JPS5910674B2 - Manufacturing method of apovincamic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides racemized or optically active compounds of the general formula (1) (
The present invention relates to a method for producing apopin camic acid ester represented by the formula (wherein R1 is a C1-4 alkyl group) and a pharmaceutically acceptable acid addition salt thereof.

It has been reported that pincamate ester and apopincamate ester exhibit useful activities as pharmaceuticals. In particular, apopin camic acid ethyl ester is important as a vasodilator. Until now, apopin camic acid ester of general formula () has been used as pinkamine (general formula 11 where R1 is methyl)
) (wherein R1 is as defined above) and converting the resulting pincamic acid (compound of general formula (5) in which R1 is hydrogen) into the desired ester, Water is then removed from the pinkamic acid ester to produce the corresponding apopincamic acid ester, or alternatively, apopincamine (a compound of general formula (1) in which R1 is methyl) is first prepared by removing water from pinkamine. The apopincamine thus obtained was converted into apopincamic acid (
It was produced by hydrolysis to a compound of general formula (1) in which R1 is hydrogen) and converting it to the corresponding ester (Pankali Patent Specification No. 163434).

The disadvantage of this process is that pinkamine must first be prepared and the corresponding apopine camic acid ester can be prepared from this pinkamine, but with a maximum yield of 60%. It has been found that apopin camic acid ester of general formula (1) and/or pin camic acid ester of general formula (1) can be produced by a much simpler and higher yielding method.

That is, racemized or optically active 14-oxo-15-hydroxy-imino-3d.17ct-E of formula (e)
- Homoieburnan is reacted with an alcohol of general formula R1-0H in the presence of an acid when producing (a) racemization or optically active apopine camic acid ester of general formula (1), or (b) racemization Or, when producing optically active apopin camic acid ester of general formula (1) and/or pin camic acid ester of general formula (n), in the presence of a base or in the presence of 1 to 20 molar equivalents of acid at 60 to 80°C. and react for 5 to 10 minutes at a temperature of and the resulting racemized or optically active apopine camic acid ester of general formula (1) and general formula (
The mixture of pincamic esters of 6) is separated and optionally the resulting apopincamic ester of general formula (4) or pincamic ester of general formula (2) is re-esterified and, if desired, , the racemized or optically active apopin camic acid ester of the general formula (1) and the general pin camic acid ester obtained in either method a) or (g) are converted into a pharmaceutically acceptable acid addition salt. converting and/or resolving the racemized or optically active apopin camic acid ester (general formula (1)) or pincamic acid ester (general formula (n)).

The racemized or optically active starting material of formula (8) is a compound of the general formula (M, where R2 is C1-4 alkyl 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 (7): (wherein R2 is as defined above) or an acid addition salt thereof, as the case may be. Without separation or after fractional crystallization and/or resolution, treatment with an alkaline agent and the resulting racemized or optically active cis and/or trans compound of formula It is produced by fractional crystallization and/or division using a curing agent, followed by reaction.

If the reaction of a compound of formula (to) with an alcohol of general formula RlOH is carried out in a base, new compounds of general formula (sub) are formed.

As bases it is possible to use alcoholates formed from alcohols of the general formula RlOH and alkali metals such as sodium. If the compound of general formula (1) is treated with dilute aqueous acid, the corresponding pincamic acid ester is converted to the compound of general formula (1).
is produced as the main product together with apopin camic acid ester. The compounds of general formulas (1) and (to) are separated from each other by crystallization. If pinkamic acid ester and apopincamic acid ester having different alkyl groups have to be prepared, for example, if pinkamine and apopincamic acid ethyl ester have to be prepared simultaneously, then the appropriate ester can be prepared by converting the said 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 can be used, such as sulfuric acid, p-toluenesulfonic acid, etc. Therefore, the reaction of the intermediate product(s) is carried out under very mild conditions of about 1 to 20 molar equivalents, preferably 6 to 10 molar equivalents of acid at 60 to 80°C for about 5 to 10 minutes. However, it can be converted to the compound of general formula (4) by using a large amount of acid, applying a higher temperature, or reacting for a long time.

The compound of general formula (1) can be converted into a pharmaceutically acceptable salt by adding a suitable acid.

