CS199591B2 - Process for preparing 8-thimethylergolines - Google Patents

Abstract

1505296 8-Thiomethylergoline derivatives ELI LILLY & CO 3 June 1975 [6 June 1974] 23869/75 Heading C2C Novel compounds of the Formula II wherein R is H, CN, COalk, phenyl or alk; R<SP>1</SP> is H, Cl or Br; alk is C 1-3 alkyl and the dotted line is an optical bond and pharmaceuticallyacceptable acid addition salts thereof, may be prepared by reacting a compound of the Formula III wherein R 2 is methanesulphonyl or p-toluene sulphonyl with an alkali metal salt of a compound R<SP>3</SP>5H, wherein R<SP>3</SP> is CN, COalk, phenyl or alk, optionally followed where R<SP>3</SP> is -COalk by hydrolysis to produce a compound II in which R is H. D - 6 - Methyl - 8 - mesyloxymethylergoline and its 9,10-didehydro derivative are prepared by reacting the corresponding 8-hydroxymethyl compound with methane sulphonyl chloride. Pharmaceutical compositions of the compounds II with the usual excipients are prolactin inhibitors when administered parenterally.

Description

The invention relates to a process for the preparation of 8-thiomethylergolines. ·;

Compounds based on the ergoline system of Formula I

have a broad spectrum of pharmaceutical activity. For example, lysergic acid and isolysergic acid can be expressed as 8-carboxy-6-methyl- ^{9 9} -ergolines (9,10-didehydroergolines). Lysergic acid amides, some of which possess valuable and unique pharmacological properties, include naturally occurring alkaloids such as ergocornine, ergocryptine, ergonovine, ergocristine, ergosine, ergotamine synthetic uterine-like alkaloids such as methergin 1, synthetic hallucinogens such as dlethylamide lysergic acid LSD.

The? -Methyl-8-carboxyergine amides, which are commonly referred to as dihydroergotic alkaloids, have lower order cytotoxic effects and also lower toxicity than the ergot alkaloids themselves. Ergotamine, i.e. ^{9 9} -ergoline, is used in the treatment of migraine and ergocornine α, 2-bromo---ergocryptine has been found to be inhibitors of the prolactin and tumors induced by dimethylbenzanthracene in rats according to Nagasax and Meltes, Why. Soc. Exp'tl. Blol. Copper. 135, 489 (1970) and Heusoh et al., Europ. J. Cancer, 353 (1970), and U.S. Pat. Nos. 3,752,888 and 3,752,814.

D-6-methyl-8-cyanomethylergoline was first made according to Semonský et al., Coll. Czech. Chem. Commun., 33, 577 (1968) and its use to prevent pregnancy in rats has been reported by the same authors in Nature, 221, 668 (1969) and US Patent No. 3,732,211. The effect of the compound appears to have been via secretion of pituitary luteotropic hormone and pituitary gonadotropins. They also appear to inhibit prolactiria secretion. [Gray et al., Réprod. Fert., 24, 263 (1971) and Mantle and Finn, ibid. 441]. Semonský et al. Cžech. Chem. Comm., 36, 220 (1971), a method for producing D-6-methyl-8-ergolinoacetamide, this compound prevented the rat from becoming pregnant and also inhibited mammary gland function. The effect of compounds of this type on tumors is unknown. Ergolines with a thlomethyl group as a substituent and derivatives of these compounds have not been prepared.

The invention relates to a process for the preparation of 8-thiomethylergolines of the general formula II

where

R is hydrogen, CN, C-alk,

II is phenyl or alkyl of 1 to 3 carbon atoms,

R ¹ is hydrogen, chlorine or bromine; alk is C 1 -C 3 alkyl and the dotted line indicates the optional presence of a double bond, as well as a process for preparing non-toxic, pharmaceutically acceptable acid salts of these compounds.

