GB2114126A

GB2114126A - Process for the preparation of hydroxyimino-E-homo-eburnane derivatives

Info

Publication number: GB2114126A
Application number: GB08236951A
Authority: GB
Inventors: Dr Csaba Szantay; Dr Lajos Szabo; Dr Gyorgy Kalaus; Dr Janos Kreidl; Dr Laszlo Czibula; Gyorgy Visky; Dr Andras Nemes; Dr Jenone Farkas
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1981-12-30
Filing date: 1982-12-30
Publication date: 1983-08-17
Also published as: HU185172B; ATA469982A; GB2114126B; AT379398B; BE895479A

Abstract

The invention relates to a new process for the preparation of racemic and optically active hydroxylimino-E- homo-eburnane derivatives of general formula (I> <IMAGE> wherein R<1> represents an alkyl group having from one to 6 carbon atoms, and acid addition salts thereof. The compounds obtained are valuable intermediates in the synthesis of other, pharmaceutically active compounds having an eburnane skeleton, on the other hand, they are biologically active themselves.

Description

SPECIFICATION Process for the preparation of hydroxyimino-E- homoeburnane derivatives The invention relates to a new process for the preparation of hydroxyimino-E-homo-eburnane derivatives. More particularly, the invention concerns a new process for preparing racemic and optically active hydroxyimino-E-homoeburnane derivatives of general formula (I)

wherein R1 represents an alkyl group having from one to six carbon atoms and acid addition salts thereof.

According to the invention racemic and optically active octahydroindolo[2,3- a]quinolizine-oxime esters of general formula (11)

(wherein R' is as hereinbefore defined and R2 represents an alkyl group containing from one to 6 carbon atoms, which may be identical to or different from R') are reacted with an alkali metal alcoholate and if desired, compounds of the general formula (I) obtained are treated with an acid.

Compounds of general formula (I) are valuable intermediates in the synthesis of other, pharmaceutically active compounds having an eburnane skeleton, e.g. vincamine, apovincaminic acid esters, etc., on the other hand, they are biologically active themselves.

In the formulae, the symbols R' and R2 (i.e.

alkyl groups having from one to 6 carbon atoms) may represent straight or branched chained alkyl groups having from one to 6 carbon atoms, i.e.

methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, tert.-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl groups.

Acid addition salts of the compounds of general formula (I) include salts formed with any inorganic or organic acid, such as hydrogen halides, e.g. hydrochloric acid, hydrobromic acid, etc.; sulfuric acid, phosphoric acid; organic carboxylic acids, e.g. formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, benzoic acid, cinnamic acid; alkylsulfonic acids, e.g. methane-sulfonic acid; arylsulfonic acids, e.g. p-toluenesulfonic acid; cyclohexylsulfonic acids; asparagic acid, glutamic acid, N-acetyl-asparagic acid, N-acetyl-glutamic acid, etc.

Compounds for general formula (I) are disclosed in the Hungarian Patent Specification 163 769 as intermediates. They are prepared by subjecting suitably substituted 1methoxycarbonylethyl-octahydroindoloquinolizines to ring closure in the presence of strong bases, e.g. alkali metal hydrides or alkali metal amides and subsequently nitrosating the oxo-E-homo-eburnanes obtained with an alkyl nitrite, in the presence of a strong base, e.g. an alkali metal hydride.

The industrial realization of this two-step synthesis is bound to more difficulties. The reactions must be carried out in the absence of water since both alkali metal hydrides and alkali metal amides react with water very vigorously which is a serious source of error, in particular in the large scale production, and requires extreme precautions.

Compounds of general formula (F) in which the hydrogen in the 3-position and the R' substituent in the 17-position have an a,a-configuration are prepared according to the Hungarian Patent Application Rl-691 by oxidizing the corresponding compounds, having a hydroxyl in place of the oxime group and subsequently reacting the dioxo E-homo-eburnane derivative obtained with hydroxyl-amine of a salt thereof. By this process both racemic and optically active compounds may be prepared. The total yield of the two subsequent reaction steps amounts to 54 to 57%.

We have surprisingly found that both racemic and all optically active 3a,1 7a-, 3, 1 7-, 3o', 1 7P- and 3,1 7a-compounds of the general formula (I) can be prepared in a single reaction step, by reacting the corresponding racemic or optically active compounds of general formula (II) with alkali metal alcoholates in an aprotic organic solvent.

