SE178968C1 - - Google Patents

Description

Inventors: L Velluz, G Muller and A Allais Priority requested from 13 April, 24 June, 18 July, 2 and 7 August, 11, 21 and 31 October, 18 November, 9, 13 and 26 December 1957 Saint 13 and 17 January 1958 (France) with the general invention The present invention relates to a saturated 20α-yohix bond derivative to produce mono-, di- and trisubstituted mein: R1 RI 3 \ 1 \ / \ II IN R3 R4 / \ .7 \ / I IeMe Me0 — C / \\ / \ O — C— / IIII \ OMe 00 \ 01 \ le Formula I.) -0Me in which R1, R „R, and R4 5ro are the same or different and denote vate, chlorine, method- oiler methyl groups.

These compounds constitute physiologically active products from the reserve resin series and have valuable pharmacodynamic properties, such as hypotensors.

The saturation according to the invention consists essentially in the condensation of 11β-carboxy-methyl-2β-methoxycarbonyl-3α-metho-d-4/3-acetoxy-616-formylcyclohexane methyl ester of the formula: 0 MeO-C CHO I \ / \ I / \ _ / \ Me0 — C. O — C — Me OMeII 00 with a tryptamine of the general formula II: R1 R2 \ 7 \ / \ II IIINH2 / N7 / R3 R4 Formula in which R ,, R ,, R, and R, have the meanings given above. The above-mentioned 1β-carboxymethyl-2/3-methoxycarbonyl-3α-methoxy-4/9-acetoxy-613-formylcyclohexane methyl ester is obtained by esterification in diazomethane of the corresponding acid, = + 42.5 ° (pyridine), prepared from 3.6 -acetoxy-2a-methoxy-7-oxo-1,2,3,4,4aa, 7,8,8aa-octahydronaphthalen-11i-carbonic acid methyl ester, which is converted to the corresponding ozonide and probed with water, 2 - - while the tryptamines II can be prepared by condensing the corresponding substituted anilindiazonium salt with 3-carboxy-2-piperidone and subsequent cyclization with hydrochloric acid of the 3-phenylhydrazone of substituted 2,3-dioxipiperidine to a substituted 1,2,3,4-tetrahydro-1-oxo- fl-carboline and preselection with subsequent decarboxylation of the latter compound. The condensation of the monocyclic aldehyde with tryptamines of formula II is carried out in neutral solvent, such as methylene chloride or tetrahydrofuran, at a temperature close to room temperature to give a compound of general formula III: R 1 corresponding to hydroxyhimbane of general formula V: Formula V. in which 111, R, R, and R, have the meanings given above.

The effect of alkali borohydride in heat makes it too possible to obtain compound V directly from compound III. If it is difficult to crystallize the compound V, the pre-digestion can be completed by adding alkali liquor, and isolating the compound of the general formula VI: \ -> (MeO-C / 0111 e011 Formula III. \, 1.11e0-CR , NR, HR, R2 \ 1 \ / \ I 'NR, / \ 1 / INTI / CH1 /) R, I7, 71 / \ \ HO, C `: OH OMe Formula VI.

In which R 1, R 2, R 3, and R 4, have the meanings given above. The condensation product III was subjected to the action of an alkali metal borohydride in the presence of a lower alcohol, whereby by reducing the double bond and subsequent cyclization a compound of the general formula IV is obtained: R, R 2, R 2, N ', NA) Ft 3 H 1 / \ A / 1 in which 111, R 1, R 2 and R 3 have the meanings given above. The latter compound is esterified with Me0 — C / // \ 0 — C — Mediazomethane in the usual manner.

One can thus always arrive at the association V from the associations IV or VI. The compound V thus obtained is esterified Formula IV with 3,4,5-trimethoxybenzoic anhydride in the presence of a pyridine base or triethylamine according to the process described in the Swedish patent which R 1, 112, R 2 and R 3 have the same meaning. 174 172, the corresponding compound being obtained by methanolysis to the resulting ester of the general formula VII: - - 3 in which R 1, R 2, R 3 and R 4 are as defined above. This compound VII is cyclized with the aid of phosphorus oxychloride and the quaternary unsaturated ammonium compound of general formula VIII is separated: R, (- ±) B, / \ \, N \\, / • HR, \ / OMe Me0 — C0 — C— 01 \ fe 0 O..me 0 OMe Formula Vffl. in which 111, 112, R 1 and R 2 have the same meaning, in the form of a mixture of inorganic salts which are easily purified by transferring to the perchlorate. Compound VIII is reduced with zinc in an acidic environment, preferably in perchloric acid in the presence of an organic solvent which is miscible with water, preferably acetone or tetrahydrofuran. After purification, the desired compound of formula I is separated on kdnt salt, e.g. crystallization.

