FI56687C - FOERFARANDE FOER FRAMSTAELLNING AV VINCAMIN- OCH APOVINCAMISYRAESTRAR MED INVERKAN PAO BLODCIRKULATIONEN OCH BLODTRYCKET - Google Patents

Description

L rB, ANNOUNCEMENT _

Ja ^ (11) UTLÄGGNI NGSSKRIFT 56687 C Patent granted 10 03 1930 (45) Patent meddelnt ^ ^ (51) Kv.lk. * / Lnt.CI. * C 07 D 519 / 04- FINLAND —FINLAND (21) Patent application - PstenUns & knlng 2929/72 (22) Htkamlsplivi - Ansökningsdsg 23 * 10.72 (23) AlkuplWI — GUtighttsdsg 23 * 10 * 72 (41) Become Public - Bllvlt offmtllg OU. 05.73

Pmtenttl · · and the National Board of Registration (44) Nshttyttaipwoo j «kuLjuitatoun pvm. ~

Patent · och registerstyrelsen Anteku uttagd och uti.ikrtft «n public · rad 30.11.79 ___ (32) (33) (31) Pietty etuoikeus — Begird prlorltet 03.11 * 71

Hungary-Hungary (HU) RI-U5U

(71) Richter Gedeon Vegyeszeti Gyfir R.T., 21, Gyömröi ut, Budapest X, "Hungary i-Ungern (HU) (72) Csaba Lörincz, Budapest, Egon Kärpäti, Budapest, Laszlo Szporny,

Budapest, Kalman Szäsz, Budapest, Lajos Kisfaludy, Budapest,

Hungary-Hungary (HU) (7 ^ -) 0y Roister Ab (5¼) Process for the preparation of vincamine and apovincaminic acid esters affecting circulatory and hypertensive levels method for the preparation of circulating and hypertensive vincamine and apovincaminic acid esters of formula

CoT1 (I)

I I J

of

R00C N

where Y is a group = C = CH- or “C-CHg-

0H

2 56687 and when X ~ Y is a group = O = 011-, R is an unsubstituted alkyl group having 2 to k carbon atoms, and when X · '*** Y is a group »^ jCHg, R is a hydroxyethyl group, a chloroethyl group, an allyl group or a benzyl group, and for the preparation of their acid addition salts and quaternary salts.

Some vincamine derivatives and vincamine-like substances with similar pharmacological properties to vincamine are known (e.g. HU patent publications 151 255, 157 687).

It has now been found that the novel eburnamine-type alkaloid esters of general formula (i) and their salts have a much higher cerebrovascular effect than vincamine.

The invention is characterized in that a) vincamine or apovincamic acid is converted to an alkali metal salt and esterified with a halide of formula RX 1 or a sulphate of formula _ (R) 2 S (V in which R is as defined above and X 1 is a halogen atom, or b) vincamine or apovincamic acid is esterified with an alcohol of formula R-OH, wherein R is as defined above, in the presence of an acid catalyst such as sulfuric acid or ethanesulfonic acid, or c) vincamine or apovincamine is transesterified with an alkali metal alcoholate of formula R above, wherein R is as defined above. and Me is an alkali metal, or d) apovincamine or vincamic acid, respectively, is reacted with apovincamine or vincamine with a carboxylic acid ester of the formula R 1 -COOR, wherein R is as defined above and R 1 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and converting the resulting compound of formula (i), if desired, into an acid addition salt or a quaternary s by reaction with an inorganic or organic acid or alkyl halide, and the resulting salt is converted to the free base or another salt, if desired. -

The preparation of vincamic acid used as a starting material in the process according to the invention is disclosed in HU patent publication 166,912 and the preparation of apovincaminic acid in HU patent publication 160,367.

3 56687

Embodiment a) of the process according to the invention is carried out as follows: if the reagent is an alkyl, alkenyl, substituted alkyl or benzyl halide, anhydrous alcohol is used as the reaction medium, or excess halide. If the esterification is carried out with an alkyl sulfate, the reaction can be carried out in an anhydrous alcohol or ester, acetone or anhydrous tetrahydrofuran. In all cases, the esterification is carried out by refluxing the reaction mixture for several hours. Separation of the crystalline ester is accomplished by phase change purification as follows: the reaction mixture is concentrated under reduced pressure, the concentrate is diluted with aqueous acid, the aqueous-acid mixture is made alkaline, the product is extracted into an organic solvent, the organic solution is concentrated and the residue is recrystallized. By this procedure, crystalline compounds of general formula (i) are obtained.

