DE2948144A1 - METHOD FOR PRODUCING HYDROXYIMINO-E-HOMO-EBURNANES - Google Patents

Description

OpL-CKem. IXL PETER WAGEt

MUNICH 4

Geoleon

METHOD FOR MANUFACTURING HYDR0XYIMIN0-E-HOM0- #EBURNANES

The invention relates to a new process for the production of racemic or optically active hydroxy-TP general formula I.

A 1644-67

(D,

030023/0872

M -

wherein R is an alkyl group having 1 to 6 carbon atoms stands, as well as acid addition salts of these .. ' Compounds, which is characterized in that racemic or optically active hydroxy-oxo-E-Aomo- ^ eburnan isomer mixtures of the general formula II

(II).

wherein R has the above meaning, or salts thereof * are given after separation of the epimeretf-oxidized, the received fraTtJwiaehen ad a ^ optiech active DioxoVeT5urnene of the general formula III

where R is the oil

CL

if necessary, neci

e has meaning, or rCMhUK) Ih Alt 9f * itOven Λκ> ι / β ResolvierungV-mit Hydr

(III),

Salts thereof _x -g

Resolvation) -reacts with hydroxylamine or with a salt thereof- and the desired traps Hydroxy obtained in this way in incy-eburnane in general Fpr.mei I converted into acid addition salts and / or

ivie

ii »

The hydroxyimino-

C30023 / 0872

29A8U4

^ eburnans of the general formula I are on the one hand valuable intermediates * -r in the preparation of therapeutically active compounds and on the other hand also show advantageous biological properties themselves. From the compounds of the general formula 1 which contain | o »p · Si ^ R an ethyl group, by reacting with lower. Alkanols in the presence of acids or bases (cf. the published Japanese patent application No. 53-147 100) in one reaction step, apovincamic acid alkyl esters which are therapeutically valuable as cerebral vasodilators, eg

the Apovincaminssjre ethyl ester (Vinpocetmum) will.

• for "

The ja-re a) R containing an ethyl group Compounds of the general formula I are already known; the other compounds of the general formula I are new, not described in previous literature Products.

In the general formulas I, II and III, R denotes any straight or branched alkyl group as an alkyl group with 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, η-butyl, isobutyl, tert-butyl , _n _P _en tyl, isopentyl, n-hexyl or isohexyl groups.

Acid addition salts of the compounds of the general

NEN formula I can be prepared, for example, with the following acids: inorganic acids such as hydrohalic acid, sulfuric acid, phosphoric acid, etc .; organic carboxylic acids, such as 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; Alkyl sulfonic acids such as methanesulfonic acid; Aryl

030023/0872

29A8HA

sulfonic acids such as p-toluenesulfonic acid _; Cyclohexyl sulfonic acid _; Amino acids such as aspartic acid, glutamic acid, N-acetylflaspartic acid, N-acetylglutamic acid and the like.

The formation of salts can be carried out in inert organic solvents, for example in aliphatic alcohols having 1 to 6 carbon atoms, in such a way that the re optically active compounds of your general formula I are dissolved in the solvents mentioned and then the solution with the appropriate Acid, or with the solution of the acid in the solvents mentioned up to the weakly acidic reaction (about pH 5 to 6). The acid addition salt which separates out can be separated off from the reaction mixture, for example by filtering it off.

The 4m method according to the invention as a course

Substances to be used compounds of the general formula II are partly new, but partly in the communication by Cs * Szäntay, L. Szabb and Gy. Kaiaus: Tetrahedron 33 , 1803 (1977) already described. The new compounds of the general formula II can also be prepared by the method described in the communication cited.

The starting materials of the general formula II can be obtained directly in their manufacture Form as 15-epimer mixture in the invention Procedure can be used without further purification. If desired but the crude 15-epimer mixture obtained during the preparation can first be subjected to epimeric separation subject, at the same time a certain cleaning of the product takes place, and then that carry out the method according to the invention with a pure epimeric compound obtained in this way.

