Process for preparing ergoline derivatives

Details Process for preparing ergoline derivatives Process for preparing ergoline derivatives

1991-09-25

1993-05-11

Tsang, Cecilia

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

544385, C07D45702

Patent

active

052101940

DESCRIPTION:

BRIEF SUMMARY
The present invention provides a process for the preparation of known ergoline derivatives having the formula I: ##STR3## wherein R represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl group; R.sub.1 represents a hydrogen, chlorine or bromine atom or a methyl group; either R.sub.2 and R.sub.3 represent hydrogen atoms or R.sub.2 and R.sub.3 together represent a chemical bond; R.sub.4 represents a hydrocarbon group having from 1 to 4 carbon atoms; each of R.sub.5, R.sub.6, R.sub.8 and R.sub.9 independently represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; R.sub.7 represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, a phenyl group or a cycloalkyl group having from 3 to 7 carbon atoms and n is 0, 1 or 2.
In the definition of R.sub.4, a hydrocarbon group having from 1 to 4 carbon atoms is intended to include alkyl, cycloalkyl and unsaturated (both ethylenically and acetylenically) groups.
Representative moieties include methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, isobutyl, methylcyclopropyl, allyl and propargyl.
The invention provides a process comprising (i) reacting an ergoline of the formula II with .alpha.-halogen derivatives of formula III to afford ergoline derivatives of formula IV ##STR4## wherein n, R, R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.8 and R.sub.9 have the above given meanings, R.sub.10 and R.sub.11 are independently C.sub.1 -C.sub.4 alkoxy group such as ethoxy or methoxy group or an amino group NH-R.sub.7 wherein R.sub.7 is as above defined, X is halogen atom such as chlorine or bromine; and R'.sub.4 represents a hydrocarbon group having from 1 to 4 carbon atoms or a N-protecting group such as acetyl, tert-butyloxycarbonyl or trichloroethyloxycarbonyl group;
(ii) if R'.sub.4 is a N-protecting group in the resultant compound of the formula IV, converting the said compound by deprotection and alkylation into a corresponding compound of the formula IV in which R'.sub.4 is C.sub.1 -C.sub.4 hydrocarbon group;
(iii) if R.sub.10 and R.sub.11 both represent alkoxy groups in the resultant compound of formula IV, converting the said compound by ammonolysis into a corresponding compound of formula IV in which R.sub.10 and R.sub.11 are both amino groups; and
(iv) cyclising a said compound of formula IV in which at least one of R.sub.10 and R.sub.11 represents an amino group NHR.sub.7 wherein R.sub.7 is as defined above.
The wavy line in formulae I, II and IV indicates that the substituent in the 8-position may be in the .alpha.-configuration, i.e. below the plane of the ring, in the .beta.-configuration, i.e. above the plane of the ring, or in both, i.e. a mixture of derivatives of formula I, II or IV is present with some having the substituent in the 8-position in the .alpha.-configuration and the rest having the substituent in the 8-position in the .beta.-configuration (a diastereoisomeric mixture).
The condensation process (i) is carried out in an organic solvent such as toluene, acetonitrile, or dimethylformamide in presence of an acid scavenger such as an inorganic carbonate or triethylamine. When the reaction is complete the solvent is removed and the residue is purified by crystallization or chromatography according to well known techniques.
If necessary, a compound of formula IV in which R'.sub.4 is a N-protecting group may be converted into another compound of the formula IV in which R'.sub.4 is a C.sub.1 -C.sub.4 hydrocarbon group by deprotection with a base, formic acid or Zn/dust followed by alkylation with an appropriate halide derivative (R.sub.4 -Hal) in the presence of an acid scavenger.
The compounds of formula IV in which R'.sub.4 is a N-protecting group are preferred starting compounds when n is 1 and the substituent in the 8-position is in the .alpha.-configuration.
If necessary, a compound of formula IV in which R.sub.10 and R.sub.11 are both alkoxy groups may be converted into another compound of the formula IV in which R.sub.10 and R.sub.11 are both amino groups by ammonolysis in a suitable solvent such as metha

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