According to embodiment b), apovincamic acid esters can be prepared from both apovincamic acid and vincamic acid, since in the presence of strong acids, vincamic acid is converted to apovincamic acid. The same method can be used to prepare vincamic acid esters in the presence of weak acids which do not have a dehydrating effect. In this case, for example, using acetic acid, no conversion to apovincaminic acid occurs in the reaction.

The reaction of embodiment b) is preferably carried out in the presence of a solvent. As solvents, for example, excess alcohol and / or anhydrous benzene or toluene can be used. The alkaline catalyst may be ammonia, while the acid catalyst may be ethanesulfonic acid. The reaction is carried out by refluxing the mixture for several hours. The resulting ester is separated and purified by phase change.

Embodiment c) of the process according to the invention is preferably carried out in a non-polar solvent or solvent mixture (more preferably benzene). The reaction mixture containing the alkali metal alcoholate - preferably sodium alcoholate - is refluxed for several hours, after which the product obtained is separated and purified by phase exchange.

Embodiment d) of the process according to the invention is preferably carried out in the presence of a solvent or solvent mixture, in particular in the presence of an excess of alcohol and / or suitable ester reagents. The reaction is carried out as described in embodiment c).

The novel products prepared according to the present invention can be used in the form of pharmaceutical preparations as medicaments. These pharmaceutical preparations may contain inert organic or mineral carriers suitable for oral or parenteral use without reacting with the new ester derivatives.

., 56687

The pharmaceutical products may contain the novel compounds alone or in combination with other known active ingredients, for example in combination with reserpine. The pharmaceutical products can be sterilized if desired. The compositions may also contain other additives, e.g. salts to adjust the osmotic pressure to the desired value, buffers, etc.

Therapeutic properties.

According to the present invention produced the following compounds are particularly cerebral vasodilator active: vinksmiinihappoetyyliesteri, vinkamiinihappoallyyliesteri, __ vinkamiinihappohydroksietyyliesteri, vinkamiinihappokloorietyyliesteri, vinkamiinihappobentsyyliesteri, (+) - apovinkamiinihappoetyyliesteri, apovinkamiinihappobutyyliesteri, etikkahappoapovinkaminoesteri, (-) - apovinkamiinihappoetyyliesteri, (+) - apovinkamiinihappoetyyliesterimetojodidi.

Of the compounds listed above, the most preferred are (+) - apovincaminic acid ethyl ester, (-) - apovincaminic acid ethyl ester and (+) - apovincaminic acid ethyl ester methiodide.

The results of the pharmacological experiments performed with the above compounds and vincamine are listed in Tables 1 and 2. The studies were performed in anesthetized dogs.

Arterial blood pressure was measured with an electromanometer from the left femoral artery. Cardial frequency was determined based on the blood pressure pulsation campaign.

Respiratory rate was measured with a pneumotachograph. Aortic flow (volume fraction per minute) and cerebral blood flow (inner carotid artery and vertebral artery flow on both sides) were measured with electromagnetic flow meters placed in corresponding parts of the body. Arterial blood oxygen pressure was measured from the femoral artery, while venous blood oxygen pressure was measured from the transverse blood drain.

The circulatory resistance of the whole body and the cerebrovascular system, the oxygen consumption and utilization of oxygen in the brain, and the cardiac output were calculated on the basis of the above-mentioned continuously measured parameters.

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Comparing the potency of the compounds of the invention with the potency of vincamine, it was found that the new compounds have more advantageous effects than vincamine. The following advantages can be mentioned: 1) The new compounds have a stronger general vasodilatory effect than vincamine (determined on the basis of whole-body vascular resistance).

2) They have a lower antihypertensive effect than vincamine (determined by mean arterial blood pressure).

3) Their cerebrovascular potency exceeds that of vincamine (as determined by cerebrovascular resistance).

it) Cerebrovascular flow increases more.

5) Cardiac output decreases.

6) The cardial frequency does not decrease but increases.

7) The amount of blood carried by the heart per minute (parts by volume per minute) does not decrease but increases.

8) Brain oxygen consumption increases significantly, so the new compounds have a stronger effect on brain tissue metabolism than vincamine (see values for brain oxygen consumption).

From the above, it can be concluded that in addition to their potent vasodilatory effect, the new compounds also have the desired effect on cardiac function and stimulate brain tissue metabolism by increasing cerebral blood volume.

