DE1138061B - Process for the preparation of the perchlorates of 18ª ‰ -acyloxy-17ª ‡ -methoxy-16ª ‰ -methoxycarbonyl-3, 4-dehydro-20ª ‡ -yohimbanes - Google Patents

Description

Process for the preparation of the perchlorates of 18β-acyloxy-17α-methoxy-16β-methoxycarbonyl-3,4-dehydro-20α-yohimbanes The invention relates to a process for the preparation of the perchlorates of 18β-acyloxy-17x-methoxy-16β-methoxycarbonyl -3,4-dehydro-20x-yohimbanes of the general formula where R is a hydrogen atom or a methoxy group and R1 is a 3,4,5-trimethoxybenzoyl or 3,4,5-trimethoxycinnamyl radical.

These compounds are obtained if a dextrorotatory 18ß-oxy-17x-methoxy-16ß-methoxycarbonyl-3-oxo-2,3-seco-20x-yohimban of the general formula esterified with the chloride or anhydride of 3,4,5-trimethoxybenzoic acid or 3,4,5-trimethoxycinnamic acid in the presence of a tertiary base, the ester thus obtained cyclized by treatment with phosphorus oxychloride at elevated temperature and the 3,4-dehydroyohimbane derivative obtained as Separates perchlorate.

The first stage of the claimed process, the esterification of the dextrorotatory compound of the general formula II with the chloride or anhydride 3,4,5-trimethoxybenzoic acid or 3,4,5-trimethoxycinnamic acid is preferred carried out in the presence of pyridine or 2-methyl-5-ethylpyridine. The received Ester is then treated with phosphorus oxychloride at elevated temperature and the 3,4-dehydroyohimbane derivative formed was isolated as a perchlorate. The so available The base on which 3,4-dehydroreserpin perchlorate is based is identical to that of Weisenborn and Diassi (cf. Journ. amer. chem. soc., 78 [1956], p. 2022) by oxidation of the 3-isoreserpins obtained with mercuric acetate and isolated in the form of the nitrate 3,4-dehydroreserpine.

The process products serve as intermediate products for production of reserpine, deserpidine and rescinnamine as they are known in and of themselves reduce in a known manner using zinc and acetic acid to the alkaloids mentioned permit.

The dextrorotatory compounds of the general formula II required as starting materials are derived from dextrorotatory lactams of the general formula or from optically active lactones of the general formula produced by methanolysis in the presence of sodium methylate.

It is already known that reserpine is derived from the racemic lactam of the formula can be produced (cf. Woodward, Journ. amer. chem. soc., 78 [1956], p. 2023). This known process requires the following process steps: a) Cyclization with phosphorus oxychloride to form the 3,4-dehydroyohimbane derivative.

b) Reduction of the 3,4-dehydroyohimbane derivative with sodium borohydride to the racemic 18-O-acetylisoreserpsic acid methyl ester.

c) Optical resolution of this racemate to give 18-O-acetyl-isoreserpsic acid methyl ester. d) saponification of the latter to isoreserpic acid.

e) Lactonization of isoreserpic acid to isoreserpic acid lactone.

f) Rearrangement of the isoreserp acid lactone with pivalic acid to form the reserp acid lactone.

g) Methanolysis of the reserp acid lactone to give the reserp acid methyl ester.

h) Esterification of the reserp acid methyl ester with trimethoxybenzoic acid chloride to reserpine.

This synthesis thus includes, apart from the optical splitting, seven steps to reserpine. On the other hand, it is by the method according to the invention possible, from the optically active lactam of the general formula III, wherein R is a Methoxy group means to produce reserpine in four stages.

It was to be expected that when combining the synthesis of Woodward with that of Weisenborn (cf. Journ. Amer. Chem. Soc., 78 [1956], p. 2023) The process described receives reserpine in four steps, but only with one yield of 22.8 ° / o. In contrast, the method according to the invention surprisingly results Reserpine with a 31.3% yield.

