KR790001074B1 - Process for preparing 8,8-di substituted-6-methylergolines - Google Patents

Abstract

8, 8-Disubstituted-6-methyl ergolin(I; R3 = carbo(C1-C3) alkoxy or CH2Z1,Z1=-H or -CN, alk =(C1-C3) alkyl) and its derivs., useful as inhibition agent fo prolactin, were prepd. Thus, compd. II(alk is given) and R2(CH2)n X (R2 = -CH3, -CN, or-C-O-alk, n = 0,1,X = halogen) was alkylated in the presence of nonhydrolyzable base, and product was recystallized to give pure I.

Description

Method for producing 8,8-disubstituted-6-methylergoline

The present invention relates to a method for producing 8,8-disubstituted-6-methylergoline and its derivatives which are prolactin inhibitors.

Compounds having the ergoline ring structure of formula (I) surprisingly have various pharmaceutical activities. For example, lysine acid and iso-lyseric acid are 8-carboxy-6-methyl-9-ergolines.

Raisginic acid amides, which have very useful and unusual pharmacological properties, include natural oxytox alkaloids-ergorna, ergokrytin, ergonobin, ergocristine, ergosin ergotamine and methergin, Synthetic hallucinogens such as diethylamide and LSD.

The corresponding amides of 6-methyl-8-carboxyserine, known as dihydro ergot alkaloids, are low strength delivery promoters and are also less toxic than ergot alkaloids themselves.

Recently, Clemens, Simonson, Metz and their collaborators have included ergokornin, dihydroergocornin, 2-bromo-α-ergocrtin and α-6-methyl-8-cyanomethyl ergoline. Many ergot-associated drugs have been found to have prolactin-sequestering activity. The following are the specific references for new findings in the ergoline pharmacology field.

Nagasawa and Meates, Proc. Soc. Exp'l. Biol. Med., 135, 469 (1970): Luthebeck dong Brit. Med. J., 228, (July 24, 1971): Huson et al., Europ. J. Cancer, 353 (1970): Coll. Czech. Chem. Commun., 33, 577 (1968): Nature, 221,666 (1969): Cedar et al., J. Reprod. Fert., 24, 263 (1971) Mantle and Finn, id, 441: Semonsky and his collaborators, Coll. Czech. Chem. Comm., 86,2200 (1971): Char and Clemens, Endocr = 90, 285-8 (1972): Clemens and Char, Proc. Soc. Exp. Biol. Med 139,659-662 (1972): Sweeney, Clemens, Confeld and Poor, April 1973. 64th Society of American Cancer Research Association.

Recently published patents on ergoline derivatives and lysginic acid derivatives are as follows. U.S. Pat.Nos. 3,704,233, 3,709,891, 3,585,201, 3,666,762, 3,586, 3,717,640 and 3,592,816

Only a few 8,8-disubstituted ergolines were produced.

Most of these compounds have substituents on indole nitrogen to form 1,8,8-trichy derivatives. For example, Becky et al. Reported 1,8-dimethyl-D-lyserginate P-bromine anide in molecular pharmacology 9, 23 (1973). Unlike this compound acid and D-riserginic acid P-bromine anhydride, it showed no intercyclic effect.

Such compounds are also mentioned in Science, 178, 614 (1922). Troxler and Hoffman produced 8-methyl derivatives of D-lyserginic acid diethylamide in Helvetica Chemica Acta, 40, 1722 (1957), but alkylating agents, such as iodine methyl and potassiumamide, have been used successfully in Lysergic acid. It is not possible to substitute the C ₈ position of the dihydrolyserginic acid methyl ester.

These authors also prepared 8-ethyl-D-isolyserginic acid diethylamide and 1,8-dimethyl-D-isolyserginic acid diethylamide. There is no introduction in the literature for 8,8-digest-9-ergolene in which the 1-position is not substituted and the substituent at the 8-position is not an amide. 6-methyl-8,8-disubstituted-ergolenes are not mentioned in the literature.