β 56687

comparison Tests

The properties of the compounds prepared by the process of the invention were compared with the corresponding properties of the known compound vincamine. The effect of test compounds on blood pressure, cerebrovascular circulation and cerebrovascular resistance was determined in anesthetized dogs when test compound was administered at 1 mg / kg intravenously. Acute toxicity was studied in mice by determining the LDj-q mg / kg given intravenously.

Score

Blood- Cerebral- Brain- LD50 ~ pressure circulation of vascular flow resistance

Known compound vincamine 1.0 1.0 1.0 80 new compounds apovincamic acid ethyl ester 2.3 5 * 3 2.6 58 apovincamine butyl ester 0 0.5 0.5 157 vincamic acid benzyl ester 1.5 2.5 1.8 29 56687

The therapeutic properties of the compounds according to the invention were compared with those of vincamine, apovincamine, apovincaminic acid amide and apovincaminic acid popentachlorophenyl ester known from DE 1 958 51 * + and DE application 2 115 718, and from the patent standard The research methods are described in the article Szporny, L., Pharmacologie de la vincamine et ses derives, published in Actualites pharmacologiques, Masson 1977- The result was:

- Known compounds MABP CBF CVR

Vincamine 1 1 1

Vincamic acid 0.9 0.8 0.7

Vincinamic acid ethyl ester

Apovincamine 1.6 2.9 2.1

Apovincaminic acid

Apovincaminic acid amide 1.0 0 0.57

Apovincaminol 1,5 1 »0 1» 25

Apovincaminic acid pentachlorophenyl ester

New compounds

Vincinamic acid oxyethyl ester 0.7 1 → 5 0.92

Vincamic acid benzyl ester 1,5 2,5 1 »52

Apovincaminic acid ethyl ester 2.3 5 »3 2.6 _ MABP = mean arterial blood pressure CBF = cerebral blood flow CVR = cerebrovascular resistance 10 56687

The invention is further illustrated by the following examples.

Example 1

Vincamic acid allyl ester 1 g (0.0029 moles) of vincamic acid and 0.11 g (0.0027 moles) of sodium hydroxide are dissolved in 120 ml of anhydrous ethanol. To the solution are added 0.5 g (0.001 * 1 mole) of allyl bromide and the reaction mixture. boil for 1 hour by refluxing. The formation of vincamic acid allyl ester is monitored by layer chromatography. When the vincamic acid spot disappears, cooking is stopped. The solution is cooled and evaporated to dryness. The dry residue is dissolved in 200 ml of a 2% aqueous solution of sulfuric acid and the solution is extracted with 2 x 200 ml of benzene. The pH of the separated aqueous phase is adjusted to 8 with 5% aqueous ammonia solution, after which the slightly alkaline solution is extracted with 5 x 200 ml of benzene. The organic solution obtained is dried over anhydrous potassium carbonate, filtered and evaporated to dryness.

The dry residue is dissolved in 10 ml of anhydrous ethanol, and then this solution is left at 0-2 ° C for 10 hours. The separated crystals are filtered and recrystallized from anhydrous ethanol.

0.8 U g of vincamic acid allyl ester are obtained (yield 8%). The product obtained by layer chromatography is of uniform quality. Sp. 236 ° C (Boetius).

Elementary:

Theoretical values; C = 72.60% H = 7.1% N = 7.39%

Observed values; C = 72, U8% H = 7, 0% N = 7, * + 1%

The structure of the product is identified by its IR spectrum (ester band at 5.72 μ).

Example 2

Vinamic acid hydroxyethyl ester 1 g (0.0029 moles) of vincamic acid and 0.11 g (0.0027 moles) of sodium hydroxide are suspended in 10 ml of ethylene chlorohydrin, after which the solids are dissolved in the reaction mixture by heating. The solution is refluxed for 3 hours. Ester formation is determined by layer chromatography.

When the spot characteristic of vincamic acid disappears, cooking is stopped. The solution is cooled and 500 ml of a $ 2 aqueous sulfuric acid solution are added. The pH of the acidic solution is adjusted to 8 by adding 5% aqueous sodium hydroxide solution.

The precipitate separates. The mixture is extracted with 5 x 200 ml of benzene. The organic solution is discarded, dried over anhydrous potassium carbonate and filtered.

