CA2337669C - Process for the preparation of alkyl mercapto methyl ergoline derivatives - Google Patents

Abstract

The present invention relates to the preparation of ingredients active in the treatment of Parkinson's disease, having general formula (VI) wherein R4 may be, independently, a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl radical, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl and octyl. The process for the synthesis of those compounds uses as starting material the compound of formula (I) wherein represents a linear, branched or cyclic, saturated or unsaturated C1-8 alkyl residue.

Description

Process for the preparation of atkylmercaptomethylergoline derivatives The present invention relates to the preparation of pharmaceutical active ingredients, and in particular to the preparation of rnedicaments 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 (vasoc:onstrictor 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 ergotamine, ergometrine, ergosine, ergocrystine 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 ergoiine structure.
Noteworthy among the above-mentioned semi-synthetic derivatives are bromocryptine, [CAS 25614-03-3], lysuride [CAS 18016-80-3] and pergoiide {Figure 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 H

10 6N _ ~Z 11 5 vESI~ 4 Pergolide Figure 1 The processes for the synthesis and purification of that molecule are described in United States patents US-4,166,182 and US-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 US-4,166,182 and US-5,463,060 are difficult to remove without significant losses in yield (J. Kennedy et _a~., Org.
Process Res. Dev. (1997), 1(1), 68-71); furthermore, the process described in US-4,166,182, has low yields and requires long operating times (J. W. Misner et ~., Book of Abstracts, 210th ACS National Meeting, Chicago, IL, August 20-24 (1995). Publisher: American Chemical Society, Wasl'nington, D.C.).
To be more precise, US-4,166,182 describes the synthesis of pergolide mesylate with 22% yields starting from D-8 -methoxycarborrylergoline. The synthesis and chromatographic purification steps make the process particularly complicated;
the basic pergolide, obtained with a 38% ~rield starting from D-8 -methoxycarbonylergoline, also requires a further purification step by salification using methanesulphonic acid.
US-5,463,060, on the other hand, describes the synthesis of the basic pergolide starting from 8,9-dihydroelymoclavine with 90.8"/o 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 ~. Pharmazie {1973), 2; S.Mirosiav e,~ ~.
Collect.Czech.Chem.Commun. (1968), 33(2), 577-82); the synthetic steps necessary to carry out the above-mentioned conversion are also especially onerous because they require, inter a~,'~,.a, 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 pro~ride an alternative process fvr the production of pergolide which permits yields and parities higher than those of US-4,166,182 and which uses a starting compound which is more readily available than 8,9-dihydroelymaclavine.
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~ may be, independently, a linear, branched or cyclic, saturated or unsaturated C,_$ alkyl radical, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tent-butyl, pentyl, cyciopentyl, hexyl, cyclohexyl and octyl; the preferred compound includes, but is not limited only to, the pergoiide (R CH ).
The process far the synthesis of those compounds, which forms the main subject of the present invention, uses as starting material the cornpound of formula I
given below, wherein R, represents a linear, branched or cyclic, saturated or unsaturated C,_$ alkyl residue, preferably methyl, ethyl, propyl, butyl, isobutyl, tent-butyl, 4.
pentyI, cyclopentyi, hexyi, cyclohexyl and octyl, and even more preferably methyl, or the well known and readily available D-8 -methoxycarbonylergoline [CAS 30341-92-5].
rT
I
In that process, the compounds of formula I are reacaed with 3-halo- and/or 2-haio-propionyl chloride in an aprotic organic solvent in the presence of a suitable proton acceptor. Solvents that may be used in that :;tep are preferably selected from acetone, methyl ethyl ketone, tetrahydrofuran and dimethylformamide; the proton acceptor is preferably selected from triethylarnine, pyridine and lutidine.
Both the proton acceptor and the 3-halo- and/or 2-lhalo-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 ins preferably present in an amount of from 2 to 8 mi 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 6S°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 acre preferably selected from pyridine, triethylamine, lutidine; the alkyisulphon.yl 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 apro~tic organic solvent with a compound of the general formula R,SX, wherein R, is a linear, branched or cyclic, saturated or unsaturated C,_g alkyl residue, preferably methyl, and X is an alkali metal, preferably sodium. The compound R,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 t:he 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.