The following examples illustrate the invention. The melting points given in the examples are instantaneous melting points determined in the Maquenne block. Example 1 a) Production of the levorotatory 18ß- (3 ', 4', 5'-trimethoxybenzoyloxy) -11,17x-dimethoxy-3 oxo-16ß-methoxycarbonyl-2,3-seco-20x-yohimbane from the dextrorotatory 18ß-oxy -11,17x-dimethoxy-3-oxo-16β-methoxycarbonyl-2,3-seco-20oc-yohimban of the formula II [R = OCH3] 8 g dextrorotatory 18β-oxy-11,17a-dimethoxy-3-oxo-16β -methoxycarbonyl-2,3-seco-20x-yohimban [Formula II: R = OCH ,; F. 188 to 189 ° C and [x] "= +31 '(c = 0.501, in pyridine)] are dissolved in 80 ccm of pyridine in a nitrogen atmosphere with 20 g of 3,4,5-trimethoxybenzoyl chloride for 16 hours to 75 The mixture is heated to 20 ° C., 80 cc of water are added, the mixture is stirred for 1/2 hour and extracted with methylene chloride. The extract is mixed with dilute hydrochloric acid to a pH of about 1.5, then with water. Ammonia and washed again with water, dried over magnesium sulfate, filtered and evaporated to dryness. The resin obtained in this way is dissolved in benzene and the solution poured over 500 g of neutral aluminum. The first elution with 1000 cc of methylene chloride gives 2 g of resin, which is not directly The second elution with 1000 cc of methylene chloride containing 10 % methanol yields 8 g (69 ° / 9 of the Theory) levorotatory 18ß- (3 ', 4', 5'-trimethoxybenzoyloxy) -11.1 7a-dimethoxy-3-oxo-16β-methoxycarbonyl-2,3-seco-20x-yohimban; M.p. 126'C; [x] δ = -37 '(c = 1 % in chloroform). Analysis: Cg3H39010N2, molecular weight: 624.67. Calculated ... C 63.5, H 6.3, O 25.67, N 4.49 ° / 9; Found ... C 63.3, H 6.4, O 25.6, N 4.4 ° / o. The connection has not yet been described in the literature. b) Preparation of 3,4-dehydroreserpine of the formula I [R1 = OC -C, H2 (O C H3) 3; R = OC H3] from levorotatory 18ß- (3 ', 4', 5'-trimethoxybenzoyloxy) -11,17a-dimethoxy-3-oxo-16ß-methoxycarbonyl-2,3-seco-20x-yohimbane is heated a solution of 4 g of the compound obtained in step a) in 8 cc of phosphorus oxychloride in a nitrogen atmosphere under reflux for 2 hours. The initially green color of the solution changes to dark red-orange. The cooled solution is introduced into a mixture of 150 g of ice and 8 cc of perchloric acid at 55 ° B6 with stirring and nitrogen. It is suctioned off and washed with water. After drying in vacuo, 4.46 g of crude perchlorate of 3,4-dehydroreserpin are obtained, which corresponds to a yield of 98%. The product can be purified by recrystallization by dissolving it in chloroform or in methylene chloride and then adding benzene or ethyl acetate. The 3,4-dehydroreserpin perchlorate purified in this way melts at 230 ° C .; [x] ö ° _ -128 ° (c = 1 ° / a in aqueous tetrahydrofuran with 55% water). Analysis: C "H390" N, Cl, molecular weight: 707.11. Calculated ... C 56.05, H 5.56, N 3.96 ° / a; Found ... C 56.01, H 5.62, N 4.04 ° / o. The connection has not yet been described in the literature.

UV spectrum in 95% alcohol: itmax = 360 m # t, 266% t; E = 25,000, 17,100.

The dextrorotatory 18ß-oxy-11,17a-dimethoxy-3-oxo-16ß-methoxycarbonyl-2,3-seco-20a-yohimbane required as starting material is prepared as follows: A solution of 120 cc of anhydrous methanol with a content of 0 is prepared . [a] 0 = -I-31 ± 2 ° (c = 0.5% in ethanol)], the preparation of which is described in German patent 1096 363. The mixture is then refluxed for 1 hour, then cooled and acidified to pH 5 by adding acetic acid (about 1 cc). By distilling off the solvent, it is concentrated to about half the volume and cooled to about 10 ° C. The dextrorotatory 18β-oxy-11,17a-dimethoxy-3-oxo-16β-methoxycarbonyl -2,3-seco-20x-yohimban crystallizes. The precipitation is completed by adding 100 cc of water, suction filtered, washed with water and dried. In this way, 8.1 g of dextrorotatory 18β-oxy-11,17a-dimethoxy-3-oxo-16β-methoxycarbonyl -2,3-seco-20a-yohimbane, which corresponds to a yield of 89%, after recrystallization from methanol, the compound has the following characteristics: mp 188 to 189 ° C; [x] δ = +31 '(c = 0.5 ° / p in pyridine). Analysis: C "Hg006N" Molecular Weight: 430. Calculated ... C 64.16, H 7.02, O 22.30, N 6.51 ° / 0; Found ... C 63.9, H 7.1, O 22.40, N 6.5 ° / o. The connection has not yet been described in the literature.

