Synthesis of 5- or 8-bromoisoquinoline derivatives

Details Synthesis of 5- or 8-bromoisoquinoline derivatives Synthesis of 5- or 8-bromoisoquinoline derivatives

2000-10-10

2002-12-31

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06500954

ABSTRACT:

TECHNICAL FIELD
The present invention is directed to a method of preparing bromoisoquinoline derivatives, in particular 5- or 8-bromoisoquinoline derivatives. Bromoisoquinoline derivatives, and in particular 5-bromoisoquinoline and 5-bromo-8-nitroisoquinoline derivatives, are key intermediates in the synthesis of pharmaceutical compounds.
BACKGROUND ART
Bromoisoquinoline derivatives, and in particular 5-bromoisoquinoline and 5-bromo-8-nitroisoquinoline derivatives, are key intermediates in the synthesis of pharmaceutical compounds.
Direct bromination of the rather electron poor isoquinoline system using elemental bromine can only be achieved by the co-use of catalysts. One such method has been described by Gordon and Pearson [see Gordon M. & Pearson D. E.,
J. Org. Chem
. 1964 29 329; and Butler J. L., Bayer F. L. & Gordon M.,
Trans K.Y. Acad. Sci
., 1977 38 15] by which 5-bromoisoquinoline was synthesised by the addition of liquid bromine to a melt of isoquinoline and aluminium chloride at 75° C., giving 43-46% yield of product after re-crystallisation. The method has been modified by Mathison and Morgan [Mathison I. W. & Morgan P. H.,
J. Org. Chem
., 1974 39 3210], who used gaseous bromine and obtained a yield of 42%. A similar method using liquid bromine and AlBr
3
has been described by Rey et al. [see Rey M., Vergnani T. & Dreiding A. S.,
Helv. Chim. Acta
., 1985 68 1828], giving a yield of 39%. Bromination using Br
2
and Ag
2
SO
4
in H
2
SO
4
could also be accomplished, however, only giving a yield of 23% [see Rey M., Vergnani T. & Dreiding A. S.,
Helv. Chim. Acta
., 1985 68 1828; De La Mare P. B. D. Kiamud-din M. & Ridd J. H.,
J. Chem. Soc
., 1960 561; and De La Mare P. B. D. Kiamud-din M. & Ridd J. H.,
Chem. Ind
. (
London
), 1958 361].
An indirect method for the synthesis of 5-bromoisoquinoline, makes uses of the fact, that nitration is much more easily achieved, i.e. nitration, reduction and finally diazotation gives 5-bromoisoquinoline [see Butler J. L., Bayer F. L. & Gordon M.,
Trans K.Y. Acad. Sci
., 1977 38 15; Glyde E. & Talor R.,
J. Chem. Soc. Perkin Trans II
, 1975 1783; Robinson R. A.,
J. Am. Chem. Soc
., 1947 69 1942; and Osburn A. R., Schofield K. & Short L. N.,
J. Chem. Soc
., 1956 4191].
The direct bromination procedure tends to give mixtures of brominated products and in unsatisfactory yield, and none of the methods described are well suited for large scale work. The indirect method is not very suitable for large scale work especially due to the diazotation step.
SUMMARY OF THE INVENTION
In the present invention we describe a high yielding method for the synthesis of 5- or 8-bromoisoquinoline and its derivatives using cheap starting materials. The method of the invention is particularly well suited for large scale work operation and for accomplishing “one-pot” synthesis.
DETAILED DISCLOSURE OF THE INVENTION
The present invention provides a method of preparing bromoisoquinoline and its derivatives. More particularly, the invention provides a high yielding method for the synthesis of 5- or 8-bromoisoquinoline and its derivatives, in particular 5-bromo-8-nitroisoquinoline. Accordingly, in its most general aspect, the invention provides a process for the preparation of 5- or 8-bromoisoisoquinoline, or a derivative thereof, which process comprises the step of reacting isoquinoline, or a derivative thereof, with a brominating agent In the presence of a catalyst.
The Brominating Agent