030023/0872

29481U

The separation of the epimers can be carried out in such a way that; the 15-epimer mixture is recrystallized from methanol; This encircling also serves the purpose of cleaning the product, since the encircling Not only 3ize the other epimert, but also the accompanying ones Impurities (starting materials, intermediate products, decomposition products, etc.) are removed. as The product of this recrystallization becomes one of the epimers Forms of the product received, the other_ epimeric form remains in the mother liquor and M can be prepared by prepara-. tive thin layer chromatography (on silica gel, ιηϊΤΥ14: 3 ~

OtUC

Mixture of benzene and methanol) can be obtained.

The starting compound of general formula II can ± m inventive / r method, both aome be as well used in optically active form ·

The preparation of compounds of the general formula I, which Ln der Stollo var (R contain an ethyl group, was first described in Belgian patent 765 006. This compound, which occurs there as an intermediate, was prepared according to the cited patent in such a way that the correspondingly substituted 1- Methoxycarbonylethyl-octahydroindolo [2,3-a] quinolizine under the action of a strong base, for example of alkali metal hydrides or alkali metal amides, cyclized and the oxoeburnan obtained, likewise in the presence of strong bases, for example of alkali metal hydrides _{, was} nitrosated with an alkyl nitrite.

The technical implementation of this process W violin * but, especially on a large industrial scale, numerous disadvantages. In the reactions with alkali metal hydrides or alkali metal amides, the presence of Water can be completely excluded, which is especially true in the case of the

030023/0872

29481U

-J-

operational implementation creates difficulties and brings with me the possibility of errors. The usage of alkyl nitrites can have harmful consequences so that particular attention must be paid to the execution of the procedure.

In the case of the method according to the invention, however, eboth claiming the use of water seal strong bases «, as well as working with harmful bases Avoided alkyl nitrites; only simple, easily accessible and harmless substances such as e.g. manganese (IV) oxide is used; the introduction of the oxime group is used instead of the harmful alkyl nitrite the easily treatable hydroxylamine ^ or carried out with its salts. As well as the total yield ^ as well as the yields of the one » Individual reaction steps are higher than the yields of the known process described above, eo that the novel process according to the invention not only in its

W (Mh Jerner
professionalism, but also * «· Economic efficiency considerable

Offers advantages.

The oxidation of the compounds of the general formula II can be carried out with any desired oxidizing agents which have the hydroxyl group in the 15-position in can convert an oxo group without causing any undesirable changes in other parts of the molecule. Such oxidizing agents are e.g. * <l «e manganese dioxide, d * e applied to Celite Silver carbonate, chromium trioxide, etc. Dae manganese dioxide can, on the weight of the starting material, be about

in 8 to 12 times, advantageously in 10 times the amount, can be used. ^^

The oxidation can occur in any, <· * # · the

030023/0872

2948HA

point of view of the reaction) inert organic solvents, e.g. in a chlorinated hydrocarbon, e.g. in dichloromethane, under mild conditions, expediently at room temperature.

After the end of the reaction, the received

tene compound of the general formula III can be obtained from the reaction mixture after filtering off the oxidizing agent by preparative methods known per se. The filtrate is expediently evaporated to dryness; the compound of the general formula III obtained as a residue can be used in the next reaction step of the process without further purification. If desired, however, the intermediate product of the general formula III obtained, for example _# for analytical purposes, can be used

(Puηn- recrystallization or purified by preparative ^ layer chromatography. To recrystallize any suitable organic solvent, suitably for example diethyl ether can be used. For preparative biÄ »m-layer chromatography label as silica gel Merck ^Rev. o54 + are used 366, while different as the eluent, expediently Depending on the properties of the compound to be cleaned, the selected solvent combinations, for example, mixtures such as benzene and methanol, come into consideration. When the compounds of the general formula III are reacted with hydroxylamine, the hydroxylamine is advantageously in the form of salts, e.g. The hydroxylamine or its salt is expediently used in a 3 to 5-fold excess.

The reaction is in a », from the point of view

the reaction / inert organic solvent ♦ «• led. Since not only water but also acid are released in this reaction, it is also expedient to give

030023/0872

an acid binder to the reaction mixture as an acid binder For example, trialkylamines such as triethylamine come into consideration.But you can also use basic solvents, e.g. * pyridine, use as reaction medium, which can then also serve as an acid binder at the same time.