Hydrochlorides, bromates, etc., phosphates; rhodates, sulfates, hydrogen sulfates, tartrates, succinates, maleates,
Salts such as nitrates, salicylates, benzoates, acetates, propionates, lactates, sulfonates, etc. can be produced. According to the method of the present invention, both racemized and optically active compounds of general formula (1) can be produced.

If the compound of general formula (b) obtained during the synthesis process is optically active, then the desired product of general formula (1) is also optically active. On the other hand, if the compound of general formula (b) is racemic, the desired product is also racemic. If desired, the general formula (1
) racemized compounds are 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 Starting material dl-14-oxo-3α・17α-E-homoeprunane production method (a) 1-(2′-methoxycarbonylethyl)-1-ethyl-1.2.3.4.6.7
-hexahydro 12H-indolo[2.3-a]-quinolidinium-chloride 27.0f (72.0 mmol) was dissolved in 300 ml of methanol and hydrogenated in the presence of palladium 10y on charcoal.

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. The residue was dissolved in 200 ml of water, the solution was made alkaline to pH 8-9 by adding 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 (2.50y) was ground with 30ml of methanol to give 19.
．． A mixture of hydrogenated isomers of 0.07 (77.5%) was precipitated. The 19.0 V isomer mixture thus obtained was recrystallized from methanol 170d.

7.07 (28.5%) of 1β-(2'-methoxycarbonyl-ethyl)-1α-ethyl-1, 2, 3, 4, 6
・7.12.12bd-octahydroindolo [2.3
-a] Quinolidine was precipitated.

Melting point: 142-143°C This mother liquor is evaporated and a mixture of cis-trans isomers rich in cis monoisomers 9,
Oy (36.7%) is crystallized and this mixture may also be subsequently ring-closed.

(b) 1β(2) prepared as described in Reference Example 1(a)
5-methoxycarbonyl-ethyl)-1αethyl-1.
2.3.4.6.7.12.12bα-octahydroindolo[2.3a]quinolidine 7.0y (20 mmol) was constantly stirred in the presence of a 50% sodium hydride suspension 17 in a nitrogen atmosphere. while anhydrous toluene 360
Boiled for 12 hours in m1.

After cooling, add this mixture to 100ml of 2.5% sulfuric acid aqueous solution.
Extracted twice. 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 and
P was filtered and the f solution was evaporated to dryness in vacuo. This residue was crystallized from methanol and thus had a melting point of 165
The target compound at 167° C. was obtained in the form of white crystals (literature melting point: 164° C., recrystallized from ether, cf. Pancalli Patent Specification No. 163,769). Yield: 5.07 (7
9%) IR spectrum (KBr): 1690 (acid amide-CO
) (c) 9.07 ml of the mixture of cis-trans esters isolated according to Reference Example 1(a) was dissolved according to Example 1(b) in 460 a of anhydrous toluene in the presence of 1.37 ml of sodium hydride suspension. The ring was closed.

The resulting mixture was treated to give 14-oxo-3α・17d
-E-homoeburnan and 14-oxo-3β/17α
-E-homoeburnan to form an isomer mixture and combine this with 20 ml of dichloromethane and 30 ml of ether.
It was recrystallized from a mixed solution of 1. Thus 4.5y (55
%) of 14-oxo3α·17α-E-homoeburnan was obtained. The overall yield relative to the starting immonium salt was 42.8%. 14-oxo-3α・17α-E
- The total weight of the Homoie Brunan was 9.5 tons.

Melting point: 165-167°C (recrystallized from methanol) Reference example 2 Production of d1-14-oxo-3α・17α-E-homoebrunane (starting material) 1-(2'-methoxycarbonyl-ethyl)-1-ethyl- 4.27 (11.2 mmol) of 1.2.3.4.6.7-hexahydro-12H-indolo[2.3-a]quinolidinium chloride in 400 ml of water in the presence of 2.07 mmol of palladium catalyst supported on charcoal. Hydrogenated.

