JPS6148839B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides racemized or optically active general formula () (wherein R ¹ is a C _1-4 alkyl group) and pharmaceutically acceptable acid addition salts thereof.

It has been reported that vincamic acid ester and apovincamic acid ester exhibit useful activities as pharmaceuticals. In particular, among vincamic acid esters, methyl ester (vincamine) is particularly important as a vasodilator.

It has been found that the vincamic acid ester of general formula () can be produced by a simple method with high yield.
i.e., racemized or optically active formula () 14-oxo-15-hydroxyimino-3α,17
When α-E-homo-eburnan is racemized with an alcohol of the general formula R ¹ -OH or when producing an optically active vincamic acid ester of the general formula (),
The reaction is carried out at a temperature of 60 to 80°C for 5 to 10 minutes in the presence of a base or in the presence of 1 to 20 molar equivalents of an acid, and the resulting novel racemized or optically active general formula () (wherein R ¹ is as defined above) and the resulting racemized or optically active apovincamic acid ester of general formula ( ) and vincamic acid of general formula ( ) Separate the mixture of esters and optionally obtain the general formula ()
re-esterifying the apovincamic acid ester of or the vincamic acid ester of general formula ( ) and, if desired, converting the racemized or optically active vincamic acid ester of general formula ( ) into a pharmaceutically acceptable acid addition salt. , and/or resolve the racemized or optically active vincamic acid ester (general formula ()).

Racemized or optically active starting materials of formula () are general formula () (wherein R ² is a C _1-4 alkyl group, and
X ^- is an acid anion) or an acid addition salt thereof, and the resulting racemized or optically active cis and/or trans compound of the following general formula (): (wherein R ² is as defined above) or its acid addition salt, optionally without separation or after fractional crystallization and/or resolution, is treated with an alkaline agent and the resulting formula ( ) The racemized or optically active cis and/or trans compound is prepared by fractional crystallization and/or resolution, optionally with a nitrosating agent, followed by reaction.

If the reaction of a compound of formula () with an alcohol of general formula R ¹ OH is carried out in a base, new compounds of general formula () are formed. As bases, alcoholates formed from alcohols of the general formula R ¹ OH and alkali metals such as sodium can be used.

If the compound of general formula () is treated with dilute aqueous acid, the corresponding vincamic acid ester is formed as the main product together with the apovincamic acid ester of general formula (). General formula () and ()
The compounds are separated from each other by crystallization.

If vincamic acid ester and apovincamic acid ester with different alkyl groups have to be prepared, for example, if vincamic acid ester and apovincamic acid ethyl ester have to be prepared simultaneously, the appropriate ester can be prepared by adding the ester after crystal separation. It can be converted to the desired ester by re-esterification. This re-esterification can be carried out by known methods, in which the compound to be re-esterified is heated in the presence of an acid with an alcohol corresponding to the ester to be introduced into the molecule. . As acid, any inorganic or organic acid, such as sulfuric acid,
p-Toluenesulfonic acid and the like can be used.

Therefore, the reaction of the intermediate product () is carried out in the presence of about 1 to 20 molar equivalents of acid, preferably 6 to 10 molar equivalents, under very mild conditions at 60 to 80°C for about 5 to 10 minutes. However, it can be converted to a compound of general formula () by using a large amount of acid, applying a higher temperature, or reacting for a long time.

Compounds of general formula () can be converted into pharmaceutically acceptable salts by addition of a suitable acid. Hydrochlorides, bromates, etc., phosphates; rhodates, sulfates, hydrogen sulfates, tartrates, succinates, maleates, nitrates, salicylates, benzoates, acetates, propionates, Salts such as lactate and sulfonate can be produced.

According to the method of the present invention, both racemized and optically active compounds of general formula () can be produced. If the compound of general formula () obtained during the synthesis process is optically active, then the desired product of general formula () is also optically active. On the other hand, if the compound of general formula () is racemic, the desired product is also racemic. If desired, the racemized compound of general formula () is resolved.

The novel process of the invention can be illustrated by the examples given below. However, these examples do not limit the scope of the invention.