11 56687

The benzene solution is evaporated to dryness and the residue is crystallized from 10 ml of ether. The ether solution is allowed to stand for 10 hours, after which the separated crystals are filtered off and recrystallized from anhydrous methanol.

0.72 g (72%) of vincamic acid hydroxyethyl ester are obtained. The product obtained from layer chromatography is of uniform quality. Mp 171 ° C (Boetius).

Elementary:

Theoretical values: C = 68.66% H = 7.36% N = 7.32% _ Values obtained: C = 69.28% H = 7.86% N = 7.58%

The structure of the product is identified by the IR spectrum (ester band at 5.79 μl).

„Example 3

Vincamic acid chloroethyl ester 1 g (0.0029 moles) of vincamic acid and 0.11 g (0.0027 moles) of sodium hydroxide are dissolved in 80 ml of anhydrous ethanol. The solution is evaporated to dryness under reduced pressure. The dry residue is dissolved in 1 * 0 ml of anhydrous acetonitrile and 20 ml of 1,2-dichloroethane are added to the solution. The resulting mixture is refluxed for k hours. Ester formation is monitored by layer chromatography. When the spot characteristic of vincamic acid disappears, cooking is stopped. The solution is evaporated to dryness under reduced pressure and the dry residue is dissolved in 200 ml of 2% aqueous sulfuric acid solution. The pH of the acidic solution is adjusted to 8 with a 5% aqueous solution of sodium hydroxide. The precipitate separates. The mixture is extracted with 5 x 200 ml of benzene and the organic phase is dried over anhydrous potassium carbonate. The benzene solution is filtered and the filtrate is evaporated to dryness under reduced pressure. The dry residue is crystallized from 10 ml of ether and the crystals obtained are recrystallized from anhydrous methanol.

0.68 g (68%) of vincamic acid chloroethyl ester are obtained. The product formed by layer chromatography is found to be of uniform quality. Sp. 218 ° C (Boetius).

Elemental analysis;

Theoretical values: C = 65.58% H = 6.75% N = 6.95%

Found: C = 65.21% H = 6.52% N = 6.89%

The structure of the compound is identified by IR spectrum (ester band at 5.72).

Example k

Vincamic acid benzyl ester tartrate Dissolve 1 g (0.0028 mol) of vincamic acid in 125 ml of anhydrous benzene. Em. 3 ml of sodium benzylate solution are added to the solution. (Sodium benzylate solution is prepared from 10 ml of benzyl alcohol and 0.2 g of metallic sodium in a manner known as $ 6687 12). The solution is refluxed for 2 hours. The reaction is monitored by layer chromatography. If chromatographic analysis shows that the reac- tio is incomplete, add an. 1 ml of sodium benzylate solution and boil for a further 1 hour. When the reaction is complete, 300 ml of benzene are added to the solution and the mixture is extracted with 200 ml portions of a 2% aqueous solution of sulfuric acid until the acid phase gives a positive Mayer reaction. The aqueous phase is separated. The pH of the aqueous phase is adjusted to 8 with 5% aqueous sodium hydroxide solution and the alkaline solution is extracted with 5 x 20 ml of dichloromethane. The organic solutions are combined and dried over anhydrous potassium carbonate. The solution is filtered and evaporated to dryness. The dry residue is dissolved in 15 ml of ether and a saturated ethereal solution of tartaric acid is added until the pH of the mixture is 3. · The solution is left to crystallize for about 10 hours. The white crystalline vincamic acid benzyl ester tartrate is filtered off and recrystallized from acetone. 0.7 * + g -_ (7 * +%) vincamic acid benzyl ester tartrate is obtained. Layer chromatography shows that the product obtained is uniform. M.p .: 115 ° C (Boetius).

Elemental analysis;

Theoretical values: C = 6 * +, 12% H = 6.25% N = U, Ö2%

Values found: C = 63.98% H = 6.33% N = 5.02%

The structure of the product is identified by the IR spectrum (ester band at 5.75).

