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    • 专利摘要:
    Novel ergoline compounds of the following formula are described: wherein R1 is ethyl, n-propyl, or allyl; Y is O, S, SO, or SO2; X is hydrogen, chloro, or bromo; the dotted line represents the optional presence of a double bond; and the pharmaceutically-acceptable acid addition salts thereof. The compounds are useful to inhibit prolactin secretion or to treat Parkinson's syndrome.
    公开号:SU912045A3
    申请号:SU792720495
    申请日:1979-02-07
    公开日:1982-03-07
    发明作者:Карл Корнфельд Эдмунд；Джеймс Бэк Николас
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    where 1 is the mesyloxy group or xnopj X - has the indicated values -, R is hydrogen, ethyl, n-propyl or allyl, is reacted in any sequence with the compound of the general formula RV-CHa, - has the indicated values, sodium or M, M, M, M-three methyl-M-benzyl ammonium methylate, with alkyl iodine, if R is hydrogen, if necessary with a halogenous routing agent, if X is hydrogen or, if necessary, hydrogenated with hydrogen on 5% palladium on carbon, if R is allyl and / or &f; or jj is present, followed by release of the target product into free in one form or as a salt. The alkylation is carried out in a medium of a polar organic solvent such as dimethylacetamide, dimethylformamide, acetonitrile or nitromethane at 20-50 ° C.  Such bases as alkali metal carbonates and bicarbonates, alkalis, tertiary amines are used as an acceptor of the acid. The reaction of a compound of general formula 2 with a compound of general formula 3 is carried out in a polar organic solvent such as dimethyl formamide, dimethylacetamide, dimethyl sulfoxide or alkanols , at a temperature from room temperature to the boiling point of the solvent.  As halogenating agents, N-chlorosuccinimide, N-chloroacetanimide, N-chlorophthalimide, N-chlorotetrachlorophenyl phthalate sd, chlorobenzotriazole, M-chloro-2,6-dichloro-4-nitroacetamide, M-chloro-2,4,6-trichlorace are used. The tamide and process are preferably carried out in dimethylformamide.  The reaction with M-bromosuccinimide is preferably carried out in dioxane.  When using thionyl chloride, the reaction is carried out in solvents such as methylene chloride, nitromethane or acetonitrile, a solution of boron trifluoride can also be used.  Halogenation is usually carried out at room temperature.  The compounds of general formula I are effective proactin inhibitors and can be used to treat Parkinson's syndrome.  Example 1  Preparation of D-6-npropyl-8-methyl-mercametramethyl ergoin.  A pacTriop is prepared from 100 g of methyldihydrolyzer and 2.5 L of methylene chloride.  100 g of cyanium bromide is added to the solution, and the vessel with the reaction mixture is plugged and the mixture is held at room temperature for about 24-25 hours.  Thin-layer chromatography of an aliquot of this solution shows the presence of one large spot with several smaller spots.  The organic layer containing 6-cyano-8-methoxycarbonyl-ergoline is washed successively with an aqueous solution of tartaric acid, water and a saturated aqueous solution of sodium chloride, and then dried, the solvent is evaporated in a vacuum, and a product is obtained which shows a large spot when examined by thin layer chromatography , less polar than the original product, which corresponds to 0-6-cyano-8-methoxycarbonyl-ergoline.  The compound obtained has a T. Ш1.  202-205 s, its output is 98.5 g.  The reaction mixture, containing 59.6 g of 0-6-cyano-8-methoxy onon ergoline 300 g of zinc dust, 2.5 liters of acetic acid and 500 ml of water, is heated with reflux under nitrogen atmosphere for 7 hours and then the mixture left at room temperature for 16 hours  Then the reaction mixture is filtered and the filtrate is poured onto ice.  The resulting aqueous mixture is alkalinized 14 n.  an aqueous solution of ammonium hydroxide, and the alkaline layer is extracted with chloroform.  The chloroform layer is separated, washed with a saturated aqueous solution of sodium chloride, and dried.  After evaporation of the chloroform, 0 8A-methoxycarbonyl ergoline is obtained, m. square  154-156 0, output 46.9 g.  A thin layer chromatography study shows one large spot and a smaller spot corresponding to the original product.  In addition, a solution containing 98.6 g of 0-6-cyano-8 L-methoxycarbonylergoline is subjected to Rane-nickel hydrogenation in dimethylformamide solution.  The initial hydrogen pressure is 3.44x10 dyn / cm. After completion, the hydrogenated mixture is filtered and the filtrate is evaporated in vacuo to a residual volume of 200 ml.  This mixture is added to an aqueous solution of tartaric acid, and the acidic layer is extracted with ethyl acetate.  Then the acidic aqueous layer is alkalinized 14 n.  an aqueous solution of ammonium hydroxide, and an alkaline layer of 3KCTparHpymt ethyl acetate.  This acetate layer is separated, washed with water, saturated aqueous sodium chloride solution and dried.  After evaporation of the solvent in vacuo, D-86-methoxycarbonyl-ergoline is obtained, having m. square  150-153 ° C, the product yield is 68.8 (76%). Prepare the reaction mixture from 19.8 g of 0-8 |) -methoxycarbonylergoline, 10 ml of n-propyl iodide, and 8.2 g of potassium carbonate in 200 ml dimethylformamide.  This reaction mixture is stirred at room temperature under nitrogen for 16 h.  A thin layer chromatography study shows one large spot with two small spots.  This reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate.  This acetate extract is separated, washed with water, with a saturated aqueous solution of sodium chloride and then dried.  After evaporation of the solvent in vacuo, a product is obtained which is dissolved in chloroform containing 2% methanol, and the solution is filtered through 200 g of phlorisil.  After evaporation of the solvent in vacuo, 8.55 g of D-6-n-propyl-8-methoxycarbonyl-ergoline with m are obtained. square 20 to 206 ° C.  720 mg of 0-6-n-prog-8 methoxycarbonyl-ergoline is dissolved in 25 ml of dioxane and 50 ml of methanol.  To the solution was added 1 g of borohydride. sodium, and the reaction mixture is heated under reflux to an atmosphere of nitrogen for 2 hours.  