
alkyl.
Preferably for compounds of formula (I)/(IA) R
1
, R
4
and R
5
are all methyl. Preferably R
2
is hydrogen and R
3
is trifluoromethyl, most preferably R
3
is in the 3-position of the phenyl ring relative to the ether linkage.
Preferred compounds of formula (IA) include 8-nitro-2,6-dimethoxy-5-(3-trifluoromethyl)phenoxy-4-methylquinoline.
Compounds of formula (II) can be prepared by nitration of a compound of formula (IV):
in which R
1
, R
4
and R
5
are as defined in formula (I) using standard nitration conditions. For example nitration can be carried out using concentrated nitric and sulphuric acid, or when R
5
is alkyl, using potassium nitrate in the presence of phosphorous pentoxide.
Compounds of formula (IV) are commercially available or can be prepared using standard procedures. For example compounds of formula (IV) where R
4
is methyl and X is chloro can be prepared using chemistry shown in the scheme shown below:
Alternatively, compounds of formula (VI) can be converted to compounds of formula (IV) by addition of the methoxy group followed by chlorination using the above conditions. Compounds of formula (IX) and (X) are commercially available. Certain intermediates of formulae (II) and (IV) are novel and form a further aspect of the invention.
As mentioned above compounds of formula (I) are useful for the preparation of certain anti-malarial agents, in particular for the preparation of 8-[(4-amino-1-methylbutyl) amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline. In a further aspect the invention provides a process for the preparation of a compound of formula (A):
which comprises:
1. reacting a compound of formula (II):
in which R
1
, R
4
and R
5
are as defined in formula (I) and X is a leaving group with a compound of formula (III):
in which R
2
and R
3
are as defined in formula (I), followed by reduction of the nitro group to give a compound of formula (I) as hereinbefore defined where R
6
is amino; and
2. reacting said compound of formula (I) with a compound of formula (XI):
where L is a leaving group and R
7
is amino or a protected amino group and optionally thereafter:
removing any protecting group;
forming a pharmaceutically acceptable salt.
Suitably L is a leaving group such as halogen such as bromo or iodo and R
7
is a protected amino group. Preferably L is iodo. Examples of appropriate protecting groups are well known in the art and include phthalimido, boc, t-boc and sulphonamide protecting groups. Preferred protecting groups include phthalimido.
Compounds of formulae (I) and (XI) are suitably reacted in the presence of a base, particularly an organic base, in an inert solvent system. For example a suitable base is diisopropylamine in NMP as solvent. Preferably the reaction is carried out at elevated temperature, for example at about 80° C. when NMP is used as solvent.
Protecting groups can be removed using procedures known in the art. For example phthalimide groups can be removed using hydrazine hydrate in an alcohol solvent at elevated temperature, for example in ethanol at reflux.
Compounds of formula (XI) can be prepared using standard chemistry as exemplified herein.
In a further aspect the present invention provides the use of the above processes for the preparation of 8-(4-amino-1-methylbutylamino)-2,6-dimethoxy4-methyl-5-(3-trifluoromethylphenoxy)quinoline and salts thereof. In a still further aspect the present invention provides the use of compounds of formulae (II) and (III) for the preparation of 8-(4-amino-1-methylbutylamino)-2,6-dimethoxy4-methyl-5-(3-trifluoromethylphenoxy)quinoline and salts thereof.
Pharmaceutically acceptable salts can be prepared using standard procedures. The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, succinic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic acids.
Preferred compounds of formula (A) which can be prepared using the procedures herein include 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy) quinoline. In another aspect the invention provides 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline or a salt thereof prepared according to the procedures herein.
REFERENCES:
patent: 4431807 (1984-02-01), Strube
patent: 4617394 (1986-10-01), Blumbergs et al.
CA 123:217615, Karle, 1995.*
CA 106:119703, Blumbergs, 1996.*
Nodiff, et
Foy James Edward
Ugwuegbulam Cletus Onwuzurike
Kinzig Charles M.
McCarthy Mary E.
Seaman D. Margaret
Sieburth Kathryn L.
SmithKline Beecham p.l.c.
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