DE1124506B - Process for the preparation of esters of 18beta-oxy-20alpha-yohimbanes and 3-oxo-2,3-seco-18beta-oxy-20alpha-yohimbanes. - Google Patents

Description

GERMAN

PATENT OFFICE

L 30181IVd / 12 ρ

REGISTRATION DATE: 12. A P R I L 1958

NOTICE THE REGISTRATION ANDOUTPUTE EDITORIAL:

I. MARCH 1962

The invention relates to an improved process for the preparation of esters of 18 /? - oxy-20a-yohimbanes and 3-0x0-2,3-5600-18 / 3-oxy-20a-yohimbanes, wherein the ring E has the general formula

Method of manufacture

of esters of 18/3-oxy-20a-yohimbanes

and 3-0x0-2.3-8600-1813-0X7-20 a-yohimbanes

H, COOC

OOC —R

in which R is an alkyl or aralkyl radical, an optionally substituted aryl radical or the 3,4,5-trimethoxystyryl radical and R 'denotes the methoxy or cyano group.

It is known that most of the pharmacologically active compounds are from the reserpine class Esterified in the 18jo position. Deserpidine and reserpine are 18- (3,4,5-trimethoxybenzoic acid esters) des Deserpidine or reserpic acid methyl ester, and the rescinnamine is the 18- (3,4,5-trimethoxycinnamic acid ester) of the reserp acid methyl ester.

In addition, there are other esters in the literature, especially aliphatic, araliphatic, aromatic and heterocyclic, deserpidine or reserp acid methyl ester.

The esterification of the reserp or deserpidic acid methyl ester was previously carried out with the acid chloride respective acid carried out in the presence of pyridine. It was also suggested initially optionally in the 9, 10, 11 and / or 12 position substituted 18 /? - oxy-17 «-methoxy-16 / J-methoxycarbonyl-3-oxo-2,3-seco-20a-yohimbane in the presence of pyridine with an acid chloride, e.g. with 3,4,5-trimethoxycinnamic acid chloride or3,4,5-trimethoxybenzoic acid chloride, to esterify, these esters to 3,4-debydroreserpine, -deserpidine or -rescinnamine to close the ring and the unsaturated esters obtained to reduce. In this way of working, especially for the total synthesis of the effective Rauwolfia alkaloids is significant, is therefore also the 18-digit Hydroxyl group esterified.

The esterification methods described in the literature, in which the chloride of the respective Carboxylic acid used in the presence of pyridine gives only moderate yields that are common around 70%, and also require rather troublesome purification of the reaction product Chromatography or crystallization. The same is true when using 3,4,5-trimethoxybenzoic anhydride and pyridine are used. It is known that the applicant:

Les Laboratoires Francais de Chimiotherapie, Paris

Representative: Dr. F. Zumstein,
Dipl.-Chem. Dr. rer. nat. E. Assmann
and DipL-Chem. Dr. R. Koenigsberger,

Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority:

France of July 25, 1957 (No. 744 092)
20th

Dr. Robert JoIy, Montmorency, Seine-et-Oise,
Dr. Robert Bucourt, Villiers-le-Bel, Seine-et-Oise,
and Dr. Edmond Toromanoff, Paris (France),
have been named as inventors

the production of carboxylic acid esters from carboxylic acid anhydrides and alcohols, the esterification rate due to the presence of tertiary Bases promoted and the equilibrium to the carboxylic acid ester is shifted, however, the favorable one Effect of tertiary aliphatic amines in the esterification of hydroxyl groups of the reserpic acid molecule not yet established.