Novel compounds of formula (VI) and their nontoxic, pharmaceutically possible acid addition salts are prepared by

Where R ³ is carbo (C ₁ -C ₃ ) alkoxy or CH ₂ Z ¹ , where Z ¹ is —H or —CN and alk is (C ₁ -C ₃ ) alkyl and the dashed line may or may not be a bond thereof.

With a compound of formula (III)

Prepared by reacting a reagent of R ² (CH ₂ ) _n X in the presence of a non-hydrolyzable base.

이고Where R ² is -CH ₃ or -CN

ego

n is 0 or 1

x is halogen.

Non-hydrolyzable strong bases such as sodium amide, lithium amide, potassium amide, and potassium diisopropyl amide are substituted for hydrogen of C ₈ to form an anion so that the anion reacts with the reagent R ² (CH ₂ ) _n X. .

Compounds of formula (VI) may be further reacted into other useful compounds. These compounds derived from formula (IV) are the compounds of formula (II) and their nontoxic, pharmaceutically possible acid addition salts,

Where R is alk or carbo (C ₁ -C ₃ ) -alkoxy

R ¹ is carboxyl, carbo (C ₁ -C ₃ ) alkoxy, CH ₂ Z

Z is H or OH, CN, OSO ₂ alk, Y-phenyl, Y-alk, Y is S or O

alk is (C ₁ -C ₃ ) alkyl,

The dotted line may or may not be a double bond.

The compound of formula (II) wherein R is carboxyl is prepared by hydrolyzing the carbo (C ₁ -C ₃ ) -alkoxy compound of formula (IV). Compounds of formula II wherein R ¹ is CH ₂ Z and Z is OH can be prepared by reducing the corresponding ester groups of formula IV with lithium aluminum hydride. A compound of formula II wherein Z is CN first prepares a mesyester of hydroxy methyl derivative (a compound of formula II wherein R ¹ is CH ₂ Z and Z is OH) and the mesylate radical is Prepared by substitution with cyanide.

Compounds of formula II wherein Z is Y-phenyl or Y-alk can be prepared in a similar manner by reacting mesylate esters with phenol or phenyl mercaptan, lower alkanol, or lower alkyl mercaptan.

Also included in the scope of the present invention are pharmaceutically possible acid addition salts of the compound of formula IV with non-toxic acids.

These salts include the following salts derived from inorganic and organic acids. Hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, amine acid and aliphatic mono or dicarboxylic acid, phenyl substituted alkanophosphoric acid, hydroxy alkanophosphoric acid, alkanediophosphoric acid, aromatic acids, aliphatic and aromatic sulfonic acids Etc. Such pharmaceutically possible salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrophosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride bromide, iodide, fluorine Ride, Acetate, Propinate, Decanoate, Caprylate, Acrylate, Formate, Isobutyrate, Caprate, Schuberate, Sebacate, Humarate, Maleate, Maleate, Butyne-1,4-diomate , Hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate dinitro benzoate, hydroxybenzoate, methoxy benzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzene Sulfonate, xylene sulfonate, phenyl acetate, phenyl propione , Phenylbutyrate, citrate lactate, β-hydroxy butyrate, glycolate, maleate, tartarate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, etc.

(C ₁ -C ₃ ) alkyl in formula (IV) includes methyl, ethyl, propyl, isopropyl. Blast furnaces (C ₁ -C ₃ ) alkoxy include methoxy, ethoxy and propoxy. Carbo (C ₁ -C ₃ ) alkoxy includes carbomethoxy, cazoethoxy, carbopropoxy and carboisopropoxy.

In structural formula (IV), when Δ ^9,10 is saturated, it is called ergoline, and when △ ^9,10 is unsaturated, it is called 9-ergolene.

The following compounds fall under the category of compounds of formula IV.