These oxime-forming reaction is advantageously carried out at moderately elevated temperatures, for example at 80 ⁰ C to 110 ⁰ C. The reaction mixture can be worked up by any customary method. The solvent is expediently removed from the reaction mixture, for example by vacuum distillation, the residue is dissolved in water and the acidic solution is made alkaline with an inorganic base, for example with concentrated ammonium hydroxide solution. The compound of the general formula I obtained can be extracted from the alkaline solution using suitable organic solvents, for example diethyl ether. The product of the general formula I obtained by evaporating the solvent can, if desired, be converted into an acid addition salt in the customary manner.

If desired, the compounds of the general formula I obtained can be purified further, for example by recrystallization from suitable solvents. The solvents for this purpose are especially dielectric ethers, such as diethyl ether _; into consideration

The * compounds of the general formula I obtained may, if desired REAI fella be decomposed in manner known per se into the optical antipodes.

The compounds of the general formula I are pure, easily identifiable by the process according to the invention Shape, which is also reflected in the

»10023/0872

nieee der Elementa £ analyeen _v as well as by the obtained values of the infrared perf and | taf Maaeenapektr ^ was confirmed

The practical implementation of the inventions Procedures are illustrated in more detail by the examples below, but the invention is in no way intended limited to the content of these examples.

example 1

(+) -cis-14,15-dioxo ~ E-homo-eburnane

The solution of 8.0 g (24.8 mmol) (, +) - € is-14-Oxo-

-15-hydroxy-E-homo-eburnan in 500 ml of dichloromethane is mixed with 80.0 g of active manganese dioxide and the mixture is stirred for 5 hours at room temperature. The reaction mixture is then filtered off and the solid oxidizing agent remaining on the filter is washed with dichloromethane
and the filtrate combined with the washing liquid
evaporated to dryness. The evaporation residue is recrystallized from diethyl ether. 6.4 g of (jH) -cis-14,15-dioxo-E-homo-eburnen (80 % of theory) are obtained in this way; F. 156 ⁰ C.

Analysis for ^c ₂ o ^H 22 ^N 2 ° 2 ^(mol * ^{& eiw} 322.40):
calculated: C 74.50 *% H 6.87 % N 8.69 %
Found: C 74.22 % H 7.02 % N 8.83 %.
IR (in KBr): 1730 cm " ¹ (CO), 1695 cm" ¹ (Amid-CP).
Mass spectrum (m / e %): 322 (M ⁺ ; 100), 294 (86.5), 266

252 (77, 237 (41), 197. (42),
169 (40), 168 (40.6).

Example 2

(+) - 3 (S), 17 (S) -14,15-dioxo-E-homo-eburnane

The solution of 4.0 g (12 mmol) (+) -ci * -14-0xo-15-

030023/0872

2948U4 4h

-hydroxy-E-homo-eburnan in 250 ml of dichloromethane is mixed with 40.0 g of active manganese dioxide and the mixture is stirred for 5 hours at room temperature. The reaction mixture is then filtered off, the oxidizing agent remaining on the filter is washed with dichloromethane and the filtrate combined with the washing liquid is evaporated to dryness in vacuo. The evaporation residue was purified by preparative thin-layer chromatography (on silica gel, mobile phase: 14: 3 mixture of benzene and methanol). Three spots are obtained, of which the spot with the highest R _f value of the desired (+) - 3 S), 17 (S) - -14,15-dioxo-E-homo-eburnan; this stain is eluted with diethyl ether. 2.9 g of (+) - 3 (S), 17 (S) -i4, 15-dioxo-E-homo-eburnane (73 % of theory ) are obtained from the eluate; M.p. 116 ° C (from diethyl ether). ° ■ + 80.3 ° ic = 0.50, chloroform),