After 1 hour, another 1 g of sodium borohydride was added.  Chromatogram obtained by thin layer chromatography method 456:.  Shows one large polar spot and one small spot.  The reaction mixture is cooled, diluted with water and the aqueous mixture is extracted with a mixture of solvents Cloroformaisopropanol.  The organic layer is separated, washed with all; aq. Sodium chloride aqueous solution and dried.  After evaporation of the organic solvent, a product is obtained consisting of 6-n-propyl-8y-hydroxymethyl-zrgoline, which is recrystallized from a solvent mixture of diethyl ether-hexane, m. square  167169 ° C. The code is 620 mg.  A solution is prepared from 31.2 g of 0-6-n-propyl-8) b-hydroxymethylergoline and 400 ml of pyridine.  To this pyridine solution, 20 ml of methanesulfonyl chloride are slowly added over 1 hour, and then it is poured into a mixture of ice with 14N.  ammonium hydroxide.  The alkaline aqueous layer is extracted with ethyl acetate.  The ethyl acetate layer is separated, washed with water and a saturated aqueous solution of sodium chloride and then dried.  After evaporation of the organic solvent, a product is obtained, the chloroform solution of which is subjected to chromatographic separation, passing through 300 g of phlorisil using chloroform with increasing amounts of methanol (from 0 to 4%) as an eluting solution.  The resulting chromatographic separation of purified D-6-n-propyl-8-mesyloxymethyl ergoline has t. square  178-180 With decomposition.  The product yield is 25.6 g.  25 g of methyl mercaptan is dissolved in 200 ml of dimethylacetamide.  The solution is cooled in a bath with a mixture of ice and water to the temperature “sfc.  Then, 44.4 g of sodium hydride (in the form of a 50% suspension in mineral oil) are added in portions to obtain the sodium salt of methyl mercultan.  This salt c.  the suspension is heated to room temperature.  To this suspension, a solution of 10.9 g of D-6-n-propyl-8 and ampyloxymetholine goline in 60 ml is slowly added.  dimethylacetamide.  The reaction mixture is stirred for 1 h under a nitrogen atmosphere and then diluted with water.  The aqueous layer was extracted with ethyl acetate, and a saturated aqueous solution of sodium chloride. After evaporation and then the solvent was dried, D-6-n-propyl-8-methyl mercaptomethyl ergoline was obtained, product yield 6.9 g, Topl, 206209 0 (by decomposition).  This product is further purified by suspending in 100 ml of boiling methanol, to which 1.6 ml of methanesulfonic acid in 10 ml of methanol is added at the boiling point, cooled, the D-6-n-11-methyl-8-methyl mercaptomethyl ergoline methanesulfonate crystals are evaporated to give 6 g salt with t. kip  255 ° С (with decomposition).  Example 2  Preparation of D-6-H-propyl-8a-methoxymethyl ergoline; Prepare a mixture of 8.4 g-6-n-propyl-8 | -mesyloxymethyl ergoline, 50 ml of 40% methanol solution H, M, M-trimethyl-M-benzyl ammonium methylate and 200 ml of dimethylacetamide are heated under reflux in nitrogen atmosphere for 1.25 hours.  The study by the method of layer chromatography shows the presence on the chromatogram of one large spot and spot corresponding to the original product.  This mixture is cooled and diluted with ethyl acetate. .  The ethyl acetate layer is separated, washed with water and a saturated aqueous solution of sodium chloride and then dried.  The solvent is removed by evaporation and upon evaporation of the solvent, 5 g of D-6-n-propyl-8) L-methoxymethyl ergoline are obtained, which melts (with simultaneous decomposition) at 223-226 The methanesulfonate of this compound is prepared, as in Example 1, to give 11 -6-n-propyl-8-methoxymethyl ergslinmethanesulfonate, which, after crystallization from a mixture of solvents, diethyl ether-ethanol has Topl.  202-204 ° C, its yield is 4.09 g.  Example 3  Preparation of D-6-H-propyl-8 L-hydroxymethyl ergoline.  Prepare a solution of 9.25 g of 1 -8-methoxycarbonyl ergoline and 100 ml of pyridine.  25 MP propionic anhydride was added to this solution, and the mixture was stirred at room temperature for 1 hour. Next, this reaction mixture was added. to a 5% aqueous solution of ammonium hydroxide and mixed with 2 liters of water.  This mixture is then cooled.  The filter cake consists of D58 -6-propionyl-8y-methoxycarbonylergoline, which melts (with simultaneous decomposition) at 260-263s, its output is 9.80 g. Prepare a suspension of 9.8 g -6-propionyl-8a-methoxycarbonylergoline in 100 ml of tetrahydrofuran.  To this reaction mixture, 5 g of lithium aluminum hydride are added in the form of individual pondiums while cooling it in a bath with an ice-water mixture, h. Then heat at boiling point under nitrogen for 16 h.  Next, the reaction mixture is cooled to 0 ° C and the excess lithium aluminum hydride and other metal ororganic compounds are decomposed by adding ethyl acetate.  ethanol and water.  The reaction mixture is then diluted with water, and the aqueous layer is extracted several times with a solvent mixture of chloroform-isopropanol.  The organic extracts are separated, mixed, and these mixed extracts are washed with a saturated aqueous solution of sodium chloride.  Next, the organic layer is dried and the solvent is evaporated, to obtain 0-6-n-prop 1-8 hydroxymethyl ergoline, which is recrystallized from methanol, to obtain 4.75 g of the desired product with t. square  174-175 ° C. As a result of the second recrystallization from methanol, D-6-n-propyl-8j-hydroxymethyl-epholin with t is obtained. square  176-178C.  This compound can be converted to the corresponding 8-methyl mercaptomethyl derivative according to example 1, or to the corresponding 8-methoxymethyl 1 derivative according to example 2 via an intermediate 1 mass methyl ester.  Example 4  Preparation of 0-6-allyl-88-methyl mercaptomethyl zrgoline  Two grams of 8-methoxycarbonyl ergoline is dissolved in 75 ml of dimethylformamide.  1.7 g of potassium carbonate and 0.71 ml of allyl bromide are added to the solution.  The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 3.5 hours.  A thin layer chromatography study shows on the chromatogram the presence of one large fast-atomizing spot. The reaction mixture is diluted with water, and the resulting aqueous layer is extracted with ethyl acetate.  