Surprisingly, it has now been found, as can also be seen from the comparative tests, that the above-mentioned esters of 18 /? - oxy-20 "-yohimbanes and 3-oxo-2,3-seco-18 /? - oxy-20a-yohimbanes with yields of over 80% and even over 90% if you get an 18/3-Oxy-20 «-yohimban or a 3-Oxo-2,3-seco-18j8-oxy-20a-yohimban with a Carboxylic anhydride of the general formula

R-CO-R-CO-

wherein R has the meaning given above, in the presence of pyridine and triethylamine in the

209 517/399

3 4

Heat in the absence of air, optionally in the cooling of the tube to 20 ° C, the presence of nitrogen, esterified, the excess contents in a flask equipped with a mechanical stirrer by adding water to the device and diluted first hydrolyzed reaction mixture and from the reaction with 60 ecm pyridine. Then add 70 ecm of distilled water or acid to the mixture, mix the resulting ester by precipitating with 5 without interrupting the stirring, or by extracting the other water, cooling in such a way that the acidified reaction mixture with a with water, the internal temperature does not exceed 20 ° C. Then immiscible organic solvents are separated off, stirring is continued for a further 10 minutes and then cooled and then purified and crystallized. then down to +5 ⁰ C. With constant stirring and In the esterification of Reserpsäuremethylesters io maintaining a temperature below 5 ⁰ C., with 3,4,5-trimethoxybenzoic in counter an additional 70 cc of distilled water. The solution obtained from pyridine and triethylamine becomes cloudy, and the crystallization is obtained by rubbing reserpine in a yield of 92%. If you initiate that on the vessel wall. The trimethoxybenzoic anhydride mixture is left to stand for a few minutes and then, without stirring, 3,4,5-trimethoxycinnamic acid, which has not yet been described, is replaced while maintaining a temperature below 5 ° C. Rescinnamine is obtained in a further 300 ecm of water, cools to 0 ° C and yield of 90% · The methyl deserpidic acid also stirs for 12 hours. The reserpine formed is abester during the reaction with 3,4,5-trimethoxy sucked and with 400 ecm of 0.5N ammonia with a benzoic anhydride in the presence of pyridine and temperature below 5 ⁰ C and then to neutral triethylamine in the deserpidine Yields of the same reaction washed with ice water. You get an order of magnitude. Reserpine containing hydrated water will give the best results. By slowly obtaining, if you heat 25 to 70 parts by volume of triethylamine in vacuo to 100 ° C, you get 4.5 g per 100 parts by volume of pyridine used, but (92% of the calculated amount) pure reserpine, which you can change these proportions without with the natural described in the literature that the yield is a substantial reduction of the product is identical. moves. When carrying out the esterification it is

the 18 /? - oxy-20 «-yohimbane or 3-oxo Example 2 2,3-seco-18j9-oxy-20'-yohimbane with the carboxylic acid anhydride in the presence of pyridine and triethyl rescinnamine of the formula II by esterification of the amin about 10 to 24 hours under pressure and from 30 reserp acid methyl ester with 3,4,5-trimethoxy cinnamon from air to a temperature of preferably acid anhydride in the presence of pyridine and tri-80 To be heated up to 100 ° C. It is also possible to use nitrogen in the ethylamine and reflux. 0.482 g of methyl reserpate, 0.820 g, are added temperature from pyridine and triethylamine work, 3,4,5-trimethoxycinnamic anhydride, 3 ecm water the 35 free pyridine and 0.75 ecm of triethylamine entrained by the gas stream are placed in a tube, Triethylamine replaced by periodic additions. that is closed under vacuum. After 21 hours After cooling the diluted reaction mixture, heating the tube to 96 ° C, it becomes clear brown one with pyridine and water is added to the over-solution with the exclusion of light to 20 ° C shot of the carboxylic anhydride used under cooled and after opening the tube with 4.5 ecm Formation of the triethylamine salt of the corresponding 40 pyridine diluted. One then adds to the mixture Hydrolyze carboxylic acid. By another dropwise within about a quarter of an hour without Addition of water, the resulting ester precipitates, to exceed 20 ° C, 7.5 ecm of water and stir which can be easily cleaned by crystallization. about% hour at 20 ° C to reduce the excess To isolate the ester, it is also possible to hydrolyze the anhydride 3,4,5-trimethoxycinnamic acid, Acidified reaction mixture with a water containing 45. It is cooled to about 0 ° C and 45 ecm of water is added non-miscible organic solvents extra- within one hour without overheating + 5 ° C and proceeding the extract in a manner known per se, whereby the rescinnamine precipitates. Man clean or the ester and the excess which sucks off the precipitate, washes it with ice water the acid derived from the carboxylic anhydride and rubs the product with isopropyl ether. To a mineral acid and the acid with bicarbonate 50 the suction, washing with isopropyl ether and Wash out naten. Drying gives 0.667 g of crude rescinnamine as The following examples explain the pink powder according to the invention (90.5% of the calculated amount). That proper procedures. The instant melt product is made by stirring with reflux points were determined on the maquenne block. Purified boiling methanol. One stirs this The formulas of the compounds obtained are then on a mixture of 1 hour at -5 ° C, sucks the reproduced in the scheme. Precipitate, dries and crystallizes it out

