DE1054460B - Process for the production of reserpine and optionally deserpidine - Google Patents

Description

GERMAN S

The invention relates to a method for obtaining reserpine and optionally deserpidine.

It is already known to separate alkaloids from their solutions in the form of a "sparingly soluble" salt (see R. H. F. Manske and H. L. Holmes, The Alkaloids, Chemistry and Physiology, Vol. 1, 1950, Pp. 12 and 13). Also the purification of reserpine by reacting with for salt formation with weak Bases suitable acids or salts is already z. As described in British Patent 734,108 been. These processes lead to the alkaloids mentioned, but to the recovery of the pure ones However, alkaloids usually required special purification methods, such as chromatography or the repeated fractional crystallization.

It has now been found that reserpine can be obtained in high purity in a simple manner and thus a good separation of reserpine and deserpidine is achieved when the reserpine is converted into the hydrohodanic acid Salt transferred.

In comparison with the known "poorly soluble" salts of reserpine (cf. Helvetica Chimica Acta, Vol. 37, 1954, p. 68), the hydrohodanic acid salt now shows surprising solubility properties, as the following information shows. ^a 5

A. Precipitation of Reserpin Salts from Aqueous
acetic acid

^{1 cm 3 of} a 50% aqueous potassium ^{thiocyanate solution or 1 cm 3 of} a 5 N sulfuric ^{acid solution or 1 cm 3 of} a 5 N hydrochloric acid solution were added to each 20 cm ^{8 of} a solution of the reserpine concentration given below in aqueous acetic acid, and the resulting solution inoculated with the appropriate reserpine salt. After standing for 1 hour, the crystals formed were filtered off, dried at 60 ° C. in a high vacuum for 5 hours and weighed.

Reserpine concentration Amount d
Rese
(to a
Rhodanide it auskrista
rpine salt 1
set R
eloquent)
sulfate IIized
n ° / o
eserpin
Hydro
chloride 1. in 5η aqueous vinegar
acid
5: 1000
5: 10000
5: 100000 ~ 100%
~ 10Q%
~ 100% ~ 80%
0%
0% ~ lOOO / o
0%
O ^e / »

Process for the production of reserpine and optionally deserpidine

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. Ε. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority: Switzerland from April 9 and July 31, 1956

Dr. Alfred Becker, New World, and Dr. Max Feurer, Riehen (Switzerland), have been named as the inventor

Reserpine concentration

2. in 2N aqueous acetic acid

5: 1000

5: 10000

5: 100000

5: 1000000

3. in 1 η aqueous acetic acid

5: 1000

5 -10000

5: 100000

5: 1000000

Amount of crystallized reserpine salt in% (based on reserpine used calculated)

Hydro

Rhodanide

~ 100% ~ 100% ~ 100% ~ 100%

~ 100% ~ 100% ~ 100% ~ 100%

sulfate

~ 95% 0% 0%

O ⁰ / «·

-85% 0% 0% 0%

chloride

400% 0% 0% 0%

B. Precipitation of reserpine salts from aqueous acetic acid (using reserpine hydrochloride or reserpine sulphate as starting compound)

Determination is carried out according to the method under A, with an equivalent in place of the reserpine base Amount of reserpine hydrochloride or reserpine sulfate was used as the starting compound.

£ 09 789/495

Reserpine concentration

Reserpine hydrochloride
in 1 η aqueous acetic acid

5: 10000

5: 100000

5: 1000000

Reserpine Sulphate in In
aqueous acetic acid

5: 10000

5: 100000

5: 1000000

Amount of crystallized reserpine salt in% (based on reserpine used calculated)

Hydro

Rhodanide

~ 100% ~ 100% ~ 95%

~ 100% ~ 100% ~ 90%

sulfate

0% 0% 0%

chloride

0% 0 ° / o 0 ° / o

C Precipitation of reserpin salts from a mixture of methanol, glacial acetic acid and ether

Reserpine concentration

1. in methanol-glacial acetic-ether = 1: 1: 8

1: 1000

1: 10000

2. in methanol-glacial acetic acid-ether = 1: 1: 8

1: 100000

Amount of crystallized reserpine salt in ° / o

(calculated on the reserpine used)

Rhodanide

~ 100% ~ 70%

Hydrochloride

-40% 0%

60% 0%

D. Precipitation of Reserpin Salts from a Mixture

of methanol, glacial acetic acid and benzene

100 mg of reserpine were dissolved in a mixture of 1 cm ^{3 of} methanol and 1 cm ^{3 of} glacial acetic acid in a 100 cm ³ measuring bottle, and the solution was made up to 100 cm ³ with benzene. To 20 cm ^{3 of} this solution were added 2 cm ^{3 of} an ethereal solution of hydrofluoric acid, with oily reserpine rhodanide immediately separating out. Rubbing the glass wall with a glass rod or inoculating the solution solidifies the oil, yield approx. 98%.