Example 5 *

Apovincaminic acid ethyl ester a) 1 g (0.0031 mol) of apovincamic acid and 0.17 g (0.003 mol) of potassium hydroxide are dissolved in 80 ml of anhydrous ethanol, followed by the addition of 0.1 g (0.0036 mol) of ethyl bromide. The solution is refluxed for 3 hours. The progress of the reaction is monitored by layer chromatography. The solution is cooled and evaporated to dryness under reduced pressure. The dry residue is dissolved in 500 ml of a 2% aqueous solution of sulfuric acid and the solution is filtered. The pH of the filtrate is adjusted to 8 with 35% aqueous sodium hydroxide solution. A small precipitate separates. -The mixture is extracted with 200 ml portions of methylene chloride until the aqueous phase shows a positive Mayer reaction. The organic phases are separated, combined, dried over anhydrous potassium carbonate, filtered and evaporated to dryness under reduced pressure. The dry residue is dissolved in 10 ml of anhydrous ethanol, and the solution is left to crystallize for 10 hours at 0-2 ° C. 0.66 g of apovincaminic acid ethyl ester is obtained (yield 6635). The product is found to be homogeneous by layer chromatography. M.p .: 1UU ° C (Boetius).

Elemental analysis:

Theoretical values: C = 75, * + 0% H = 7 »* + 8% N = 7.99 35 Observed values: C = 75.20% H = 7.52 35 N = 8.02% 56667

The structure of the product is identified by the IR spectrum (ester band at 5.75 μl).

b) 1 g (0.0029 mol) of vincamic acid and 0.11 g (0.0027 mol) of sodium hydroxide are dissolved in 200 ml of absolute ethanol. The solution is heated to reflux and when boiling begins, 10 ml of concentrated ethanesulfonic acid are added to the solution. The formation of apovincaminic acid ethyl ester is monitored by layer chromatography. After boiling for 3 hours, the solution is concentrated under reduced pressure to about 20 ml. To the concentrated solution is added 500 ml of distilled water and the mixture is transferred to a separatory funnel. The pH of the solution is adjusted to 8 with 5% aqueous sodium hydroxide solution. The precipitate separates. The mixture is extracted with 5 x 200 ml of methylene chloride and the organic solution is dried over anhydrous potassium carbonate. The solution is filtered and evaporated to dryness under reduced pressure. The dry residue is dissolved in 20 ml of ethanol, and then the solution is left to crystallize at 0-2 ° C. 0.86 g (86%) of apovincaminic acid ethyl ester are obtained. The product is found to be homogeneous by layer chromatography. M.p .: 14U ° C (Boetius). Example 6

Apovincamine Butyl Ester 1 g (0.0031 moles) of apovincamic acid and 0.12 g (0.003 moles) of sodium hydroxide are dissolved in 80 ml of anhydrous ethanol, followed by the addition of 0.5 g (0.03 moles) of butyl bromide. . The solution is refluxed for 1+ hours. The progress of the reaction is monitored by layer chromatography. When the reaction is complete, the solution is cooled and evaporated to dryness under reduced pressure. The dry residue is dissolved in 500 ml of a 2% aqueous solution of sulfuric acid and the pH of the solution is adjusted to 8 by adding 5% aqueous sodium hydroxide solution. The alkaline solution obtained is extracted with 5 x 200 ml of benzene. The benzene solutions are combined, dried over anhydrous potassium carbonate, filtered and evaporated to dryness under reduced pressure. The dry residue is crystallized from 10 ml of ether. The obtained crystalline substance is recrystallized from acetone. 0.70 g (70%) of apovincaminic acid butyl ester are obtained. The product is found to be homogeneous by layer chromatography. Sp. = 175 ° C (decomposition point) (Boetius).

Elemental analysis:

Theoretical values: C = 76.15% H = 7.99% N = 7.0%

Values found: C = 76.18% H = 7.83% N = 7.39%

The structure of the product is identified by the IR spectrum (ester band at 5.75jO-

IU

56687

Example 7 (-) - Apovincaminic acid ethyl ester 1 g (0.0028 moles) of (-) - vincamine {&] = 1 + 0.0 °, m.p. 231 DEG C. (Boetius)) is dissolved in 25 ml of methanol containing 0.1 + 1 g (0.007 mol of potassium hydroxide) while heating, and the solution is refluxed for 5 hours, during which time the saponification of the methyl ester is monitored by layer chromatography. When the saponification is complete, the solution is cooled and the pH is adjusted to neutral with glacial acetic acid, (-) - vincamic acid begins to crystallize immediately, leaving the solution to crystallize at 0 to 2 ° C for 12 to 1 hour, after which the crystallized ai - filtered off to give 0.95 g (98%) of (-) - vincamic acid, mp = -85.2 ° C (c = 1 in 0.1 N sodium hydroxide solution), m.p .: 257 ° C (Boetius) .