10 volumes of warm butanol around. According to the example 1, act the solution with activated carbon in the heat ".," _1TJ , _T7 . . ■ j τ, is allowed to crystallize and pure rescinnamine, reserpine of the formula I is obtained by esterifying the reserp- _{6o R 24} o _{c {gt] f =} _ _{84 ± 6} p _{(c = p /} chloroform); acid methyl ester with S ^^ rtrimethoxybenzoesaure- _{dag m ÄthaQol be8tim} mte. UV spectrum shows l _max anhydride in the presence of Pyndm and triethylamine _{= m m [A> £ = 54900;} ^ ₌ 3 ^ ₀₄ ^ _{β =} ^e ₂ 6500;

3.32 g reserp acid methyl ester, m.p. 255 ° C, 5 g um- X _min = 258 ΐημ, ε = 7420.

crystallized 3,4,5-triniethoxybenzoic anhydride, the 3,4,5-trimethoxy required as starting material

F. 156 ° C, 10 ecm of pure anhydrous pyridine and 65 cinnamic anhydride is produced in the following way

5 ecm of pure anhydrous triethylamine are put in:

one sealed under vacuum or nitrogen. Dissolve with stirring and exclusion of light

NEN tube heated to 95 to 98 ° C for 14 hours. After 4.76 g of 3,4,5-trimethoxy cinnamon in a stream of nitrogen

5 6

acid in 2.8 ecm triethylamine and 20 ecm technical holding product is with the natural deserpidine Acetone. Without interrupting the stirring, the same mixture is added, the clear yellow solution is mixed with 1.92 g of p-toluene - Example 4

sulfonic acid chloride. After the instant- .. ",,,. ,,, _T. ,,. . , _ ..

The solution immediately forms a white lower 5, ¹ W A , 5 -trimethoxybenzoyloxy) -17 _a -methoxyschlag. The mixture V is heated for ₂ hours for 16 £ methoxycarbo _n yl-3-oxo-2 S-seco ^ -yohimbane boiling under reflux, cooled, 5 drops of formula IV are added by esterifying the 18 ^ -oxy-l 7 " meth-Triäthylanim to to the mixture alkaline to _on oxy-lo ^ methoxycarbonyl-S-oxo ^ 3-seco do cooled on ice and leaves 10 minutes under 20 "-yohirnban _S with 3,4,5-Tnmethoxybenzoesaure-stirring stand. Then one sucks off the precipitate ίο anhydnd in the presence of Pyndm and Triathylamm, washed with ice water and dried over phosphorus. 6 g of 18/3-Oxy-17 «-methoxy-16ß-meth-