D-6-Methyl-8α-ethyl-8β-carbomethoxyergoline sulfate

D-8α-isopropyl lysine acid

D-8α-ethyliserseric acid

D-8α-ethyl dihydrolyserginic acid

D-8β-Methyl Eraserginic Acid

D-6-Methyl-8β-ethyl-8α-carbo-n-propoxy-9-ethgolene maleate

D-6-Methyl-8β-cyanomethyl-8α-carboethoxy-9-ergoline

D-6-Methyl-8α-methoxymethyl-8β-carboethoxy-9-ergoline citrate

D-6-Methyl-8β-ethoxymethyl-8α-carboisopropoxy-9-ergoline lactate

D-6-Methyl-8α-phenoxymethyl-8β-carbomethoxy-ergoline methanesulfonate

D-6-Methyl-8β-phenoxymethyl-8α-carboethoxy-9-ergolgen

D-8α-phenyl mercapto methyl lyserginic acid

D-8α-methyl mercapto methyl lyserginate toluenesulfonate

D-8β-n-propyl mercapto methyl isolicerinic acid

The compounds of formula (IV) are white, crystalline solids and their acid addition salts as well.

Compounds of formula IV have useful prolactin inhibitors and / or actions on the central nervous system. It can be seen from the following experiment that the compound of formula (IV) inhibits the separation of prolactin.

Spraque-Daweyl male rats weighing 200g are fed with lab chow and libritic additives while the C-light is controlled from 6 am to 8 am while the lighting is controlled in the air conditioning room. In each experiment, rats are beheaded and a small amount of 150 μl of serum is tested for prolactin. Eighteen hours prior to the administration of the ergoline derivatives, 2.0 g of leucine is suspended in water and injected intraperitoneally. The reason for the administration of leucine is to keep the amount of prolactin constant. The test drug ergoline derivative is dissolved in 10% ethanol to a concentration of 10 μg / ml, and each compound is administered to a group of 10 rats, and only 10% ethanol is administered to one of the 10 groups as a control. One hour after treatment, all rats were beheaded and serum was collected to measure prolactin.

Dividing the difference between the prolactin content of the control rats and the control group by the prolactin content of the control group results in% of the prolactin inhibition of the compound of formula (II).

The following table shows the percent prolactin inhibition tested at 10 μg / rat of the compound of formula II.

[table]

Other compounds of formula II also have prolactin inhibitory activity at 10 μg / rat, but at higher doses (100 μg to 1 mg).

As prolactin inhibitors, the compounds are useful for the treatment of inappropriate milk secretions such as milk secretion or excessive milk secretion after unnecessary delivery. It can also be used to treat prolactin-dependent papillary adenocarcinoma or pituitary tumors that secrete prolactin and the following diseases. Estrogen to treat breast hypertrophy due to psychoactive medications such as Forbes-Albright symptoms, Chiiri-prommel symptoms, gynecopathy itself and prostatic hypertrophy and breast fibrocytosis (positive cytokines), breast cancer prevention, psychotropic drugs Gynecologic disease, hypertrophy of the prostate caused by the administration of sex steroids.

The use of compounds of formula IV to inhibit prolactin secretion involves the use of 8,8-disubstituted-6-methylergoline or their pharmaceutically possible salts in corn oil and 0.01 to 10 mg / kg / day. Parenteral or oral administration is better than oral administration. When parenteral administration, it is good to prepare appropriately and subcutaneous injection.

The effect is the same as intraperitoneal, muscle and sperm administration. Especially for intravenous or intramuscular administration, water-soluble acid addition salts of 8,8-disubstituted-6-methyl ergoline are used, preferably methanesulfonate.

In addition, the compound of formula (IV) is mixed with conventional pharmaceutical excipients in free base or in the form of acid addition salts and filled into gelatin capsules or tableted.

The compound also has a CNS inhibitory action and thus is useful as a sedative. For example D-6-methyl-8α-carbomethoxy-8β-cyanomethyl-9-ergolene maleate and its corresponding 8α-carbomethoxy-8β-methyl compounds exhibit such action.

The following alphabetical example illustrates the compound of formula (II) which can be obtained by further reacting the compound of formula (IV).

