Fused pyridines

Details Fused pyridines Fused pyridines

1979-06-08

1983-03-01

Ford, John M.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546115, 546116, 546113, 546180, 546183, 546 80, 546171, 546 89, 546101, C07D21518, C07D49504

Patent

active

043755445

DESCRIPTION:

BRIEF SUMMARY
This invention relates to aromatic {b} fused pyridines, that is to say compounds comprising a pyridine ring fused to another aromatic ring in a position such that one of the carbon atoms bonded to the nitrogen of the pyridine ring is part of the aromatic ring. These compounds have the formula ##STR1## where Y are the atoms necessary to complete an aromatic ring. The aromatic ring may be monocyclic or polycyclic and may be carbocyclic, e.g. benzene or naphthalene, or heterocyclic, e.g. thiophen, furan, pyrrole or indole (including of course benzo-derivatives such as benzothiophen and benzofuran), and any or all rings in the compounds may carry one or more substituents. Examples are thienopyridines and quinolines.
Aromatic {b} fused pyridines are useful intermediates in the preparation of compounds having pharmaceutical and other utilities. It is generally desired that these compounds should carry one or more substituents, the substituents being chosen according to the desired end use of the compounds.
Various methods are known for making aromatic {b} fused pyridines and aromatic {c} fused pyridines. For instance one method of making a thienopyridine comprises starting from a pyridine and subjecting this to appropriate reactions so as to form a fused ring on it. However these reactions tend to be rather difficult to conduct, to give rather low yields and also it tends to be difficult to form thienopyridines having a range of substituents.
Another method of making aromatic pyridines comprises starting with an aromatic nucleus and subjecting it to condensation processes with other small molecules followed by cyclisation, in order to construct a fused pyridine moiety on to the existing homo- or heteroaromatic structure. However, these reactions in general tend to be rather difficult to conduct, often give poor yields and are of limited application.
There is a useful review of methods of making thieno {b} pyridines and thieno {c} pyridines in International Journal Sulphur Chemistry, B, volume 7, No. 4, 1972 pages 309 to 316 by Schneller, and more recently in Advances in Heterocyclic Chemistry 1977, 21, 65, by J. M. Barker.
Methods of making particular aromatic {c} fused pyridines have recently been described by Koyama et al in Chem. Pharm. Bull 1975, 23 (3) pages 497 to 500. In these methods an aromatic acetonitrile was reacted with dimethylformamide and phosphorus oxychloride using approximately equimolar quantities of the three components. Paulmier et al in J. Chem Research (S) 1977 pages 318 and 319 and in J. Chem. Research (M) 1977 pages 3660 to 3672 describe a similar process starting from .beta.-thienyl acetonitrile, to form a thieno{c}pyridine. They also describe a modified process starting from an acetamido thiophen to produce thieno{b}pyridines of the formula ##STR2## where R is H or CHO. The described process comprises reacting substantially equimolar amounts of acetamido thiophen and phosphorus oxychloride and a large excess of dimethylformamide and is said to give a mixture containing 23% of the compound where R is H, 5% of the compound where R is CHO and about 25% of other thiophen derivatives. Thus the method gives low yields of a mixture and is not satisfactory for commercial use. Also there is no suggestion that the method could be used for the production of compounds where either or both of the rings carry other substituents.
We have now discovered a new method for making thienopyridines, quinolines and other aromatic {b} fused pyridines which has the advantages that it can be carried out relatively easily in good yield and that it can be used to produce such compounds having a wide range of substituents, including substituents that render the compounds of particular use as intermediates in the production of pharmaceutical and other commercially useful compounds.
The compounds made by the method of the invention are aromatic-.alpha.-halo{b} fused pyridines, namely compounds in which there is a halo group on the carbon atom bonded to the nitrogen of the pyridine ring but which is not part of the

REFERENCES:
patent: 4006148 (1977-02-01), Wehrmeister
Nickel et al., Chemical Abstracts, vol. 87, entry 23006s (1977).
Meth-Cohn et al., Tetrahedron Letters, No. 23, pp. 2045-2048 (1978).
C. Jones(Ed) "The Chemistry of Heterocyclic Compounds", vol. 32, Pt. 1 (1977) Quinolines, Wiley Publishers, N.Y., pp. 405-406, 408-410, 413, 415, 425-426, 431-433, 441, 444, 469, 602, 704-707, 709-711, 714-715, 717-720, 725-729, 731, 732 and 735.
Paulmier et al., Chemical Abstracts, vol. 88, 121019g, (1978).
Yoshikawa, Chemical Abstracts, vol. 56, entry 11567g (1962).
Klemm et al., J. of Heterocyclic Chemistry, vol. 13, No. 6, pp. 1197-1200 (1976).
Schneller, Int. J. Sulfur Chem., B, vol. 7, No. 4 (1972) "Thienopyridines", pp. 309-317.
Barker, Advances in Heterocyclic Chem., "The Thieonpyridines" (1977), pp. 117-118.
Giles., Chemical Abstracts, vol. 89, entry 129437.
Klemm et al., Chem. Abstracts, vol. 72, entry 90155t.
Drugs of the Future, vol. 11, pp. 196-197, 359, and 432-433 (1977).

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