The resulting (-) - vincamic acid is dissolved in a mixture of 1 + 0 ml of anhydrous ethanol and 3 ml of concentrated (97%) sulfuric acid. The solution is refluxed for 8 hours.

During this time, the progress of the reaction is monitored by layer chromatography. When the reaction is complete, the solution is cooled, evaporated to a volume of 7 ml under reduced pressure and the residue is transferred to a separatory funnel together with 100 ml of distilled water. The pH of the solution is adjusted to 8.5 with 10% aqueous sodium hydroxide solution. The precipitate separates. The mixture is extracted with 5 x 30 ml of dichloromethane. The organic phases are combined, dried over anhydrous potassium carbonate, the desiccant is filtered off and the filtrate is evaporated to dryness under reduced pressure. The oily residue is dissolved in 15 ml of anhydrous ethanol, the ethyl ester of (-) - apovincaminic acid begins to crystallize immediately. The mixture is left to crystallize at 0-2 ° C for 8-10 hours and the crystallized material is filtered off. 0.71 g (75%) of (-) - apovincamine acid ethyl ester are obtained. M.p .: 153 ° C (Boetius). C ° t] = -112.5 ° (c = 1 in pyridine).

Example 8

Apovincaminic acid ethyl ester methiodide 1 g (0.0028 mol) of apovincaminic acid ethyl ester is dissolved in 25 ml of anhydrous acetone and 0.1 * 1 + g (0.003 mol) of methyl iodide are added to the solution. The mixture is left at room temperature for 2k hours. During this time, the reaction is monitored by layer chromatography. Needle-like crystals begin to separate from the reaction mixture already at room temperature. The mixture is evaporated under reduced pressure to a concentration of about 10 ml and the concentrated solution is allowed to stand at crystallization temperature 0-2 ° C for 8-10 hours. The crystals are filtered and washed with a small amount of cold acetone. 1.29 g (92/5) of apovincaminic acid ethyl ester methiodide are obtained. M.p .: 20 l + ° C.

Elemental analysis:

Theoretical values: C = 56.12% H = 5.93% N = 5.69% I = 25.77%

Values found: C = 56.02% H = 5.88% N = 5.70% I = 25.79% 56687

Example 9

Apovincaminic acid ethyl ester To 1.0 g (0.003 moles) of apovincaminic acid is added 20 ml of ethanol and 3 drops of concentrated sulfuric acid. The mixture is refluxed for 3 hours. The progress of the reaction is monitored by thin layer chromatography. After completion of the reaction, the reaction mixture is cooled and the excess ethanol is distilled off under reduced pressure. To the obtained oily residue is added 30 ml of 2- to 2% aqueous sulfuric acid solution, and the pH is adjusted to 8 with 10% aqueous sodium hydroxide solution. The alkaline solution is extracted 3 times with 30 ml of dichloromethane. The combined dichloromethane phases are dried over anhydrous potassium carbonate and then evaporated to dryness under reduced pressure.

0.4 g of dry residue is obtained, which is purified by column chromatography using three times the amount of alumina (activity III). The product is eluted with benzene and 5 nil fractions are collected from the eluate. The desired apovincamic acid ethyl ester is obtained from fractions 1 and 2, which are combined and evaporated to dryness under reduced pressure. 0.3 g of apovincaminic acid ethyl ester are obtained as a residue, mp 144 ° C.

Example 10

Apovincamic acid tert-butyl ester citrate Dissolve 0.25 g (0.00074 mol) of apovincamine in 15 ml of toluene. 0.1 g (0.0089 mol) of potassium tert-butylate is added to the solution and the mixture is refluxed for 10 hours. The reaction is monitored by thin layer chromatography (alumina as adsorbent and a mixture of benzene and acetonitrile (10: 1) as solvent. After completion of the reaction, 20 ml of water and 20 ml of benzene are added to the reaction mixture, the mixture is stirred for 2 minutes and allowed to stand. The organic phase is dried over potassium carbonate and then evaporated to dryness under reduced pressure, the residue is dissolved in 1 ml of benzene and filtered through a 1-2 cm thick layer of alumina (5 g of alumina, activity III) and washed with a further 10 ml of benzene. The desired ester is in a benzene solution which is evaporated to dryness under reduced pressure.

0.06 g of apovincamine tert-butyl ester (21% of theory) are obtained, R_ 0.31.

-1 1 IR spectrum: 3100-3000 can CH aromatic 3000-2800 cm'1 CH ?, CH-.

-1 d ^.