Example A

To a 700 mg solution of D-6,8β-dimethyl-8α-carbomethoxy ergoline in 100 ml of THF was added 700 mg of lithium aluminum hydride in small portions. Stir for 45 minutes under ambient temperature and nitrogen gas.

The reaction mixture is cooled and ethyl acetate is added to decompose the excess lithium aluminum hydride. The reaction mixture is diluted with water and the resulting D-6,8β-dimethyl-8α-hydroxymethyl ergoline is extracted with chloroform. The chloroform layer was separated, dehydrated, and the solvent was evaporated to yield D-6,8β-dimethyl-8α-hydroxymethyl ergoline, and recrystallized from ether-hexane to have a melting point of 219-221 ° C. (decomposition).

Analytical calculation: C 75.52; H 18.20; N 10.36

Found: C 75.46; H 8.24; N 10.08

In the above reaction, D-6,8α-dimethyl-8β-hydroxymethyl ergoline having a melting point of 222-4 ° C. after recrystallization with ethyl acetate with D-6,8α-dimethyl-8β-carbomethoxy ergoline was obtained. Manufacture.

Analytical calculation: C 75.52; H 8.20; N 10.36

Found: C 75.43; H 8.37; N 10.11

Example B

In the same manner as in Example A, 2.1 g of D-6,8α-dimethyl-8β-carbomethoxy ergoline was reduced with lithium aluminum hydride to prepare a corresponding 8β-hydroxymethyl derivative. This crude product is taken up in 50 ml of pyridine and 0.9 ml of methanesulfonylchloride (mesyl chloride) is added. The reaction compound was capped and stirred at ambient temperature for 20 minutes, poured into an aqueous solution of sodium bicarbonate, and the resulting D-6,8α-dimethyl-8β-mesyloxymethylergoline was extracted with chloroform.

After separating and dehydrating the chloroform layer, the solvent was evaporated to recrystallize D-6,8α-dimethyl-8β-mesyloxymethylergoline with ethanol to have a melting point of 176-8 ° C.

Analytical calculation: C 62.04; H 6.94; N 8.04

Found: C 61.98; H 7.10; N 7.96

In the above reaction, D-6,8β-dimethyl- having a melting point of 160 ° C. (decomposition) after recrystallization with ether using D-6,8β-dimethyl-8α-carbomethoxy ergoline as starting material as a starting material. Prepare 8α-methyloxymethyl ergoline.

Analytical calculation: C 62.04; H 6.94; N 8.04; S 9.20

Found: C 61.75; H 7.20; N 8.31; S 9.19

Example C

200 mg of D-6,8β-dimethyl-8α-mesyloxymethylergoline 200 mg dimethyl sulfoxide (DMSO) The reaction mixture of 200 mg of sodium cyanide is heated to 100-200 ° C. for 2.25 hours. The reaction mixture is then poured into water to yield the resulting D-6,8β-dimethyl-8α-cyanomethyl ergoline.

Analytical Calcd: C 77.38; H 7.58; N 15.04

Found: C 77.58; H 7.78; N 15.12

According to the above method, D-6,8β-dimethyl-8β-mesyloxy methylergoline is reacted with sodium cyanide to prepare the rising 8β-cyanomethyl compound. The compound was chromatographed on a florisil using chloroform containing 2% of methanol to separate the starting material. The product thus obtained was recrystallized from benzene-hexane to give D-6,8α-dimethyl- at a melting point of 195-6 ° C. 8β-cyanomethylergoline is obtained purely.

Analytical Calcd: C 77.38; H 7.58; N 15.04

Found: C 77.72; H 7.57; N 14.63

Example D

In the same manner as in Example C, D-6,8β-dimethyl-8α-mesyloxymethyl ergoline was reacted with a sodium thorium salt of thiophenol in DMF to give D-6,8β-dimethyl-8α-phenylmercapto methylergoline To prepare.