The ethyl acetate layered aqueous solution of sodium chloride and then dried.  After evaporation of the solvent in vacuo to obtain a product, after recrystallization of which from methanol, 570 m of O-b-allyl-methoxycarbonyl ergoline is obtained with m. square  146-148 C.  0-6-allyl-8-methoxycarboxylicine in the amount of 4.8 g was dissolved in a mixture of 50 ml of dioxane and 100 ml of methanol. To the resulting solution was added 5 g of sodium borohydride and the resulting reaction mixture was heated to boiling point for 2 hours.  After I h, a second portion of sodium borohydride in the amount of 2 g is added.  This reaction mixture is diluted with water and 14N.  aqueous solution of ammotg oxide hydrate.  Alkaline water layer several times extra GIR. CoLB with a solvent mixture of chloroform-isopropanol.  The organic extracts are mixed and the combined extras are washed with a saturated aqueous solution of sodium chloride and dried.  After evaporation of the solvent, 0-6-allyl-8r-gvdroxymethyl is obtained.  ergoline, which, after recrystallized from a mixture of methanol-di-ETID solvents. ROUTE AIR has t. square  204-206С.  A solution is prepared from 3.77 g of 0-6-allyl-8b-hydroxymethyl-zrgoline and 100 ml of pyridine. 2.5 ml of methanesulfonyl chloride is added to the solution, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is then diluted with water. and. 14 N, an aqueous solution of ammonium hydroxide.  The aqueous layer was extracted several times with ethyl acetate.  The ethyl acetate extracts were combined and the combined extracts were washed with water and a saturated aqueous solution of sodium chloride, and then dried.  After evaporation of the solvent, 0-6-allyl-8y-methyloxymethylergoline with m is obtained. square  196 ° C (with decomposition) after recrystallization of it from a mixture of chloroform-methanol solvents, the product yield is 3.5 g.  Under the conditions of Example I, a sodium salt is obtained from 12 g of methyl mercaptan, an excess of sodium hydride and 150 ml of dimethylformamide.  To a mixture of methyl mercaptide sodium is quickly added a solution of 4.3 g of 0-6-allyl-8J-mesyloxy-methyl-ergoline and 50 ml of dimerashreda for 1 h in a nitrogen atmosphere, and then diluted with water.  The aqueous layer is extracted with ethyl acetate.  The ethyl acetate layer is separated, washed with water and a saturated aqueous solution of sodium eilide and dried.  After evaporation of ethyl acetate, 0-6-allyl-8-methyl mercaptomethyl ergoline is obtained, which is dissolved in chloroform, and the chloroform solution is subjected to chromatography (separation, passing it through flor etyl, using chloroform with increasing methanol content (0-2%) as eluent) I get 3 grams of grams of 0-6-allyl-8 & methylmercaptomethylergoline with t. square   WITH.  Prepare the methanesulfonate, as in example 1.  t. square  this salt (with decomposition) is 272-274 ° C, the yield is 3.05 g.  Example 5  Preparation of D-6-n-propyl-8-methoxycarbonyl-ergoline  0-6-allyl-8-methoxycarbonyl ergoline obtained by the method described in the previous example, in an amount of 1.7. g is dissolved in 40 ml of tetrahydrofuran and hydrogenated using 0.5 g of 5% palladium on a carbon carrier at room temperature and an initial pressure of hydrogen of 4.1.  dyn / cm  After 233 hours, the hydrogenation is stopped and the mixture is filtered.  The solvent is evaporated from the filtrate in vacuo.  Examination of the obtained product by thin layer chromatography shows the presence of two spots on the chromatogram, one new spot and the other spot corresponding to the 6-terminal.  This product is dissolved in chloroform, and the chloroform solution is subjected to chromatographic separation, dropping it through. 30 g of phlorisil using chloroform with an increasing methanol content (from 0 to 4%) as an elution solution.  Fractions containing 0-6-n-propyl-8-methoxycarbonyl-ergoline are collected and a crystalline product is obtained with m. mp 204206 C, the yield of this product is 740 ml, after recrystallization from a mixture of solvents methanol-chloroform, 0-6-n-propyl-8) -methoxycarbonyl-ergoline with t is obtained. square  209-2P C, the product yield is 465 mg.  P Example 6, Preparation of 0-6-these -8 & amphoxy-mercaptomethyl ergoline.  A solution is prepared from 6.5 g of Og6-methyl-8E-hydroxymethylergoline (dihydrolisergol) and 250 ml of dimethylphosphine. 8 g of cyanium bromide is added to the solution, and the reaction mixture is stirred at room temperature under a nitrogen atmosphere for 16 hours.  The solvent is removed in vacuo and the residue after evaporation is diluted with water and filtered, the precipitate is washed with ethanol and diethyl ether.  The resulting 0-6-cyano-8 -hydroxymethyl ergoline has m. square  .  To 100 ml 6n.  4.3 g of 0-6-cyano-8-hydroxymethylergoline are added to an aqueous solution of hydrochloric acid, boiled under nitrogen for 2 hours, poured into ice, and then alkalinized 14N.  aqueous solution of ammonium hydroxide, the precipitate is separated, composed. secondary amino-0-8 | -hydroxymethyl ergoline, the yield is 3.65 g.  A solution of 3.65 g of 0-8 & hydroxymethyl ergoline in 100 ml of dimethylformamide is prepared, to which 4.1 g of potassium carbonate and 1.4 g of ethyl iodide are added, and the reaction mixture is stirred at room temperature under a nitrogen atmosphere for 16 hours .  The solvent is removed in vacuo and the evaporation residue is diluted with water and filtered, the precipitate is washed with ethanol and diethyl ether.  The resulting 0-6-cyano-8 -hydroxymethyl ergoline has m. pl, 260. WITH.  To 100 ml of 6 N, an aqueous solution of hydrochloric acid, 4.3 g of D-6-1AH-8P-hydroxymethylergoline are added, boiled under nitrogen for 2 hours, poured into ice, and then basified with 14 N, an aqueous solution ammonium hydroxide, the sediment is separated out of secondary amino-0-8 | -hydroxymethyl ergoline, yield is 3.65 g.  A solution of 3.65 g of D-86-hydroxymethylergoline in 100 ml, a mixture of formamide, to which 4.1 g of potassium carbonate and 1.4 g of ethyl iodide are added, is prepared and the reaction mixture is stirred at room temperature under a nitrogen atmosphere for TH h. after which water is added.  