acid anhydride. 3.98 g of crude product are obtained (87% oxycarbonyl-3-oxo-2,3-seco-20a-yohimbane, 9 g of the calculated amount); F. 190 to 192 ° C. For 3,4,5-trimethoxybenzoic anhydride, 36 ecm water purification, the product is dissolved in the dark in 80 ecm free pyridine and 24 ecm anhydrous triethylamine dichloroethane under refluxing and 15 24 hours under nitrogen and stirring filtered to 95 ° C. in the heat. After cooling, the triethylamine is continuously added so that crystallization begins; 80 ecm of isopropyl ether is added until the end of the reaction, the mixture is cooled ^{on ice for 1} J for ₂ hours, and the amount of triethylamine present is suctioned off. The pale yellow solution and wash with isopropyl ether. Is then cooled to 2O ⁰ C and dried in vacuo with stirring and with the exclusion of light. 20 Cooling to about 20 ° C within a few minutes The yield of the purification stage is 81%, which is mixed with 36 ecm of water. Stirring is continued, melting point 196 to 197 ° C. The yellow reflections at 20 ° C. continue for 10 minutes, then the 3,4,5-trimethoxycinnamic anhydride, which shows the solution, is poured into a mixture of 300 g of ice and is soluble in without stirring Ether and isopropyl ether, partially soluble 50 ecm hydrochloric acid (35.4%) and brings the pH value in warm acetone and soluble in heat in 25 by adding hydrochloric acid to 1 to 2, whereby 80 times the volume of benzene, in 25 times the volume a precipitate forms. It is extracted with dioxane, in 70 times the volume of ethyl acetate 300 ecm of methylene chloride, poured off, the aqueous and 20 times the volume of dichloroethane is drawn off. Layer with the same solvent again

Analysis: C ₂₄ H ₂₆ O ₉ (molecular weight = 458.4) ^ ⁵ 'combine the organic extracts and wash

r? <: \ _O nai ttctuw _ni , ,,, 3 ° they are calculated with 2N hydrochloric acid, water, a saturated ... C 62.87%, H 5.72%, O 31.4%; Sodium bicarbonate solution and finally with water

found ... C 62.6 / ₀ , H 5.7 / ₀ , O 31.6 / ₀ . _{until a neutral} reaction. The one after drying

The UV spectrum of the extract determined in dioxane solution over sodium sulfate, filter off and shows a maximum at 332 πιμ (ε = 31 800). Reverse obtained for evaporation to dryness in vacuo Process for the preparation of the 3,4,5-trimethoxy- 35 stand is dissolved in 60 ecm acetone, and the acetone cinnamic anhydride is in the context of this invention solution is gradually stirred while stirring Protection not desired. Poured 650 g of ice. The white precipitate formed

is ^{sucked off after x} / 2 hours of stirring and on

Example 3 the filter washed with ice water. After this

Drying in vacuo gives 8.33 g (93.5%

Deserpidine of the formula III by esterifying the de- the calculated amount) 18β- (3 ', 4', 5 ') -trimethoxyserpidic acid methyl ester withSAS-trimethoxybenzoebenzoyloxy-na-methoxy-ie / S-methoxycarbonyl-S-oxo acid anhydride in the presence of pyridine and tri- 2,3-seco-20a-yohimban of the formula IV; 130 ° C .;

ethylamine [ "] *>_=" ^ - [- ΐ ^ ⁰ _(c = i <y i _{o n} chloroform).

500 mg of methyl deserpidate are mixed with 45. . ₁

850 mg of 3,4,5-trimethoxybenzoic anhydride in Example 5

presence of 2 ecm anhydrous pyridine and 1 ecm £ 18 - (3 ', 4', 5'-trimethoxycmnamoyloxy) -11, 17 "-di

anhydrous triethylamine by dissolving Er- methoxy-lö / S-methoxycarbonyl-S-oxo - ^ - seco-

heat to 80 ° C. in a closed reaction vessel 20'-yohimbane of the formula V made from 18 / S-Oxy-II, 17a-diunter Esterified nitrogen. After cooling, there are 50 methoxy-iess-methoxycarbonyl-S-oxo - ^ - secoman to the mixture 2 ecm of water, it leaves 30 mi-20 "-yohimbane by esterification with 3,4,5-trimethoxynutene stand at 20 ° C and acidified with hydrochloric acid to cinnamic anhydride in the presence of pyridine and to a ρπ value of 1, creating a lower triethylamine

blow forms. It is extracted with methylene chloride The procedure is as in Example 1, but with