Reference example 1 Production of starting material dl-14-oxo-3α,17α-E-homo-eburnan a 1-(2'-methoxycarbonylethyl)-1
27.0 g (72.0 mmol) of ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]-quinolidinium chloride was dissolved in 300 ml of methanol, and 10 g of palladium supported on charcoal. hydrogenated in the presence of Consumption of the theoretical amount of hydrogen was completed in 5 hours. The catalyst was then filtered, washed with methanol and the liquid was evaporated in vacuo. Water this residue
The solution was made alkaline to pH 8-9 by adding an aqueous sodium carbonate solution, and extracted several times with dichloromethane. The dichloromethane extract was dried over magnesium sulphate and the solvent was evaporated off in vacuo.
This residue (2.50 g) was triturated with 30 ml of methanol to precipitate 19.0 g (77.5%) of the hydrogenated isomer mixture.

19.0 g of the isomer mixture thus obtained was recrystallized from 170 ml of methanol. 7.0g (28.5
%) of 1β-(2′-methoxycarbonyl-ethyl)-1α-ethyl-1,2,3,4,6,
7,12,12bα-octahydroindolo [2,
3-a] Quinolidine was precipitated. Melting point: 142
-143℃ Evaporate this mother liquor and obtain 9.0g of cis-trans isomer mixture containing a large amount of cis-isomer.
(36.7%) is crystallized and this mixture may also be subsequently ring-closed.

b 1β- prepared as described in Reference Example 1a
(2′-methoxycarbonyl-ethyl)-1α-
Ethyl-1,2,3,4,6,7,12,12bα
-Octahydro-indolo[2,3-a]quinolidine 7.0 g (20 mmol) was dissolved in 360 ml of anhydrous toluene with constant stirring in the presence of 1 g of 50% sodium hydride suspension in a nitrogen atmosphere for 12 hours.
Boil for an hour. After cooling, this mixture was extracted three times with 100 ml portions of a 2.5% aqueous sulfuric acid solution. The acid layer was made alkaline to pH=9 by adding concentrated ammonium hydroxide solution under ice cooling, and the alkaline solution was extracted several times with dichloromethane. The combined organic solutions were dried over magnesium sulfate, filtered, and the liquid was evaporated to dryness in vacuo. This residue was crystallized from methanol, thus giving the target compound in the form of white crystals with a melting point of 165-167°C (literature melting point: 164°C,
Recrystallization from ether, Hungarian patent specification
(See No. 163769).

Yield: 5.0g (79%) IR spectrum (KBr): 1690 (acid amide)
CO) c 9.0 g of the mixture of cis-trans esters isolated according to Reference Example 1a were ring-closed according to Example 1b in 460 ml of anhydrous toluene in the presence of 1.3 g of sodium hydride suspension. The resulting mixture was treated to give 14-oxo-3α,17α-E-homo-
An isomer mixture of eburnan and 14-oxo-3β,17α-E-homo-eburnan was produced and mixed with 20 ml of dichloromethane and 30 ml of ether.
ml of the mixture. Thus 4.5g
(55%) of 14-oxo-3α,17α-E-homo-eburnan was obtained.

The overall yield relative to the starting immonium salt is
It was 42.8%. 14-oxo-3α, 17α-E-
The total weight of the homo-ebrunan was 9.5 g.

Melting point: 165-167℃ (recrystallized from methanol) Reference example 2 Production of dl-14-oxo-3α,17α-E-homo-eburnan (starting material) 1-(2'-methoxycarbonyl-ethyl)-1
-Ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidinium chloride (4.2 g (11.2 mmol)) was added to 400 ml of water in the presence of 2.0 g of palladium catalyst supported on charcoal. Hydrogenation was carried out in the tank. Consumption of the theoretical amount of hydrogen was completed in 3 hours. The catalyst was filtered and washed several times with water, the resulting liquid was made alkaline (PH=9) by adding 5% aqueous sodium carbonate solution and extracted three times with dichloromethane. The organic phase was dried, the solvent removed, 3.9 g of dl-14-oxo-3α,17α-E-homo-eburnane and dl
The residual mixture consisting of -14-oxo-3β,17α-E-homo-eburnan was heated as described in Example 1b in the presence of a suspension of 0.6 g of sodium hydride in 200 ml of anhydrous toluene.