Scheme 1 TT TT TT
uu ....
m IT
v CI VI
wherein R, represents a linear, branched or cyclic, saturated or unsaturated C,_g alkyl residue, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tent-butyl, pentyl, cyclopentyl, hexyl, cyciohexyl and octyl, preferably a methyl group; R, is a halogen (Cl, I, Br), preferably chlorine (Cl), X is an iodine molecule or a compound of the general formula R,;S03_ wherein RS is methyl, ethyl or p-tolyl, preferably methyl; R4 is, independently, a linear, branched or cyclic, saturated or unsaturated C,_$ alkyl residue, such as, for example; the I

radicals methyl, ethyl, propyl, butyl, isobutyl, tent=butyl, pentyl, cyciopentyl, hexyl, cyclohexyi, preferahly a methyl group.
Scheme 2 " I i Rz lia LT
!11 ~v TT
TT

wherein R" R" R, and ~ have been defined above.

ii Scheme 3 TT
1 _ uu TT

TT
y vl wherein R" RQ and X have been defined above.
The novel intermediates of formula II, III, IV and V, which are given individually below for greater clarity, constitute a further subject of the invention.
TS
n ,,~.

wherein R, and R3 may be a halogen (Ci, I, Br) and hydrogen (H), respectively;
. alternatively, R, and R, may be bonded to one another directly giving rise to a double bond; and R, represents a linear, branched or cyclic, saturated or unsaturated C,_g ~kyl residue, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tent-butyl, pentyl, cyclopentyl; hexyl, cyclohexyl and octyl; the preferred molecules are represented by t'he compounds IIa (R3=H;
R,_--Cl; R,=CH3) and IIb (R3 and RZ ,joined together to give rise to a double bond;
R,=CH3).
II,T
TT
wherein X is a halogen (X=I, compound IVb) or a compound of the general formula R5SO3- wherein RS is methyl, ethyl or p-to:lyl; the preferred molecule is represented by the compound IVa(X=CH3S03-).
v wherein R~ is, independently, a linear, branched or cyclic, saturated or unsaturated C,_a allcyi residue, such as, for example, the radicals methyl, ethyl, propyl, butyl, isobutyl, tent-butyl, pentyl, cyclopentyl; hexyi, cyclohexyl; the preferred molecule is represented by the compound Va (RQ CH3).
Detailed description of the invention In order to obtain quantitative conversion of the 8 -methoxycarbonylergoline into the intermediate III, a series of acyiating agents, such as 3-halo- and 2-halo-propionyl chlorides, were evaluated. The halogen derivatives tested were chlorine, iodine and bromine derivatives.
As is well known to experts in the field, the presence of an electron-attracting group (such as a chlorine, bromine or iodine atom) in the alpha or beta position to an acid chloride increases the latter's reactivity in acylation reactions.
During the research work which Ied to the present invention, it was hoped to find, by screening reducing agents, a reagent which exhibited a high degree of chemoselectivity towards the intermediate chlorine derivative of formula II
(R,=halogen, R3=H or R,=H, R3 halogen). The reducing agent was intended to replace the halogen in the alpha (or beta) position to the acyiamide function with a hydrogen atom and reduce the methoxycarbonyl function in the 8 position to an alcoholic function without reducing the amide group in position 6.
We ascertained experimentally that by using an equimolar amount of 3-chloropropionyl chloride in the presence of a proton acceptor in acetone solution under stirring at room temperature, D-8 -methoxycarbonylergoline gave, in addition to the desired product (D-6-(3'-chloropropionyl)-8 -methoxycarbonylergoline; compound IIa), a side product which was subsequently identified ~cs D-6-(acryloyl)-8 -methoxycarbonylergoline (compound ZIb). The presence of this side product IIb was initially regarded as a critical factor' for the industrial development of the process because, even if the presence of compound IIb could be contained by suitably varying the experimental conditions (slow addition of the acylating agent, low reaction temperatures, low concentrations of tlne reagents) nothing was known of the possible influence of that secondary product on the subsequent synthetic steps.