and washes the extract with η-hydrochloric acid, water, 55 turns of 1.640 g of the ammonia prepared according to Example 2 and again with water, dried it over trimethoxycinnamic anhydride, 1 gl8 ^ -oxy-11,17 -di-magnesium sulfate, filtered, treated methoxy-16ß-methoxycarbonyl-3-oxo-2, 3 -seco- with activated charcoal and evaporated to dryness in vacuo. The back 20a-yohimban, 6 ecm anhydrous pyridine and 1.5ccm was taken up in 10 ecm methanol and anhydrous triethylamine. After dilution, 6 drops of 2.2 η-nitric acid are added, whereby 60 9 ecm of pyridine and, after the slow addition of 15 ecm, the nitrate of deserpidine crystallizes out. Water is suctioned off, the reaction mixture is poured into a precipitate, rubbed with acetone and neutralized from 60 g of ice and 20 ecm of hydrochloric acid (35.4%). lized with a few drops of ammonia, whereby the resulting fine slurry is released into solution. It is filtered, water is added dropwise, and the mixture is washed with water. The precipitate is added, sucks off and dries. Deserpidine 65 is then obtained in 20 ecm of a cooled to 5 ° C. in a yield of 80%. After the recrystallized aqueous saturated sodium carbonate solution has been sucked up from acetone, the melting point is 235 ^° C .; slurries. After suctioning off, repeat the [«] ?? = -136 ° (c = 0.5% in chloroform). The treatment with sodium bicarbonate solution, sucks off,

7 8

dries and dissolves in 10 ecm acetone. Bonyl-17a-cyan-3 / ?, 20a-yohimbane is treated according to the solution with activated charcoal described in the two and poured under good game 4, with stirring and in a nitrogen environment in a region of the low solubility of this compound from 100 ecm of water, 50 g of ice and 0.5 g of sodium, 20 volumes of pyridine and 10 volumes of triethylamine bicarbonate. The mixture is then stirred for a further 5 works. The yield is 40% of the melt for 1 hour at a temperature of 0 to 5 ° C, sucks point 298 ⁰ C. the precipitate off, washed by trituration with Vergleichsversuehe water and dried in vacuo. The yield 1 «» * · tj -j- - ι. ι the I-esterification of 10-Methoxydeserpidmsauremethylester pure product sufficient for conversion into rescinnamine is 95% of the calculated amount; io a) Experiment in pyridine alone F. = 12O ⁰ C. The following compounds are added to a reaction tube: Example 6:

lSjg-CS '^' ^ '- trimethoxybenzoyloxy-ll.na-dimeth-10-methoxydeserpidic acid ester

oxy-lö / J-methoxycarbonylJ-oxo - ^ - seco- (with 5% water of crystallization) 500 mg

20a-yohimban of the formula VI from 18ß-Oxy-II, 17 «-di- ⁵ 3,4,5-trimethoxybenzoic acid-