This reaction mixture was treated as described in Example 1b and
Thus 1.5g (43.4%) of dl-14-oxo-3
α,17α-E-homo-eburnan was obtained.

Melting point: 165-167℃ (from methanol) Reference example 3 Production of starting material dl-14-oxo-3α,17α-E-homo-eburnan Ethanol in the presence of 3 g of palladium supported on charcoal
In 360 ml, 1-(2'-ethoxycarbonyl-ethyl)-1-ethyl-1,2,3,4,
6,7-hexahydro-12H-indolo[2,3
-a] 7.0 g (18 mmol) of quinolidium chloride was hydrogenated. The calculated amount of hydrogen was consumed in about 3 hours, after which time the catalyst was filtered and washed with ethanol and the liquid was evaporated to dryness in vacuo. The residue was dissolved in 200 ml of water, the solution was made alkaline with 5% aqueous sodium carbonate solution and extracted several times with dichloromethane. The organic phase was dried over magnesium sulfate, the liquid was evaporated to dryness,
The resulting isomer mixture was then recrystallized from 10 ml of ethanol.

3.7 g (57%) of dl-1β-(2'-ethoxycarbonyl-ethyl)-1α-ethyl-1,2,3,
4,6,7,12,12bα-octahydro-indolo[2,3-a]quinolidine was precipitated.

Melting point: 136-138℃ (recrystallized from ethanol) IR spectrum (KBr): 3400 (indole
NH), 1730cm ^-1 ( _CO2C2H5 ) NMR spectrum ( _CDCl3 ): _δ = _8.12ppm1H ,
S (indole-NH), 7.48-6.99 (4H, m, aromatic proton, 4.00 (2H, J = 7.3cps,
COOCH ₂ CH ₃ ), 1.27―1.04 (6H, 2t, J=
7.3 cps, COOCH ₂ CH ₃ and CH ₂ CH ₃ ) Analysis for C ₂₂ H ₃₀ N ₂ O ₂ : Molecular weight = 354.48 Calculated value: C74.53% H8.53% N7.90% Actual value: C74.50% H8.47% N7.69% When left alone, 0.60g (9%) of 1β-(2′-ethoxycarbonyl-ethyl)-1α-ethyl-
1,2,3,4,6,7,12,12bβ-octahydro-indolo[2,3-a]-quinolidine precipitated from the mother liquor.

Melting point: 105-107℃ (recrystallized from ethanol) IR spectrum (KBr): 3320 (indole-
NH), 1712 cm ^-1 (CO ₂ C ₂ H ₅ ) NMR spectrum (CDCl ₃ ): δ = 8.78 ppm:
(IH, s, indole-NH), 7.46-6.90 (4H,
m, aromatic proton, 4.16 (2H, d, J=
7.3cps, COOCH ₂ CH ₃ ), 1.33 (3H, t, J=
7.3cps, CH ₂ CH ₃ ), 0.66 (3H, t, J=
7.3cps, COOCH ₂ CH ₃ ) Analysis for C ₂₂ H ₃₀ N ₂ O: Molecular weight = 543.48 Calculated value: C74.53% H8.53% N7.90% Actual value: C74.12% H8.44% N7. 72% 3.7 g (10.4 mmol) produced as above
dl-1β-(2'-ethoxycarbonyl-ethyl)-1α-ethyl-1,2,3,4,6,7,
12,12bα-octahydro-indolo [2,3-
a) The quinolidine was ring closed in 170 ml of anhydrous toluene as described in the previous example. This reaction produced 2.4 g (74.5%) of the target compound.