Surprisingly, the screening carried out on a number of reducing agents under various experimental conditions on a mixture constituted to the extent of 50%
by compound IIb and compound IIa demonstrated not only that calcium borohydride in tetrahydrofuran was capable of showing the desired chemoselectivity (removal of the chlorine in position 3' and reduction of the. 8 -methoxycarbonyl group without reducing the amide in position 6) but ais~o that compound IIb was converted into the desired compound of formula III.
The surprising reactivity of the double bond of compound IIb with calcium borohydride in tetrahydrofuran gave us the possibility, which was not foreseeable from the literature, of using the reaction mixture obtained directly from the acylation reaction of D-8 -methoxycarbonylergoline without purification in the subsequent reaction step.
Thus, by reacting a mixture of D-8 -methoxycarlbonylergoline in an aprotic solvent, in concentrations ranging from 8 to 18% weight/volume, under stizring at room termperature, with an equimolar amount of a suitable proton acceptor and one equivalent of 3-halo- or 2-halo-propionyl chloride for a period ranging from 30 minutes to 2 hours, we obtained, after dilution with water and filtration, a mixture of which approximately 50% was constituted by compound IIa and compound IIb.
Aprotic solvents that may be used in that step are represented by acetone, methyl ethyl ketone; tetrahydrofizran, dimethylformamide" preferably acetone; proton acceptors that may be used are triethylamine, pyridine and lutidine, preferably triethyiamine.
The mixture of compound IIa and compound Ilb is, dispersed in tetrahydrofuran with sodium borohydride (from 5 to .9 moles per mole of substrate) and the suspension so obtained is added, at a temperature hanging from 0 to +15°C and under vigorous stirring, to a tetrahydrofuran solution or to an alcoholic solution (methanol, ethanol or isopropanol) or an aqueous-alcoholic solution containing calcium chloride (from 1.5 to 2 moles per mole of sodium borohydride). When the addition is complete, the temperature is increased to 60°C and the reaction mixture is maintained under stirring for a period ranging from 20 minutes to minutes. The compound III so obtained is precipitated from the reaction mixture (after acidification of the reaction mixture, evaporation of the organic phase and treatment with aqueous carbonate) and recovered by filixation.
Alternatively, the calcium borohydride, instead of being produced "in situ", can be used already preformed in the commercially available forms (for example, as a bis-THF complex).
On the basis of the data obtained, compound III can be prepared in accordance with Scheme 1 with total yields of 81°ro starting from D-8 -methoxycarbonylergoline.
It was clear from the results obtained that, in order to synthesise the compound of formula III, it would have been equally advantageous to acylate compound I
directly with acryioyl chloride (Scheme 3) or to use the intermediate IIa with a high degree of chemical purity {obtainable by the acylation of compound I with chloropropionyl chloride carried out at low temperatures (0-5°C) and high dilutions (0.05-0.2 molar); Scheme 2) and to reduce the intermediate IIb or IIa so obtained with calcium borohydride in the next step. An experimental check carried out on those two variants confirmed total yields of compound III from compound i superimposable on those obtained by synthesis Scheme 1, confrming the validity thereof as alternatives for obtaining compound III.
Compound III was subsequently reacted, in solution with a proton acceptor, with an alkylsulphonyl chloride under stirring at room tempE;rature for a period ranging from 1 .to 2 hours to give compound IV (X=RSS03; wherein RS is methyl, ethyl or p-tolyl) with yields ranging from 88 to 95%. .
Suitable proton acceptors are represented by pyridine, .triethyiamine, lutidine, preferably pyridine. Alkylsulphonyl chlorides. that riiay be used are represented by, but not limited to, methanesulphonyl chloride, ethanesulphonyl chloride or p-toluenesulphonyl chloride, preferably methanesulphonyl chloride.