The aqueous mixture is extracted with several portions of etxta acetate, the ethyl acetate extracts are combined, and the combined extracts are washed with water and with a saturated aqueous solution of sodium chloride and dried.  After evaporation of the solvent, 0-6-ethyl-8b-hydroxymethylergoline is obtained, which is recrystallized from a mixture of chloroform and methanol; its yield is 1.06 g.  A solution is prepared from 2.7 g of 0-6-ethyl-8-hydroxymethylergoline and 100 ml of pyridine, lls ml of mesyl chloride is added, and the resulting reaction mixture is stirred for 1 hour.  This reaction mixture is then diluted with water and made alkaline by the addition of 14N.  ammonium hydroxide aqueous solution.  The alkaline layer is extracted several times with ethyl acetate, and the ethyl acetate extracts are combined.  The extracts are washed with water, a saturated aqueous solution of sodium chloride and dried.  After evaporation of the solvent, 0-6-ethyl-8 and ampysyloxymethyl ergoline is obtained, which is subjected to chromatographic separation, passing it through 200 g of florisil, using chloroform containing increasing amounts of methanol (from O to 5%) as an eluting solution According to the chromatographic study, they contain D-6-ethyl-8p-meseno-oxymethylergoline; 1.5 g of crystalline product are obtained, having, after recrystallization, t. square  184-18 C (with decomposition).  A solution of 2.9 g of methyl mercaptan in 75 ml of dimethylformamide is cooled in a mixture of ice and water.  Separate portions of sodium hydride are introduced into this solution in the form of a 50% suspension in mineral oil, and methyl mercaptan sodium salt is obtained.  At room temperature, a solution of 1.8 g of 0-6-ethyl-8-mesyloxymethyl ergoline 3 is added to this mixture dropwise with 25 ml of dimethylformamide.  Then the reaction mixture was stirred at room temperature under a nitrogen atmosphere for i / D h, after which it was diluted with water.  The aqueous mixture is extracted with ethyl acetate.  The ethyl acetate extract is washed with water and with a saturated aqueous solution. Sodium chloride and then dried.  After evaporation of the solvent, D-6-ethyl-8-methyl mercaptomethyl ergoline is obtained, which, after recrystallization from a mixture of diethyl ether and hexai, has t. square  201-202 C (with decomposition).  0-6-eth1-8-8-methyl mercaptomethyl ergoline, suspended in 30 ml of methane, heated on a steam bath, and added with 0.33 ml of methanesulfonic acid, to obtain methanesulfonate.  This reaction mixture is cooled to room temperature and then diluted with about 50 ml of diethyl ether.  0-6-methyl-8b-methylmercaptometr1 ergolin methane sulfonate precipitated upon cooling are separated, t. mp, this substance is 254-256 ° C (with decomposition), the yield is 1.8 Example 7.  Getting 0-6-n-shsh-8-methylmercaptometyl-8-ergo lia.  . An amount of 1I g of elimoclavine is sponsored by 8 203 ml of dimethylformamide, and g of cyanium bromide is added, and the resulting mixture is stirred at a cotton temperature under an atmosphere of nitrogen for 16 h, then diluted with water.  6-Cyano-8-hydroxymethyl-8-ergoln, precipitates, its yield is 8.2 g, t. square  215-222 С (with decomposition).  The precipitate formed on the filter, without further purification, is mixed with 300 m of acetic acid, 60 ml of water and 41 g of zinc, heated under reflux in a nitrogen atmosphere for 20 hours.  Then this reaction mixture is filtered and the filtrate is poured into ice.  Then the filtrate is strongly alkalinized 14 n.  ammonium hydroxide aqueous solution.  The alkaline layer is extracted several times with a mixture of chloroform and isopropanol.  The extracts are combined and the combined extracts are washed with a saturated aqueous solution of sodium chloride and then dried.  After removal of the solvent, 0-8-hydroxymethyl-8-ergoline and its acetic acid ester are obtained.  This product, without further purification, was dissolved in 200 dimethylformamide, to which was added 6.2 g of potassium carbonate and 8 ml of n-propyl iodide.  The reaction mixture was stirred under nitrogen for 6 hours and then diluted with water.  The aqueous layer was extracted several times with 4514 ethyl acetate and the ethyl acetate extracts were combined with each other and washed with water and a saturated aqueous solution of sodium chloride and then dried.  After evaporation of the solvent, a product is obtained, which shows on the chromatogram (upon examination by thin layer chromatography) the presence of two large spots.  This product is dissolved in 100 ml of methanol and 100 ml of dioxane, 25 ml of 2N is added.  aqueous sodium hydroxide solution and stirred under nitrogen for 1.25 hours at room temperature, then diluted with water, and the aqueous layer was extracted several times with a solvent mixture of chloroform-isopropanol.  The organic kvie extracts are combined and the combined first extracts are washed with an aqueous solution of sodium chloride and then dried.  After evaporation of the solvent, a product is obtained which is dissolved in chloroform, and the chloroform solution is subjected to chromatographic separation, passing it through 200 g of phlorisil.  Chloroform containing increasing amounts of methanol (2-5%) "fractions, which, as shown by chromatographic study (thin layer chromatography) contain 0-6-n-propyl-3-hydroxymethyl-8-ergoline, are combined as with a friend.  The solvent is evaporated to dryness and the product obtained after evaporation is recrystallized from diethyl ether, to obtain D-6-n-propyl-8 -hydroxymethyl-8 ergoline having m. square  189-191 ° C (with decomposition), the product yield is 2.9 g.  0 6-n-propyl-8 -hydroxymethyl-8-ergoline in the amount of 8.1 g is suspended in 1000 ml of acetonitrile, which contains 39.3 g of triphenylphosphine and 14.4 ml of carbon tetrachloride.  Next, this reaction mixture is stirred at room temperature B under a nitrogen atmosphere for 9 hours.  The volatile component components are then removed in vacuo and the product is diluted with an aqueous solution of tartaric acid.  The acidic aqueous layer was extracted several times with toluene, and the toluene extracts were removed.  