Process for preparing N-benzyl indoles

Details Process for preparing N-benzyl indoles Process for preparing N-benzyl indoles

2000-08-11

2003-01-21

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S518000, C514S414000, C514S415000

Reexamination Certificate

active

06509476

ABSTRACT:

This invention relates to a process for the preparation of N-benzyl indoles, and to intermediates for use in the 5 process, and to certain substantially optically pure N-benzyl indoles obtained by the process.
EP-A-0469833 discloses a class of N-benzyl indoles including compounds of the formula
in which R
1
is hydrogen, halo, C
1-4
alkyl, C
1-4
alkoxy, nitrile, optionally protected carboxy, optionally protected tetrazolyl, trihalomethyl, hydroxy-C
1-4
alkyl, aldehyde, —CH
2
Z, —CH═CH—Z or —CH
2
CH
2
Z where Z is optionally protected carboxy or optionally protected tetrazolyl; R
2
is halo, nitrile, an optionally protected acid group or —CONR
7
R
8
where R
7
and R
8
are hydrogen or C
1-4
alkyl; R
4
is C
2-4
alkyl, or C
2-4
alkyl substituted by —CONR
7
R
8
or an optionally protected acid group; R
5
is
where W is —CH═CH—, —CH═N—, —N═CH—, —O— or —S—, R
9
is hydrogen, halo, C
1-4
alkyl, C
1-4
alkoxy or trihalomethyl, and R
10
is hydrogen, C
1-4
alkyl, C
3-6
alkenyl, C
3-6
cycloalkyl or C
1-4
alkyl-C
3-6
cycloalkyl; R
6
is hydrogen or C
1-4
alkyl; X is —O—(CH
2
)
n
CR
11
R
12
—, —CR
11
R
12
—, —CR
11
R
12
.(CH
2
)
n
—CR
13
R
14
— or —CR
11
═CR
12
— where R
11
, R
12
, R
13
and R
14
are each hydrogen or C
1-4
alkyl, and n is 0, 1 or 2; and Y is —O—CR
15
R
16
—, —CR
15
═CR
16
— or —CR
15
R
16
. CR
17
R
18
— where R
15
, R
16
, R
17
and R
18
are each hydrogen or C
1-4
alkyl; and salts thereof.
Amongst the compounds disclosed in EP-A-0469833, one particularly important compound has the formula
The compounds disclosed in EP-A-0469883 are leukotriene antagonists, and are accordingly indicated for therapeutic use in the treatment of diseases in which leukotrienes are implicated. These include allergic reactions of the pulmonary system in which leukotrienes are thought to be causal mediators of bronchospasm, for example, in allergic lung disorders such as extrinsic asthma and industrial asthmas such as Farmers Lung, and in other inflanmmatory disorders, for example, associated with acute or chronic infectious diseases such as allergic skin diseases, ectopic and atopic eczemas, psoriasis, contact hypersensitivity and angioneurotic oedema, bronchitis and cystic fibrosis and rheumatic fever. The compounds disclosed in EP-A-0469833 also have potential in the treatment of vascular diseases such as shock and ischaemic heart diseases for example coronary artery disease and myocardial infarction, cerebrovascular diseases, and renal diseases such as renal ischaemia.
EP-A-0469833 discloses certain processes for the preparation of the N-benzyl indoles disclosed therein. However, the overall yield which is obtainable using the processes disclosed in EP-A-0469833 is not high, and the compounds are generally obtained in the form of racemates. In many cases, including the case of the compound of Formula (I′) above, separation of enantiomers by conventional techniques, such as by reaction with a chiral amine followed by fractional recrystallisation, or separation on a chiral chromatographic support has been found to be extremely difficult. Nevertheless it has now been found that the S-enantiomer of the above compound of Formula (I′) is preferred and pharmacologically superior.
It is accordingly an object of the present invention to provide an improved process for preparing the N-benzyl indoles described above. It is a further object of the invention to provide a process for preparing such N-benzyl indoles in the form of their substantially pure enantiomers.
According to one aspect of the present invention, there is provided a process which comprises the step of reacting an indoline compound of the formula
with epoxide compound of the formula
to form a compound of the formula
wherein R
2a
is selected from the groups recited above for R
2
, or R
2a
—X— is a protected hydroxyl group, and wherein Z′ is a group of formula —Y—R
5
