DE2722718A1 - METHOD FOR PRODUCING HYDROXY-10-AJMALICIN - Google Patents

Description

J. RICHTER F. WERDERMANN R. SPLANEMANN dr. B. REITZNER

DlPL-ING. DIPL-ING. DIPL-ING. DtPL-CHEM.

HAMBURG T MUNICH

2OOO HAMBURG 3β 18.V.BX 1977 NEW WALL 1O TEL. (OAO) 34 CX) 45 34 OO 56 TELEGRAMS: INVENTIUS HAMBURG

OUR ACTS: 3618-1-3 ^ 0? YOUR SIGN:

PATENT APPLICATION

PRIORITY: dated May 31, 1976 No. 76 163 ^ 5 France

TITLE: Process for the production of hydroxy

lo-ajmalicin

APPLICANT: OMNIUM CHIMIQUE SA, Brussels, Belgium

INVENTORS: Jean, Alfred, Alphonse, Joseph Hannart, Brussels, Belgium

709850/0779

Κο · ιΐ. · Η 0> · ιιΚι4, ·· Π .-. Ι Λ «<■; Μ.ιπιΙ · ιιΐ: ι (ΠΙ 7? W7 <r <t \ -i \ γ ..., · M ₁ ρ'ίπιΐ ". Ι .. ι -.tiicHisirit H.imbutg (BLZ 200 lOOJO) account No. 26 »» JO I

272/718

The invention relates to a process for the preparation of hydroxy-10-ajmalicin by oxidation of ajmalicin.

The hydroxy-10-ajmalicin provides a well-known and available Treatment of cardiovascular disorders interesting compound exhibiting pharmacological properties,

This compound, which is given below by its structural formula (IV), is prepared in a known manner up to now starting from ajmalicin of the formula (I) by a process of microbiological oxidation (P. Bellet and T. van Thuong, Ann. Pharm. Fr . 1970, 28 , 119).

In the general structural formula R given below

CH,

H ₃ COC = O

R can have the following meanings: In formula IV: R = OH; in formula I: R

= H

The invention is based on the object of a novel process that is not based on microbiological oxidation to create hydroxy-10-ajmalicin.

The method proposed to solve the problem is characterized according to the invention in that

709850/0779

ajnialicin is oxidized chemically.

According to a further embodiment of the invention-'jf-mäR proposed method, the production takes place in three successive process steps. In Ajmalicin is involved in a very difficult process step of the formula (I) to dihydro-2,7-ajmalicin of the formula (II)

II

(ID

CII _n

reduced. In the second process step , the dihydro-2,7-ajmalicin (II) is oxidized into an intermediate compound with the structural formula given below

(III)
O

(HD

CH.

H ₃ CO-C = O

convicted. In the third process step this Intermediate compound (III) to hydroxy-1O-ajmalicin (IV) reduced.

709850/0779

According to a further embodiment of the process, the first process step is after the in German

Patent (according to the patent application

Current number P 24 10 657.2, AT March 6, 1974 with priority to Belgian patent application No. 796 521 of March 9, 1973) carried out in such a way that ajmalicin in the presence of an acid such as trifluoroacetic acid has the effect of Is exposed to sodium cyanoborohide.

In the second process step, a reagent that generates free residues, such as in particular potassium nitrosdisulfonate (Teuber, Angew. Chem. 1956, 6i8, 628) are used in a solvent which, for example, from a mixture of acetone, water and acetic acid.

In the third process step, the intermediate compound (III) is reduced, for example by means of sodium dithionite.

According to a further embodiment of the method, the intermediate connection obtained in the second method step is of the formula (III) not only separated, but directly to the reducing conditions of the third Process step subject.

The method according to the invention is based on the following of two illustrative embodiments explained in more detail.