Compound IVa is then treated with from 4 to 8 equivalents of sodium alkyl rnercaptide (compound of the general formula R,SNa; wherein R4 is, independently, a linear, branched or cyclic, saturated or unsaturated C,~
alkyl residue) in dimethylformamide with agitation at from 90 to 100°C for a period ranging from 2 to 5 hours to give compound V with yields ranging from 90 to 95°.'° and an HPLC titre of 97%.
If the R~ group of the allcyl mercaptide is an alkyl radical larger than methyl or ethyl, compound IVa (X=RSS03; wherein RS is methyl, ethyl or p-tolyl) can be converted beforehand into a halogenated derivative IVb (preferably X=I) in order to facilitate nucleophilic substitution. That last step is carried out in acetone solution with agitation at reflux temperature in the presence of lithium iodide to dive compound IVb in quantitative yields.
Compound V is converted into the final compound VI by treating a heterogeneous mixture of compound V in an aprotic solvent with a reducing agent at a temperature ranging from 20 to 45°C for from 2 to 6 hours. Reducing agents that may be used in that step are lithium aluminium hydride or sodium dihydrido-bis(2-methoxyethoxy) aluminate; the preferred reducing agent is sodium dihydridro-bis(2-methoxyethoxy) aluminate. Aprotic solvents that may be used in that step are tetrahydrofuran, dioxane and toluene; the preferred solvent is toluene.
The yields of that step are from 80 to 99%.
The physico-chemical characteristics of the product VI obtained (Ra=CH,) are in good agreement with the data reported in literature for this product; the HPLC
purity is 96%.
The high degree of purity of the pergolide base obtained (HPLC titre of 96% on the crude reaction material), the high global yields of the process (66%) starting from D-8 -methoxycarbonylergoline and the ready availability of the primary starting material make this process competitive compared with those known from the prior art.
Several salts of compound VI (Pergolide) may 'be prepared, including acid addiction salts of inorganic acids as well as salts derived from non toxic organic salts. The preparation of the above salts, and particularly the methanesulfonate (mesylate), may be easily realised following known literature procedures, as for example US-4, I66, I 82 and EP-0003667, EXAMPLES
Example I
Prepararion of D-6-n-propionyi-8 -hydroxymethyiergoiine (compound III) according to reaction scheme 1 A mixture of D-8 -methoxycarbonylergoline (compound I) (10.8 g; 0.04 mol) is heated with vigorous agitation in acetone (100 ml) at: 40°C for 30 minutes, and then at 55°C for a further 30 minutes. After cooling to ambient temperature, triethylarnine (0.04 mol) is added. After a few minutes, a solution of 3-chloropropionyl chloride {5.08 g; 3.84 ml; 0.04 moI) in acetone (5 mI) is added dropwise while maintaining the reaction temperature at from 20 to 25°C.
When the addition is complete, the reaction mixture is maint~uned under stirring at room temperature for 30 minutes, then it is poured into water (150 ml) and the suspension so obtained is maintained under stirring for 30 minutes. After that time, the precipitated solid is recovered by filtration, vvashed with water (i00 ml) and dried overnight under vacuum at a temperature of ti0°C to give 12.8 g of a 6/4 mixture of compound IIa and compound IIb.
For analysis purposes, the two compounds IIa and lib can be isolated by chromatography on silica gel while eluting with dichloromethane/methanol =
9/1.
D-6-(3'-chloropropionyi)-8 -methoxyearbonyiergoiine (compound IIa):
TLC=Rf: 0.72 (eluant dichloromethanelmethanol = 911}
'H-NMR (60 MHz, DMSO-db) gives the diagnostic sig:aals (ppm):
0.50-1.50 (m); 2.I0-2.90 (m); 3.30 (s); 2.90-4.00 (m); Ei.30-6.75 (m, 4H, aromatic) Elemental analysis: calculated for C,9Hz,NzO,CI
theoretical- C: 63.24%; H:5.87%; N:7.76%; 0:13.30%:. CI:9.83%
found- C:63.29%; H:5.84%; N:7.67%; C1:9.88%
D-6-(acryloyi)-8 -methoxycarbonyiergoiine (compound IIb) TLC=Rf:0.61 (eluant dichloromethane/methanol = 9/1}
MS(EI)- M+: mie=324 'H-NMR (60 MHz, DMSO-d6) gives the diagnostic signals (ppm):