The dextrorotatory 18ß-Oxy-11,17a-dimethoxy-3-oxo-16ß-methoxycarbonyl-2,3-seco-20x-yohimban can also be prepared in the following way: 2 g levorotatory lactone des 18ß-Oxy-11,17a- dimethoxy-3-oxo-16β-carboxy-2,3-seco-20x-yohimbans of the formula IV [R = OCH ,; M.p. 175 ° C; [a] ö = -83 ° (c = 0.25% in ethanol)] are dissolved in 100 cc of anhydrous methanol and mixed with 12 cc of a sodium methylate solution containing 1 mg of sodium per cc of methanol. The mixture is refluxed for 2 hours, cooled to 20 ° C., acidified to pH 5 with acetic acid and the methanol is evaporated off in vacuo. The residue is dissolved in methylene chloride, the solution is washed with dilute ammonia up to pH 10 and then with water and finally dried over magnesium sulfate. After filtering and distilling off the methylene chloride, the residue is recrystallized from acetone and 2 g of the desired compound is thus obtained, which corresponds to a yield of 92%. Example 2 a) Production of levorotatory (chloroform) 18β - (3 ', 4', 5'-trimethoxybenzoyloxy) - 17x - methoxy-16ß-methoxycarbonyl-3-oxo-2,3-seco-20x-yohimbane from dextrorotatory (tetrahydrofuran with 50% water) 18ß-Oxy-17a-methoxy-16ß-methoxycarbonyl-3-oxo-2,3-seco-20ca-yohimban of the formula II [R = H] 6 g right-handed (tetrahydrofuran with 5001, water) 18β-Oxy-17α-methoxy-16β-methoxycarbonyl-3-oxo-2,3-seco-20oc-yohimbane, dissolved in 60 cc of anhydrous pyridine, are heated to 75 ° C. with 15 g of trimethoxybenzoyl chloride under nitrogen for 16 hours. The mixture is cooled to 20 ° C., 60 cc of water are added, the mixture is stirred for 1/2 hour and extracted with methylene chloride. The extract is washed with dilute hydrochloric acid to a pH of about 1.5, then with water, ammonia and again with water, dried over magnesium sulphate, filtered and evaporated to dryness. The resin thus obtained is purified by chromatography on aluminum oxide. It is dissolved in benzene and passed through 400 g of neutral aluminum oxide and a first elution is then carried out with 800 cc of methylene chloride, which gives a resinous product. A second elution with methylene chloride containing 1 % methanol gives a partially crystallized product which is purified by dissolving in 50 cc of acetone and precipitation in 500 cc of ice-cold water. The yield of levorotatory 18β- (3 ', 4', 5'-trimethoxybenzoyloxy) -17ca-methoxy-16β-methoxycarbonyl-3-oxo-2,3-seco-20x-yohimbane is 7 g; M.p. 130'C, [«] δ ° _ -40 ± 1.5 ° (c = 10 /, in chloroform). The product forms microscopic prisms that solvate with water. The connection is slightly hygroscopic. Left to stand in the air, it absorbs 1 to 1.7 per cent of water. It is insoluble in water, dilute aqueous acids, dilute aqueous alkalis and isopropyl ether, sparingly soluble in ether and carbon tetrachloride and soluble in benzene, chloroform, acetone and ethanol. Analysis: C "H" 08N2, molecular weight: 594.64. Calculated ... C 64.63, H 6.44, O 24.22, N 4.71% ; Found ... C 64.8, H 6.4, O 24.5, N 4.6 ° / o. The connection has not yet been described in the literature.