Consumption of the theoretical amount of hydrogen was completed in 3 hours. This catalyst is P
The resulting ▲ solution was made alkaline (PH=
9) and extracted three times with dichloromethane. The organic phase was dried, the solvent removed, and the 3.9y d1-
The residual mixture consisting of 14-oxo-13α-17α-E-homoeburnan and dl-14-oxo-3β·17α-E-homoeburnan was mixed with 0.0% sodium hydride in 200 ml of anhydrous toluene as described in Example 1(b). 67
Heated in the presence of suspension. This reaction mixture is Example 1(b)
1.5y (43.4%
) was obtained.

Melting point: 165-167℃ (from methanol) Reference example 3
Production of starting material dl-14-oxo-3ct-17αE-homoeburnan In the presence of charcoal-supported palladium 3t,
Ethanol 3607fLI! ．． Inside, 1-(2'
(monoethoxycarbonyl-ethyl)-1-ethyl-1,2
・3,4,6,7-hexahydro-12H-indolo [
2.3-a] 7.01 (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 with F, washed with ethanol and the liquor was evaporated to dryness in vacuo. The residue was dissolved in 200 d 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 solution was evaporated to dryness, and the resulting isomer mixture was recrystallized from 10 d of ethanol. 3.7r (57%) of dl-1β-(2-ethoxycarbonyl-ethyl)-1d-ethyl-1.2.3.4.
6・7・12・12bα-octahydroindro [2
・3-a] Quinolidine was precipitated.

Melting point: 136-138°C (recrystallized from ethanol) IR
Spectrum (KBr): 3400 (indole NH) 1
730crn-1 (CO2C2H5) NMR spectrum (CDCl3): δ=8.12ppm1H. S (indole-NH), 7.48-6.99 (4H, .m1 aromatic proton, 4.00 (2H, .J=7.3CPS, .
C00CH2CH3), 1.27-1.04 (6H12
t,. J=7.3cps1C00CH2CH3 and CH
Analysis for 2CH3) C22H3ON2O2: Molecular weight = 354.48 Calculated value: C74.53% H8.53
% N7.9O% Actual value: C74.5O% H8.47
% N7.65% If left alone, 1 of 0.607 (9%)
β-(2'-Ethoxycarbonyl-ethyl)-1α-ethyl 1,2,3,4,6,7,12,12bβ-octahydroindro[2,3-a]-quinolidine precipitated from the mother liquor.

Melting point: 105-107°C (recrystallized from ethanol) IR
Vector (KBr): 3320 (indole-NH)
1712礪-1 (CO2C2H,) NMR spectrum (
CDCl3): δ = 8.78 ppm: (1H', s, indole-NH), 7.46-6.90 (4H,.m1
Aromatic proton, 4.16 (2H,.d,.J=7.3
CPS,. C00CH2CH3), 1.33(3H.t
、． J=7.3CPS,. CH2CH3), 0.66(
3H. t,. J=7.3CPS,. C00CH2CH3
) Analysis for C22H3ON2O: Molecular weight = 543
．． 48 calculated value: C74.53% H8.53% N7,
90% actual value: C74.

l2% H8.44% N7.72% 3.7t (10.4 mmol) of dl-1β-(
2′-ethoxycarbonyl-ethyl)-1α-ethyl-1,2,3,4,6,7,12,12bα-octahydroindro[2,3-a]quinolidine as described in the previous example. The ring was closed in 170 ml of anhydrous toluene.

This reaction produced 2.4t (74.5%) of the target compound. Melting point: 165-167℃ (from methanol)
Reference example 4 Starting material d1-14-oxo-3α・17α
- Manufacture of E-homoe burnan Palladium on charcoal 2.
6.0 V (15
. did.

The calculated amount of hydrogen was consumed in about 2 hours, after which time the catalyst was filtered through F and washed with water. This f solution was made alkaline (PH=9) by adding 5% aqueous sodium carbonate solution, and extracted several times with dichloromethane. The organic phase was dried over magnesium sulfate, the solvent was removed, and 5.5 f of the resulting isomer mixture was dissolved in 250 d of anhydrous toluene in the presence of 0.8 f of a sodium hydride suspension as described in the previous example. Ring closure was performed as described. The resulting isomer mixture was recrystallized from a mixture of dichloromethane and ether or methanol, and 2.97 (61%) of the desired compound was thus obtained. Melting point: 165-167°C (recrystallized from methanol) Reference example 5 Production of starting material dl-14-oxo-15-hydroxyimino-3α·17α-E-homoeburnane 5.8y (18.8 mmol) in 40 ml of anhydrous toluene )'s dl
-14-oxo-3α·17α-E homoeburunan was suspended.