2.15-2.40 {m, 3H); 2.40-3.20 {m, 3H); 3.25 (s, 3H, CO,CH3); 3.60-3.70 (m, 3H);

5.35-5.70 (m, 2H, CHI CH); 6.15 (m, IH, CHZ ~CI~; 6.30-7.i5 (m, 4H, aromatic); 9.25-9.50 (sb, 1H, N-H) Elemental analysis calculated for C,9H,oN~03 theoretical- C:70.35%; H:6.21%; N:8.64%; 0:14.80%
found- C:70.31 %; H:6.26%; N:8.73%.
The mixture of compounds IIa and LIb (1 g), which are obtained directly from the previous reaction, is dispersed in tetrahydrofuran (4 mI) with sodium borohydride (870 mg): The suspension so obtained is added, under vigorous stirring at a temperature of 10°C, to a solution constituted by calcium chloride (14.5 mmol) in ethanol (16 ml). When the addition is complete, the temperature of the reaction mixture is slowly increased to 60°C and the mixture i:~ maintained under stirring at that temperature for 30 minutes. After that time, the reaction mixture is concentrated under vacuum and the residue so obtainedl is acidified with 2N
HCl;
the suspension so obtained is maintained under stirrin;; for 1.5 hours at ambient temperature and then the precipitate is recovered b;y f ltration. The solid so obtained is resuspended in methanol (8 ml); the heterogeneous mixture is heated to reflux temperature and is maintained at that temperature for 10 minutes:
When the suspension has been cooled to 15°C, a 10% (I5 ml) potassium carbonate solution is added with vigorous stirring. The crystalline solid so obtained is recovered by filtration, washed with a Iarge amount of water and dried under vacuum at a temperature of 60°C to give 965 mg of compound IiI (81 %
total yield from compound n.
TLC=Rf: 0.55 (eluant dichloromethane/methanol = 9/1) Melting point: 2I4-216°C
MS{EI)- M': m/e=298 'H-NMR (60 MHz, DMSO-db) gives the diagnostic signals (ppm):
0.85-1.25 (t, 3H, CH,CH,C=O); 2.15-2.80 (rn); 2.85-4.00(m); 4.55-4.85 (sb, 1H, O-H); 6.35-7.05 (m, 4H, aromatic); 10.25-10.50 (sb, 1H, N-H).
Example 2 Preparation of D-6-{propionyl)-8 -mesyoxymetf~ylergoline (compound IYa) i6 Methanesulphonyl chloride (0.962 g) is added slowly to a solution of compound III (0.984 g) and pyridine (5.900 g) under vigorous stirring and while maintaining the reaction temperature comprise between 15 and 20°C. When the addition is complete, the reaction mixture is maintained under stirring at room temperature for 1 hour, then it is worked up by adding a 10% aqueous solution of potassium carbonate ( 1 S ml) and continuing agitation until a crystalline solid is obtained which is recovered by filtration, washed with a large ~unount of water and dried under vacuum at 60°C to give 1.091 g of compound IV (88% yields).
HPLC (column: LICHROCART 125x4 mm packed with LICHROSPHER RP-18, m; mobile phase: 60% buffer 20 mM of K,HP04 adjn~sted to pH 6.5 using H3P0~
(85%) and 10 mM triethylamine; 40% acetonitrile; flow 1.2 ml/minute): rt 4'266".
Elemental analysis calculated for C,gFiz4NZO4S
theoretical- C:60.62%; H:6.43%; N:7.44%; 0:17.00%; 5:8.52%
found- C:60.66%; H:6.49%; N:7.45%; 5:8.48%
Example 3 Preparation of D-6-{propionyl)-8 -methylthiomethylf:rgoline (compound V) Compound IV (1.091 g) is suspended in anhydrous dimethylformamide (6.825 g) and the reaction mixture so obtained is heated (60-80°C) under stirring until a homogeneous solution is obtained. After cooling to ambient temperature, a 20%
solution of sodium methyl mercaptide (5.250 g) in nnethanol is added rapidly under vigorous stirring. After 1 hour, the reaction mixti:~re is slowly heated until a temperature of 90-95°C is reached, distilling off alI of the methanol.
The reacrion mixture then continues to be heated under vigorous stirring for 4 hours. The reaction.mixture is cooled to 10°C and 7.5 ml of water are added under stirring.
The precipitated product is recovered by f ltration, washed with water and dried under vacuum at a temperature of 60°C to give 0.905 g of compound V
(95%
yield).
TLC=Rt.:0.81 (eluant dichloromethane/methanol = 9/1 ) HPLC (same experimental conditions as in Example 2) == rt:l 1'070"
Melting point:268°C (decomposition) Elemental analysis calculated for C,9H,4N~OS