The reaction mixture is washed with 5% potassium hydroxide to remove unreacted thiolphenol. The resulting D-6,8β-dimethyl-8α-phenylmercaptomethylergoline was purified by chromatography using chloroform containing 2% of ethanol on Florisil, and the residue obtained by evaporating the chlorolole aliquot was ethanol. Recrystallization with D-6,8 (beta) -dimethyl-8 (alpha) -phenyl mercapto methyl ergoline of melting | fusing point 157-8 degreeC is obtained.

Analytical C calculated: C 76.20; H 7.23; N 7.73; S 8.24

Found: C 75.99; H 7.04; N 7.50; S 8.99

By the above method, the melting point after recrystallization with ethanol using the corresponding 8β-mesyloxy as a starting material is obtained to obtain D-6,8α-dimethyl-8β-phenylmercaptomethylergoline having a melting point of 217-8 ° C.

Analytical calculation: C 76.20; H 7.23; N 7.73

Found: C 76.14; H 7.39; N 7.79

Example E

About 215 mg of D-6,8α-dimethyl-8β-phenylmercaptomethylergoline is reacted with about 3 g of wet raninickel in 25 ml of 95% ethanol as solvent. The reaction mixture is heated to reflux temperature under nitrogen gas for about 35 minutes and filtered when hot to wash the catalyst well with 95% ethanol. Recrystallization of the residue obtained by evaporation of the filtrate with methanol yields D-6,8,8-trimethylergoline with a melting point of 221-2 ° C.

Analytical Calcd: C 80.27; H 8.72; N 11.01

Found: C 80.33; H 8.84; N 11.21

This reaction yields the same D-6,8,8-trimethyl ergoline of the same melting point using the corresponding 8α-phenylmercapto methyl isomer.

Example F

Approximately 1 g of D-6,8β-dimethyl-8α-carbomethoxy-9-ergoline was refluxed under 50 ml of 10% potassium hydroxide as a maleate salt (methyl α-messulisolysate maleate) for 3 hours under nitrogen gas. Let's do it. The reaction mixture is cooled and filtered to acidify the filtrate with acetic acid. Precipitation is not produced, and it is made basic again with an aqueous solution of ammonium hydroxide so that no precipitation is produced. The alkaline layer is extracted with chloroform and discarded, and the alkaline aqueous layer is concentrated to about 50 ml and filtered. The filter cake is washed with water, ethanol, ether and dissolved in a small amount of ammonium hydroxide to dilute the resulting solution with water. The resulting alkaline aqueous solution is concentrated in vacuo and diluted with water to a volume of about 50 ml.

Cool down to 0 ° C., overnight, and precipitate the resulting precipitate by filtration. The filter cake was washed again with water, ethanol, ether and dried to give D-6,8β-dimethyl-8α-carboxy-9-ergoline (α-methylisolyserginic acid) with a melting point of 230-2 ° (decomposition). .

Analytical Calcd: C 72.32; H 6.43; N 9.92

Found: C 72.04; H 6.22; N 9.64

The invention is further illustrated by the following examples which illustrate the preparation of compounds of formula IV.

Example 1

The solution containing 11.5 g of tetramethylpiperidine in 100 ml of THF was cooled to about -10 deg. C and 50 ml of 1.6 M n-butyl lithium in hexane was added at a rate such that the temperature was kept between -10 and 2 deg. Cool for 20 minutes under nitrogen gas. To this, 5.7 g of methyl dihydro riser gate in 125 ml of THF was added at a rate capable of maintaining a temperature of -10 to -5 deg. C, followed by stirring for 15 minutes while cooling under nitrogen gas. Apply quickly. Increase the temperature from -9 ° C to -1 ° C and continue to 6 ° C over 35 minutes. Acetic acid is added thereto to decompose the reaction mixture, and the acidic layer is diluted with water, followed by addition of sodium bicarbonate solid to make it basic. The resulting D-6,8-dimethyl-8-carbomethoxyergoline, which is alkaline insoluble, is isolated and extracted with chloroform. Chromatography of the residue obtained by separating and dehydrating the chloroform layer and then evaporating reveals two spots of weaker polarity than the starting material methyl dihydro riser.