The aqueous layer was basified with atri bicarbonate, and the alkaline layer was extracted several times with a mixture of chloroform and isopropanol.  The organic extracts are separated and the separated extracts are washed with an aqueous saturated sodium chloride solution and then dried.  After solvent extraction, a product is obtained, the solution of which in chloroform-methanol (2%) is subjected to chromatographic separation, passing it through 200 g of phlorisyl, fractions which, as shown by a thin layer chromatography method, contain 6-n-prop 1-8-chloroethyl- 8-ergolene is combined together and the solvent is removed by vacuum distillation.  The crystallization of this product from chloroform / methanol gives 0-6-n-propyl-8-chloromethyl-8-ergoline having a decomposition temperature; fel85 ° C, the yield of this product was 4.65 g, the yield of the second fraction was 2.30 g.  50 ml of a solution of 25 g of methyl mercaptan in 100 ml of dimethylacetamide are diluted with 100 ml of dimethylacetamide, the resulting solution is cooled in an ice-water mixture.  Sodium hydride (10.6 g) as a 50% suspension in mineral oil is added in portions to the prepared solution.  This reaction mixture is heated to, and when this temperature is reached, a solution of 6.7 g of 0-6-n-propyl-8-chloromethane-1-ergolene in 75 ml of dimethylacetamide is quickly added dropwise to it.  The reaction mixture is stirred for 2 hours at room temperature under a nitrogen atmosphere, then cooled, diluted with water, and the aqueous mixture extracted with ethyl acetate.  The ethyl acetate solution is separated, washed with water and a saturated aqueous solution of sodium chloride and then dried.  After evaporation of the organic solvent, a product is obtained, the chloroform solution of which is subjected to chromatographic separation, passing it through 200 g of phlorisil, using chloroform containing increasing amounts of methanol (0-3% Fraction, which, as shown by a thin-layer chromatography study, contain 0 -6-n-propyl-8-methyl mercaptomethyl-8-ergrlin was combined with each other and these combined extracts were removed and the 516 gel was dissolved.  After recrystallization of this product from diethyl ether, and then with ethanol, 2.7 g of 6-n-propyl-8-methyl mercaptomethyl-8-ergoline are obtained with m. square  180-183 C (with decomposition).  After treating this product with maleic acid, maleate 0-6-n-propyl-8-methyl mercaptomethyl-8-ergoline is obtained as an amorphous solid.  Example 8  Obtaining O-bn; -proshsh-8 & methylmercaptomethyl-8-ergoline.  25 g of methyl melantergate is dissolved in 750 ml of methylene chloride, 35 g of cyanium bromide is added, and the mixture is stirred at room temperature under a nitrogen atmosphere for 22 hours.  The organic layer is washed with an aqueous solution of tartaric acid, water, and a saturated aqueous solution of sodium chloride.  The organic layer is then dried and the organic solvent is removed from it by evaporation.  The resulting D-6-cyano-8-methoxycarbonyl-9-ergolene is dissolved in 600 m of acetic acid and 120 ml of water, to which 80 g of zinc dust have been added.  The resulting mixture is heated at boiling point under a nitrogen atmosphere for 18.5 hours.  Then this reaction mixture is cooled and filtered.  The filtrate is poured into ice, after which it is alkalinized 14 n.  vrdm solution of ammonium hydroxide.  The alkaline mixture is extracted several times with chloroform.  The chloroform extracts are combined and the combined extracts are washed with a saturated aqueous solution of sodium chloride and then dried.  The product of this reaction, netil-0-6-desmethyl-algate, contains a small amount of the corresponding isolate.  This product was dissolved in dimethylformamide and without further purification.  Alkylated with n-propyl iodide and potassium carbonate according to the method described in Example 7, 0-6-n-Shch-8 {-methoxycar6onyl-9-ergolane containing a small amount of the OL-methoxycarbonyl isomer is obtained.  This product is suspended in diethyl ether, and the suspension is subjected to chromatographic separation, passing it through 150 g of phlorisil, using diethyl ether as eluting. solution.  . Those fractions that, as indicated by a thin layer chromatography assay, consist of the α-isomer, are combined with each other and the diethyl ether is evaporated.  The product obtained after evaporation of the ether is dissolved in ethyl acetate, and the organic layer is extracted with an aqueous solution of tartaric acid.  This aqueous extract is separated and then basified with 14N.  ammonium hydroxide aqueous solution.  The resulting alkaline layer is extracted several times with chloroform, the chloroform extracts are combined with each other, and washed with a saturated aqueous solution of sodium chloride, and then dried.  After evaporation of chloroform, a product is obtained which is subjected to chromatographic separation by passing it through.  30 g of phlorisil, using as an elution solution a mixture of solvents diethyl ether-hexa in a ratio of 1: 1 fraction,. which, t-contain -6-n-propyl-8-methoxycarbonyl-9-ergoline, are combined with each other and carry out the reduction of this compound with Ti-4-d hydride in the following way: 0.6 I.  the product is dissolved in 75 ml of tetrahydrofuran, and 0.5 g of lithium aluminum hydride is added in portions to this solution in separate portions.  The reaction mixture was stirred at room temperature for 70 minutes, and then cooled in an ice-water bath.  The organometallic compounds and the excess hydride are decomposed by the addition of ethyl acetate and a 10% aqueous solution of sodium hydroxide.  This reaction mixture is filtered and the filtrate is diluted.  The aqueous mixture is extracted several times with a mixture of chloroform-isopropanol solvents.  The organic extracts are combined with each other, and washed with a saturated aqueous solution of sodium chloride and then. dried.  After solvent extraction, a product is obtained, the chloroform solution of which was subjected to chromatographic separation, passing it through 30 g of Florisil, using chloroform with increasing methanol content (2-10%) as an elution solution, four fractions are obtained, each of which is treated with 4518 but 10 ml pyridine containing 0.5 ml of methanesulfonyl chloride.  