theoretical- C:69.48%; H:7.36%; N:8.53%; 0:4.87%; 5:9.76%
found- C:69.51 %; H:7.31 %; N:8.48%; 5:9.78%.
Example 4 Preparation of D-6-n-propyi-8 -methylthiomethylerg;oline (compound VI) 4.0 g of a 70% solution of sodium dihydridro-bis(2-methoxyethoxy) aluminate in toluene are added slowly to a suspension of compound V {0.905 g) in toluene ( 13.8 ml) undr stirring at room temperature. When the; addition is complete, the reaction is maintained under stirring for 1 hour then heating to a final temperature of 45°C; this temperature is maintained for 4 hours. At the end of that time, the reaction mixture is cooled to ambient temperature and acidified with 5% HCl (25 ml). The two-phase mixture is distilled under vacuum until the organic phase has been eliminated; the aqueous suspension which remains is filtered under vacuum and the solid so recovered is washed with water. The cmde material so obtained is resuspended in methanol (6 ml) and the suspension so obtained is heated under reflex for 30 minutes, then cooled to room temperattu~e and treated with a 10%
aqueous solution of potassium carbonate (12 ml) under vigorous stirring. After hours under stirring at room temperature, the suspension is filtered and the solid so recovered is washed with water and dried under vaicuum at a temperature of 60°C to give 0.826 g of compound VI (95% yield).
The physico-chemical characteristics of the product obtained are in goad agreement with the literature data (as reported in US-4,166,182).
The HPLC titre (same experimental conditions as those given in Example 2) of compound VI so obtained (rt 11'070"} is 96%.
Example 5 Preparation of D-b-(propionyl)-8 -hydroxymethylergoline (compound III}
according to reaction scheme 3 6 g ( 18.49 mmol) of D-8 -methoxycarbonyiergoline {nompound I) are dispersed in acetone (50 ml) and the reaction mixture is heated at 40"C for 30 minutes and then at 55°C for a further 30 minutes. After cooliirg to ambient temperature, triethylamine {2.24 g; 3.1 ml; 22.18 mmol) and a solutiion of acryloyl chloride (2 g; I.8 ml; 22.18 mmol) in acetone (5 mi) are added in succession while maintaining the reaction teriiperature comprise between 20 and 2S°C.
When the addition is complete, the reaction mixture is maintained under stirring at room temperature for I hour. The reaction mixture is worked up by being poured into water (I00 mi) and maintaining the resulting suspension under stirring for 30 minutes. After that time, the precipitated solid is recovered by filtration, washed with water (80 ml) and dried under vacuum at a temperature of 60°C to give (S.4 g; I 6.64 mrnol; 90% yield) of compound IIb.