The brominating agent used according to the present invention may be any suitable brominating agent. However, in a preferred embodiment, a suitable brominating agent is an agent of the general formula Z—Br, wherein Z represents a suitable leaving group.
In a most preferred embodiment the leaving group may be a secondary amino group of the general formula R
2
N—Br, wherein R is alkyl, aryl, acyl or sulfonyl, or R
2
N—Br describes a cyclic structure [e.g. N-bromosuccinimide (NBS), N,N′-dibromoisocyanuric acid (DBI) or N,N′-dibromohydantoin (DBH)]:
Catalyst and Catalytic Solvents
The catalyst contemplated in the method of the invention may be any suitable H
+
or a Lewis acid. The Lewis acid may in particular be a compound of the formula M′
m
X
n′
, where M′ represents a metal, and X represents halogen. Preferred Lewis acids are e.g. BF
3
, AlX
3
, TiX
4
, ZnX
2
, MnX
2
, FeX
3
, FeX
2
, SnX
2
, PbX
2
, SbX
3
, and SbX
5
.
The solvent is an acid with or without H
2
O, e.g. FSO
3
H, ClSO
3
H, CF
3
SO
3
H, H
2
SO
4
, CH
3
SO
3
H, H
3
PO
4
, polyphosphoric acid, H
3
PO
3
, HXO
4
, HXO
3
, HXO
2
, HXO, HX, CF
3
COOH, CH
3
COOH and others, where X represents halogen.
In a preferred aspect of the invention the solvent is an acid with or without H
2
O i.e. HCl (0.1 N to conc.), CF
3
SO
3
H, H
2
SO
4
, CH
3
SO
3
H, CF
3
COOH or CH
3
COOH.
In another preferred aspect of the invention the solvent functions as a catalyst.
Nitrating Reagent
MNO3 is a nitrating reagent as known in the art, wherein M represents a metal or H
+
. The active component being NO
2
+
formed in situ in the reaction mixture.
Process Conditions
The method of the invention may be conducted at temperatures ranging from −50° C. to 200° C. with the temperature range between −30° C. to −15° C. being the preferred for the preparation of the 5- or 8-bromoisoquinolines.
The method of the invention may be conducted from 0.1 g to 500 kg scale with the preferred scale being 1 g to 50 kg. Finally, the reaction may be conducted at 0.1 M to 5 M concentration with a preferred concentration of 0.5-1 M.
The method of the invention may be quenched after bromination giving 5-bromo or 8-bromoisoquinoline or continued by addition of metal nitrate, whereby 5-bromo-8-nitroisoquinoline or 8-bromo-5-nitroisoquinoline may be isolated from a “ONE POT” reaction.
The synthesis of 5-bromoisoquinoline and 5-bromo-8-nitroisoquinoline may in broad terms be described as a transformation of isoquinoline to 5-bromoisoquinoline using strong acid, preferably conc. H
2
SO
4
, and a brominating agent, preferably NBS. The bromination is preferably conducted at 0.5-1 M scale at a temperature of −30° C. to −15° C. 5-Bromoisoquinoline may be worked up and isolated as pure material or it may be further transformed, without prior isolation into 5-bromo-8-nitroisoquinoline by addition of potassium nitrate to the reaction mixture. Workup and recrystalization gives pure 5-bromo-8-nitroisoquinoline.


REFERENCES:
Gordon et. al., “The Swamping Catalyst Effect. VI. The Halogenation of Isoquinoline and Quinoline”, J. Org. Chem. 29 (2), pp. 329-332.*
Gordon et al., Holgenation of Isoquinoline, vol. 29, pp. 329-332 (1964).
Mathison et al., Journal of Organic Chemistry, vol. 39, No. 22, pp. 3210-5 (1974).
Rey et al., Helvetica Chemica Acta, vol. 68, pp. 1828-1834 (1985).
De La Mare et al., J. Chem. Soc., pp. 561-565 (1960).
Dickerman et al., Chemistry and Industry, pp. 360-361 (1958).
Butler et al., Trans. KY Acad., vol. 38, No. 15, pp. 15-20 (1977).
Glyde et al., J. Chem. Soc., pp. 1783-1791 (1975).
Robinson, J. Am. Chem. Soc., vol. 69, pp. 1942-1943 (1947).
Osborn et al., Studies of the Amino-isoquinolines . . . , pp. 4191-4204 (1956).

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