Under the appropriate conditions, hydrochloric acid does not precipitate, only a slight cloudiness, which disappears again when heated to 50 to 60 ° C.

E. Precipitation of Reserpine and Deserpidine Rhodanide

from a chloroform solution

Reserpine dissolves in any amount in chloroform. A saturated solution is added to such a solution Solution of hydrofluoric acid in chloroform and such an amount of ether as that obtained Total volume corresponds. The reserpine rhodanide crystallizes out immediately. After filtering off it is washed and dried in vacuo at 0.3 torr and 60 ° C for 3 hours; the yield is 95%, calculated on the reserpine used.

Under the same conditions, starting from deserpidine instead of reserpine, deserpidine rhodanide falls not from. The deserpidine rhodanide is only obtained in crystalline form, yield about 90%, when 15 times the amount of ether is added to the chloroform solution.

The starting materials to be used for salt formation according to the process of the invention can be of various origins, e.g. B. It can be reserpine and other weakly basic alkaloids, such as deserpidine, containing extracts from plants of the Rauwolfia or Alstonia species. Are particularly suitable from ίο following plant extracts obtained: Rauwolfia vomitoria Afzelius, Rauwolfia canescens, Rauwolfia serpentina Benth, Rauwolfia inebrians, Rauwolfia indecora and Alstonia constricta F. Mueller whose recovery is known.. It is Z. B. possible to use a benzene or toluene extract from these plants, which was advantageously made from moistened plants, especially from roots, as starting materials. Chloroform, ethylene dichloride or trichlorethylene ao or acetone extracts also serve as such. It is also possible to start from an impure reserpine or to use a Rauwolfia or Alstonia extract from which most of the reserpine has already been removed and which contains a mixture of residual reserpine and deserpidine. One can also start from mother liquors which are obtained after the first crystallization of reserpine, preferably from those which contain deserpidine and the remaining reserpine in an approximate ratio of 1: 1.
Depending on the choice of starting materials, the process can be used to obtain reserpine and deserpidine, to purify reserpine, to work up reserpine mother liquors for reserpine and deserpidine or to separate reserpine-deserpidine mixtures.

One embodiment of the method consists in that the solutions containing the reserpine treated with hydrofluoric acid, separating the poorly soluble alkaloid rhodanides formed, this is converted into the free bases and the reserpine is separated from it by crystallization and, if it it is desirable that the deserpidine be obtained from the mother liquors obtained in both cases.

Another possibility to make the mentioned separation is that you are in a reserpine containing solution only the reserpine precipitates as a rhodanhydrous acid salt, namely with the for the conversion of the reserpin present into the hydrohodanic acid salt calculated amount of hydrohodanic acid.

A solution of the starting material in an organic solvent, in which the reserpine rhodanide is sparingly soluble, optionally mixed with water. It are suitable z. B. Solutions in halogenated aliphatic hydrocarbons, such as chloroform, methylene chloride, Ethylene chloride, trichloroethane, low molecular weight alcohols such as ethanol or methanol, ethers, such as Dimethyl ether, or fatty acids, such as acetic acid, or mixtures thereof, such as chloroform-ether, chloroform-methanol, Methanol-water or methanol-acetic acid. The rhodanic acid can used as such or also only formed in the reaction solution. You can z. B. in the Form of their salts, such as the alkali or alkaline earth salts, e.g. B. potassium, calcium or ammonium rhodanide, use. In this case the reaction solution should contain an acid, preferably acetic acid or phosphoric acid to release the Rhodanwasser-

chemical acid is used. However, it is also possible to start from a reserpine salt, with hydrofluoric acid is obtained by double conversion and the reserpine rhodanide is formed at the same time.