The physico-chemical characteristics of the resulting product IIb are the same as those of the product obtained by chromatographic purification in Example 1.
Compound IIb is then reduced using calcium borohydride produced "in situ", as already described in Example l, to give compound ITl with total yields of 78%
starting from compound I.
Example 6 Preparation of D-b-(propionyl)-8 -hydroxymethylergoline (compound III) according to reaction scheme 2 A mixture of D-8 -methoxycarbonylergoiine (compound I) (3.48 g; I2.9 mmol) is heated, under vigorous stirring in acetone {6S ml) at 40"C for 30 minutes and then at SS°C for a further 30 minutes. When the reaction mixture has been cooled to 5°C, triethylamine {13 mmol) is added and, while maintaining that temperature., a solution of 3-chioropropionyl chloride (1.64 g; 1.24 ml; 12.9 mol) in acetone (6.S
mi) is added within a period of 30 minutes under vigorous stinting. When tt~e addition is camplete, the reaction mixture is maintained under stirring at room temperature for 30 minutes and then it is poured into water (100 ml), the resulting suspension being maintained under stirring for 30 minutes. After that time, the precipitated solid is recovered by filtration, washed with water (35 ml) and dried overnight under vacuum at a temperature of .60°C to. dive 3.6 g of compound IIa (contaminated to the extent of S% with coiripound IIb). The crude product can be reduced using calcium borohydride produced "in situ" .as described in Example to give compound III with total yields, starting from intermediate I, of 80%_ Example 7 Preparation of D-6-(propionyl)-$ -iodomethylergoline (IVb) starting from compound IVa.
A mixture constituted by compound IVa (1 mmol; 376 mg) and lithium iodide (4 mmol; 455 mg) in acetone (20 ml) is stirred at reflux for 8 hours. After that time, the reaction mixture is worked up by diluting it with water {20 ml) and recovering the resulting solid by filtration, washing it with a large amount of water on the filter and drying it overnight under vacuum at 60°C. 392 mg (0.96 mmol) of compound IVb are recovered.
MS(EI)- M+: m/e = 408 Elemental analysis calculated for C,BH,,N,OI
theoretical- C:52.95%; H:5.18%; N:6.86%; 0:3.92%; I::31.08%
found- C:52.90%; H:5.12%; N:6.8I%; I:31.12%