Example 3

(jO-ci8-i4-exo-15-hydroxyimino-E-homo-eburnen 1.00 g (3.10 mmol) (jO-cis ~ i4,15-DioxO "E-homo- -eburnan (prepared according to Example 1) is abs in 5.0 ml. Dissolved pyridine; 1.00 g (14.3 mmol) is added to the solution Phosphorus pentoxide dried hydroxylamine hydrochloride added and the mixture was heated on the water bath for 2 hours. Then the solvent is evaporated in vacuo, 15 ml of water are added to the residue and the mixture is adjusted to pH with concentrated aqueous ammonium hydroxide solution set to 9 and the mixture, which has been made alkaline, is extracted three times with 10 ml of diethyl ether each time. The combined atherpheeen are anhydrous with

Magnesium sulfate dried, filtered and the Filtret

evaporated to dryness in vacuo. That as a residue

030023/0872

29A8U4

■ A-

retained oil (θ, 93 g) is crystallized from ether. In this way 0.73 g of (jt) -cis-14-0xo-15-hydroxyimino-E-homo-eburnan (70.5 % of theory ) are obtained, mp 254 ° C. (from diethyl ether) .
IR (in KBr): 3200 cm " ¹ (OH), 1705 cm" ¹ (Lactam-CO),

1642 cm " ¹ (C = N). '

Analysis for ^c ₂ o ^H 23 ^N 3 ° 2 ^ ^mol » ^wt · 337.40): calculated: C 71.19 % H 6.87% N 12.45 % found: C 71.24 % H 6.68 % N 12.50 %.

Example 4

(+) - 3 (S), 17 (S) -14-0x0-15-hydroxyimino-E-homo- -eburnan

0.40 g (1.24 mmol) (+) -3 (S), 17 (S) -14, 15-dioxo-E -.- homo-eburnane (prepared according to Example 2) are in 2.0 ml of abs. Dissolved pyridine; 0.40 g are added to this solution (5.75 mmol) hydroxylamine hydrochloride dried over phosphorus pentoxide added and the mixture was heated on the water bath for 2 hours. The pyridine is then im Evaporated in vacuo, the residue mixed with 10 ml of water, the pH of the mixture with concentrated aqueous ammonium hydroxide solution set to 9 and the mixture left to stand. The product obtained is filtered through separated, washed with water and dried. In this way, 0.44 g of raw (+) - 3 (S), 17 (S) -14-Oxo- -15-hydroxyimino-E-homo-eburnan obtained; M.p. 190 C (Zere ·); [a] p = + 61 ° (c = 1, dichloromethane).

The product obtained in the above manner (0.44 g) is in abs. Dissolved methanol and the pH of the solution adjusted to 5 with methanolic hydrochloric acid solution.

The hydrochloride which separates out is filtered off separated, washed with methanol and dried. It

030 0 23/0872

29A8U4

0.34 g of (+) - 3 (S), 17 (S) -i4-0xo-15-hydroxyimino-E- -hono-eburnene hydrochloride (74 % of theory ) obtained <F 256-257 ⁰ C (au · methanol).

030023/0872

Claims (1)

PATENT CLAIMS ÜK Process for the production of optically active
«A formula I. HO- N (D, wherein R is an alkyl group having 1 to 6 carbon atoms and acid addition salts of these compounds, characterized in that 15-epimer mixtures by emew eeif optically active 14-oxo- -15-hydroxy-E-homo-eburneneiT \ of the general formula II (II), wherein R has the above meaning, or salts thereof ^ - optionally after separation of the epimers from each other ;: oxidized, the obtained, jamh od optically active dioxo urnaB) of the general formula III 090023/0872 (III) in which R has the above meaning - or a salt thereof ^ - given case naTh ^ (recolving) -> with hydroxylamine or with a salt thereof, and if desired converts the product of the general formula I obtained into an acid addition and / odeVyJFeif **** * - ** Ü! £ 2. The method according to claim Λ, characterized in that the oxidation is carried out with mega-dioxide. 3. The method according to claim 1, characterized that one considers the oxidation in a yiewj point of view of the reaction inert organic Solvent carries out. 4. The method according to claim 1, characterized in that that the implementation of the dioxo-eburnans of the general formula III with hydroxylamine or with a salt thereof in an organic solvent. 5. The method according to claim 4, characterized in that the solvent used is a liquid organic base is used. 090023/0872