The following examples illustrate the invention without limiting it. One can thus apply other reaction temperatures, use other release agents, other acids or bases, apply a different order when adding the reaction components and other reaction times, without therefore exceeding the scope of the invention. The invention is a joke limited to the production of an optically active form of these new compounds, for it can also be applied to ph corresponding enantiomorphs and racemates.

The specified melting points are the instantaneous melting points determined on the Maquenne block.

The reactions are shown in the attached schedule.

Example 1. Preparation of the methyl ester of 1813-acetoxy-10,17a-dimethoxy-16β-methoxycarbonyl2-3,3-4-diseco- (Y21) 20α-yohimben-3-oic acid (formal III) R, H, R , = AND „R3 = H, R, = H. 2 g hOgervride (pyridine) 1/3-carboxymethyl-2,8-methoxycarbonyl-3α-methoxy-416-acetoxy-6/3-formyryloclohexane methylated with diazomethane in 20 ml of methylene chloride. After concentration, the methyl ester II formed was continued with 1 g of 5-methcodtryptamine (formula I), prepared according to H. Wieland et al., Ann. 1934, 513, 1, and the reaction mixture is allowed to stand at room temperature for 15 minutes. A solution of compound III is thus obtained, which is used directly for Rasta steps in the synthesis. This product is new.

Example 2. Preparation of dextrorotatory (chloroform) 1813-acetoxy-10,17a-dimethoxy-16,6-methocodecarbonyl-3-oxo-2-3-seco-20a-yohimbane (formula IV) R 1 = H, R 1 = AND , R, H, R, = H.

The solution of the Schiff base (formal III) in methylene chloride obtained from 1 g of 5-methoxytryptamine (formal II) according to the previous example was continued with 20 ml of methanol. Cool to -1- 5 ° C, add 1 g of potassium borohydride and heat the mixture at + 5 ° C for 15 minutes and then for 30 minutes at 20 ° C, after which the excess of the double hydride is removed with the least possible amount of attic acid. Evaporation takes place to dryness in vacuo at a temperature not exceeding 20 ° C.

The residue is taken up in acetone and filtered and concentrated by evaporation to a very small volume. Then ether was added and the solution was processed by scraping, inoculating, cooling and suction filtered to give 1.6 g of compound IV (i.e. a yield of 66% of theory), m.p. 141-142 ° C, [c] g - 13.5 ° (c - = 1%, chloroform). This new compound is readily soluble in chloroform and acetone in heat and insoluble in water. It has not been described in the literature.

Analysis: C, H, O, N, = 472.52 Calculated: C% 63, H% 6.8N% 5.9 Found: 63.87, 15.9 Example 3. Preparation of right-turning (ethanol) 1613 -carboxy-18β-hydroxy-10,17α-dimethoxy-3-oxo-2-3-seco-20α-yohimbane (Formula VI) R 1 = H, R 2 = AND, 113 = H, R 2 - H 4.7 g of the compound IV obtained according to Example 2 were added to 23 ml of water and 2.3 ml of 10 N sodium hydroxide solution. The resulting mixture, a Mlles 1.5 hours with stirring at 85 ° C, then cooled and acidified to pH 4 by the addition of acetic acid. The clear brown solution is extracted once with methylene chloride to reduce a small amount of colored fluorine impurities. The solution is decanted and the aqueous phase is cooled for 1 hour, suction filtered, washed with a few milliliters of water and dried at 40 ° C. to obtain 3.6 g (ie a yield ph 85%). Melting point 162 ° C, [a] to = + 29 ° (c = 1 ° / „, R / \ / \ / \ T / 0 / \ 3 1H / \\ / \ / 1 OMe I \ / - \ - 0Me Me0 — C OMe \ 00 OMe Formula Vfl. 1- ethanol). These constants do not change upon recrystallization from methanol.

