DE1116678B - Process for reducing quaternary salts of 3,4-dehydroreserpine, 3,4-dehydrodeserpidine, 3,4-dehydrorescinnamine and 3,4-dehydro-11-methyldeserpidine - Google Patents

Description

See Journal of the Organic Chemistry, Vol. 22, 1957, 30

P. 1261, stressed. y

From Experientia, Vol. 12, 1956, pp. 249 and 250 is

it can be seen that there is a 3,4-dehydro derivative used in the acidic environment between the starting compound Reserpine and 3-isoreserpine establish an equilibrium; arises.

in this equilibrium, however, there is at most 15% 35 The reduction is advantageous with the perchlorate Contains reserpine. the 3,4-dehydro compound carried out, but can

In Journal of the Organic Chemistry, Vol. 22, 1957, one also of the crude, through action of p. 1262, is about the reduction of 3,4-dehydro-phosphorus oxychloride on the optically active ester of reserpic acid lactone with sodium borohydride to the reserve 18 / S-Oxy-17 «- methoxy - 3 - oxo - 6ß- methoxycarbonylpinic acid lactone reported. However, this reduction of a compound obtained from Lac-40 2,3-seco-20'-yohimbane, the tons, cannot easily be transferred to the reduction of dehydroreserpsic acid from a mixture of phosphate and hydrochloride. consists, go out, these acids in each case

It has now been found that the stronger perchloric acid can be used in the reduction. as of the above-mentioned 3,4-dehydro compounds with zinc used water-soluble organic solvents and aqueous perchloric acid in the presence of water, for example tetrahydrofuran, dioxane or soluble organic solvents the 3/3-isomers acetone or ethanol or dimethylformamide, obtained in yields of about 80%. To be quantitative individually or as a mixture, in the presence of To obtain yields, the resulting isomeric water becomes the perchloric acid just as good as the perchlorate Mixture with a solvent in which the 3a-iso- of the 3,4-dehydro compound dissolve. The reduction mers is more soluble, and the 3a isomer in the 50 is preferably under refluxing the Recirculated by first adding a solvent or a mixture of the aqueous dehydrated, e.g. B. with mercuric acetate, which carried out as a water-soluble solvent, but

109 738/410

3 4

can also be reduced at low temperature. sucks off the zinc and removes the solvents in the

The perchloric acid is in aqueous solution in a general vacuum at 20 ° C. The reserpine perchlorate crystallizes

mean in a concentration between 2 and 20% siert in the course of the distillation, if the

used. You can also in the presence of crystallization by scratching the walls of the aqueous ferric chloride solution, which is introduced into a volume 5 vessel. The crystals are filtered off with suction and washed

ratio of about 5%> based on the perchlorate mix them with water and dissolve them in without drying them

of the dehydro compound used. 69 ecm boiling acetone with a content of 40%

The ratio of water to the solvents water. The still warm one is added while stirring

exercises a considerable amount. Influence on the reducing solution with 2 ecm concentrated ammonia. It run out. If the proportion of water falls to 10, a cloudiness forms and crystallization sets in

Organic solvent cost, e.g. B. of a. After 2 to 3 minutes, the mixture is cooled

Acetone, is increased, the reduction comes about for about 15 minutes in an ice-water bath. After this

Standstill. The solvent does not only have a suction of the crystals one washes them on the

Influence on the separation of the isomers, but also filters four times with 10 ecm acetone each with a content and mainly on the course of the reduction. 15 of 40% water. They are dried at 90 ^° C. and

When using perchloric acid, 3.4 g of pure reserpine with a temperature of 297 to 298 ° C are obtained

yields obtained by the process of the invention and [<x] l ° = -124 ° ± 3 ° C (c = 1% in chloroform),

of 80% are not solely due to the strength of the acid corresponding to a yield of 76% of the calculated

attributed because the remaining strong acids amount.