12 ml of tert-butyl nitrile were added to this suspension and a suspension of 4.0 y (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. The reaction was followed by layer chromatography (KG-benzenrimethanol-14:3, Rf value of starting material higher than Rf value of target compound). After the completion of this reaction, the resulting reaction mixture contains 15% of water containing 127% of ammonium chloride.
The aqueous layer was extracted twice with 30 ml of toluene. The combined toluene layers were dried over magnesium sulfate, filtered and the solution was diluted in vacuo for 10 minutes.
It was concentrated to ml. The precipitated oxime was filtered and washed with cold toluene. Yield: 4.47 (69%) Melting point: 258°C (Melting point in literature: 260°C, Yield: 60
% (see Pankari Patent No. 163769)) IR spectrum (KBr): 3200 (0H), 1705 (lactam CO), 1640 crrL-1 (CN) Example
1 d1-14-methoxycarbonyl-14-hydroxyamino-3α・16α-eburnan under anhydrous conditions, 1.17
Dll4-oxo-15-hydroxyimino- prepared as in Reference Example 5 in 40 ml of absolute methanol in the presence of 7 (21.6 mmol) sodium methylate.
3α・17α-E-homoeburnan 3.2y (9.5
mmol) was heated for 1 hour.

After cooling, the sodium methylate was decomposed with acetic acid and the solution was evaporated to dryness in vacuo. Add 3 liters of water to this residue
0 ml was added, 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 is dried, filtered, the P solution is evaporated and the residue is dissolved in 20 TfL of methanol! , was recrystallized from . Yield: Target compound 2.427 (69%) Melting point: 2179°C (methanol) IR spectrum: (KBr): 3420 (NH, 0H)
, 1710-1(CO2CH3) NMR spectrum (
CDCl3): δ-8.05ppm (1N,.NH),
7.6-7. O(4H,.m1 aromatic proton) 3.5
(3H.s.C02CH3), 1.1(3H,.t.C
H2CH3) Mass spectrum: m/E7OeVM+=3
Analysis for formula 69 C2lH27N3O3: Molecular weight -369.44 Calculated value: C68.27% H7.36%
Nll. 38% actual value: C68.58% H7.29%
Nll. 28% The Rf value of this starting material is the Rf of the target compound (KG-G1 benzene-methanol = 14.3)
It was more expensive.

Example 2 d1-14-Ethoxycarbonyl-14-hydroxyamino-3α·16α-epurnan 0.57 (1 .5
mmol) in 20 ml of absolute ethanol under anhydrous conditions in the presence of 0.197 sodium ethylate.
Heat for half an hour.

Excess sodium ethylate was destroyed with acetic acid and the solvent was removed in vacuo. To this residue was added 20 ml of water, and to this mixture was then slowly added a 1:1 dilute aqueous ammonium hydroxide solution to make it alkaline (PH=8).
and the alkaline solution was extracted several times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, the filtrate was evaporated to dryness, and the residue was recrystallized from ethanol. Yield: Target compound 0.287 (49.3%) Melting point: 156-158°C
(from ethanol) 1R spectrum (KBr): 340
0 (Nll.OH), 1700 I-1 (CO2C2H5
) X criminal spectrum (CDCl3): δ = 8.3 ppm (
1H,. NH), 4.0 (2H,.q,.J=7.3c
ps1C00CH2CH3), 1.18(3H,.t,
．． J=7.3c COOCH2CH,), 1.18(3
H. t,. J=7.3cpsC00CH2CH,)C2
Analysis of 2H2, N3O: Molecular weight = 383.4
7 Calculated values C68.9O% Hl62% NlO. 95
% actual value C68.69% H7.45% NlO. 6
5% Example 3 d1-Apopinkamine 2.0 y (5.42 mmol) of d1-14-methoxycarbonyl-14-hydroxyamino-3α·16α-ebrunan, prepared as described in Example 1, is mixed with 37.5 d of methanol. The mixture was heated on a water bath for 1 hour in a mixture with 13.5 mt of concentrated sulfuric acid.