b) Production of levorotatory (chloroform) 18ß - (3 ', 4', 5'-trimethoxybenzoyloxy) - 17x - methoxy-16β-methoxycarbonyl-3,4-dehydro-20x-yohimban of the formula 1 [R = H; R, = CO - C., H2 (OCH3) 3] from levorotatory (chloroform) 18ß- (3 ', 4', 5'-trimethoxybenzoyloxy) -17a-methoxy-16ß-methoxycarbonyl-3-oxo-2, 3-seco-20a-yohimban Mix 3 g of the according to step with stirring and nitrogen a) obtained ester and 6 cc of phosphorus oxychloride and heated slowly to boiling under Reflux. Solution occurs. After boiling for 31/2 hours cools the solution is reduced to 20 ° C., diluted with 6 cc of acetone and slowly accommodated Stir in a mixture of 120 g pieces of ice and 6 cc perchloric acid at 55 ° Be a. The yellow perchlorate of 3,4-dehydrodeserpidine formed is suctioned off and washes it with water until the pH of the wash water reaches 4. To the distance dissolves of existing traces of phosphate and hydrochloride of 3,4-dehydrodeserpidine the compound thus obtained in 350 cc of a mixture of ice and water, the Contains 10 cc of perchloric acid of 55 ° B6, stirs for 10 minutes and sucks the yellow crystalline Precipitate off, wash it with water until the wash water has a pH of 3 to 4, and dry it in a vacuum. 3.23 g of the perchlorate are obtained in this way of 3,4-dehydrodeserpidine, which corresponds to a yield of 940 / q. For analysis the salt is purified by dissolving it in chloroform or methylene chloride and adding Ethyl acetate. The product then forms small, light yellow sticks. It is solvated to 4 to 4.5 0 / Q. The melting point is 214 ° C, the optical rotation [x] '1)' = -50 ± 3 ° (c = 10 / Q in aqueous tetrahydrofuran with 55 0 / Q of water) for the solvated product, which gives a [a] .ö = -52 ± 3 ° for the dry substance is equivalent to. The compound is insoluble in water, ether, benzene and absolute alcohol, Slightly soluble in aqueous ethanol and chloroform and in methylene chloride and aqueous Tetrahydrofuran readily soluble in 50% water.

The UV spectrum in n / 10 alcoholic hydrochloric acid determined and calculated with the dry product has the following bands: a.ax 356 m (t, a = 24 400.), Max 253 to 254 mp., A = 15 800. Analysis : C32H37012N, Cl; Molecular weight: 677.10. Calculated C 56.76, H 5.51, O 28.36, N 4.13, Cl 5.24 ° / o; Found C 58.8, H 5.5, O 28.7, N 4.3, Cl 5.2 O / Q. The dextrorotatory (tetrahydrofuran with 50% of water) 18ß-oxy-17a-methoxy-16ß-methoxycarbonyl-3-oxo-2,3-seco-20a-yohimbane of the formula 1I (R = H) is used as starting material Prepared way: a) A suspension, cooled to a temperature between -10 ° and 0 ° C., of 8.5 g of 1β-carboxymethyl-2β-methoxycarbonyl-3a-methoxy-4β-acetoxy-6β-formyl-cyclohexane in 34 cc of methylene chloride is added with mechanical stirring and under nitrogen, a solution of diazomethane in methylene chloride is added until a slight excess of the methylating agent is found. Methylene chloride is distilled off in vacuo without exceeding 5 ° C. until the volume of the starting suspension is reached again. The mixture is then cooled to -10 to -15 ° C., 4.8 g of tryptamine are added while stirring, the mixture is stirred for a further 3 hours at the same temperature, cooled to -20 to -30 ° C., diluted by adding 34 cc anhydrous methanol, 1.3 g of potassium borohydride are added, stirring is continued for 15 minutes at -10 ° C. and the temperature is then allowed to rise to 20 ° C. in about 1/2 hour. When the reduction is complete, the excess potassium borohydride is destroyed by adding acetic acid up to a pH of 4 to 5 and evaporated to dryness in vacuo. The greasy residue obtained in this way is taken up in 80 cc of chloroform and 30 cc of water. The aqueous layer is decanted and extracted again with chloroform, the chloroform extracts are combined and washed first with 2N hydrochloric acid, then with a saturated aqueous sodium bicarbonate solution and finally with water until neutral. The chloroform extract is dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is taken up in the warmth in 60 cc of isopropanol, from which about 25 cc is distilled off in vacuo. The levorotatory 18ß-acetoxy -17a-methoxy -16ß-methoxycarbonyl-3-oxo- 2,3 seco-20a-yohimbane crystallizes. The mixture is left to crystallize overnight, filtered off with suction, washed with isopropanol and dried. 7.8 g of levorotatory 18ß-acetoxy-17a-methoxy-16ß-methoxycarbonyl-3-oxo-2,3-seco-20a-yohimbane are obtained in this way; M.p. 180.5 ° C; [a] δ = -14.5 ± 1.5 ° (c = 10 / Q in chloroform). The product is insoluble in water and dilute aqueous acids, sparingly soluble in alcohol, ether and benzene and soluble in acetone and chloroform. It can easily be recrystallized from isopropanol or 2 volumes of methyl isobutyl ketone. Neither the melting point nor the rotational ability of the substance are changed by the recrystallization. Analysis: C2qHg006N2, molecular weight: 442.50. Calculated ... C 65.14, H 6.83, O 21.70, N 6.33 O / Q; Found ... C 65.1, H 6.8, O 21.5, N 6.3 O / Q. The connection has not yet been described in the literature.