Each batch is diluted with water and then basified with concentrated ammonium hydroxide.  In each case, the alkaline solution is extracted with ethyl acetate, and the ethyl acetate extract is washed with a saturated aqueous solution of sodium chloride i and then dried.  The fourth fraction, obtained by chromatographic separation, treated as indicated, consists of 0-6-n-propyl-8 5-mesyloxymethyl-9-ergolene.  This compound is again filtered through florisil, get 250 mg of the product with so on. square   (with decomposition).  Next, 1.4 ml of a solution containing 25 g of methyl mercaptan in 100 ml of dimethylacetamide is added to 40 ml of dimethylacetamide, and the mixture is cooled in an ice bath.  240 mg of sodium hydride is introduced into the cooled solution in separate portions as a 50% suspension in mineral oil.  This reaction mixture is heated to.  and a solution of 250 ml of i-b-n-propyl-83-mesyloxnmethyl-9 - rholen in 10 ml of dimethylacetamide is quickly dropwise to Nea.  The resulting reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1.25 hours, after which it was cooled and diluted with water.  The resulting aqueous mixture is extracted several times with ethyl acetate. The ethyl acetate layers are separated and combined with each other.  The combined layers were washed with water and a saturated aqueous solution of sodium chloride.  The combined organic layer was dried and the organic solvent was evaporated.  A solution of this product in diethyl ether is filtered through phloisyl, and the florisil layer is washed with ethyl ether.  Then the ether C solution is diluted with hexane, and crystalline Bnn-propyl8 & methyl mercaptomethyl-9-ergolene is obtained.  This compound decomposes at "197 ° C."  1 product yield was 100 mg.  Example 9  Preparation of D-2br om-6-n-pr sawdust-8 J-meelmerc aptoethylergoline.  A solution of 1.62 g of N-bromosuccinim in 50 MP dioxane is rapidly added to the solution to a solution of 2.6 g of D-6H-B-8B-methoxycarbonylergoin in 100 ml of dioxane at.  This
    199
    the reaction mixture is heated for 2 hours at a temperature of from 60 to nitrogen atmosphere, then it is poured onto ice in 14 n. ammonium hydroxide aqueous solution. The alkaline mixture is extracted with ethyl acetate, and the ethyl acetate extract is separated and washed with water and then with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried and the solvent was evaporated. The chloroform solution of the reaction product consisting of 0-2-bromo-6-n-propyl-8-methoxycarbonyl-ergoline is subjected to chromatographic separation, passing it through 35 g of florisil using chloroform containing 1% methanol as the elution solution. The fractions, which, as indicated by thin layer chromatography, contain one large spot, are combined with each other, to obtain 1.64 g of D-2-bromo-b-n-propyl-8b-methoxycarbonyl-ergoline with T.Sh1. 167-168C. After recrystallization from methanol, the resulting product has so pl. 168-169 ° C.
    A solution of 1.4 g of D-2-6poM-6-H-npo drank-8 & m-methoxycarbonyl13 rgoline in 100 ml of tetrahydrofuran is cooled in an ice-water mixture. 1.5 g of lithium aluminum hydride are added to this solution in separate portions. The reaction mixture is stirred at room temperature for 1 hour and then cooled. The excess lithium amino acid hydride and organometallic compounds, which are present in the reaction mixture, are decomposed by the sequential addition of ethyl acetate and a 10% aqueous solution of sodium hydroxide into it. Next, the reaction mixture is diluted with water, and the aqueous layer is extracted with a mixture of chloroform and isopropanol. The organic extract is separated, washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the chloroform, a product is obtained, after recrystallization of which from methanol, 0-2-bromo-6-n-propyl-8-hydroxymethyl ergoline is obtained, m.p. 208-210С, yield 1.19 g.
    A solution of 1.3 g of D-2-bromo-6-n-ml-8-hydroxymethyl ergoline in 50 ml of pyridine is prepared. To the solution was added 1.5 ml of methaneulfonyl-chloropolymer, and the resulting reaction
    20
    2045
    the mixture is stirred for 1.3 hours. Then the reaction mixture is poured into a mixture of ice with 14 n. ammonium hydroxide aqueous solution. The alkaline aqueous layer is extracted with ethyl acetate, and the ethyl acetate layer is separated and washed with water and a saturated aqueous solution of sodium chloride. The ethyl acetate solution is dried and the ethyl acetate is extruded. After recrystallization of the product from methanol, 0-2-bromo-6-n-propyl-8-mesyloxymethyl-ergoline is obtained, yield 1.43 g. 40 mmol methyl mercaptan in dimethylacetaiide are prepared. 8 ml of this freshly prepared solution 100 ml of dimethylacetamide are mixed together and cooled in an ice bath. Sodium hydride in an amount of 16 g per
    the form. A 50% suspension in mineral oil is added to this solution in separate portions. The mixture is heated to 15 ° C and when this temperature is reached, a solution of 1.5 g of D-2-bromo-6-n-1-8b-mesyloxymethyl ergoline in 40 ml of dimethylacetamide is quickly added dropwise to it. After that, the reaction mixture is stirred at room temperature in at-
    over a period of 1.5 hours, then cool and dilute with water. The aqueous layer is extracted several times with ethyl acetate, and the ethyl acetate extracts are washed with water and the aqueous solution
    sodium chloride solution and then dried. After evaporation of the solvent in vacuo, a product is obtained, after recrystallization of which from methanol, D-2-bromo-b-n-propyl-8-methyl mercaptomethyl ergoline is obtained, m.p. 159-161s, yield 1.08 g
    Methanesulfonate is prepared by folding 950 ml of 0-2-bromo-6-n-propyl-8-methyl mercaptomethylergoline in 25 ml of hot methanol. 1.6 ml of a methanesulfonic acid solution containing 2.5 millimole of acid is added to the solution, and the solution is cooled. This reaction mixture is then diluted with diethyl ether, and 940 mg of methanesulfonate are obtained, m.p. 256С (with decomposition).