The term alk in the above formula means an alkyl radical of 1 to 3 carbon atoms and thus includes methyl, ethyl, n-propyl and isopropyl. In formula (II), when the 9,10 bond is saturated, the compounds may be called D-8-methyl-8-thlomethyl (or mercaptomethyljergolls). If the bond is unsaturated, the compounds may be called D- 6-Methyl-8-thlomethyl (or mercaptomethyl) -9,10-didehydroergolines. Compounds which can be prepared by the process of the invention and which fall within the scope of formula II include, for example, the following substances:

D-2-chloro-6-methyl-8-propionylthlomethylergoline,

D-2-chloro-6-methyl-8-butyrylthiomethyl-9,10-di-dihydroxyergine, D-2-chloro-6-methyl-8-phenylmercaptomethyl-9,10-didehydroergoline, D-2-bromo-6- methyl-8-phenylmercaptomethyl-9,10-dihydroergoline, D-2-chloro-6-methyl-8-ethylmercaptomethyl9,10-didehydroergoline, D-6-methyl-8-n-propylmercaptomethylergoline and D-6-methyl-8- isopropyl mercaptoethylergoline.

Compounds of formula (II) may be prepared by reacting a compound of formula (III)

where

R ¹ and - - - - have the above meanings, and

R ² represents a radical methanesulfonate or p-toluenesulfonate with nukleofllním agent of formula IV

HSR ³ (IV)

R ³ is CN, C-alk, II of phenyl or alkyl of 1 to 3 carbon atoms, and alk is as defined above, or with an alkali salt thereof, followed by hydrolysis when R ³ is a group

C-alk,

II o

the resulting product is to be a compound of formula (II) wherein R is hydrogen and the products obtained are optionally converted to non-toxic pharmaceutically acceptable acid addition salts.

Compounds of the invention in which R is other than hydrogen can be prepared by nucleophilic exchange of the ester groups of D-6-methyl-8-hydroxymethylergoline or 9,10-didehydroergolines optionally substituted at the 2-position with chlorine or bromine atoms by treatment with thiocyanates, thiophenols, thioalkanesin (alk-COSH) or alkylthiols (alk-SH). Esters used as starting materials for this synthesis include mesyl ester (methanesulfonyl), p-toluenesulfonyl ester (p-tosyl) and similar esters formed with the hydroxy group of 8-hydroxymethyl-6-methylergoline, 8-hydroxymethyl-6-methyl-9 10-didehydroergoline or 2-halo derivative of Δ ⁹ -derivative of formula II. These mesyloxy and p-alkoxy derivatives are known or can be prepared from the corresponding hydroxy derivatives in a known manner. When performed with thiophenol or alkylthol, a mercaptan group sodium salt is usually formed. Sodium methylate, sodium hydride or alkali metal thiocyanate may also be used. The reaction is carried out in an inert solvent such as dimethylformamide or dimethylsulfoxide at room temperature or, optionally, with heating up to 100 ° C. The reaction products are usually isolated in conventional manner and purified by chromatography, preferably on florlsil. Compounds of the invention in which R is a hydrogen atom may be prepared by hydrolysis of the corresponding compounds in which R is a group

C-alk.

II o

The compounds of the invention are white, crystalline solids which form pharmaceutically acceptable salts with non-toxic acids.

The non-toxic acids suitable for forming the salts of the invention are inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, nitrous, phosphoric and the like; it is also possible to use non-toxic organic acids, in particular aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and alkanedic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Pharmaceutically acceptable salts are, for example, sulphates, pyrosulphates, acid sulphates, sulphites, acid sulphites, nitrates, phosphates, middle phosphates, acid phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, propionates, propionates, propionates, propionates 'formates, isobutyrates, capronates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butylene-1,4-dioates, hexln-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenyl propionates, phenylbutyrates, _in citrates, lactates, d-hydroxybutyrates, glyclates, malate, tartrates, methanesulfonates to methanesulfonates 1-methanesulfonates -sulfonates.

The compounds of the invention are prolactin inhibitors. It inhibits prolactin secretion, as can be shown. following attempt. Male Spraque-Dawley rats weighing 200 g were used for the experiment. All rats were housed in an air conditioner. chamber, which was illuminated from 6 am to 8 pm and was fed with normal laboratory food and plenty of water.