ß) 1.68 g of the compound obtained in step a) above, 17 cc of methanol and 3.4 cc of an anhydrous solution of sodium methylate containing 5 g of sodium methylate per liter are heated to reflux for 1 hour. It is then cooled to 20 ° C., acidified to a pH of 4 to 5 by adding 0.1 cc of acetic acid and 10 cc of methanol is distilled off under nitrogen. On cooling, the dextrorotatory (tetrahydrofuran with 50 ° 10 water) 18β-oxy-17a-methoxy-16β-methoxycarbonyl-3-oxo-2,3-seco-20a-yohimbane of the formula II [R = H] crystallizes out. 16 ccm of water are added slowly while stirring, the product is filtered off with suction, washed with water, again filtered off with suction and dried. 1.45 g of the desired product are thus obtained, which corresponds to a yield of 94%; 192.5 to 193.5 ° C. For analysis, it is recrystallized from boiling methanol. The compound then has a melting point of 193 to 194 ° C. and an optical rotation value [a] δ = +38 ± 1.5 ° (c = 10 / Ω in tetrahydrofuran with 500 / Ω water). The compound is insoluble in water, dilute aqueous acids, dilute aqueous alkalis and benzene, very sparingly soluble in acetone, chloroform and ether, sparingly soluble in ethanol and soluble in 9 volumes of boiling methanol and in tetrahydrofuran with 500/0 water. Analysis: C22H2805N2; Molecular weight: 400.46. Calculated ... C 65.98, H 7.05, O 19.98, N 7.00 O / Q; Found ... C 66.1, H 7.0, O 20.2, N 7.2 O / Q. The connection has not yet been described in the literature. Example 3 a) Preparation of dextrorotatory (chloroform) 18β- (3 ', 4', 5'-trimethoxycinnamyloxy) -11,17a-dimethoxy-16.-methoxycarbonyl-3-oxo-2,3-seco-20a-yohimbane from dextrorotatory (pyridine) 18ß-oxy-11,17oc-dimethoxy-16ß-methoxycarbonyl-3-oxo-2,3-seco-20a-yohimbane of the formula 11 [R = OCHS] esterified under the conditions described in Example 2 1 g dextrorotatory (pyridine) 18ß-oxy-11,17a-dimethoxy-16ß-methoxycarbonyl-3-oxo -2,3-seco-20a-yohimbane, which was obtained according to the procedures given in the preceding examples for the preparation of the starting materials, with 2.8 g of 3,4,5-trimethoxycinnamic acid chloride. After the product obtained has been chromatographed on aluminum oxide and the fraction rich in the desired compound has been separated off, it is evaporated to dryness, taken up in a minimum of acetone and the solution is poured into a large amount of water. The precipitated compound is suctioned off, stirred with 15 to 20 cc of ice-cold water, suctioned off again and dried in vacuo at 70.degree. The yield of 18ß- (3 ', 4', 5'-trimethoxycinnamyloxy) -11,17a-dimethoxy-16ß-methoxycarbonyl-3-oxo-2,3-seco-20a-yohimbane, which is sufficiently pure for cyclization with phosphorus oxychloride, is 67 ° /O. To prepare the analytically pure product, a second crystallization from aqueous acetone is carried out. After drying in vacuo at 70 ° C, the compound melts at 123 to 125 ° C; [x] o ° = -r7 y1.5 ° (in chloroform). The undried compound contains about 1.7% water of solvation. The compound thus obtained is insoluble in water, dilute aqueous acids, dilute aqueous alkalis and ethers, and is readily soluble in alcohol, acetone, benzene and chloroform. Analysis: C35H42010N2, Molecular Weight: 650.71. Calculated ... C 64.59, H 6.51, O 24.58, N 4.31%; Found ... C 64.5, H 6.5, O 24.7, N 4.2 ° / o. The connection has not yet been described in the literature.