1700 cm CO esters

1635 and 1612 cm-1 C = C

1455 cm-1 CH 3

1286 cm -1 C0C

745 cm -1 CH.

l6 66667

To the obtained oily product is added a saturated diethyl ether solution of citric acid until the pH reaches U. The citrate immediately begins to precipitate. The mixture is allowed to refrigerate for 12 hours and the separated salt is filtered off, washed with 8-10 ml of chilled diethyl ether and dried. 0.052 g of apovincamine tert-butyl ester citrate (12.0% of theory) are obtained, m.p. 100-108 [deg.] C., [.alpha.] D @ 20 - + 60.2 DEG (c = 1 in pyridine).

Analysis for C ^ qH ^ qNN ^ O ^:

Calculated: C 63.1% H 6.6% N U, 9%

Found: C 63.0% H 6.5% N 9.9%.

Example 11

Auxiliary acid butyl ester tartrate To 2 ml of n-butyl alcohol is added a catalytic amount of sodium metal. After the metal has dissolved, 5 nil of n-butyl acetate and 0.2 g of apovincamine are added. The mixture is refluxed for J hours, at which time the methyl acetate formed is continuously removed. The progress of the reaction is monitored by thin layer chromatography. After completion of the reaction, 10 ml of water are added to the reaction mixture, and the mixture is extracted 3 times with 10 ml of dichloromethane. The dichloromethane phases are combined, dried over anhydrous potassium carbonate and evaporated to dryness under reduced pressure. The residue is chromatographed using alumina (activity III). Elute with benzene and collect 10 ml fractions. The desired apovincaminic acid butyl ester is obtained from fraction 1, which is evaporated to dryness under reduced pressure. Yield: 0.0i * g. The properties of the product are the same as those of the compound of Example 6. The ester obtained is converted to tartrate in the same manner as in Example 5. The pour point of the tartrate obtained is 175 ° C, / k / p ° = 62.1 ° (c = 1 in pyridine).

Example 12

Vincamic acid benzyl ester tartrate 0.5 g (0.001 μmol) of vincamic acid and 0.05 g of sodium hydroxide in 60 ml of ethanol. 0.2 g (0.0015 mol) of benzyl chloride are added to the solution and the mixture is refluxed for 8 hours. The progress of the esterification reaction is monitored by thin-layer chromatography. After completion of the reaction, the solution is cooled and ethanol is distilled off under reduced pressure. To the oily residue obtained is added 30 ml of 2N aqueous sulfuric acid solution and the pH is adjusted to 8 with 10% aqueous sodium hydroxide solution. The alkaline solution is extracted 3 times with 30 ml of dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The resulting dry residue is purified by column chromatography using alumina (Breckmann, activity lii). Elute with benzene to give 8-16 fractions. The fractions are combined and evaporated to dryness. 0.1 g of vincamic acid benzyl ester is obtained. The product is converted to tartrate as in Example 1. The properties of the tartrate obtained are the same as those of the compound of Example 1.

Claims (1)

A process for the preparation of circulating and hypertensive vincamine and apovincaminic acid esters of the formula OnO (I> ROOC "wherein X '"' - Y is a group = C = CH- or = C-CHg-OH and when Χ'- '^' Υ is a group = C = CH-, then R is an alkyl group containing 2-h carbon atoms, And when X ^ Y is a group = C-CH2-, then R is a hydroxyethyl group, a chloroethyl group, an OH allyl group or a benzyl group, and for the preparation of their acid addition salts and quaternary salts, characterized in that a) vincamine or apovincaminic acid is converted into an alkali metal salt and esterified with a halide of formula RX1 or a sulphate of formula (R) 2SO4, in which R is as defined above and X ^ is a halogen atom, or b) the vincamine or apovincamic acid is esterified with an alcohol of the formula R-OH, in which R is as defined above, in the presence of an acid catalyst such as sulfuric acid or ethanesulfonic acid, or c) vincamine or apovincamine transesterification with an alkali metal alcoholate of the formula RQMe, wherein R is as defined above and Me is an alkali metal, or d) apovincamine or vincamic acid, respectively, is reacted with apovincamine or vincamine with a carboxylic acid ester of the formula R 1 -COOR, where R is the same as above and R 1 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and the obtained compound of formula (I) is converted, if desired, into an acid addition salt or a quaternary salt by reaction with an inorganic or organic acid or an alkyl halide, and the resulting salt is converted to the free base. or another salt.