In each experiment, rats were sacrificed by decapitation and 150 microliter serum was assayed for prolactin content. Each rat - '- alone was treated. . an intraperltoneal dose of 2.0 mg of reserpine as an aqueous suspension 18 hours prior to administration of the ergoline derivative. Reserpine was administered to 'cause a steady increase in the prolactin level. Ergoline derivatives were dissolved in 10% 'ethanol' to a concentration of 10 µg / ml and were then administered 'intraperltoneally' at a single dose of 50 µg / kg. Each compound was administered to a group of 10 rats, a control group of 10 rats, received only an equivalent amount of 10% ethanol. One hour after administration of the test substances, all rats were sacrificed by decapitation and serum prolactin determination was performed. The results were evaluated statistically using Student's “t”, a 'comparison between' the mean to 'determine' the probability level 'p'.

The difference between the prolactin level of the treated rats and the prolactin level of the control rats, divided by the prolactin level in the control rats, indicates the percentage inhibition of prolactin by the compounds of the invention. The following table shows the percent 'inhibition for a number of compounds' of formula II. The first column shows the name of the compound, the second column its dose, the third column the percentage of prolactin inhibition and the fourth column the statistical one. significance.

As prolactin inhibitors, the compounds of the invention are useful for inhibiting the growth of mammary adenocarcinomas in female mammals. For example, D-6-methyl-8-thiocyanomethylergoline inhibits the growth of adenocarcinomas induced by dimethylbenzenanthracene in rats at a dose of 1.2 mg / kg. The compound is administered as a suspension in corn oil, but can also be administered in the form of a pharmaceutically acceptable acid addition salt in the form. aqueous solution.

The invention will be illustrated by the following Examples 1 to 6.

Compound

TABLE

Dose% inhibition of prolactin

Value "p"

D-6-methyl-8-phenylmercaptomethyl-9,10-dihydrohydrooline

D-6-methyl-8-methylmercaptomethyl-9,10-didehydroergoline

D-6-methyl-18-acetylthiomethylergol

D-6-me (thyl-8-mercaptomethylergoline

D-6-methyl-8-methylmercaptomethylergoline

D-2-chloro-6-methyl-8-methylmercaptomethylergoline

D-6-methyl-8-hiocyanomethylergoline

D-6-methyl-8-acetylthiomethyl-9,10-didehydroergoline

10 pg 50 <0.05 10 pg 62 <0.01 10 40 0.01 10 pg 66 <0.001 10 'pg 49 <0.001 10 'pg 46 <0.001 10 pg 41 <0.001 Ю pg 44 <0.01

Example · 1

The reaction mixture was prepared from 2 g of D-6-methyl-8 * p-toluenesulfonyloxymethylergoline, 2 g of sodium thiocyanate and 100 ml of dimethylsulfoxide. The mixture was heated to 100-110 ^° C for 4.5 hours. The reaction mixture was cooled and poured into a mixture of water and ice.

6-methyl-8-thiocyanomethylergoline, which is insoluble in water, precipitates. The precipitate is collected by filtration, melting at 181 DEG-183 DEG C. with decomposition after recrystallization from ether / hexane.

Analysis: Calculated: 68.65% С, · 6.44% H, 14.13% N, 10.78% S, found *

% C, 68.31;% H, 6.66;% N, 13.99.

Example 2 '

Prepare a suspension of 10 g of N, N-methyl-N-hydroxymethylyline in 200 ml of pyridine. To this suspension was slowly added a solution of 6.0 mL of mythansulfonyl chloride and 200 mL of pyridine. The resulting reaction mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 hours and then poured into 2.5 liters of saturated aqueous sodium bicarbonate solution. The alkaline aqueous layer is diluted to 6 liters with water and allowed to stand at room temperature. During this time, the formed D-6-methyl-18-methoxymethylerghlin slowly crystallizes. The solution is cooled to 0 ° C to precipitate more of the compound. Then the solution is filtered and the filter cake is allowed to recrystallize from ethanol. An additional portion of D-S-methyl-4-mesyloxymethylene ether is obtained by extraction of the filtrate with ethyl acetate. The resulting 'D-6-methyl-6-mesyl-methoxymethyl-ether is recrystallized from ethanol to give a material with a melting point of 192-194 ° C with decomposition.

Analysis: Calculated: C, 81.05; H, 6.63; N, 8.38; S, 9.59. Found:

80.85% / o C · 6.46% H · 8.45% N · 9.30% S.