Analysis: CO2H0806N, = 416.46 Calculated: C% 63.4H% 6.8N% 6.7 Found: 63.36.86.6 This compound has not been described in the literature. Example 4. Preparation of higher turn (pyridine) 1818-hydroxy-10,17a-dimethoxy-1616-methoxycarbonyl-3-oxo-2-3-seco-20a-yohimbane (formula V) from the compound III, R, H, R , = AND ,, R, = H, R4 = H.

To the solution of Compound III obtained according to Example 1 was added 20 ml of methanol and, while cooling, 1 g of potassium borohydride, after which the reaction mixture was allowed to stand for 15 minutes. Heat to boiling for 1 hour, cool and add methylene chloride, water and hydrochloric acid to pH 1. The solution is decanted, washed with a matt aqueous solution of sodium bicarbonate, dried and evaporated to dryness. The residue gives solution in ethyl acetate after 30 minutes on an ice bath 1.76 g of compound V (i.e. a yield of 76%), m.p. 190 DEG C. For analysis, this product is recrystallized from acetone to give 1 g of white crystals. Melting point 190 ° C, [α] D = 31 ° (c = 0.5%, pyridine), which were soluble in chloroform and acetone was insoluble in ether.

Analysis: C 10 H 2 O, N 2 = 430.49 Calculated: C% 64.17 H% 7.02 C% 22, N% 6.51 Found: 64.3 7.2 22.3 6.8 This compound has not described in the literature.

Example 5. Preparation of 18,8-hydroxy10,17α-dimethoxy-16β-methoxycarbonyl-3-oxo-2-3-seco-20α-yohimbane (formula V) from compound IV. R 1 = H, R 2 = AND, R 1 = H, R 4 = H.

A mixture of 1 g of compound IV, obtained according to Example 2, with 8 ml of methanol containing 8 mg of anhydrous sodium is boiled at 45 mm under reflux, after which it is cooled to 20 ° C, acidified to pH 6 by adding acetic acid and evaporated to dryness in vacuum. The residue is taken up in acetone and the resin is allowed to crystallize. The suction filter is obtained and 700 mg (i.e. a yield of 80%) of the compound V are obtained, which is identical to the compound obtained according to Example 4.

Example 6. Preparation of 1813-hydrod10,17a-dimethoxy-16β-methoxycarbonyl-3-oxo-2-3-seco-20α-yohimbane (formula V) from the compound VI, R, H, R., = AND, R 0.5 g The compound VI is diluted with 1 ml of methanol, and diazomethane dissolved in methylene chloride was added in small portions until a permanent yellowing is obtained. The solution thus obtained is evaporated to dryness in vacuo at 20 DEG C. and the residue is taken up in acetone. 0.35 g (ie a yield of 68%) of compound V. are obtained which is identical to that prepared according to Example 4.

Example 7. Preparation of left-handed (pyridine) 181.4-3 ', 4', 5'-trimethoxybenzoyloxy) -10,17α-dimethyl-16β-methoxycarbonyl-3-oxo-2-3-seco-20α-yohimbane (Formula VII) . R 1 = H, R 2 = OGH 2 R 1 = H, R 2 = H. 0.75 g of the compound V prepared according to Example 4 are dissolved in 4.5 ml of pyridine and 1.5 ml of triethylamine, after which in a gas stream stream is added 1.15 g of 3,4,5-trimethoxybenzoic anhydride and then the mixture is allowed to stand for 24 hours at 95 ° C. After cooling, excess anhydride is enlarged by adding water. Methylene chloride, ice and hydrochloric acid were added to pH 1, washing with water and with sodium bicarbonate, after which drying and evaporation took place to dryness. The residue in a mixture of ethyl acetate and ether precipitates, after which it is allowed to stand. 0.5 h in an ice bath, 0.84 g (ie a yield of 77%) of compound VII, m.p. 240 ° C. For purification, this product is dissolved in methylene chloride and chromatographed over aluminum, eluting with the same solvent and evaporated to dryness. The residue is crystallized from a mixture of ethyl acetate and ether to give 0.69 g of the pure product, m.p. 240 DEG C. [.alpha. = DEG-89 DEG (c = 0.5%, pyridine) having the form of white crystals which are soluble in ethyl acetate, chloroform and acetone and insoluble in water and ether.

Analysis: C 33 HON 2 = 624.67 Berdknat: C% 63.45 H% 6.45 0% 25.61 N% 4.48 Found: 63.36.625.64.6 The infrared spectrum coats the specified structural formula. This association has not been described in the literature.