The reaction mixture was poured into ice water and made alkaline (PH=9) by addition of concentrated aqueous ammonium hydroxide solution, and the alkaline solution was extracted three times with dichloromethane. The combined dichloromethane solutions were dried over magnesium sulfate, filtered, the f solution was evaporated to dryness, and the residue was recrystallized from 5 ml of methanol. Yield: Target compound 1.32f (72.5%) Melting point: 133-135°C (from methanol) 3IR spectrum (KBr): 1735 (CO2CH3), 163
5 (C=C), 1610 (1-JMoV!-1 (aromatic) N
MR spectrum (CDCl3) δ = 7.2-7.0 (4
H. m, aromatic proton), 6.1 (1H.s, pinyl-H), 4.1 (1H13H), 3.9 (3H13S,
．． C02CH3), 1. O(3H,.t,.J=7.3
,CPS,. Analysis for CH2CH3)C2lH24N2O2: Molecular weight = 336.42 Calculated value: C74.9
4% H7.28% N8.234% Actual value: C74.
77% H7.2O% N8.28%Example 4 d1-Apopincamic acid ethyl ester d1-14-Ethoxy-carbonyl-14-hydroxyamino-3α·16d prepared as described in Example 2
- 2.0 t (5.22 mmol) of eburnan was heated for 40 minutes in a mixture of 45 d of absolute ethanol and 16 a of concentrated sulfuric acid.

The reaction mixture was poured into ice water, made alkaline (PH=9) by addition of concentrated aqueous ammonium hydroxide solution, and the alkaline solution was extracted three times with dichloromethane. The combined dichloromethane solution was dried over magnesium sulphate, filtered, the sap was evaporated and the residue was crystallized from 5 ml of ethanol. Yield: target compound
1.5t (82%) Melting point: 122°C (from ethanol) 1R spectrum (KBr): 1735 (CO2C2H5), 1638 (C=C), 1615?
-1 (aromatic) NMR spectrum: (CDCl3): δ
=76-7.0ppm (4H.m, aromatic proton)6
．． 12 (1H1s1 vinyl-H), 4.45 (2H, .
q, J=7.3cps. C00CH2CH,), 4.1
5 (1H13H), 1.40 (3H.t,.J=7.3
cps1CH2CH3), 1.02(3H,.t,.J
=7.3cps1C00CH2CH3)C22H26N
Analysis for 2O3: Molecular weight = 350.34 Calculated value:
C75.39% H747% N7.99% Actual value: C
75.4O% H 7.42% N 7.75% Example 5 dl-Pinkamine and dl-Apopinkamine dl-14-methoxycarbonyl-14-hydroxyamino-3α·16α-eburnan prepared as described in Example 1 0.44y (1.19 mmol) to 1.6Tn of glacial acetic acid
1 in a medium with gentle heating, and add 5 to this solution.
% aqueous sulfuric acid solution was added 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, and the solvent was removed from the solution by evaporation in vacuo. To the residue containing dl-pinkamine, dl-apopinkamine and starting materials was added 1.5 d of anhydrous methanol and 907 d of sodium methylate.

The starting hydroxyamino compound remained in solution. The precipitated pure dl-pinkamine was filtered off and washed with methanol. Yield: dl-pinkamine 0.181 (
42%) Melting point: 234 DEG C. (chlorobenzene) The mass and IR spectra of this product were identical to those of dl-pinkamine prepared by Pancalli Patent Specification No. 163,143.

A solution of sulfuric acid in methanol (37 d of methanol and 13 d of concentrated sulfuric acid) was added to this sodium methylate-containing sap.
1 ml was added and the solution was heated for 1.5 hours.

The mixture was then poured into ice water, made alkaline with concentrated aqueous ammonium hydroxide, and extracted several times with dichloromethane. The combined solutions were dried over magnesium sulfate, the liquid was evaporated and the residue was crystallized from methanol 2d. Yield: 0.137 (32%) This product matched the dl-apopinkamine described in Example 8 in all physical and chemical characteristics.