Example 1; Dihydro-2,7-ajmalicin (II)

50 g of ajmalicin (I) are dissolved in 500 ml of trifluoroacetic acid. Then 50 g of sodium cyanoborohydrocarbon are gradually added. The reaction mixture is 15 minutes

709850/0779

ten kept moving under an inert atmosphere at ambient temperature for a long time. Then, the solution is diluted with water, basified with ammonia in the presence of ice and extracted by methylene chloride. The methylene chloride, washed with water and dried over sodium sulfate, is evaporated to dryness under vacuum and yields a varnish (50 g) which is purified by chromatography on 10 parts of alumina. Benzene is used as a washout agent. 39.5 g of dihydro-2,7-ajmalicin (II) are obtained, which are crystallized in methanol and have the following properties:

Dihydro-2,7-ajmalicin (II):
F = 193-195 °

(CK) = + 101 ° (MeOH, c = 1.02 g %)

-3

UV spectrum: (c = 10.25 χ 10 g / l)

neutral methanol: 242 (4.23); 294 (3.46) IR spectrum: KBr, band at U (cm ~ ¹ ): 3450 (NH)

Mass spectrum: M, calculated for C_, H ₀ -O ₀ N ₀ = 354

ΖΛ Zo j * ■

Found value: 354 RMN spectrum: CgD, + 4 drops of CDCl ₃

Signals at δ ppm 3.52: singlet off

3 protons

3.25: quadruplet of 1 proton

Analysis calculated for ^C 2i ^H 26 ° 3 ^N 2

% C% H% N

Calculated: 71.16 7.39 7.90

Found: 71.18 7.35 7.88

Example 2: Hydroxy-10-ajmalicin (IV)

A solution of dihydro-2,7-ajmalicin (II) of 30 g in 600 ml of acetone is added to a prepared solution

709850/0779

272? ^r ' ⁷ 1S

from 60 g of potassium nitrosdxsulfonate and 1600 ml of a mixture of water and acetic acid in the ratio 98: 2 The reaction is maintained at ambient temperature for 28 hours and then sodium dithionite is added in added in an amount sufficient to discolor the solution. The mixture is then washed with water, alkalized and extracted with methylene chloride. The washed with water and dried over sodium sulfate Methylene chloride is evaporated to dryness in vacuo and gives a varnish (29 g) which can be chromatographed is cleaned on 15 parts of alumina (aluminum oxide). The washout agent or eluent is benzene. 15.4 g of hydroxy-10-ajmalicin (IV) are obtained which are crystallized in methanol. The characteristics of this Product are as follows:

Hydroxy-10-ajmalicin (IV)

F = 290 ° (lit. 285 °)

((X) ₀ = -35 ° (MeOH, c = 0.32) (Lit. -38 °) UV spectrum: (c = 8 χ 10 g / l)

neutral methanol: 229 (4.51), 280 (4.404);

300 (3.91); 310 (3.66)

IR spectrum: KBr

Band at V (cm " ¹ ): 3400 (NH)

Mass spectrum: M calculated for C ₂₁ H ₃₄ O ₄ N ₂ = 368

found: 368 % H % N Analysis, calculated for ^C 21 ^H 24 ° 4 ^N 2 6th , 56 7th , 60 % C 6th , 49 7th , 64 Calculated: 68.46 Found: 68.41

J09850 / 0779

Claims (6)

Patent claims: Process for the preparation of hydroxy-1O-ajmalicin by oxidation of ajmalicin, characterized in that the oxidation takes place chemically. 2. The method according to claim 1, characterized in that in a first step the ajmalicin with the formula CH, to dihydro-2,7-ajmalicin of the formula ..CH (D (ID H-COC = O is reduced, and this in a second process step by oxidation into an intermediate compound of formula 709850/0779 ORIGINAL INSPECTED (III) CH, H ₃ COC = O is converted, which in a third process step to hydroxy-10-ajmalicin with the formula OH .1 ° (IV) H ₃ COC = O is reduced. 3. The method according to claim 2, characterized in that the first process step after that in patent (corresponding to German patent application P 24 10 657.2, AT March 6, 1974) is carried out by exposing ajmalicin to the action of sodium cyanoboride in the presence of an acid such as trifluoroacetic acid. 4. The method according to claim 2, characterized in that in the second process step a reagent which generates free residues such as potassium nitrosdisulfonate in one 709850/0779 Solvent, which consists of a mixture of acetone, water and acetic acid, is used. 5. The method according to claim 2, characterized in that the reduction taking place in the third process step the intermediate compound of formula (III) is carried out by means of sodium dithionite. 6. The method according to any one of claims 2-5, characterized in that that the intermediate compound of the formula (III) obtained in the second process step does not only separated, but directly subjected to the reducing conditions of the third process step will. 709850/0779