give poor results, but it is 20 By evaporating the mother liquors to dryness

a special, unpredictable property of which a mixture of isoreserpine and reserpine is obtained,

Perchloric acid and an effect of the applied which one turns to dehydroreserpine after cleaning

Solvents, such as comparative experiments, which can be dehydrogenated with isodehydration, which is reduced again, reserpine and reserpine were shown

to have. 25 Example 2

The method of the invention therefore consists in one

stereospecific synthesis in which the selected reduction of the perchlorate of 3,4-dehydroreserpin

Acid and the solvent ^{mixture used one with Zmk and} perchloric acid in aqueous acetone as

Exercise directional effect, and not in a different solvent

exercise of equilibrium due to solubilities. 30 Ig 3,4-dehydroreserpine perchlorate is in a

In the method of the invention, the mixture consists of 8 ecm acetone, 4 ecm water and 0.5 ecm

Problem of separating off the isomer is not, since 66% perchloric acid is dissolved. One gives to the solution

z. B. the reserpine perchlorate, which is after the 1 g of zinc powder and brings the mixture under mechanical

Hydrogenation separates, is already very pure, and the niche is stirring and in a nitrogen environment

Base can then be obtained with ammonia at reflux for about 10 minutes. Man

will. The reserpine obtained in this way is colorless and sustains for about 10 minutes while stirring while boiling

has the same melting point as very pure reflux, the zinc sucks off in the heat and washes

Reserpine (m.p. = 298 ⁰ C). This also distinguishes the filter residue twice, each with 1 ecm boiling

the process of the invention differs from the already acetone. The acetone washes are mixed with the

known processes in which impure, colored filtrate is combined. From these combined fluids

Products are obtained. the reserpine perchlorate crystallizes on cooling

In summary, it can be stated that from. The mixture is cooled in ice and then added

according to the method of the invention, not just one stirring at 5 ° C. slowly with 56 ecm of water

slight improvement of previously known processes for 15 minutes at 5 ^° C. and sucks off the crystals. To

achieved by simple trial and error, but that washing with water makes the still damp

It was found completely surprising that the reserpine perchlorate in 13 ecm acetone with a

Use of aqueous perchloric acid and zinc in a content of 40% water dissolved at the boiling point.

Presence of one or more water-soluble solutions. The solution is then added with stirring in the

medium causes a stereospecific reduction, so heat with 0.4 ecm concentrated ammonia. That

that the desired alkaloid of the reserpine series with 50 reserpine crystallizes out. Cool the mixture

unexpectedly high yield in very pure form- 1 hour at 5 ⁰ C, sucks the crystals off, washes them

will hold. on the filter twice with 1 ecm acetone each time with a

The following examples explain the process, the content of 40% water, suction again and drying

Invention. them at 90 ⁰ C. The 748 mg obtained in this way

Example 1 55 Reserpine are made by pasting in 2 volumes of vinegar

_,,. , ",, i -, .. ^ ,, · acid methyl ester and then twice

Reduction of the perchlorate of the 3,4-dehydroreserpin _{paste in 2} volumes of methanol. After this

obtained with zinc and perchloric acid in the presence of Tetra suction and drying in vacuo at 90 ° C

hydrofuran and aqueous acetone as the solvent _{, 645 mg of reserpine from R = 298} o _{C) ent} .

5 g of 3,4-dehydroreserpin perchlorate with a temperature of 230 ° C. 60, corresponding to a yield of 75% of the calculated and [*]!? = -124 ° ± 5 ° C (c = 0.5% in aqueous amount.

Tetrahydrofuran) are in a mixture of 50 ecm One works with the above

Tetrahydrofuran, 50 ecm acetone and 45 ecm water quantities of 3,4-dehydroreserpin perchlorate, dissolved perchlorate. Then 5 cc of 66% acid and zinc powder are added to the mixture, but the aqueous solution is replaced Perchloric acid and 5 g of zinc powder, stir and bring 65% acetone through aqueous dimethylformamide, aqueous reflux the mixture in about 10 minutes in a nitrogen dioxane, aqueous ethanol or aqueous tetrahydro environment under reflux. After 15 minutes furan and in this way almost equal stirring and boiling under reflux are obtained when they are cooled, results.