Example 6 d1-pincamine and dl-apopincamic acid ethyl ester The procedure of Example 5 was followed.

However, the mother liquor containing sodium methylate obtained after filtering the dl-pinkamine was neutralized with acetic acid, the solvent was removed in vacuo, and the residue was heated with sulfuric acid in ethanol for 1 hour. After treatment of this mixture according to Example 10 and recrystallization from ethanol, d1-apopincamic acid ethyl ester 0.107 (23%) was obtained.
Melting point: 122°C Example 7d1-Apopinkamine dl-14-oxo-15 prepared as described in Example 5
-Hydroxyimino-3d.16α-E-homoeburunane 2.07 (5.93 mmol) was dissolved in sulfuric acid (372 ml of methanol and 135 ml of concentrated sulfuric acid solution) in methanol on a water bath.
ml), heated for 2 and a half hours in 60 ml.

The reaction mixture was poured onto ice water, made alkaline by addition of concentrated aqueous ammonium hydroxide solution, and extracted several times with dichloromethane. The solvent was removed by drying over magnesium sulfate, the residue was filtered and the sap was removed and the resulting residue was crystallized from 5 ml of methanol.
Yield: dl-apopinkamine 1.27 (60%), melting point: 133-135°C Example 8 d1-apopinkamine acid ethyl ester d1-14-oxo-15- produced according to Reference Example 5
2.07 (5.93 mmol) of hydroxyimino-3α·17α-E-homoeburunan was heated for 3 hours in a mixture of 37 ml of absolute ethanol and 13 m 2 of concentrated sulfuric acid on a water bath.

The mixture was then poured into ice water and made alkaline (PH-9) with concentrated aqueous ammonium hydroxide, and the alkaline solution was extracted three times with dichloromethane. The combined organic solutions were dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo. Add this residue to 5 d of ethanol.
It was crystallized from. Yield: d1-apopincamic acid ethyl ester 1.3V (62.5%) Melting point: 122°C Example 9 d1-14-oxo-15-hydroxyimino-3α・
Production of d1-apopinkamine from 16d-E-homoeburnan 100η (0.29 mmol) of dl-14-oxo-15-hydroxyimino-3α·17α-E-homoeburnan produced in Reference Example 5 was heated in a water bath. The top was heated in dilute sulfuric acid in ethanol (37 ml of ethanol and 1.3 ml of concentrated sulfuric acid solution).

After heating the reaction mixture for 10 minutes, sample 3d was poured into ice water, the pH was adjusted to 8 by slow addition of a 1:1 dilute aqueous ammonium hydroxide solution, and the alkaline solution was diluted with dichloromethane. Extracted. This dried dichloromethane solution was subjected to layer chromatography (K
G-PF254+366, 1 with benzene and methanol
4:3 mixture).

(The Rf value of the starting dl-14-oxo-15-hydroxyimino-3α・17α-E homoeburunane is dl-
After eluting from the adsorbent, dl-14-methoxy -carbonyl-14-hydroxyamino-3α·16α-eburnan 10rf9 (melting point 179°C) and unchanged dl-14-
Oxo-15-hydroxyimino 3ct・16d,-
E-homoe burnan (melting point 258℃) 30ml! could be isolated. Half of this reaction mixture was heated for 6 hours.

After working up this mixture in the customary manner, dl-apopinkamine 25η (50%) was obtained. Melting point: 133-135°C Reference example 6 Starting material (-F) Production of -14-oxo-13α-17α-1E-homoeburnan In the presence of 1.8 t of 50% sodium hydride suspension in 450 d of anhydrous toluene , with constant stirring, (c)-1β-(2'-methoxycarbonyl)ethyl-1-ethyl-1,2,3,4
・6・7・12-12d-octahydroindro [2
-3a]-Quinolidine 9.8r (28.8 mmol) was heated for 5 hours.

