Method for the synthesis of quinoline derivatives

Details Method for the synthesis of quinoline derivatives Method for the synthesis of quinoline derivatives

2000-03-09

2002-01-01

Seaman, D. Margaret (Department: 1675)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S170000

Reexamination Certificate

active

06335448

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel intermediates and processes for preparing pharmaceutically active quinoline compounds, including (−)-(S)-N-(&agr;-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide.
BACKGROUND OF THE INVENTION
Compounds of the structural formula (I)
or a pharmaceutically acceptable salt form thereof, wherein:
Ar is an optionally substituted phenyl group, or a naphthyl or C
5-7
cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
R is linear or branched C
1-8
alkyl, C
3-7
cycloalkyl, C
4-7
cycloalkylalkyl, an optionally substituted phenyl group or a phenyl C
1-6
alkyl group, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatom selected from O and N, hydroxy C
1-6
alkyl, di C
1-6
alkylaminoalkyl, C
1-6
acylaminoalkyl, C
1-6
alkoxyalkyl, C
1-6
alkylcarbonyl, carboxy, C
1-6
alkoxycarbonyl, C
1-6
alkoxycarbonyl C
1-6
alkyl, aminocarbonyl, C
1-6
alkylaminocarbonyl, di C
1-6
alkylaminocarbonyl; or is a group —(CH
2
)
p
— when cyclized onto Ar, where p is 2 or 3;
R
1
and R
2
, which may be the same or different, are independently hydrogen or C
1-6
linear or branched alkyl, or together form a —(CH
2
)
n
— group in which n represents 3, 4, or 5; or R
1
together with R forms a group —(CH
2
)
q
—, in which q is 2, 3,4 or 5;
R
3
and R
4
, which may be the same or different, are independently hydrogen, C
1-6
linear or branched alkyl, C
1-6
alkenyl, aryl, C
1-6
alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, trifluoromethyl, amino, mono- and di-C
1-6
alkylamino, —O(CH
2
)
r
—NT
2
, in which r is 2, 3, or 4 and T is C
1-6
alkyl or it forms a heterocyclic group
in which V and V
1
are hydrogen and u is 0, 1 or 2;
—O(CH
2
)
s
—OW
2
in which s is 2, 3, or 4 and W is C
1-6
alkyl; hydroxyalkyl, mono-or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with up to four R
3
substituents being present in the quinoline nucleus;
or R
4
is a group —(CH
2
)
t
— when cyclized onto R
5
as aryl, in which t is 1, 2, or 3; and
R
5
is branched or linear C
1-6
alkyl, C
3-7
cycloalkyl, C
4-7
cycloalkylalkyl, optionally substituted aryl, wherein the optional substituent is one of hydroxy, halogen, C
1-6
alkoxy or C
1-6
alkyl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N; are NK-3 antagonists and are useful in treating pulmonary disorders (asthma, chronic obstructive pulmonary diseases (COPD), airway hyperreactivity, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation, CNS disorders (Parkinson's disease, movement disorders, anxiety), convulsive disorders (for example epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease, and depression. A particularly useful NK-3 receptor antagonist falling within the genus of formula (I) is (−)-(S)-N-(&agr;-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide. Such compounds, and methods for preparing the compounds, are disclosed in PCT/EP95/02000, published Dec. 7, 1995, as WO 95/32948, the disclosures of which are incorporated herein by reference.
NK-3 receptor antagonists are useful in treating the symptoms of COPD and urinary incontinence in mammals. An example of such a compound is the potent antagonist (−)-(S)-N-(&agr;-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide. While the route published in PCT/EP95/02000, published Dec. 7, 1995, as WO 95/32948, requires only three steps, the synthesis is plagued with costly starting materials (e.g., 2-Scheme 1, &agr;-methoxyacetophenone) and chromatography in the low-yielding final step. As is illustrated in Scheme 1, the DCC-mediated (dicyclohexyl carbodiimide) coupling of 4-Scheme 1, 3-hydroxy-2-phenylquinoline-4-carboxylic acid, with (S)-1-phenyl propylamine led to a 30-50% isolated yield of (−)-(S)-N-(&agr;-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide along with 10-20% of compound 6-Scheme 1, (S)-2-Phenyl-4-[[(1-phenylpropyl)-amino]carbonyl]-3-quinolinyl-3-hydroxy-2-phenyl-4-quinolinecarboxylate, requiring chromatography for its removal. Without being bound to any particular theory, (S)-2-Phenyl-4-[[(1-phenylpropyl)amino]carbonyl]-3-quinolinyl-3-hydroxy-2-phenyl-4-quinoline-carboxylate appears to form as a by-product of an attack of the phenolic oxygen of (−)-(S)-N-(&agr;-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide to the DCC-activated acid of 3-hydroxy-2-phenylquinoline-4-carboxylic acid.
Given the known synthesis for quinoline NK-3 receptor antagonists of formula (I), there was a need for an environmentally favorable, commercially feasible, cheaper and more efficient process, with increased yields, for coupling an ortho-hydroxy acid with an amine to provide (−)-(S)-N-(&agr;-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide and related compounds. The present invention provides new synthetic processes for the synthesis of (−)-(S)-N-(&agr;-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide and related compounds, which eliminates the need for the use of (2-Scheme 1, &agr;-methoxyacetophenone), the need for the use of a chromatography step to remove 6-Scheme 1, (S)-2-Phenyl-4-[[(1-phenylpropyl)-amino]carbonyl]-3-quinolinyl-3-hydroxy-2-phenyl-4-quinolinecarboxylate, and which increases the yield of desired product from between 30 and 50% to greater than 70%. In addition, according to this invention, the hydrochloride salt of the free base of (−)-(S)-N-(&agr;-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide and related compounds is optionally prepared, in one reaction vessel, without the need to isolate and purify the free base.
Cragoe et al.,
J. Org. Chem.,
1953, 19, pp. 561-569, discloses the reaction of 7-carboxy-substituted isatins with substituted phenacyl acetates to provide derivatives of 3-hydroxycinchoninic acid. Phenacyl acetates are known and/or can be prepared according to Normant et al.,
Synthesis,
1975, pp. 805-807, which discloses reacting potassium acetate with alkyl bromides catalyzed by diamines in acetonitrile to provide such acetates. An optimized method for preparing anhydro-O-carboxysalicylic acid and anhydro-O-carboxyglycolic acid is disclosed in Davies, W. H.,
J. Chem. Soc.,
1951, pp. 1357-1359. A preparation for five-membered ring sulfites from the reaction of thionyl chloride and &agr;-hydroxycarboxylic acids is discussed in Blackbourn et al.,
J. Chem. Soc.
(C), 1971, pp. 257-259.
None of the above-cited documents describe the methods of the present invention for the synthesis of quinoline NK-3 receptor antagonists of formula (I) or formula (Ia) or the compounds of the invention which are useful as intermediates for the synthesis of such quinoline NK-3 receptor antagonists.
SUMMARY OF THE INVENTION
The objects of this invention are to provide novel intermediates and processes for preparing these intermediates which are useful in the preparation of pharmaceutically active compounds.
Accordingly, in one aspect, this invention is in a method for preparing a compound of formula (I):
or a pharmaceutically acceptable salt form thereof, wherein:
Ar is an optionally substituted phenyl group, or a naphthyl or C
5-7
cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N;
R

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