Melting point: 165-167℃ (from methanol) Reference example 4 Production of starting material dl-14-oxo-3α-17α-E-homo-eburnan In the presence of 2.0 g of palladium supported on charcoal, 6.0 g (15.4 mmol) in 500 ml of water ) of 1-(2'ethoxycarbonyl-ethyl)-1-ethyl-1,2,
3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolidinium chloride was hydrogenated. The calculated amount of hydrogen was consumed in about 2 hours, after which time the catalyst was filtered and washed with water. 5 times this liquid
% aqueous sodium carbonate solution was added to make alkaline (PH=9) and extracted several times with dichloromethane. The organic phase was dried over magnesium sulfate, the solvent was removed, and 5.5 g of the resulting isomer mixture was dissolved in the presence of 0.8 g of sodium hydrogen suspension.
Ring closure was carried out in 250 ml of anhydrous toluene as described in the previous example. The resulting isomer mixture was recrystallized from a mixture of dichloromethane and ether or methanol, and in this way 2.9 g
(61%) of the target compound was obtained.

Melting point: 165-167℃ (recrystallized from methanol) Reference example 5 Production of starting material dl-14-oxo-15-hydroxyimino-3α,17α-E-homo-eburnan 5.8 g (18.8 mmol) in 40 ml of anhydrous toluene
dl-14-oxo-3α-17α-E-homo-eburnan was suspended. 12 ml of tert-butylnitrile were added to this suspension and a suspension of 4.0 g (35.4 mmol) of potassium tert-butyrate in 40 ml of anhydrous toluene was added to this mixture under nitrogen atmosphere and with constant stirring. This stirring was continued for 1 hour at room temperature.
A homogeneous solution was produced. This reaction was carried out using layer chromatography (KG-G-benzene:methanol=
14:3, the Rf value of the starting material is higher than the Rf value of the target compound). After the completion of this reaction, the reaction mixture obtained is 150 g of water containing 12 g of ammonium chloride.
ml and the aqueous layer was extracted twice with 30 ml of toluene. The combined toluene layers were dried over magnesium sulfate, filtered, and the liquid was concentrated in vacuo to 10 ml. The precipitated oxime was washed with perfused and cold toluene.

Yield: 4.4g (69%) Melting point: 258℃ (Literature melting point: 260℃, Yield: 60
% (see Hungarian Patent No. 163769)) IR spectrum (KBr): 3200 (OH), 1705 (lactam CO), 1640 cm ^-1 (C=N) Example 1 dl-14-methoxycarbonyl-14-hydroxyamino- 3α,16α-Ebrunan dl-14-oxo-15-hydroxyimino-3α,17α- prepared as in Reference Example 5 in 40 ml of anhydrous methanol in the presence of 1.17 g (21.6 mmol) of sodium methylate under anhydrous conditions. 3.2 g (9.5 mmol) of E-homo-eburnan was heated for 1 hour. After cooling, the sodium methylate was decomposed with acetic acid and the solution was evaporated to dryness in vacuo. 30 ml of water were added to the residue, the pH was slowly adjusted to 8 by addition of 1:1 aqueous ammonium hydroxide solution, and the alkaline solution was extracted three times with dichloromethane. The organic phase was dried, filtered, the liquid was evaporated and the residue was recrystallized from 20 ml of methanol.

Yield: 2.42g (69%) of target compound Melting point: 179℃ (methanol) IR spectrum: (KBr): 3420 (NH, OH),
1710cm ^-1 (CO ₂ CH ₃ ) NMR spectrum (CDCl ₃ ): δ=8.05ppm
(1H, NH), 7.6-7.0 (4H, m, aromatic proton) 3.5 (3H, s, CO ₂ CH ₃ ), 1.1 (3H, t,
CH ₂ CH ₃ ) Mass spectrum: m/e70eVM ⁺ = 369 Analysis for formula C ₂₁ H ₂₇ N ₃ O ₃ : Molecular weight =
369.44 Calculated value: C68.27% H7.36% N11.38% Actual value: C68.58% H7.29% N11.28% The Rf value of this starting material is the Rr (KG
-G, benzene-methanol = 14.3).

