Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-21
2002-05-28
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S089000
Reexamination Certificate
active
06395901
ABSTRACT:
The present invention relates to the preparation of pharmaceutical active ingredients, and in particular to the preparation of medicaments active in the treatment of Parkinson's disease.
PRIOR ART
Alkaloids having an ergoline structure exhibit a wide spectrum of biological effects which include both peripheral effects (vasoconstrictor and contractile effect on the smooth muscle of the uterus) and effects on the central nervous system (various sites of action are located in vasomotor centres and cardiac inhibitor centres found in the medulla oblongata and in sympathetic structures found in the diencephalon).
Some of those alkaloids, such as ergotamnine, ergometrinc, ergosine, crgocrystine and ergocryptine, are entirely of natural origin because they can be isolated from the fungus
Claviceps purpurea
. That fungus is a member of the class of Ascomycetes which is capable of infesting many cereals, such as rye, barley and wheat; its sclerotium contains a high percentage (0.5-0.8% by weight) of alkaloids having an ergoline structure which are responsible for its known toxic properties. Other compounds are of a semi-synthetic nature and are prepared by chemical modification of naturally occurring alkaloids having an ergoline structure. Noteworthy among the above-mentioned semi-synthetic derivatives are bromocryptine, [CAS 25614-03-3], lysuride [CAS 18016-80-3) and pergolide (FIG.
1
), namely (8)-8-[(methylthio)methyl]-6-propylergoline [CAS 66104-22-1]; this last-mentioned compound in particular is a semi-synthetic ergoline used in therapy for the treatment of Parkinson's disease
The processes for the synthesis and purification of that molecule are described in U.S. Pat. No. 4,166,182 and U.S. Pat. No. 5,463,060; those patents, however, describe synthetic approaches which, according to the authors themselves, are not entirely satisfactory from several points of view. The impurities which arise during the synthesis processes described in U.S. Pat. No. 4,166,182 and U.S. Pat. No. 5,463,060 are difficult to remove without significant losses in yield (J. Kennedy et al., Org. Process Res. Dev. (1997), 1(1), 68-71); furthermore, the process described in U.S. Pat. No. 4,166,182, has low yields and requires long operating times (J. W. Misner et al., Book of Abstracts, 210th ACS National Meeting, Chicago, Ill., Aug. 20-24 (995). Publisher: American Chemical Society, Washington, D.C.).
To be more precise, U.S. Pat. No. 4,166,182 describes the synthesis of pergolide mesylate with 22% yields starting from D-8-methoxycarbonylergoline. The synthesis and chromatographic purification steps make the process particularly complicated; the basic pergolide, obtained with a 38% yield starting from D-8-methoxycarbonylergoline, also requires a further purification step by salification using methanesulphonic acid.
U.S. Pat. No. 5,463,060, on the other hand, describes the synthesis of the basic pergolide starting from 8,9-dihydroelymoclavine with 90.8% yields and with a titre of 94.1%. 8,9-dihydroelymoclavine (CAS 18051-16-6) is, however, a semi-synthetic alkaloid derivative which is not readily available because it is obtained from lysergic acid by means of numerous synthesis steps (see, for example: HU 89-3223 890627; R. Voigt et al.
Phanirazie
(1973), 2; S. Miroslav et al. Collect.Czech.Chem.Commun. (1968), 33(2), 577-82); the synthetic steps necessary to carry out the above-mentioned conversion arc also especially onerous because they require, inter alia, stereoselective hydrogenation of the double bond in the 9,10 position and the reduction of the 8 carboxylic function to an alcoholic function (upon conversion into methyl ester).
The object of the present invention is therefore to provide an alternative process for the production of pergolide which permits yields and purities higher than those of U.S. Pat. No. 4,166,182 and which uses a starting compound which is more readily available than 8,9-dihydroelymoclavine.
SUBJECT-MATTER OF THE INVENTION
Medicaments active in the treatment of Parkinson's disease which can be prepared in accordance with the process of the present invention comprise products which have the following general formula VI:
wherein R
4
may be, independently, a linear, branched or cyclic, saturated or unsaturated C
1-8
alkyl radical, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and octyl; the preferred compound includes, but is not limited only to, the pergolide (R
4
=CH
3
).
The process for the synthesis of those compounds, which forms the main subject of the present invention, uses as starting material the compound of formula I given below, wherein R
1
represents a linear, branched or cyclic, saturated or unsaturated C
1-8
akyl residue, preferably methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and octyl, and even more preferably methyl, or the well known and readily available D-8-methoxycarbonylergoline [CAS 30341-92-5].
In that process, the compounds of formula I are reacted with 3-halo- and/or 2-halo-propionyl chloride in an aprotic organic solvent in the presence of a suitable proton acceptor. Solvents that may be used in that step are preferably selected from acetone, methyl ethyl ketone, tetrahydrofuran and dimethylformamide; the proton acceptor is preferably selected from triethylaniine, pyridine and lutidine. Both the proton acceptor and the 3-halo- and/or 2-halo-propionyl chloride are preferably used in equimolar amounts relative to the compound of formula I.
The compound or mixture of compounds IIa and IIb so obtained is then reacted with calcium borohydride in an amount of preferably from 5 to 9 moles/mole of substrate in tetrahydrofuran. The tetrahydrofuran is preferably present in an amount of from 2 to 8 ml per gram of substrate; optionally, it may be used in admixture with protic organic solvents, such as methanol, ethanol or isopropanol, or with an aqueous-alcoholic solution thereof. The reaction is carried out at a temperature of from 10 to 65° C., preferably at 60° C.
Compound III so obtained is then reacted in an aprotic organic solvent with an alkylsulphonyl chloride in the presence of a proton acceptor at a temperature of preferably from 10 to 30° C.; the proton acceptors are preferably selected from pyridine, triethylaniine, lutidine; the alkylsulphonyl chlorides are preferably selected from methanesulphonyl chloride, ethanesulphonyl chloride and p-toluenesulphonyl chloride. The proton acceptor and the alkylsulphonyl chloride are preferably used in amounts of from 20 to 30 and from 1.2 to 3 moles/mole of substrate, respectively.
Compound IV so obtained is then reacted in an aprotic organic solvent with a compound of the general formula R
4
SX, wherein R
4
is a linear, branched or cyclic, saturated or unsaturated C
1-8
alkyl residue, preferably methyl, and X is an alkali metal, preferably sodium. The compound R
4
SX is preferably used in an amount equal to 4-8 equivalents relative to the substrate; the apolar organic solvent is preferably dimethylformamide; the reaction is preferably carried out at a temperature of from 90 to 100° C.
Finally, compound V so obtained is converted into the desired end product by treatment with a reducing agent in an aprotic organic solvent at a temperature of preferably from 20 to 45° C. Reducing agents that may be used in that step are preferably selected from lithium aluminium hydride and sodium dihydro-bis(2-methoxyethoxy)aluminate; aprotic solvents that may be used in that step are preferably selected from tetrahydrofuran, dioxane and toluene.
For greater clarity, the novel process according to the present invention is shown in the following reaction schemes 1, 2 and 3.
wherein R
1
represents a linear, branched or cyclic, saturated or unsaturated C
1-8
alkyl residue, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and octyl, preferably a methyl grou
Grisenti Paride
Mangia Alberto
Aulakh Charanjit S.
Darby & Darby
Poli Industria Chimica S.p A.
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