From the reaction solution, the Alkaloidrhodanid can in a simple manner, for. B. by filtering, be separated. It can be in the usual way, for. B. by treating with alkaline agents such as Ammonia, or caustic soda, convert into the free bases that make up the reserpine by the usual Crystallization can be obtained in pure form. It is particularly advantageous to use the salt in aqueous methanol Treat solution with ammonia, whereby the pure reserpine crystallizes out.

Depending on the amount of deserpidine present in the starting material and the amount of hydrofluoric acid used the separated salt can also contain deserpidine thiocyanate. Upon release of the bases and the subsequent crystallization, deserpidine remains as a more soluble alkaloid in the Solution and can be obtained therefrom in a known manner.

The invention is described in more detail in the examples below. Between part by weight and Volume part has the same relationship as that between grams and cubic centimeters.

example 1

1 part by weight of powdered extract from Rauwolfia vomitoria Afz. or Rauwolfia serpentina Benthic roots is dissolved warm in a mixture of 2 parts by volume of glacial acetic acid and 8 parts by volume of methanol, 6 parts by volume of water are added to the solution while stirring and the precipitate is filtered off. The filtrate is inoculated with reserpine rhodanide at 60 ° C. With stirring, 1 part by volume of 50% aqueous solution is added to the mixture Potassium rhodanide solution given. The mixture is left to stand for a few hours at room temperature and then sucks off the reserpine rhodanide formed. The residue is washed with methanol. the Yield is 0.21 part by weight of crude reserpine rhodanide.

1 part by weight of reserpine rhodanide is dissolved in 8 parts by volume of methanol and 4 parts by volume of 3.5% ammonia slurried and the mixture stirred at 60 ° C internal temperature for 30 minutes. After cooling down the mixture is allowed to stand for a few hours at room temperature and then the released is sucked off Reserpine off. It is washed with water, methanol and methanol-ether. 0.82 parts by weight are obtained pure reserpine, F. = 265 to 270 ° C.

The extract used as the starting material can be prepared according to those described in US Pat. No. 2,752,351 Procedures are obtained. You can z. B. 1 part by weight of ground roots of Rauwolfia serpentina Benth. or Rauwolfia vomitoria Afz. Moisten evenly with 1 volume part of water. the Roots are then refluxed with 5 to 10 parts by volume of toluene for 5 to 7 hours, with the boiling temperature of the toluene is adjusted to about 65 ° C. with an appropriate vacuum. The bright Brownish toluene extract is separated from the water present and evaporated to dryness in vacuo.

65

Example 2

1 part by weight of raw reserpine is in a mixture of 2 parts by volume of methanol and 2 parts by volume Glacial acetic acid dissolved at about 60 ° C. At 60 ° C internal temperature and with stirring, the solution

6 parts by volume of water are added and the resulting deposits are filtered off. The clear filtrate is inoculated with reserpine rhodanide, and 0.4 parts by volume of 50% aqueous potassium rhodanide solution are added at 60 ° C. with stirring. After cooling, the mixture is left to stand for a few hours and then filtered. The suction filtered reserpine rhodanide is washed with methanol, the yield is 1.1 parts by weight of reserpine rhodanide.
1 part by weight of reserpine rhodanide is suspended in 8 parts by volume of methanol and 4 parts by volume of 3.5% ammonia and stirred at an internal temperature of 60 ° C. for 30 minutes. After cooling, the mixture is left to stand for a few hours at room temperature and the reserpine is then filtered off with suction. The residue is washed with water, methanol and methanol-ether. Pure reserpine is obtained in a yield of 0.93 parts by weight.

Example 3

A mixture of 0.05 parts by weight of reserpine and 0.05 parts by weight of deserpidine is dissolved in 2 parts by volume of chloroform and 50 parts by volume of ether and drop 10 parts by volume of a solution of rhodanic acid, the 0.1 η methanolic ammonium thiocyanate solution by adding 10 parts by volume 10 parts by volume of methanol and 2 parts by volume of glacial acetic acid and make up with ether to a volume of 100 parts by volume is obtained, with stirring. This mixture is made with 25 parts by volume of petroleum ether offset. After 15 minutes, the reserpine rhodanide which has separated out is filtered off and washed with ether. 0.066 parts by weight of reserpine rhodanide are obtained; F. = 239 to 240 ° C with decomposition. The filtrate that contains essentially deserpine, is extracted 7 times with 25 parts by volume of 2N acetic acid, the acidic solution made alkaline with ammonia with cooling and the resulting base mixture through Separated by filtration. 0.037 part by weight of a mixture consisting of 85% deserpidine and 15% Reserpine exists.