b) Production of levorotatory (tetrahydrofuran with 50% water) 3,4-dehydrorescinnamine I [R = O C H 3; R1 = O C - C H = CH-C, H2 (OCH3) 3] from clockwise (Chloroform) 18β- (3 ', 4', 5'-trimethoxycinnamyloxy) -11,17a-dimethoxy-16β-methoxycarbonyl-3-oxo-2,3-seco-20a-yohimbane 2 g of the compound prepared in step a) and completely dehydrated are added one under nitrogen with 4 cc of phosphorus oxychloride and heated without the gas flow interrupt, reflux for 2 hours. Then it is left at room temperature cool, dilute with 2 cc of acetone and quickly pour the solution into a mixture 80 g ice and 4 cc perchloric acid of 55 ° Be. The light yellow substance thus formed is sucked off, made into a paste with 15 to 20 ccm of water in several portions until the The pH of the wash water is 4 to 5. It is filtered off with suction, dried in vacuo and obtained in theoretical yield (2.26 g) 3,4-dehydrorescinnamine perchlorate.

For analysis, the perchlorate is purified by dissolving it in methylene chloride and adding benzene until there are 3 volumes of benzene per volume of methylene chloride. After cooling, the precipitated substance is suctioned off, washed with benzene and dries. The melting point of the compound is 190: L2 °. The product is about 8% solvated; [a] ö = -116 ± 3 '(c = 10 /, in tetrahydrofuran with 55% water), which corresponds to an [oc] ö = -126 ± 3 ° for the dehydrated product.

The UV spectrum in n / 10-ethanolic hydrochloric acid, determined with a product solvated to be 6.60 /, shows the following bands: @max 314 m # L, E = 19,900, corresponding to 21,400 for the dehydrated product.

amax 268 mtj ,, e = 9 550 corresponding to 10 250 for the dehydrated product. @ ma @ 389 m # t, a = 22 850 corresponding to 24 5000 for the dehydrated product. The connection is insoluble in water, dilute aqueous acids, ether and benzene, in alcohol sparingly soluble and readily soluble in acetone and chloroform. Analysis: C "H" 01aN, Cl, molecular weight: 733.22. Calculated C 57.33, H 5.64, O 28.37, N 3.82, Cl 4.83%; found: C 57.2, H 5.8, O 28.1, N 3.8, Cl 5.1%. The connection is not yet in the literature described.

Claims (1)

PATENT CLAIM: Process for the preparation of the perchlorates of 18ß-acyloxy-17a-methoxy-16ß-methoxycarbonyl-3,4-dehydro-20a-yohimbanes of the general formula wherein R is a hydrogen atom or a methoxy group and R1 is a 3,4,5-trimethoxybenzoyl or 3,4,5-trimethoxycinnamyl radical, characterized in that a dextrorotatory 18β-oxy-17oc-methoxy-16β-methoxycarbonyl-3-oxo -2,3-seco-20a-yohimban of the general formula esterified with the chloride or anhydride of 3,4,5-trimethoxybenzoic acid or 3,4,5-trimethoxycinnamic acid in the presence of a tertiary base, the ester thus obtained cyclized by treatment with phosphorus oxychloride at elevated temperature and the 3,4-dehydroyohimbane derivative obtained as Separates perchlorate. Publications considered: Journ. amer. chem. soc., 78 (1956), pp. 2023 and 2024; Helv. Chim, acta, 37 (1954), pp. 69 and 70. Older patents considered: German Patent No. 1088 062.