methoxy - ^ - methoxycarbonyM-oxo- ^ S-seco-anhydride (150% + excess

20 «-yohimbane by esterification with 3,4,5-trimethoxy- for the water) 750 mg

benzoic anhydride in the presence of pyridine and dried over sodium hydroxide

_{Triethylamine 20} netes pyridine 2.25 ecm

4 g of IS ^ -Oxy-lljna-dimethoxy-lo ^ -methoxycar- The tube is closed under pressure bonyl-3-oxo-2,3-seco-20ix; -yohimbane, 5.8 g of trimeth- of 4 mm of mercury After it was cooled in a chlorooxybenzoic anhydride, 24 ecm of anhydrous pyridine form-dry ice bath, and heated it and 8 ecm of anhydrous triethylamine are then in a bath for 15 hours at 95 to 97 ° C, cools the in the closed vessel under nitrogen to 95 ° C 25 it off, transfers the contents to a flask, which is heated with. After diluting the reaction mixture, a stirrer, a thermometer, a device with 6 ecm pyridine and hydrolysis of the anhydride by means of nitrogen and an addition-addition of 30 ecm water and leaving the device is equipped, with 9 ecm pyridine mixture at 20 ° C is poured into a mixture of rinsing. To set the temperature to 2O ⁰ C 120 g of ice and 37.5 cc of concentrated hydrochloric acid. One 30 is added, 10.5 ecm of water are added in 10 minutes, the mixture is extracted with methylene chloride and the mixture is stirred for 10 minutes at 20 ± 1 ° C., cooled to ⁰ ° C., extract as in example 4. The mixture is added by evaporation of the The residue obtained for 38 minutes at 0 ± 5 ° C. with 68.5 ecm of methylene chloride is dissolved in 50 ecm of water, the crystallization being dissolved by scraping acetone; the resulting acetone solution is excited as soon as the solution gradually becomes cloudy in about 600 g. The mixture is stirred for 1 hour and poured over ice. After suctioning off the temperature between 0 and + 5 ° C, suctioning off the precipitate, washing with water and drying it, washes it with 60 ecm of 0.5N ammonium, you get 5.23 g (90.2% of the calculated amount) hydroxide solution, then abundantly with ice water. One LŠSS-iS ^ S'-Trimethoxybenzoyloxy-lljna-dimeth heating it at a pressure of 4 mm of mercury oxy-Io / S-methoxycarbonyl-S-oxo ^ S-seco ^ Oa-yohim- 40 at 95 to 100 ⁰ C to for constant weight and receives ban of the formula VI; M.p. 126 to 129 ° C; [κ]% = -35 0.66 g of crude product (calculated 0.69 g), corresponding to ± 1.5 °. a yield of 95.5% · The compound melts Example 7 at 140 to 164 ^° C. It is stirred in the heat, "" ,,, ... '". ,,",, ,,. with 3 volumes of methanol, cools to ⁰ ° C., sucks off, 10-Chlordeserprdm of the formula VII by esterification _{45 washes the filter} residue twice with 0.5 ecm of IS ^ oxy-10-chloro ^ - methoxycarbonyl-methanol and heated a pressure of 4mm 17 _Ä methoxy-3ft20 "-yohimban (10 Chlordeser- mercury to a constant weight at 70 to 8O ⁰ C. pidinsauremethylester) with 3,4,5-trimethoxy obtained still impure 10-Methoxydeserpidin; benzoic anhydride in the presence of Pyndm and _{p> 154 to 175} " _{c Nadl dQJ} . _Purification (yield the Iriathylamin _{5o Remigung:} 78.1 o /) amounts to the total yield of 10-Chlordeserpidin is obtained by esterifying 10-Methoxydeserpidin 74.5%.

1.7 g of lO-chlorodeserpidic acid methyl ester according to the procedure described in _{b) γ & ηηάί in p Mia the triethy} i _amine , Example 1 contains 2.54 g,. ^ ₁ . ', " _{,, Tr,.} 2,4,5-trimethoxybenzoic in the presence, ⁱⁿ the reaction tube the following ^em Verbmvon be 6 cc of anhydrous pyridine and 3 cc of water 55 ^dun 8 ^en optionally, free triethylamine in a yield of 81% 10-Methoxydeserpidinsäurevom melting point of 160 to 17O ⁰ C. methylester (with 5% crystal water) 500 mg

Example 8 3,4,5-trimethoxybenzoic acid

Left-handed 18/3 (3 ', 4', 5'-trimethoxybenzoyl- 60 anhydride (150% + excess

oxy) -ll-methoxy-lojS-methoxycarbonyl-noc-cyan- for the water) 750 mg

3 / S, 20 & -yohimbane of the formula VIII dried by esterification over sodium hydroxide

of LS3-Oxy-II-methoxy-lo / S-methoxycarbonyl-netes pyridine 1.5 ecm

17 "-cayn-3 / 3,20a-yohimban with 3,4,5-trimeth- dried over sodium hydroxide-

oxybenzoic anhydride in the presence of pyridine 65 netes triethylamine 0.75 ecm

and triethylamine The procedure is as indicated under a) and is obtained

The compound of formula VIII is obtained by a yield of crude 10-methoxydeserpidine of

Esterification of lSß-Oxy-II-methoxy-lojff-metrioxycar- 94.8%, F. 177 to 184 ⁰ C. The yield of the pure

generation with methanol is 93.7%; F. 178.5 to 184 ⁰ C (the normal melting point is 178.5 ⁰ C). The overall yield of 10-methoxydeserpidine is 88.8%.