Example 4

If you take only 9 parts by volume instead of the 10 parts by volume of the rhodanic acid solution and proceed Otherwise, as in Example 3, 0.062 part by weight of reserpine rhodanide and 0.041 part by weight are obtained Deserpidine, which still contains 22% reserpine.

Example 5

0.065 parts by weight of a deserpidine-reserpine mixture obtained according to Example 4, the 22% reserpine contains, are dissolved in 2 parts by volume of chloroform and mixed with 100 parts by volume of ether. To do this there 2.5 parts by volume of the methanolic rhodanic acid solution described in Example 1 are added Add 5 parts by volume of petroleum ether, stir the mixture for 15 minutes and filter it. 0.016 part by weight is obtained Reserpine rhodanide and 0.045 part by weight of a mixture consisting of 87% deserpidine and 13% Reserpine exists.

The reserpine rhodanide obtained in Examples 3 to 5 can, as in Examples 1 and 2, in pure reserpine can be converted.

Example 6

1 part by weight of extract from the roots of Rauwolfia vomitoria Afz. or Rauwolfia serpentina Benth. is in a mixture of 4 parts by volume

Claims (6)

Ethanol and 1 part by volume of glacial acetic acid dissolved at about 60 ° C, treated with 6 parts by volume of water while stirring and the precipitate was filtered off from the still warm water. The filtrate is inoculated with reserpine rhodanide at about 0 ° C., and 0.5 parts by volume of 50% aqueous aluminum rhodanide solution is added while stirring. After standing for a few hours at room temperature, the crude reserpin thodanide is filtered off with suction and washed with methanol. The salt obtained can be introduced into the reserpine as in Example 1. Example 7 1 part by weight of ethylene chloride extract from roots of Rauwolfia vomitoria Afz. or Rauwolfia serpenina Benth. is dissolved in a mixture of 8 parts by volume of methanol and 2 parts by volume of glacial acetic acid at approximately> 0 ° C. At an internal temperature of about 40 ° C. and with thorough stirring, 6 parts by volume of water are added and the precipitate is filtered off from the still warm mixture. The clear filtrate is inoculated with reserpine rhodanide and at an internal temperature of about 60 ° C. with 2 parts by volume of 50% After cooling, the mixture is left to stand for several hours and then filtered. The suction filtered, crude reserpine rhodanide is washed with methanol. It can be converted into free reserpine as in Example 1. Patent claims: 1. Process for the production of reserpine and optionally deserpidine by treating a Solution or mixture containing reserpine and other weakly basic alkaloids, especially deserpidine, contains, with acids or salts suitable for salt formation with weak bases, characterized in that that from the solution or mixture containing the reserpine and deserpidine in As is known, the reserpine salt of hydrofluoric acid precipitates, the resulting reserpine rhodanide converted in the usual way into the free reserpine and optionally from the mother liquors the deserpidine wins. 2. The method according to claim 1, characterized in that the starting solution or - mixture uses an extract, especially benzene, toluene or trichlorethylene extract, ίο from plants of the Rauwolfia or Alstonia species, such as Rauwolfia vomitoria Afz., Rauwolfia canescens or Rauwolfia serpentina Benth., has been obtained. 3. The method according to claim 1 and 2, characterized in that the mother liquor, which was obtained in the first separation of the reserpine by crystallization from the extracts obtained from Rauwolfia plants, is used as the starting solution or mixture.
4. The method according to claim 1 to 3, characterized in that an aqueous, acetic acid and methanolic solution or mixture is used for the reaction. 5. The method according to claim 1 to 4, characterized in that the starting solution is treated with the amount necessary for the conversion of the Reser pine present in its rhodanic acid salt. 6. The method according to claim 1 to 5, characterized in that the reaction is carried out with Carries out hydrofluoric acid in the form of a salt in the presence of an acid. Pamphlets considered;
R. H ₁ F. Manske and HL Holmes, The Alkaloids, Chemistry and Physiology, Vol. 1, 1950, pp. 12 and 13; Helvetica Chimica Acta, vol. 37, 1954, p. 68;
British Patent No. 734 108.