Claims (30)

1. A process for the preparation of a compound of formula VI, wherein R4 is a saturated or unsaturated C1-8 alkyl radical, comprising the following steps:

a) a compound of formula I

wherein R1 represents a saturated or unsaturated C1-8 alkyl residue, is reacted with 3-halo- and/or 2-halo-propionyl chloride in an aprotic organic solvent in the presence of a proton acceptor;
b) the compound or mixture of compounds so obtained in point a) is then reacted with calcium borohydride in tetrahydrofuran at a temperature between 10 and 65°C;
c) the compound so obtained in point b) is reacted in an aprotic organic solvent with an alkylsulphonyl chloride in the presence of a proton acceptor;
d) the compound so obtained in point c} is then reacted in an aprotic organic solvent with a compound of formula R4SX, wherein R4 has the meaning given above and X is an alkali metal;

e) the compound so obtained in point d) is converted into compound VI by treatment with a reducing agent in an aprotic organic solvent.

2. A process according to claim 1, characterised in that the aprotic organic solvent mentioned in point a) is selected from acetone, methyl ethyl ketone, tetrahydrofuran and dimethylformamide.

3. A process according to claim 1, characterised in that the proton acceptor mentioned in point a) is selected from triethylamine, pyridine and lutidine.

4. A process according to claim 1, characterised in that both the proton acceptor and the 3-halo- and/or 2-halo- propionyl chloride mentioned in point a) are used in equimolar amounts relative to compound I.

5. A process according to claim 1, characterised in that reaction a) is carried out at ambient temperature.

6. A process according to claim 1, characterised in that, in reaction b), the calcium borohydride is used in amounts of from 5 to 9 moles/mole of substrate.

7. A process according to claim 1, characterised in that, in reaction b), the tetrahydrofuran is present in amounts of from 2 to 8 ml per gram of substrate.

8. A process according to claim 1, characterised in that, in reaction b), the tetrahydrofuran is used in admixture with protic organic solvents or with an aqueous-alcoholic solution thereof.

9. A process according to claim 8, characterised in that the protic organic solvents are selected from methanol, ethanol and isopropanol.

10. A process according to claim 1, characterised in that reaction b) is carried out at a temperature of 60°C.

11. A process according to claim 1, characterised in that reaction c) is carried out at a temperature comprise between 10 and 30°C.

12. A process according to claim 1, characterised in that the proton acceptors mentioned in point c) are selected from pyridine, triethylamine, lutidine.

13. A process according to claim 1, characterised in that the alkylsulphonyl chlorides mentioned in point c) are selected from methanesulphonyl chloride, ethanesulphonyl chloride and p-toluenesulphonyl chloride.

14. A process according to claim 1, characterised in that the proton acceptor mentioned in point c) is used in amounts of from 20 to 30 moles per mole of substrate and the alkylsulphonyl chloride mentioned in point c) is used in an amount of 1.2 to 3 moles per mole of substrate.

15. A process according to claim 1, characterised in that R4 is methyl.

16. A process according to claim 1, characterised in that, in reaction d), X
is sodium.

17. A process according to claim 1, characterised in that the compound R4SX
mentioned in point d) is used in an amount of from 4 to 8 equivalents relative to the substrate.

18. A process according to claim 1, characterised in that the apolar organic solvent mentioned in point d) is dimethylformamide.

19. A process according to claim 1, characterised in that reaction d) is carried out at a temperature of from 90 to 100°C.

20. A process according to claim 1, characterised in that reaction e) is carried out at a temperature of from 20 to 45°C.

21. A process according to claim 1, characterised in that the reducing agents mentioned in point e) are selected from lithium aluminium hydride and sodium dihydridro-bis(2-methoxyethoxy) aluminate.

22. A process according to claim 1, characterised in that the aprotic solvents mentioned in point e) are selected from tetrahydrofuran, dioxane and toluene.

23. A process according to claim 1, characterised in that, before carrying out reaction d), the compound obtained by reaction c) is converted into the corresponding halogenated derivative.

24. A process according to claim 1, characterised in that said 3-halo-propionyl chloride is 3-chloro-propionyl chloride.

25. A process according to any one of claims 1 to 24, further comprising converting said compound of formula VI to pergolide mesylate.

26. A compound of formula II

wherein R2 is halogen, R3 is hydrogen and R1 represents a saturated or unsaturated C1-8 alkyl residue.

27. A compound of formula III

28. A compound of formula IV

wherein X is a halogen or a compound of the general formula R5SO3- and R5 is selected from methyl, ethyl, p-tolyl.

29. A compound of formula V

wherein R4 is a saturated or unsaturated C1-8 alkyl residue.

30. Use of any one of the compounds according to claims 26 to 29 as intermediates in the preparation of a compound of formula VI

wherein R4 is a saturated or unsaturated C1-8 alkyl residue.