Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-01-23
1999-01-05
Huang, Evelyn
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546124, 546125, 546126, C07D22122, C07D45102, C07D45114
Patent
active
058564896
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/EP95/02824, filed Jul. 18, 1995, issued as WO96/03401 on Feb. 8, 1996.
The present invention relates to a new process for preparing key intermediates to pharmaceutically active compounds.
U.S. Pat. No. 4,886,808 and EP-A-247266 (Beecham Group plc) describe certain compounds which are granatane and tropane derivatives having 5-HT.sub.3 receptor antagonist activity which are described as possessing a number of potential therapeutic utilities, including inter alia the treatment of cytotoxic agent induced emesis. Example 6 of U.S. Pat. No. 4,886,808 describes the preparation of granisetron, which is a granatane derivative and Example 5 of EP-A-247266 describes the preparation of BRL 46470A, which is a tropane derivative.
GB 2125398 (Sandoz Limited) describes the preparation of granatyl amines from the corresponding oxime using alane. The use of alane on a large industrial scale is disadvantageous, because it is usually generated by the addition of concentrated sulphuric acid to lithium aluminium hydride, and is a potentially hazardous reducing agent, requiring special precautionary measures.
The method described in EP-A-247266 for preparing the tropane side chain intermediate results in the formation of a considerable amount of the unwanted exo product. A new process has been devised which is convenient to use on an industrial scale, has a rapid reaction rate and results in a high ratio of desired endo product.
Accordingly, the present invention provides a process for preparing a compound of formula (I): ##STR2## wherein
n is 2 or 3; ##STR3## wherein R.sup.1 is hydrogen or C.sub.1-4 alkyl and n is 2 or 3; by catalytic hydrogenation in the presence of a rhodium catalyst.
Examples of R.sup.1 when C.sub.1-4 alkyl include methyl, ethyl, propyl and butyl, in all possible isomers. Preferably R.sup.1 is hydrogen or methyl.
Preferably n is 2.
The catalytic hydrogenation is normally carried out in an organic solvent such as dry methanol, industrial methylated spirits, ethanol and isopropanol or an aqueous/organic solvent mixture such as in aqueous methanol, industrial methylated spirits, ethanol and isopropanol at elevated temperature such as 25.degree. to 70.degree. C. preferably about 50.degree. C. and at elevated pressure such as 20 to 200 psi (137.9 to 1379 kPa), preferably at 25 to 50 psi (172.4 to 344.8 kPa). The rhodium catalyst is usually used on a conventional support medium such as carbon.
The percentage of rhodium to carbon is usually I to 10% by weight, preferably around 5%. The catalyst is usually used in a proportion of 1 to 20% by weight of the starting material, preferably at about 10%.
The reaction is optionally carried out in the presence of ammonia which may be added as an aqueous solution or as dry ammonia gas. The addition of ammonia gives a faster, cleaner reaction and reduces the formation of side products. Ammonia is usually added at a molar ratio of 2:1 to 15:1 to the starting material, preferably at a molar ratio of about 9:1.
Compounds of formula (II) are prepared according to conventional procedures, such as those described in Descriptions 1, 2 and 3.
The following Examples illustrate the present invention.
Description 1
##STR4## 0.71 mole), O-methylhydroxylamine hydrochloride (71.0 g, 0.85 mole) and water (215 ml) was stirred at ambient temperature for 0.5 h. The clear solution was basified to pH 12 with 40% aqueous NaOH and extracted with toluene (3.times.400 ml). The combined organic phase was dried (K.sub.2 CO.sub.3), filtered and the solvent removed in vacuo. The residue was purified by fractional distillation under reduced pressure to afford the title compound as a colourless oil, 111.1 g (93%). (m,4H), .delta.2.37 (s,3H), .delta.2.55 .delta.(m,1H), .delta.3.27 (m, 2H) and .delta.3.80 (s, 3H). Mass Spec (JEOL DX 303) CI; m/z 168 (M.sup.+), 137, 96, 82, 42.
Description 2
##STR5## in industrial methylated spirits (IMS) (9.0 L) was treated portion-wise with hydroxylamine hydrochloride (1.2 kg). The resulting suspension was stirred and he
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Dustman Wayne J.
Huang Evelyn
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham p.l.c.
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