After cooling, the solution was shaken three times with 120Tn of 2.5% aqueous sulfuric acid, the aqueous layer was made alkaline (PH=9) by adding concentrated aqueous ammonium hydroxide solution under cooling, and the solution was diluted with dichloromethane. Extracted several times. The extract was dried over magnesium sulfate, filtered, the solvent was removed from the P solution in vacuo, and the residue was crystallized from methanol. Yield: 5.3V (60%
), melting point: 152-154°C (decomposition) (a) D = +32
．． 5: (CH2Cl2, C=1.35) Reference example 7 (-1r>-14-oxo-15-hydroxyimino3
ct・17d-E-homoeburnan (starting material) 12 ml of anhydrous toluene and 4.8 ml of tert-butylnitrile
(v)-14-oxo-3α,16αE-homoeburnan 2,10 V (6,8 mmol) was suspended in m1 and potassium tert-butyrate suspended in anhydrous toluene 12a was added to this suspension. 1.53t (13.
1 mmol) was added under nitrogen atmosphere with constant stirring.

The mixture was stirred at room temperature for 1 hour, then 4.2 f7 ammonium chloride in 80 d water was added and 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 liquors were evaporated to dryness in vacuo. A residue of 1.97 was obtained which was dissolved in methanol 8a 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: 1.4y (55%) of the hydrochloride of the target compound was obtained.

Melting point: 254-257°C (from methanol) IR spectrum (KBr): 1730 (CO), 1635 1 (C
=N) This base converts the hydrochloride of the target compound into 5
% aqueous sodium carbonate solution, and this solution was extracted with dichloromethane, the extract was dried, filtered,
This f solution was then evaporated to dryness.

The base of the target compound was obtained as an oily residue. (
Support) D=+61 substance (C=1, CH2Cl2) Example 1
0(e)-apopinkamic acid ethyl ester anhydrous ethanol 5.5a and concentrated sulfuric acid 1.95T! 0.30 t (0.8 mmol) of (a)- in a mixture of Ll on a water bath
14-oxo-15-hydroxyimino-3d・17α
-E-homoeburnan hydrochloride was heated for 4 and a half hours.

Claims (1)

[Claims] 1. A racemized or optically active apovincamic acid ester represented by the general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a C_1_-_4 alkyl group) or a pharmaceutically acceptable acid addition salt thereof, the general formula (IV)▲mathematical formula, chemical formula,
The racemized or optically active hydroxyamino-eburnane derivative represented by ▼ (wherein R^1 is as defined above) is treated with an acid and then, if desired, the resulting general formula The above general formula (I) is characterized by converting the racemized or optically active apovin camic acid ester represented by (I) into a pharmaceutically acceptable salt and/or resolving the obtained racemized apovin camic acid ester. I) A process for producing a racemized or optically active apovincamic acid ester or a pharmaceutically acceptable acid addition salt thereof. 2 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is a C_1_-_4 alkyl group) Racemized or optically active apovin camic acid ester or pharmaceutically acceptable apovincamic acid ester In producing those acid addition salts, the formula (III)▲mathematical formula, chemical formula,
Racemized or optically active 14-oxo-15-hydroxyimino-3α・17 represented by ▼
α-E-homo-eburnan is expressed by the general formula R^1OH (wherein,
R^1 is as defined above) in the presence of an acid, and then, if desired, the resulting racemized or optically active apovincamic acid represented by general formula (I) A racemized or optically active apovin camic acid ester represented by the general formula (I), characterized by converting the ester into a pharmaceutically acceptable salt and/or resolving the obtained racemized apovin camic ester. or a method for preparing a pharmaceutically acceptable acid addition salt thereof. 3 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R
In producing racemized or optically active apovin camic acid ester represented by (^1 is a C_1_-_4 alkyl group) or a pharmaceutically acceptable acid addition salt thereof, formula (III) ▲ mathematical formula, chemical formula, table etc. ▼ Racemized or optically active 14-oxo-15-hydroxyimino-3α・17α-E-homo-
Ebrunan is reacted with an alcohol represented by the general formula R^1OH (in the formula, R^1 is as defined above) in the presence of a base, and the resulting general formula (IV) ▲ Numerical formula, chemical formula, table etc. A racemized or optically active hydroxyamino-eburnane derivative of the formula ▼ (where R^1 is as defined above) is treated with an acid and then, if desired, the resulting general formula ( The above general formula (I) is characterized by converting the racemized or optically active apovin camic acid ester represented by I) A process for producing a racemized or optically active apovincamic acid ester or a pharmaceutically acceptable acid addition salt thereof.