The yield and purity of 10-methoxydeserpidine are clearly increased when the esterification is carried out in the presence of triethylamine will.

2. Esterification of reserp acid methyl ester a) Experiment in pyridine alone

The following connections are made in a reaction tube brought:

Reserp acid methyl ester 500 mg

3,4,5-trimethoxybenzoic acid

anhydride 750 mg

Pyridine (water content: 0.15 ecm
per ecm of pyridine) 2.25 ecm

The tube, previously cooled in a chloroform dry ice bath, is closed at a pressure of 3 mm of mercury and heated for 16 hours in a bath, the temperature of which is kept between 95 and 97 ° C., after the contents of the tube have completely dissolved. Cool the tube to 20 ⁰ C, performs the content in a three-necked flask and rinsed with 9 cc of pyridine. Is added to the mixture under cooling in 9 min 10.5 cc of water, with 20 ⁰ C are not exceeded, it is stirred for 10 minutes at 20 ± 2 ° C, cooled and treated at + 6 + J ⁰ C in 4 minutes 10.5 ecm of water. Crystallization does not occur. In 20 minutes at +3 45 cc of water are added to to +5 ⁰ C. The mixture is stirred then for 2 minutes and 30 seconds at a temperature between +2 and +5 ⁰ C, filtered off the precipitate, washed with 60 cc of 0.5 η ammonium hydroxide solution, then with an excess of ice-water. It is dried to constant weight at a pressure of 3 mm of mercury in a bath at 95 to 97 ⁰ C. This gives 634mg reserpine; F. 160 ⁰ C. After recrystallization melt the compound at 228 to 295 ° C.. The reserpine yield is 86.3%.

b) Experiment in pyridine containing triethylamine

The following compounds are placed in a reaction tube:

Reserp acid methyl ester 500 mg

3,4,5-trimethoxybenzoic anhydride 750 mg

Pyridine (water content: 0.15 ecm ^ ⁰

per ecm of pyridine) 1.5 ecm

Triethylamine that was kept overnight 0.75 ecm

It is worked as under a). Crystallization can be achieved easily. 686 mg of reserpine with a melting point of 295 ^° C. are obtained in a yield of 93.4%.

During the esterification of the reserp acid methyl ester with 3,4,5-trimethoxybenzoic anhydride in the presence triethylamine increases the yield and purity of reserpine.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of esters of 18 /? - oxy-20 "-yohimbanes and 3-oxo-2,3-seco-18/3-oxy-20" -yohimbanes, wherein the ring E has the general formula CH OOC —R R ' has, in which R is an alkyl or aralkyl group, an optionally substituted aryl group or the 3,4,5-trimethoxystyryl group and R ' denotes the methoxy or cyano group, characterized in that a 18 /? - oxy-20Ä-yohimbane is used or a 3-oxo-2,3-seco-18 / e-oxy-20 «-yohimbane with a carboxylic acid anhydride of the general formula R-CO- R-CO :O in the presence of pyridine and triethylamine in the heat with the exclusion of air, if appropriate in the presence of nitrogen, esterified the excess acid anhydride by adding water to the reaction mixture hydrolyzed and the resulting ester from the reaction mixture by precipitation with water or Acid or by extracting the acidified reaction mixture with one with water not miscible organic solvents are separated off and then purified and crystallized. 2. The method according to claim 1, characterized in that the esterification is carried out in the presence from 25 to 70 parts by volume of triethylamine per 100 parts by volume of pyridine at one temperature between 80 and 100 ° C. Considered publications:
British Patent No. 744 290;
Helvetica Chimica Acta, 37 [1954], pp. 59 to 75. For this purpose, 1 sheet of drawings © 209 517/399 2.