Example 8. Preparation of the perchlorate of 1813- (3 ', 4', 5'-trimethoxybenzoyloxy) -10,17a-dimethoxy-1616-methoxycarbonyl-13-20a-yohimbane (Formula VIII). R, = H, R, = AND ,, R, = H, R, = H.

Under reflux, 11 g of 1.1 g of the compound VII prepared according to Example 7 are boiled in 5 ml of phosphorus oxychloride, the product is evaporated to dryness in vacuo and the residue is taken up in 10 ml of methanol. While cooling, 1 ml of 65% perchloric acid (d = 1.61) was added, followed by 30 ml of water, after which the yellow precipitate formed was filtered off with suction and washed with water. The precipitation is caused by the perchlorate of compound VIII, which is new and has not been described in the literature.

Example 9. Preparation of dextrorotatory (chloroform) 10-methoxide serpidine, (formula I). R 1 = - H, R 2 - OCH 2, R 2 = H, R 4 = H.

A mixture consisting of the crude perchlorate of compound VIII obtained according to Example 8, ml of acetone, 10 ml of tetrahydrofuran, 10 ml of 13% perchloric acid, 0.1 ml of ferric chloride and 1 g of zinc powder is boiled for 0.5 hour under reflux. It is filtered, evaporated, water is added and extracted with methylene chloride. The extracts are washed with dilute ammonia, dried over magnesium sulphate and evaporated to dryness. The residue dissolved in methanol was added with 0.5 ml of dilute nitric acid. The ice is cooled and the crystallization of the clear yellow nitrate, which is filtered off with suction and suspended in methanol, is carried out by scraping. Crystallization of 10-methoxy-deserpidine (formula I) is obtained by the addition of ammonia. The product is suction filtered, washed with methanol and dried. The yield of 250 mg (ie 23% of theory) of white crystals, m.p. 171 DEG C., [.alpha.] D @ 20 = 142 DEG (c = 0.5% chloroform), which are very readily soluble in chloroform, soluble in acetone and unresponsive in methanol. They are insoluble in water and ether.

Analysis: C "H" O, N, = 608.67 Calculated: C% 65.11 H% 6.62 0% 23.66 N% 4.60 Found: 65.26.823, 44.7 The infrared spectrum confirms that This compound has not been described in the literature.

By proceeding in the same manner as in the previous example, one can prepare the compounds given in the attached table, in which the constants of the obtained deserpidins are given as well as the common intermediates which have been used for their preparation. The figures in the table indicate for each formation in the order indicated: 1. the melting point, 2. the turning shape and 3. the concentration in the specified solvent when feeding the turning shape6- gam RR 113 Bry It III H CI HH 296- amorphous 297 ° chlorohydrate HH Cl H 113 ° c: a 130 ° (prob.) -50 °, 0.5% ethanol HHH Cl 96 ° amorphous Cl HH Cl 124 ° 90 ° -8 °, 0.5% pyridine HH Cl Cl 101 ° amorphous HH CH , H 141 ° amorphous HHH CH, 130 ° amorphous H OCH, HH 120- amorphous 121 ° H HH OCH, 135- amorphous 136 ° OCH, OCH, OCH, H146 ° amorphous ClHHOCH, 156.5 ° amorphous General formulas VVI 180- 190 ° 160-170 ° solvate ± 31 °, 0.5 terad 1/2 H, 0% ethanol 147 °, 0.5% chloroform 160-165 ° 280 ° - 125 °, 0.5% + 28 °, 0.5 ethanol% ethanol anionf179 ° - 116 °, 0,% chloroform 127 ° + 35 °, 172 ° -119 °, 0.5% 0.5% chloroform pyridine 240 ° + 34 °, c: a 160 °, then 0.5% 222 ° -97 °, 0.5% pyridine doroform 218 ° + 30 °, 275 ° -132 °, 0, 0.5 %% chloroform pyridine 180 ° + 25 °, 231 ° -124 °, 0.5% 0.5% chloroform pyridine 190 ° + 31 °, 162 ° ± 29 °, 171 ° -142 °, 0, 0.5% 1% ethanol% chlorophore m pyridine c: a 125 ° + 200 ° - 120 °, 0.5% 38 °, 0.5% chloroform ethanol Table IV c: a 130 ° -F 34 °, 0.5% ethanol 210 ° -10 °, 0.5% pyridine 180 ° + 7 °, 0.5% pyridine 226 ° -14 °, 0.5% pyridine 141-142 ° -13.5 °, 1% chloroform 180 ° -I- 23 °, 0, 25% ethanol 230 ° -38 °, amorphous 0.5% chloroform amorphous slow melting 171-173 ° -114 °, 0.5% chloroform amorphous - 132 °, 0.25 °, / „chloroform - - R311, II IIIIV RIR2 Cl HH General formulas VVI amorphous 300 ° (stinder divided) - 120 °, 0.5% chloroform 183 ° -129 °, 0.5% chloroform 210 or 240 ° two crystallized forms 1060, 0.25% chloroform AND, H163— amorphous 232 ° 22 °, 164 ° 0.5% chloroform ClOCH, 113.5 ° amorphous188 ° + 0, amorphous 0.5 ° /, pyridine AND, C 0.5% 0.5 c / pyridine pyridine