    Example 10. Preparation of D-6-n-Shch-8-methylsulfonylmethyl Ergoline.
    权利要求:
    Claims (1)
    [1]
    A solution is prepared from 1.2 g of methanesulfonate 0-6-n-propyl-methyl mercaptomethyl ergoline in 100 ml of water, a solution containing 685 mg of sodium periodate in 25 ml of water is added to it, and the resulting reaction mixture is stirred at room temperature for 17 The reaction mixture is then diluted with an aqueous solution of sodium bicarbonate and the alkaline layer is extracted with a mixture of chloroform and isopropanol. The organic extract is separated, washed with a saturated aqueous solution of sodium chloride and dried. After evaporation of the solvent, a product is obtained, which is dissolved in boiling methanol, to which 0.2 ml of methanesulfonic acid is previously added. This solution is cooled to room temperature and diluted with an equal volume of diethyl ether. The diluents are removed in vacuo and the product, after removal of the solvents, is dissolved in 100 MP of boiling acetone. The acetone solution is filtered and cooled to give 0-6-n-propyl-8 crystalline methanesulfonate | -methylsulfonylmethyl ergoline, having so pl. 200-209 C (with decomposition). Standard methods are used to prepare the corresponding free base of the compound indicated, which has mp. 173-175 C (with decomposition), Example P. Preparation of D-6-n-propyl-8e-methylesulfonyl ergoline. A reaction mixture is prepared from 3.6 g of O-b-n-propyl-Sy-Meti-Loxymethyl-ergoline, 10 g of sodium methanesulfinate and 200 ml of dimethylformamide. This mixture is heated at 110 ° C under nitrogen for 3.75 hours and diluted with water, the aqueous mixture is extracted several times with ethyl acetate. The ethyl acetate layers are combined with each other, and washed with water, a saturated aqueous solution of sodium chloride and then dried, after evaporation of ethyl acetate, 0-6 n-propyl-8 | -methylsulfonylmethyl ergoline, which is dissolved in chloroform, and the chloroform solution is subjected to chromatographic separation, passing through 200 g of florisil using chloroform with increasing methanol content (from 2 to 4%) as an eluting solution. After evaporation of the solvent and recrystallization of the product from methanol, crystalline D-604522 -n-propyl-8e-methylsulfonylmethyl ergoline, having so pl. 184-186 C (yield 690 mg). Example 12. Getting 0-2-chloro-6-n-proshsh-8b-methylmercaptomethylergoline. In the amount of 7.2 g, 0-6-n-prop1-1-8 in mesonloxymethyl ergoline is dissolved in 100 ml of methylene dichoride and 380 ml of acetonichril. 6.3 ml of boron trifluoride ethereal ether was added to the solution, and the mixture was cooled at 0-5 ° C. Then a solution of 1.80 ml of sulfuryl chloride in 30 ml of methylene dichloride is introduced dropwise into this solution {m. The reaction mixture is stirred under cooling for 30 minutes and then diluted with an aqueous 5% solution of hydroxide monoxide. The alkaline layer is extracted several times with a mixture of chloroform and isopropanol. The organic extrachids are combined with each other, washed with a saturated aqueous solution of sodium chloride, and then dried. The solvent is evaporated. The product obtained after evaporation is dissolved in methylene dichloride. A solution of methylene dichloride is subjected to chromatographic separation, passing it through 300 g of phlorisil, using methylene dichloride with increasing methanol content (23%) o as the eluent solution. The fractions containing the product moving slower than the original substance are combined and removed: Ute from them solvent by evaporation in vacuo. The fraction consisting of 0-2-chloro-6-n-propyl-8-mesyl xymethyl ergoline, recrystallized from methanol, gives a crystalline product with mp. 130-131 ° C, yield 82%. After the second recrystallization from methanol, a product with m.p. 133-135 ° C. A solution of 7 g of methyl mercaptan in 200 ml of dimethylformamide is cooled in an ice bath until. To this solution, 9.6 g of sodium hydride are added in separate portions in the form of a 50% suspension in mineral oil to obtain methyl mercaptide. The cooling bath is removed and the solution is continued to be stirred for a period of .1 U min, after which a solution of 6.2 g of D-2-chloro-bn-propyl-mesyloxymethyl ergoline 75 ml of dimethylformamide is quickly added dropwise to it. This reaction mixture was stirred for 1 hour under a nitrogen atmosphere, and then diluted with water. The aqueous solution is extracted several times with ethyl acetate. The ethyl acetate extracts were combined and the combined layers were washed with water and then with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried and ethyl acetate was evaporated. The residue is washed with diethyl ether and the ether bath is diluted with hexane to give 4.4 g of 0-2-chloro-6-n-propyl-8 (α-methyl mercaptomethyl ergoline, mp 183-186 ° C. This compound is converted to the methane sulfonic acid salt , after recrystallization from the solvent mixture, methanol-diethyl ether has a melting point of 267-269 ° C (with decomposition). Example 13. Preparation of D-6-n-propyl-8y-methyl mercaptomethyl ergoline. , using 312 mg of O-B-methyl mercaptomethyl ergoline. About, 2. ml iodine n-pro saw and 275 ml of potassium carbonate in 10 ml of dimethyl of formamide at room temperature under nitrogen atmosphere for 22.5 hours, and carrying out a subsequent treatment, D-6-n-propyl-8b-methyl mercaptomethyl salt is obtained. This product is converted into the methanesulfonic acid salt according to the method described in Example 1, 250 are obtained. mg 0-6-n-propyl-8 & methylmercaptomethyl ergoline methane sulfonate, having a mp of 295-262 ° C (with decomposition). Example 14. Preparation of D-6-n-propyl-Bp-methyl mercaptomethyl ergoline. 