By the single reaction step according to the invention a yield of 80 to 87% can be achieved, which is considerably higher than the yield of any of the syntheses known in the art.

Starting compounds of general formula (II) can be prepared according to the process disclosed in the Hungarian Patent Application 1753/81 by treating the corresponding octahydroindolo[2,3 a]-quinolizine ester derivatives with a tertiary butyl nitrite in an aromatic hydrocarbon and subsequently with an alkali metal alcoholate optionally followed by treatment with an aprotic dipolar solvent and if desired, an alkanol.

Starting from racemic compounds of general formula (II) racemic end products of general formula (I) are obtained, while the treatment of optically active compounds of general formula (II) yields optically active compounds of general formula (I). The process according to the invention has no effect on the 3-hydrogen and the R' substituent in the 17-position either, accordingly, 3a, 17a-, 3P, 17P-, 3rw, 17P-and 3P,17a- compounds, respectively yield the corresponding end product with the same configuration.

In the process according to the invention as an aprotic organic solvent aromatic hydrocarbons, such as benzene, toluene, xylene may be used.

The alkali metal alcoholates include for example sodium or potassium alcoholates, preferably having one to 6 carbon atoms, more preferably having a branched chain, such as potassium or sodium tert-butylate or potassium or sodium tert.amylate, etc.

The process according to the invention is preferably carried out in the absence of water.

The reaction temperature preferably varies between 60 and 1000C, more preferably 80 and 900 C.

The reaction time is a function of the reaction temperature employed and generally is between 30 minutes and 3 hours.

The compounds of general formula (I) prepared according to the invention may be separated from the reaction mixture by techniques known per se.

Alternatively, compounds of general formula (I) can be converted into their acid addition salts in the reaction mixture by treatment with the corresponding acid and the acid addition salts obtained may be isolated from the reaction mixture. Compounds of general formula (I) are then set free from their acid addition salts by an inorganic base.

The invention will now be illustrated in greater detail in the following Examples, which are given for illustration and not limitation of our invention.

Example 1 (+)-14-Oxo-15-hydroxyimino-E-homo- eburnane-[3α,17α]hydrochloride 36.9 g (0.1 moles) of(-)-1a-ethyl-1-(2'- methoxycarbonyl-2'-hydroxyiminoethyl) 1,2,3,4,6,7,12,1 2bct-octahydroindolo[2,3-a]- quinolizine and 11.2 g. (10.1 moles) of potassium tert.-butylate are dissolved in 300 ml. of anhydrous toluene. The solution is stirred at 800C for one hour whereupon the solvent is distilled off in vacuo. To the residue 300 ml. of water are added and the pH of the mixture is adjusted to 3 with concentrated aqueous hydrogen chloride solution. The crystalline precipitate is filtered off, washed with two 30-ml. portions of water and dried. 30 g. of the title compound are obtained.

Yield 80%.

Melting point: 256 to 2570C [ai20=+S60 (c=1, dimethyl formamide) Example 2 (-)-14-Oxo-15-hydroxyimino-E-homo- eburnane-[3ss,17ss]hydrochloride Following the procedure described in Example 1 but starting from 36.9 g. (0.1 moles) of (+)-1ss- ethyl-1 α-(2'-methoxycarbonyl-2'-hydroxyimino- ethyl)-1,2,3,4,5,7,12,12bB-octahydroindolo[2,3- a]-quinolizine. 31 g. of the title compound are obtained. Yield: 83%.