This spot means isomers of α-methyl and β-methyl produced in the reaction. The residue is taken up again in chloroform and filtered through 250 g of Prorisil to give a mixture of two isomers of D-6,8-dimethyl-8-carbomethoxy girgoline. Chromatography of this mixture with chloroform-ether on 250 g of Florisil yielded D-6,8β-dimethyl-8α-carbomethoxy ergoline with a melting point of 136-8 ° C. as a yield of 18% and a melting point of 35% as a yield. The corresponding 8α-methyl-8β-carbomethoxy isomer of 223-5 ° C. (decomposition) is obtained.

Analysis of D-6,8β-dimethyl-8α-carbomethoxyergoline

Calc .: C 72.46; H 7.43; N 9.39

Found: C 72.73; H 7.69; N 9.64

Analysis of D-6,8α-dimethyl-8β-carbomethoxyergoline

Calc .: C 72.46; H 7.43; N 9.39

Found: C 72.73; H 7.69; N 9.64

Example 2

In the same manner as in Example 1, methyl-9,10-dihydro riser was alkylated with chloro acetonitrile in THF in the presence of tetramethylpiperidine and n-butyl lithium to 8α-carbomethoxy-8β-cyanomethyl And a mixture of 8α-cyanomethyl-8β-carbomethoxy-isomers. The original reaction mixture is extracted with chloroform and the mixture of isomers obtained by evaporation is chromatographed with chloroform containing 5% of ethanol on Florisil.

The aliquots containing each isomer are combined (identified by thin layer chromatography) to evaporate the solvent and recrystallize the residue.

A weak polar methyl D-6-methyl-8β-cyano methyl-8α-carboethoxyergoline was obtained from the aliquot, and the recrystallization with ether-hexane gave a melting point of 179-180 ° C.

Analytical Calcd: C 70.57; H 6.55; N 12.99

Found: C 70.41; H 6.55; N 13.19

D-6-methyl-8α-cyanomethyl-8β-carbomethoxy ergoline is more polar than its isomer but weaker than the starting material.

Chromatography and recrystallization with ether-hexane have a melting point of 220-3 ° C. (decomposition).

Analytical Calcd: C 70.57; H 6.55; N 12.99

Found: C 70.32; H 6.79; N 13.27

Example 3

D-6-methyl-8,8 produced by reacting methyl-9,10-dihydro riser with methylchlorocarbonate in THF in the presence of tetramethylpiperidine and n-butyl lithium in the same manner as in Example 1 -Dicarbomethoxy ergoline is isolated in the same manner as in Example 1 and purified by chromatography on a Florisil with a 1: 1 mixture of chloroform-ether. An aliquot containing D-6-methyl-8,8-dicarbomethoxyergoline is collected and evaporated to recrystallize the residue with ether-hexane to obtain a crystalline material having a melting point of 164-5 ° C.

Analytical Calcd: C 66.65; H 6.48; N 8.18

Found: C 66.78; H 6.51; N 7.95

Example 4

A 10 g solution of diisopropylamine in 150 ml THF is cooled to about −75 ° C. and 60 ml of 1.6 Mn-butyl lithium solution in hexane is slowly added. Then a solution of 7.0 g of methyl riser in 120 ml of THF is added dropwise. Increase the viscosity of the resulting precipitate solution and add 120 ml of THF. Then a solution of 12.4 ml of iodine methyl in 100 ml of THF is added quickly and the temperature is raised to about -49 ° C during the addition. The reaction mixture is treated with acetic acid to decompose the organometallic compounds present and dilute with water. The aqueous layer was made basic with a dihydrate ammonium hydroxide solution to separate insoluble D-6,8β-dimethyl-8α-carbomethoxy-9-ergolene and its isomer 8a-methyl-8β-carbomethoxy and Extract with ethyl. After washing with water, it is washed with saturated aqueous sodium chloride solution.