as defined herein, or Z′ is a substituent that can be converted into a group of formula —Y—R
5
. In any event, the group W must be chemically stable during the above-described reaction between compounds of formulae (II) and (III). Since the linking group Y is preferably a vinyl group —CR
15
═CR
15
═CR
16
—, the substituent Z′ is preferably a group that can be converted into a vinyl group by an olefination reaction. The preferred olefination method is palladium salt catalyzed Heck coupling, as described further below, and accordingly Z′ is preferably a leaving group such as Cl, Br, I, or a sulfonate such as trifluoromethylsulfonate or tosylate. The most preferred substituent Z′ in this case is Br. Other preferred olefinations include Wittig reactions, in which case the substituent Z′ is preferably —CHO, or protected —CHO, such as an acetal.
The reaction is carried out in a suitable solvent such as dry acetonitrile, and is preferably conducted in the presence of a Lewis acid catalyst such as magnesium perchlorate.
In the above formula (I), a halo substituent can be for example, chloro, bromo and fluoro and is preferably chloro. A C
1-4
alkyl group includes methyl, ethyl, propyl, isopropyl, butyl and tert butyl and is preferably methyl or ethyl, and a C
1-4
alkoxy group is one such alkyl group attached through oxygen. A hydroxy C
1-4
alkyl group is a hydroxy-substituted C
1-4
alkyl group preferably of the formula HO(CH
2
)
n
— where n is 1 to 4, a preferred example being hydroxymethyl. A C
3-6
cycloalkyl group includes for example cyclopropyl, cyclopentyl and cyclohexyl, and is preferably cyclopropyl. The C
3-6
cycloalkyl group can be substituted by a C
1-4
alkyl. A C
2-6
alkenyl group is preferably propenyl or isopropenyl. A trihalomethyl group is preferably trifluoromethyl. An optionally substituted phenyl group is phenyl itself, or phenyl substituted with one or more, preferably 1 to 3, substituents selected from C
1-4
alkyl, especially methyl, C
1-4
alkoxy, especially methoxy and ethoxy, hydroxy, nitro, cyano, halo, especially chloro or fluoro, trihalomethyl, especially trifluoromethyl, carboxy C
1-4
alkoxy-carbonyl, and optionally protected tetrazolyl.
An acid group can be any acid group conventionally used in pharmaceutical chemistry and the term includes, for example tetrazolyl (1H-tetrazol-5-yl), carboxy (—COOH), phosphonate (—PO(OH)
2
), sulphonate (—SO
2
OH), acyl sulphonamido (—CONHSO
2
R, where R is preferably C
1-4
alkyl or optionally substituted phenyl) or cyanoguanidinyl (—NHC (NH
2
)═NCN). Especially preferred examples are tetrazolyl and carboxy.
When R
5
is the group
it comprises groups of the following type
and the quinolin-2-yl group is the most preferred.
R
1
is preferably hydrogen or halogen, and especially hydrogen, and when it is other than hydrogen it is preferably attached to the indole nucleus at the 4-position.
The group R
2
—X— is attached to the indole nucleus at the 6- or 7-position, and when X is —O—(CH
2
)
n
CR
11
CR
12
— via the oxygen atom. R
2
is preferably an acid group especially tetrazolyl or carboxyl.
The R
5
group is preferably quinolin-2-yl where the substituent R
9
, which is preferably hydrogen or halo, is attached at the 7-position. The group R
5
—Y— can be attached with the 2-, 3- or 4-positions to the phenyl nucleus, and when R is —O—CR
15
R
16
— via the oxygen atom. R
5
—Y— is preferably attached at the 3-position.
The R
6
group is preferably hydrogen and when it is C
1-4
alkyl is preferably attached at the 3-position.
The linking group X is preferably —O—CR
11
R
12
— or CR
11
R
12
.CR
13
R
14
—, and R
11
, R
12
, R
13
and R
14
are preferably hydrogen. Linking group Y is preferably of the formula —O—CR
15
R
16
, or —CR
15
═CR
16
—, and R
15
, R
16
, R
17
, and R
18
are preferably hydrogen.
When acid substituents on the compound of formula (I) require protection during preparation they may be protected by conventional protecting groups. Such protected compounds are included in the scope of the invention, though the preferred compounds with optimum biological properties are the unprotecte

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