Claims (2)

Patent claim: Salt to produce as a sedative usable 20α-yohimhanderivatives, characterized in that a tryptamine of the general formula II: 114 Formula II. which R 1, 113, R 1, and R 3, may be the same or different and represent irate, chlorine, methoxy or methyl groups, were reacted with higher-order (pyridine) 1,8-carboxymethyl-2,3-methoxycarbonyl-3α-methoxy4 / 3- acetoxy-613-formyleyclohexane methyl ester in organic solvent and that the compound formed of the general formula III: R, R., '\ / 0: 1N / MeO — C iiI R, \\ / \ I) Me0 — C / \\ NOH Olkle Formula V. In which 113, R1, 113 and 114 have the meanings given above, after which the latter compound, with the aid of 3,4,5-trimethoxybenzoic anhydride, is transferred to the corresponding ester of the general formula VII: 114 NH, R1, R2. \ IN 113 / '\ / - \ N / O - // \ \ / „- Me0 — C' '\, / \ Formula III. 0 \. OMe O — C — Me icc Me0 — C / \ 0 Formula V \ O — C— / 131 V \ 0 VII. In which 111, 11.2, R, and R 1 have the meanings given above are hydrogenated by means of a mixed hydride in solution in a lower alcohol, so that a compound of the general formula V: in which R "R" R., and 114 having the above meaning, which formation is cyclized by means of phosphorus oxychloride to an unsaturated, quaternary ammonium compound of the general formula VIII: - - // ° Me Me0 — C / \ // \ O —C-7 - \ - 0Me 0 OMe 011 OMe Formula VIII. in which R 1, R 2, R 3 and R 4 have the meaning given above, after which the cyclized compound is reduced with zinc in an acidic environment and the desired compound of the general formula I is separated after ordinary treatment, e.g. crystallization: R, R, "'\ / \ I II R4HI \ / 7 \ Me01 // \ o (mille \ ° —C1' -N. \ 570 ° —MMCIeeMe 2. 11 00 Formula I. 3. Set according to the patent claim 1, can be characterized in that the condensation with tryptamine II is carried out in methylene chloride or tetrahydrofuran 4. Set according to patent claim 1 or 2, can be characterized in that compound III is hydrated with potassium borohydride in methanol solution 5. Set according to patent claim 1-3, can be drawn therefrom, that the compound of the general formula V is prepared by hydrolysis of a form of the general formula IV: Request publications: Patentskri ter frail Sverige 166 674. / \ / ". Me0 — C0 - C — Me I OMe 00 Formula IV. in which R 1, R 2, R 3, and R 4 are as defined above, which compound is partially fortified on its own edge, for example by heating in the presence of an alkali borohydride or by heating sodium methylate. claims 1-3, can be characterized in that the compound of the general formula V is prepared by cyclization a v a compound of the general formula VI: R, Formula VI. in which R 1, R 2, R 3 and R 4 have the meaning given above in the presence of phosphorus oxychloride, and that this compound is esterified on its own edge. 7. SRI according to claims 1-5, characterized in that the reaction with 3,4,5-trimethoxybenzoic anhydride is carried out in the presence of a pyridine base or triethylamine. 8. Set according to claims 1-6, characterized therefrom, after reduction with zinc is carried out in perchloric acid dissolved in a water-miscible solvent consisting of acetone or tetrahydrofuran. Other publications: Journal of the American chemical society 78 (1956) p. 2023. Stockholm 196 2. Kungl. Boktr. P. A. Norstedt & Sbner. 620089