Melting point: 256 to 2570C a[a]020= 550 (c=1, dimethyl formamide) Example 3 ( 4-Oxo-1 5-hydroxyimino-E-homo- eburnane-[3,17ss]hydrochloride Following the procedure described in Example 1 but starting from 36.9 g. (0.1 moles) of (-)-1- ethyl-1 α-(2'-methoxycarbonyl-2'-hydroxyimino- ethyl)-1 2,3,4,6,7,12,1 2ba-octahydroindolo[2,3- a]-quinolizine, 30.5 g. of the title compound are obtained.Yield: 81.5% Melting point: 2280C (decomp.) [a] 20+3770 (c=1, dichloromethane and ammonia) Example 4 (-)-14-Oxo-15-hydroxyimino-E-homo- eburnane-[3ss,17cr]hydrochloride Following the procedure described in Example 1 but starting from 36.9 g. (0.1 moles) of (+)-1 aethyl-1 ss-(2'-methoxycarbonyl-2'-hydroxyimino- ethyl)-1,2,3,4,6,7,12,12bss-octahydroindolo[2,3- a]-quinolizine, 30 g. of the title compound are obtained.Yield: 80% Melting point: 2270C (decomp.) [α]D20=-38 (c=1, dichloromethane and ammonia) Example 5 ()-14-Oxo-15-hydroxyimino-E-homo- eburnane-[3a,17a]hydrochloride Following the procedure described in Example 1 but starting from 36.9 g. (0.1 moles) of (+)-1 a- ethyl-1 ss-(2'-methoxycarbonyl-2'-hydroxyimino- ethyl)- 1,2,3,4,6,7,12, 1 2ba-octahydro- indolo[2,3-a]quinolizine, 32.7 g. of the title compound are obtained. Yield: 87% Melting point: 263 to 2640C (decomp.) [(:g]D =0 (c=1, dimethyl formamide) Example 6 ()-14-Oxo-15-hydroxyimino-E-homo- eburnane-[3α,17α] 32.7 g of ()-14-oxo-15-hydroxyimino-E- homo-eburnane-[3a,1 7a]hydrochloride, 150 ml.

of water, 3 g. of solid sodium hydroxide and 60 ml. of dichloromethane are stirred at room temperature for half an hour and the aqueous phase is separated from the organic one. The aqueous phase is extracted with two 20 ml.

portions of dichloromethane, the combined organic phases are dried over solid anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness. 26.5 g. of the title compound are obtained.

Melting point: 2600C (decomp.) from ethanol [a] 2000 (c=1, dichíoromethane) Example 7 ()-14-Oxo-15-hydroxyimino-E-homo- eburnane-[3a,1 7hydrnchloride Following the procedure described in Example 1 but starting from 36.9 g. (0.1 moles of ()-1ss- ethyl-1 α-(2'-methoxycarbonyl-2'-hydroxyimino- ethyl)-1,2,3,4,6,7,12,12ba-octahydroindolo[2,3- a]quinolizine, 32.3 g. of the title compound are obtained.Yield: 86% Melting point: 239 to 2400C (decomp.) [a]O=OO (c=1, dimethyl formamide) Example 8 (I)-14-Oxo-1 5-hydroxyimino-E-homo- eburnane-[3a,17,B] 32.3 g. of (f)-14-oxo-l 5-hydroxyimino-E- homo-eburnanel3a,l 7P]hydrochloride prepared according to Example 7, 1 50 ml. of water, 3 g. of solid sodium hydroxide and 60 ml. of dichloromethane are stirred at room temperature for half an hour, and the aqueous phase is separated from the organic one. The aqueous phase is extracted with two 20 ml. portions of dichloromethane, the combined organic phases are dried with solid, anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness.

26.0 g. of the title compound are obtained.

Melting point: 2260C (decomp.) from cyclohexane [ai20=O0 (c=l, dichloromethane)

Claims

1. A process for the preparation of racemic and optically active hydroxyimino-E-homo-eburnane derivatives of general formula (i)

wherein R1 represents an alkyl group having from one to 6 carbon atoms and acid addition salts thereof, which comprises reacting a racemic or optically active octahydroindolo-[2,3-a]quinolizine-oxime ester derivative of general formula (II)

(wherein R' is as hereinbefore defined and R2 represents an alkyl group having from one to 6 carbon atoms, which may be identical to or different from R') with an alkali metal alcoholate, in an aprotic organic solvent, and if desired, treating a compound of general formula (I) obtained with an acid.

2. A process as claimed in claim 1 wherein the aprotic organic solvent used in benzene, toluene or xylene.

3. A process as claimed in either of the preceding claims wherein the alkali metal alcoholate used is potassium or sodium tert.butylate or potassium or sodium tert.-amylate.

4. A process as claimed in any preceding claim substantially as herein described.

5. A process as claimed in any preceding claim substantially as herein described in any of the Examples.

6. Compounds of formula I

(wherein B1 represents an alkyl group containing 1 to 6 carbon atoms) and acid addition salts thereof, when prepared by a process as claimed in any preceding claim.

7. Compounds as claimed in claim 6 as herein specifically described.