Example 3

Reduction of the perchlorate of 3,4-dehydrodeserpidine with zinc and perchloric acid in the presence of Tetrahydrofuran and aqueous acetone as solvents

The procedure is as in Example 1, but with the perchlorate of the solvated 3,4-dehydrodeserpidine, which contains 3 to 4% water as crystal solvent, with a temperature of 214 ° C and [«] ?? = -50 ° ± 3 ° C (c = 1% in tetrahydrofuran with 55% water) and thus receives pure deserpidine in a yield of about 75% of the calculated amount.

Example 4

Reduction of the perchlorate of 3,4-dehydrorescinnamine with zinc and perchloric acid in the presence of Tetrahydrofuran and aqueous acetone

The procedure is as in Example 1, but with the perchlorate of 3,4-dehydrorescinnamine with a temperature of 190 ° ± 2 ° C and [a] l ° = -116 ° ± 3 ° C (c = 1% in tetrahydrofuran with 55 % Water) and receives pure rescinnamine in a yield of 79% of the calculated amount.

Example 5

Reduction of the perchlorate of 3,4-dehydro-l 1-methyldeserpidine with zinc and perchloric acid in the presence of tetrahydrofuran and aqueous acetone as solvents

The perchlorate of 3,4-dehydro-l 1-methyldeserpidine is prepared by ring closure of 17 ° -methoxy-aqueous perchloric acid solution of a 65% perchloric acid which is prepared by diluting 0.5 cm of 65% perchloric acid with 9.5 cm of distilled water the mixture after adding 500 mg of zinc powder V to boiling under reflux for _{4 hours.} After pouring the mixture into ice, it is made alkaline with ammonia and extracted with methylene chloride. After the extract has been dried over magnesium sulfate and evaporated to dryness, the base is dissolved in methanol and dilute nitric acid is added to the solution, whereby the nitrate crystallizes out. From this, treatment with ammonia gives 300 mg of 11-methyldeserpidine from F. = 275 ° C and [<x]% ° = -132 ° ± 10 ° C = 0.25% in chloroform).

oxybenzoyloxy) -3 - oxo -2,3 - seco - 20 «- yohimbans with Phosphorus oxychloride and recrystallization of the reaction product from ethyl acetate and subsequent Conversion into the perchlorate. For the production of 3,4-dehydro-l 1-methyldeserpidine Protection is not sought in the context of this invention. 480 mg of the perchlorate of 3,4-dehydro-11-methyldeserpidine 10 ecm of acetone, 10 ecm of tetrahydrofuran and 10 ecm of a 5% strength are added

Claims (2)

PATENT CLAIMS: 1. A process for reducing quaternary salts of 3,4-dehydroreserpins, 3,4-dehydrodeserpidine, 3,4-dehydrorescinnamine and 3,4-dehydro-II-methyldeserpidine, characterized in that these 3,4-dehydro compounds , especially their perchlorates, are reduced with dilute aqueous perchloric acid and zinc in the presence of one or more water-soluble organic solvents and the reserpine, deserpidine, rescinnamine or 11-methyldeserpidine is separated from the reaction mixture in a manner known per se as a salt or as a free base. 2. The method according to claim 1, characterized in that the reduction is carried out in the presence of acetone, tetrahydrofuran, dimethylformamide, ethanol or dioxane as water-soluble organic Solvent carries out. Papers considered: Journal of the American Chemical Society, Vol. 77, 1955, pp. 4335 to 4343; Vol. 78, 1956, pp. 2022-2023; Experientia, Vol. 12, 1956, pp. 249 and 250; Journal of the Organic Chemistry, Vol. 22, 1957> Pp. 1261 and 1262.