Example 2 dl-14-ethoxycarbonyl-14-hydroxyamino-3α,16α-ebrunan dl-14-oxo-15-hydroxyimino-3α,17α-E-homo-ebrunan produced as described in Reference Example 5 0.5 g (1.5 mmol) was heated in 20 ml of absolute ethanol under anhydrous conditions for 1.5 hours in the presence of 0.19 g of sodium ethylate. Excess sodium ethylate was destroyed with acetic acid and the solvent was removed in vacuo. Water 20 to this residue
ml and the mixture was then made alkaline (PH=8) by slowly adding 1:1 dilute aqueous ammonium hydroxide solution and the alkaline solution was extracted several times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, the liquid was evaporated to dryness, and the residue was recrystallized from ethanol.

Yield: Target compound 0.28g (49.3%) Melting point 156-158℃ (from ethanol) IR spectrum (KBr): 3400 (NH, OH),
1700cm ^-1 (CO ₂ C ₂ H ₅ ) NMR spectrum (CDCl ₃ ): δ=8.3ppm
(1H, NH), 4.0 (2H, q, J = 7.3cps,
COOCH ₂ CH ₃ ), 1.18 (3H, t, J = 7.3cps,
COOCH ₂ CH ₃ ), 1.18 (3H, t, J = 7.3cps
COOCH ₂ CH ₃ ) Analysis of C ₂₂ H ₂₉ N ₃ O ₃ : Molecular weight = 383.47 Calculated value: C68.90% H7.62% N10.95% Actual value: C68.69% H7.45% N10.95% Example 3 dl-vincamine and dl-apovincamine dl-14-methoxy-carbonyl-14-hydroxyamino-3 prepared as described in Example 1
0.44 g (1.19 mmol) of α,16α-eburnan was dissolved in 1.6 ml of glacial acetic acid with gentle heating, 16 ml of a 5% aqueous sulfuric acid solution was added to this solution, and the solution was heated on a water bath for 2 hours. The mixture was made alkaline by adding a concentrated aqueous ammonium hydroxide solution under ice cooling, and the resulting alkaline solution was extracted three times with dichloromethane. The combined organic solutions were dried over magnesium sulfate and filtered,
The solvent was removed from this solution by vacuum evaporation.

To the residue containing dl-vincamine, dl-apovincamine and starting materials, 1.5 ml of anhydrous methanol and 90 g of sodium methylate were added. The starting hydroxyamino compound remained in solution. The precipitated pure dl-vincamine was filtered and washed with methanol.

Yield: 0.18 g (42%) of dl-vincamine Melting point: 234°C (chlorobenzene) The mass and IR spectra of this product were identical to those of dl-vincamine produced according to Hungarian Patent Specification No. 163143. .

To this solution containing sodium methylate was added 11 ml of a solution of sulfuric acid in methanol (37 ml methanol and 13 ml concentrated sulfuric acid) and the solution was heated for 1.5 hours. The mixture was then poured onto ice water, made alkaline with concentrated aqueous ammonium hydroxide solution, and extruded several times with dichloromethane. The combined solutions were dried over magnesium sulfate, the liquid was evaporated and the residue was crystallized from 2 ml of methanol.

Yield: 0.13 g (32%) This product matched the dl-apovincamine described in Example 8 in all physical and chemical characteristics.

Reference example 6 Starting material (+)-14-oxo-3α,17α-E
-Production of homo-eburnan In the presence of 1.8 g of 50% sodium hydride suspension,
In 450 ml of anhydrous toluene, with constant stirring, (-)-1β-(2'-methoxycarbonyl)-ethyl-1-ethyl-1,2,3,4,
9.8 g (28.8 mmol) of 6,7,12,12α-octahydro-indolo[2,3-a]-quinolidine was heated for 5 hours. After cooling, add this solution to 2.5
% aqueous sulfuric acid solution, the aqueous layer was made alkaline (PH=9) by adding a concentrated aqueous ammonium hydroxide solution under cooling, and the solution was extracted several times with dichloromethane. The extract was dried over magnesium sulfate, filtered, the solvent was removed from the liquor in vacuo, and the residue was crystallized from methanol.