0-6-allyl-8 (b-methyl mercaptomethyl ergolin methane sulfonate in an amount of 51 mg, is subjected to hydrogenation using 10 mg of 5% Pd on a carbon carrier, and 5 ml of 80% ethanol 20% water at a hydrogen pressure, 1.01 10 d / cm, stirred for 20 hours. The catalyst is filtered off and the filtrate is evaporated in vacuo at 45 ° C. The product obtained after evaporation is dissolved in 10 ml of methanol, added to 0.5 g of florisil, and methanol is removed in vacuo at 45 ° C. Carry out chromatographic separation of the product from florilosilone using 5 24 as an eluting plant. Chloroform with increasing methanol content (1-10%). The fractions containing the product moving faster than the starting material is collected and the solvent contained therein is evaporated in a vacuum. The product remaining after evaporation of the solvent is recrystallized from diethyl ether and dried in a vacuum , 31 mg of D-6-n-propyl-8p-methyl mercaptomethyl ergoline are obtained with a melting point of 253-256 ° C (decomposition) Example 15 Preparation of 0-2-chloro-6-i-prop 1-8 b-methylsulfonylmethyl ergoline. . A solution of 1.05 g (3.0 mmol) of D-2-chloro-6-n-propyl-8 L-methylmercaptometr tylergoline and 0.2 ml (3, 1 mmol) of methyl sulfonic acid in 50 ml of methanol are introduced into a solution of 665 g (3.3 mmol) of 85% chloroperbenzoic acid and 25 ml of chloroform. The mixture is stirred for 0.5 h under a nitrogen atmosphere. The organic solvent is removed in vacuo. The residue is dissolved in chloroform, filtered, passed through 50 g of AliQj, filtered, passed through florisil. Florizil washed with methanol (2-4%). The combined solvents are diluted with diethyl ether, from which 0-2-chloro-6-n-propyl-8-methylsulfonylmethyl ergoline crystallizes with m.p. 142-150 C, product yield 250 mg. Example 16. Poluchelyue 0-2-chloro-6-n-propyl-8-methylsulfonone 1meergoline. 0-2-chloro-6-n-propyl-8 (α-methylsulfonylmethyl ergrlin in the amount of 0.49 g (1.3 mmol) and 0.1 ml (1.5 mmol) of methyl sulfonic acid are dissolved in 50 ml of methanol. This solution is added to a solution of 295 mg (1.5 mmol) of m-chloroperbenzoic acid in 25 ml of chloroform, the mixture is stirred under a nitrogen atmosphere for 0.5 h. The organic solvent is removed in vacuo, the residue after removal of the solvent is dissolved in chloroform, filtered through phlorisyl. These solutions are then diluted with diethyl ether, from which 0-2-chloro-6-n-propyl-86-methylsulfonylmethyl is crystallized lergoline with a melting point of 212-215 ° C (with decomposition), product yield 275 mg. Claim , Y - oxygen, sulfur or S group., Hydrogen, chlorine or bromine) - double or simple carbon carbon bond, or their salts, that is, and the connection of the common forms dH, Q 5 where Q is a mesyloxy group or a chlorine atom has the indicated values; f is hydrogen, 3R1, AND-propyl or allyl, is reacted in any sequence with HAND general formula. -C "C, where V has the indicated values, 1E is sodium or the group H, H, M-trimethyl-N-beisyl ammonium methylate, with alkyl iodide, if hydrogen, if necessary with a halogenyroxy agent, if X is hydrogen, or when necessary, hydrogenation is carried out with hydrogen at 5% palladium on carbon, if allyl and / or a or L "bond is present, followed by isolation of the desired product in free form or as a salt. Sources of information taken into account in the examination I. Weigand-Hilgetag Experimental methods in organic chemistry. M., Himi, 1968, p. 333
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    同族专利:
    公开号 | 公开日
    LU80886A1|1979-06-07|
    LU88294I2|1994-05-04|
    IE47827B1|1984-06-27|
    US4166182A|1979-08-28|
    IL56581A|1982-05-31|
    GB2014140B|1982-08-04|
    ES477547A1|1980-04-16|
    CH639088A5|1983-10-31|
    RO81857B|1983-05-30|
    DD141928A5|1980-05-28|
    PL120849B1|1982-03-31|
    RO81856A|1983-06-01|
    HU179970B|1983-01-28|
    NZ189561A|1981-12-15|
    GR72776B|1983-12-05|
    IL56581D0|1979-05-31|
    DK147362C|1988-06-27|
    PH14903A|1982-01-29|
    AR228341A1|1983-02-28|
    AU4391779A|1979-08-16|
    RO81856B|1983-05-30|
    CA1114368A|1981-12-15|
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    YU28279A|1983-02-28|
    MY8500597A|1985-12-31|
    FR2416891B1|1981-10-16|
    FR2416891A1|1979-09-07|
    EG14076A|1983-12-31|
    FI65777C|1984-07-10|
    PL213283A1|1980-02-25|
    RO76889A|1981-08-30|
    ATA91479A|1982-12-15|
    IE790232L|1979-08-08|
    DE19375112I2|2003-06-12|
    NL930106I1|1993-10-18|
    PT69172B|1992-05-29|
    ZA79453B|1980-09-24|
    PT69172A|1979-03-01|
    BG30474A3|1981-06-15|
    EP0003667A1|1979-08-22|
    JPS54115400A|1979-09-07|
    PL126313B1|1983-07-30|
    DE2963320D1|1982-09-02|
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    CS203951B2|1981-03-31|
    NL930106I2|1997-02-03|
    AU523172B2|1982-07-15|
    UA6082A1|1994-12-29|
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    FI790351A|1979-08-09|
    EP0003667B1|1982-07-14|
    MX9203107A|1992-07-31|
    GB2014140A|1979-08-22|
    AT371817B|1983-08-10|
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    US05/875,978|US4166182A|1978-02-08|1978-02-08|6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds|
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