A solution of 2.5 ml of thiophylene in 25 ml of dimethyl sulfoxide is treated with 1.1 g of sodium methylate. To the resulting mixture was added dropwise a solution of 700 mg of D-6-methyl-8-mesyloxymethyl ether in 50 ml of dimethyl sulfoxide. After the addition was complete, the reaction mixture was stirred at room temperature. under a nitrogen atmosphere for 2 hours and then poured into a saturated aqueous solution of tartaric acid. The acidic layer was extracted with chloroform. The chloroform extract is separated and discarded and the acidic layer is alkalinized with an excess of 14 N ammonium hydroxide and the alkaline layer is then extracted with chloroform. The chloroform extract is separated, dehumidified and evaporated, the residue obtained is dissolved in ethyl acetate, washed thoroughly with water and then with aqueous sodium chloride solution. The ethyl acetate layer is then freed of water and the ethyl acetate is evaporated off under vacuum to give a dimethyl-B-phenylmercaptomethylthrebetin which is recrystallized from ethanol and then at a temperature of. mp 194-195 ° C with decomposition. The resulting material is then dissolved in chloroform and chromatographed on 25 g of florisil. The chromatograph is developed with a mixture of chloroform and methanol in a ratio of 19.:1. Fractions containing D-6-meteyl-8-phenylmethoxymethylyrgholine were detected by thin-layer chromatography and decanted. Evaporation of the solvent from the alloyed fractions and recrystallization of the residue from ether / hexane gave D-6-methyl-8-phenylmercaptomethylergoline, m.p. 195-196 cc, decomposed .

Analysis:

calculated:

75.82% C · 6.95% H · 8.04% N · '9.20% S, found:

75.85% С · '6.69% · · 7 & 7 · 9.19 ·% · S.

The reaction is carried out as described above in the reaction of D-6-methyl-8-mesyloxymethyl-9,10-didehydroergoline with thlotolin to give D-6-methyl-8-phenylmercaptomethyl-9 H -didohydrohydrogen peroxide. m.p. 200 DEG-203 DEG C. with decomposition after recrystallization from methanol.

Analysis:

calculated:

78.26% C · 6.40% H · 8.08% N, 9.25 ° / o $, found:

H, 6.42; N, 7.99; N, 9.02.

The corresponding 9H-dimethyldromalylate is prepared by dissolving the resulting compound in tetrahydrofuran and adding an equivalent amount of maleic acid in tetrahydrofuran solution. The maleate melts at 188-189 ° C after recrystallization from methane.

Analysis:

calculated:

67.51 ° / o C · 5.67% · H, 6.06% N, -6.93% S, not glued:

67.29% c, 5.89 ° C / H, 5.79 ° C / N, 6.71% S.

Example 3 3 ml of dimethylformamide are cooled to

95.-91

0 ° C, 1 ml of methanethiol is added, followed by 1.0 g of sodium hydride as a 50% suspension. v. mineral oil. The addition was carried out in portions and the resulting mixture was stirred for an additional hour and then allowed to warm to room temperature. A solution of 1-g of D-6-methyl-8-mesyloxymethylergoline in 50 ml of dimethylformamide is then added dropwise to the resulting methanethiol sodium salt by the method of Example 2. The resulting product is isolated and purified according to Example 2 to give D-6-methyl-8-methylmercaptomethylergoline, m.p. 153-155 ° C. The resulting product is recrystallized. from a mixture of ether - and - hexane without the chromatographic purification of Example 2 to give - D-6-methyl-8-methylmercaptomethylergoline, m.p. 153-154 ^° C.

Analysis:

calculated:

% C, 71.28;% H, 7.74;% N, 9.78.

% C, 71.08;% H, 7.59;% N, 9.83.

The above procedure afforded D-6-methyl-8-m-ethylmercaptomethyl-9,10-didehydroergoline - from the corresponding 8-mesyloxymethyl derivative by reaction with - methylmercaptanemide. Mp 181-183 ° C dec. After recrystallization from ether / hexane.

Analysis: Calculated for 71.79 / ₀ C, 7.09 - Oo H, 9.85% N, 11.27% S, nal1zeno:

% C, 72.01;% H, 6.84;% N, 9.62.