After separation and dehydration, the volatile components of the organic layer are evaporated off, the residue is dissolved in chloroform and filtered through Florisil to crystallize D-6,8β-dimethyl-8α-carbomethoxy-9-ergolene. Recrystallization with ether-hexane affords D-6,8β-dimethyl-8α-carbomethoxy-9-ergolene with a melting point of 117-9 ° C.

Analytical calculation: C 72.95; H 6.80; N 9.45

Found: C 73.17; H 6.89; N 9.24

The residue obtained by evaporation of the mother liquor was chromatographed with chloroform on Florisil to recrystallize with ether from the starting material D-6,8β-dimethyl-8α-carmethoxy-9-ergolene and melting point 206. D-6,8α-dimethyl-8β-carbomethoxy-9-ergolene is obtained, which is −8 ° C. (decomposition).

Analytical calculation: C 72.95; H 6.80; N 9.45

Found: C 72.68; H 7.05; N 9.43

Example 5

A solution containing 1.6 g of diisopropylamine in 20 ml of THF is prepared and cooled to -45 [deg.] C. and 10 ml of n-butyl lithium solution is added at a rate capable of maintaining this temperature at -45 to -35 [deg.] C.

After the addition of n-butyl lithium is complete, the reaction mixture is stirred for 15 minutes and cooled under nitrogen gas. The concentration of n-butyl lithium is 1.6 M in hexane. A solution of 1.15 g of methyl riser in 25 ml of THF is added at a rate such that the temperature remains below -35 ° C. 10 ml of THF is added to lower the viscosity of the solution and stirred for 15 minutes while cooling under nitrogen gas.

Next, 1.2 g of chloroacetonitrile in 10 ml of THF was added, the temperature was raised to 6 ° C. in 25 minutes, and the reaction mixture was decomposed with acetic acid. The acidic reaction mixture is diluted with water and made basic by addition of a sodium bicarbonate solid. The basic layer was extracted with chloroform to transfer D-6-methyl-8-cyanomethyl-8-carbomethoxy-9-ergoline to the chloroform layer, separated and dehydrated, and the residue obtained by evaporating chloroform was purified on florisil. Chromatography using chloroform. D-6-methyl-8-cyanomethyl-8-carbomethoxy-9-ergolene is the secondary component of the eluate.

The aliquots containing this compound were collected, the solvent was evaporated, the residue was dissolved in ether, and maleic acid was added. Obtain oxy-9-ergolenemaleate. The maleate salt is converted back to the free base and standard acid-base extraction is performed.

Re-extracting Buddha D-6-methyl-8-cyano methyl-8-carbomethoxy-9-ergolene from the alkali layer and preparing maleate salt again, the melting point after recrystallization with ether is 176-7 ° C. (decomposition) Phosphorus D-6-methyl-8-cyano methyl-8-carbomethoxy-9-ergolene maleate is obtained.

Analytical calculation: C 63.15; H 5.30; N 9.61

Found: C 63.43; H 5.05; N 9.87

Example 6

Salts of compounds of formula (IV) other than maleic acid salts are prepared by dissolving the free base in ether and adding an equivalent equivalent of a nontoxic acid. The salts thus prepared, such as sulfates or phosphates, are insoluble in ether and can be separated by filtration. It can also be prepared by dissolving this amine base in ethanol and adding an ethanol solution to the same equivalent acid.

In this case, the salt thus prepared is soluble in ethanol, and the solvent can be separated by vacuum evaporation. Salts that can be prepared include hydrochloride, sulfate, hydrobromide, phosphate, phosphate monohydrochloride, phosphate dihydrochloride, acetate, maleate, succinate, tartarate, citrate, benzoate, and P-toluenesulfonate. have.

Claims (1)

A process for preparing a compound of formula (IV) by reacting a compound of formula (III) with a compound of formula R ² (CH ₂ ) ₃ X in the presence of a non-hydrolysable base.