Yield: 5.3g (60%), melting point 152-154℃ (decomposition)
[α] _D = +32.5° (CH ₂ Cl ₂ , C = 1.35) Reference example 7 (+) -14-oxo-15-hydroxyimino-
3α,17α-E-homo-eburnan (starting material) 12 ml of anhydrous toluene and tert-butylnitrile
(+)-14-oxo-3α, 16α-E in 4.8ml
- Suspend 2.10 g (6.8 mmol) of homo-ebrunan, and add 12 ml of anhydrous toluene to this suspension.
1.53 g of potassium tert-butyrate suspended in
(13.1 mmol) was added under nitrogen atmosphere with constant stirring. This mixture was stirred at room temperature for 1 hour, after which 4.2 g of ammonium chloride in 80 ml of water was added.
was added and then stirred for 15 minutes. The toluene layer was separated and the aqueous phase was extracted twice with toluene. The combined toluene solutions were dried over magnesium sulfate, filtered, and the liquid was evaporated to dryness in vacuo. 1.9 g of this residue was obtained, which was dissolved in 8 ml of methanol, and the pH of the solution was adjusted to 5 by adding hydrochloric acid in methanol. The precipitated hydrochloride salt was filtered and washed with methanol.

Yield: 1.40 g (55%) of the hydrochloride of the target compound was obtained.

Melting point: 254-257℃ (from methanol) IR spectrum (KBr): 1730 (CO), 1635cm ^-1
(C=N) The base is obtained from the hydrochloride salt of the target compound by dissolving it in 5% aqueous sodium carbonate solution, extracting the solution with dichloromethane, drying the extract, filtering, and evaporating the solution. I made it by drying it. The base of the target compound was obtained as an oily residue.

[α] _D = +61° (C = 1, CH ₂ Cl ₂ )

Claims (1)

[Claims] 1 General formula () (wherein R ¹ is a C _1-4 alkyl group) When producing racemized or optically active vincamic acid esters and pharmaceutically acceptable acid addition salts thereof, the general formula () (wherein R ¹ is as defined above) is treated with an acid and then, if desired, the resulting racemic compound of the general formula () is treated with an acid. The racemization or optically active vincamic acid ester represented by the above general formula () is characterized by converting the optically active vincamic acid ester into a pharmaceutically acceptable salt and/or resolving the obtained racemized vincamic acid ester. A method for producing optically active vincamic acid esters or pharmaceutically acceptable acid addition salts thereof. 2 General formula () In producing racemized or optically active vincamic acid esters represented by the formula (wherein R ¹ is a C _1-4 alkyl group) and pharmaceutically acceptable acid addition salts thereof, the formula () Racemized or optically active 14-oxo-15-hydroxyimino-3α,17α-E-
Homo-ebrunan or its racemate with the general formula
reaction with an alcohol of the formula R ¹ OH, in which R ¹ is as defined above, in the presence of an acid, and then, if desired, racemization or Racemization or optical activity represented by the general formula () characterized by converting an optically active vincamic acid ester into a pharmaceutically acceptable salt and/or resolving the obtained racemized vincamic acid ester A process for preparing vincamic acid esters or pharmaceutically acceptable acid addition salts thereof. 3 General formula () In producing racemized or optically active vincamic acid esters represented by the formula (wherein R ¹ is a C _1-4 alkyl group) and pharmaceutically acceptable acid addition salts thereof, the formula () Racemized or optically active 14-oxo-15-hydroxyimino-3α,17α-E-
Homo-eburnan is reacted with an alcohol represented by the general formula R ¹ OH (wherein R ¹ is as defined above) in the presence of a base, resulting in the general formula () (wherein R ¹ is as defined above) is treated with an acid and then, if desired, the resulting racemic compound of the general formula () is treated with an acid. converting the optically active vincamic acid ester into a pharmaceutically acceptable salt thereof;
and/or the general formula () characterized in that the obtained racemized vincamic acid ester is resolved.
A method for producing a racemized or optically active vincamic acid ester represented by: or a pharmaceutically acceptable acid addition salt thereof.