The corresponding 9,10-didehydro maleate was prepared by dissolving the resulting product in ether and adding an equivalent amount of a solution of maleic acid in the ether solution. The salt melts at 159-160 ° C with decomposition.

Analysis: · calculated:

% C, 62.98;% H, 6.07;% N, 6.99%;

62.99 O / o c, 6.13% H, 6.78% N, 7.86% S.

Example 4

Method '. of Example 2 is the acid. The sodium thioacetate is reacted with D-6-methyl-8-mesyloxymethylergoline in dimethylformamide solution to give D-6-methyl-8-acetylmercaptomethylergoline, which is isolated and purified according to Example 2. Chromatography of the crude product on - florisil using chloroform 10 mu - containing - 2 o / o - ethanol as the eluent afforded - D-6-methyl-8-acetylmercaptomethylergoline, m.p. 153-155 ° C; decomposition.

Analysis:

calculated: '

68.75% - C, 7.05 -% - H, 8.91% N, - 10.20% - S, found: '

68.70% C, 7.22% H, 8.62% N 10.47% S.

From the above, D-6-methyl-8-acetylmercaptomethyl-9,10-didehydroergoline can be prepared from the corresponding 8-mesyloxymethyl compound. The purified product thus obtained - has a melting point of 165 - 167 ° C with decomposition - after recrystallization from. of a mixture of ether and hexane.

Analysis: Calculated:

69.20% C, 6.45% H, 8.97% N, 10.26% S, found:

69.48% C, - 6.71% H, 9.00% N, - 10.5.6% S.

The 9,10-didehydromaleate salt can be prepared as described above by dissolving the free base in ether and adding an equivalent amount of ether acid solution. - maleic. The maleate melts at 178-179 ° C with decomposition.

Analysis: calculated: 61.67% C, 5.65 »/ o H, 6.54% o / o 'N7.48 - O / ο s, found-

% C, 61.95;% H, 5.50;% N, 6.84.

D-2-chloro-6-methyl-8-acetylmercaptomethylergoline can be prepared in a similar manner. The chromatographic purification fractions in which the presence of D-2-chloro-6-methyl-8-acetylmercaptomethylergoline by thin-layer chromatography was shown were combined, evaporated, and the residue was recrystallized from ether-hexane to give the title compound. purified final product, m.p. 140-141 ° C.

Analysis: calculated:

61.97% .C-6, (7-% H- 8.03% N- 9.19 ® / o S,

10.16 θ / ο Cl, found .. · -

61.75 θ / o C, - 5.78 ’% H, 7.75% N, 9.41% - S,

10.32 e / ο Cl. ·

Example - - 5

Reaction mixture containing 1.0 g of D-6-methyl-8-acetylmercaptomethylergoline (according to

199391 of clade 4), 100 ml of ethanol and 100 ml of a 4N aqueous hydrochloric acid solution, are refluxed under a nitrogen atmosphere for 5.5 hours. The reaction mixture was cooled and basified with excess 14 N ammonium hydroxide. The aqueous alkaline layer was extracted with chloroform and the chloroform layer was evaporated to give a residue consisting of D-6-methyl-8-mercaptomethylergoline. This residue is chromatographed on 75 g of chlorisil using chloroform containing 5% ethanol as eluent. D-6-methyl-8-mercaptomethylergoline is identified in the chromatographic fractions as more polar and therefore less mobile than the starting material by thin layer chromatography. Fractions containing D-6-methyl-8-mercaptomethylergoline were combined and recrystallized from ethanol to give the purified product, m.p. 255-257 ° C with decomposition.

Analysis:

calculated:

70.55% C, 7.40 o / o H, 10.28 θ / ο N, 11.77% S, Π & ΙθΖβΠΟ *

70.31% C, 7.65% H, 10.04% N, 12.00% S.

The above procedure was repeated except that methyl mercaptan was used in place of thioacetic acid in reaction with D-2-chloro-8-methyl-8-mesyloxymethylergoline to give D-2-chloro-6-methyl-8-methylmercaptomethylergoline. The chromatographic fractions containing the resulting material were combined; Evaporate to dryness, and chromatograph the residue on florisil using ether / hexane to recrystallize the title compound. The resulting product is D-2-chloro-6-methyl-8-methylmercaptomethylergoline, m.p. 194-195 ° C.

Analysis:

1Ϊ calculated:

63.63 ° C, 6.60% H, 8.73% N, 9.99%. S, 11.05 θ / ο Cl, found:

63.42 θ / ο C, 6.55 θ / ο H, 8.47 θ / ₀ N, 10.12 θ / ο S,

11.35% Cl.

Example 6

Reaction mixture containing 2.16 g of D-8-methyl-8-mesyloxymethyl-9,10-dihydro-dier. The goilne prepared according to the method of Example 2 from the corresponding 8-hydroxymethyl derivative and 2 g of sodium thloocyanate in 100 ml of dimethyl sulfoxide was heated at 50-70 ° C under nitrogen for 1 hour and then at 70-100 ° C for an additional hour. The reaction mixture was cooled, diluted with water, and the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was separated and filtered to remove the insoluble magenta decay product. The ethyl acetate layer was washed with water and saturated sodium chloride solution and freed from water. The solvent was removed by evaporation in vacuo; The resulting residue is chromatographed on 30 g of florlsil using chloroform containing 15% ethanol as eluent. Fractions shown to be D-6-methyl-8-thiocyanomethyl-9,10-didehydroergoline by TLC can be combined and the solvent is evaporated. Recrystallization of the residue from ether / hexane gave purified D-6-methyl-8-thlocyanomethyl-9,10-didehydroergoline, m.p. 190-191 ° C with decomposition.

Analysis:

calculated:

69.12 θ / ο C, 5.80 θ / ο H, 14.22 θ / ο N, 10.85 θ / ο S, found:

69.03 O / o C, 5.85 o / _o H, 14.40 o / _o N, 11.32% S.

Claims (7)

A process for the preparation of 8-thiomethylergolines of the general formula II R @ ¹ is hydrogen, chlorine bromine, alk is C1 -C3 alkyl and the dotted line represents the optional presence of a double bond, as well as non-toxic, pharmaceutically acceptable acid addition salts thereof, characterized in that: reacting a compound of formula III wherein R represents a hydrogen atom, a CN group, a C12 o group -alk, phenyl or C 1 -C 3 alkyl, wherein R 1 and --- are as defined above, and R ² represents a radical metSnzsulfhzátu or P-toluene sulfonate with a nucleophile of the formula IV HSR ³ (IV), wherein R ³ is CN, C-alk, phenyl or O-C 1 -C 3 alkyl - carbon and alk. has from above. or an alkali salt thereof, followed by hydrolysis when R3 is C-alk The resulting product is to be a compound of formula (II) wherein R is hydrogen, and the products obtained are optionally converted to non-toxic pharmaceutically acceptable acid addition salts. 2. A process according to claim 1 for the preparation of D-6-methyl-8-phenylmeocynthomethyl-9,10-eehydroergoline, characterized in that D-6-methyl-8-mesyloxymethyl-9 is reacted in the reaction. 10-dihyeroeogoline with thiophenol. 3. A process according to claim 1 for the preparation of D-6-methyl-8-methylmercaptomethyl-9,10-eidehydroergoline, characterized in that D-6-methyl-8-mexyloxymethyl-9,10 is reacted in the reaction. -didehydroergoline - with -methylmeocrptane. 4. A process according to claim 1 for the preparation of D-6-methyl-8-methylmeocynthomethylergoline, characterized in that D-6-methyl-8-mesyloxymethylergoline is reacted with methanthiol. 5. A process according to claim 1 for the preparation of D-6-methyl-8-thloocyanomethylgolin, which comprises reacting D-6-methyl-8-p-toluenesulfonyloxymethylergoline with sodium thiocyanate. 6. The process of claim 1 for the preparation of D-6-methyl-8-acetylmercaptomethyleogoline, which comprises reacting D-6-methyl-8-mesyloxymethylergoline with sodium thionacetate. 7. A process according to claim 1 for the preparation of D-6-methyl-8-mercaptomethyleoglyl by reacting D-6-methyl-8-mesyloxymethylergoline with sodium trisodium to form D-6-methyl. -8-acetylenomethylmethyleogoline, which is then subjected to hydrolysis.