JPS5993078A - Hydroxyamino-eburnane derivative and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

Present invention-1, racemization or di-optical activity, 5.・Novel/(racemized or optically active 7r hydroxyl 7
Amino-eprunane derivative (so) 1. As a pharmaceutical product, it relates to a method for producing salt, fJ', 'g) hiniso.A novel hydrogear'fminoeburnan derivative represented by the above formula (IV). Q'', F' F for f1 as a medicine
t+, expressed by equation (1); 1. It is used as an intermediate for the production of apovincamine (11) and (1/)vincamine iW ester. 2II5 (in the formula, RVJ-, C1-4 is an alkyl group)C2
■15 (In the formula, +t is Jlm defined above) I'll
ill+J vincamic acid esters, especially methylenol (vincamine) and iiJ-apovincamic acid nisder, apovincamic acid ethyl ester t
'', as a vasodilator. A novel hydroquinoaminoeprunane fat conductor, expressed by the formula 0ν), as a vasodilator. Racemization or optics 2.
-Oxo-15-hydroxyimino-3α,17rx-
E-homoeburnan is expressed by the general formula ROll (wherein Rl
By reacting with the alcohol and the presence of a base (F) (as per the previous 6), ↓) Rano 1. stomach,
. f! ) Rano1, expressed by the formula (IV), has a chemical activity of 7. rhi 1 "Roya/aminoeprunan preparation υJ, if it is ra, it is used as a medicine "f
The salts that can be converted into 1tc-/) and the resulting racemized derivatives are resolved. Racemized or optically active starting material t of formula θ11)
, (wherein R&, J:C,, argyl, and X
- is the anion of the acid) or its acid addition salt (7, and Iq et al.) 1. Racemization is also possible.
Chemically active = cis and/or trans f compounds of the general formula (b): 2H5 (in the formula, R is 11) or its acid salt; without separation or by fractional crystallization and/or (7〈after separation, treated with an alkaline agent,
Soshi-Ci! J et al.) 1, the racemization of formula (6) is also 17<
It is produced by subjecting optically active cis and/or trans compounds to fractional crystallization and/or resolution, optionally with a nitrifying agent, followed by reaction. If the reaction of the compound of the formula (110) with the alcohol of the general formula R10H is carried out in a base, the new J of the general formula
(A compound of the general formula It
Alcoholates (formed with OH alcohols and alkali metals such as sodium) can be used. If the compound of general formula (IV) is treated with dilute aqueous acid,
The corresponding vincamic ester is produced as the main product together with the apovincamic ester of general formula (1). Compounds V of the general formulas (1) and (It) are separated by 1·jl from each other in the crystallization process. If vincamic acid ester and hyapovincamic acid ester having different argyl groups have to be prepared, for example, if vincamine and ethyl nisder apovincamate must be prepared simultaneously, the appropriate ester When the crystal molecule is ≦, t
)'J M+: Can be converted to the desired ester by re-esterifying the ester. This re-esterification can be carried out by known methods, and by one such method:
The compound to be re-esterified is heated in the presence of an acid with the alcohol corresponding to the ester to be introduced into the molecule. As an acid, an inorganic or organic acid, +4'
For example, sulfuric acid, p-toluenesulfonic acid, etc. can be used. Therefore, if the intermediate product (rv+) is 2, the reaction is about 41+&, preferably 6 to 10 mol/(r)
Existence of Shun 1: It can be obtained under very mild conditions of 60 to 80℃, 5 to J-09, but it can be obtained by using a high Rk acid or applying a higher Wδ hot water temperature. It is converted into the compound of the general formula (1) by long-term reaction. Conventionally, apovincamic acid Nisder Q of the general formula (1), vincamine (It' is methyl, the general formula (TI
), and the resulting vincamic acid (compound of general formula (11) where R1 is hydrogen) is converted to the desired ester, and water is removed from the vincamic acid ester to form the -C corresponding compound. Apovincamic acid ester is produced, or alternatively, apovincamino (a compound of general formula (1) in which R is methyl) is prepared by removing water from ic vincamine, and Apovincamic acid (general formula (1 where R+ is hydrogen)
) were prepared by K hydrolysis and conversion of the corresponding ester VC (Hungarian Patent No. 163434). The disadvantage of this method is that vincamine must first be produced;
Apovincamic acid ester can be produced from this vincamine (44), but the maximum commercial yield is 60%. However, if the method goes through the compound of the present invention (1), then A, I? of general formula (1)? Vincamic acid ester and/or vincamic acid ester of general formula (11) is Q
', by a method with good yield in much f7i'i
! Can be built. The resulting racemized or optically active 7 of general formula (1)
Month? The mixture of the vincamic ester and the vincamic ester of the general formula C11) is separated and optionally obtained the apovincamic ester of the general formula (1) or the vincamic ester of the general formula (II)'/,
r Hq esterification and, if desired, converting the racemized or optically active avivin camic acid ester of general formula (1) and the vincamic acid ester of general formula (11) into pharmaceutically acceptable acid addition salts 17; /Mata U
The racemized or optically active apovincamic acid ester (general formula (I)) or vincamic acid ester (general formula (I)) is resolved. If the compound of general formula (b) is optically active, then the desired products of general formulas (1) and (11) are also optically active. On the other hand, if the compound of general formula (b) is racemic, the desired product is also racemic. Compound (V) of the present invention and general formulas (1) and (11
The compound IrJ1 of ) can be converted into a medicinal salt by adding an appropriate acid. Hydrochloride, bromate, etc., phosphate; rhodate, sulfate, hydrogen sulfate, tartrate, conophosphate, maleate, nitrate, salicylate, benzoate, acetate, propionate salt, lactate,
Salts such as sulfonates can be produced. The novel manufacturing method of the present invention can be explained by the examples described below. However, these examples do not limit the scope of the invention. Reference example 1 a) 1-(2'-methoxycarbonylethyl)-1
-ethyl-1,2,3,4,6,7-hexahydro
1.2H-indolo[2,3-a]-quinolinonium-
Chloride 27.0.9 (72.0 mmol) was dissolved in 300 ml of methanol and hydrogenated in the presence of Pandium 10.9 on charcoal. It took 5 hours to consume the theoretical limit of hydrogen. The catalyst was then vortexed, washed with methanol, and the P solution was evaporated in vacuo. The residue was dissolved in 200 ml of water (intoxicated), 0.0 mL of aqueous sodium carbonate was added, the solution was strained with Pll++-9 alkaline solution (I), and extracted several times with dichloromethane.
child. The nochloromecne extract was dried over 100 ml of magnesium sulfate, and the solvent was evaporated in the air to 4°C. The residue (2,50, V) was dissolved in 30 m
19.0.9 (77,5%) hydrogenated S
A mixed white proboscis was precipitated. Thus obtained 19.0. ? The isomer mixture was recrystallized from methanol 170me. 7.0 g (28,
Section 5) lβ-(2'-methoxycarvinyl-ethyl)
-1α-ethyl-1,2,3,4,6,7,12゜12
bα-A phtahydroindolo[2,3-a]quinolinone was precipitated. Melting point: 142-143°C. Evaporate the mother liquor and give a cis-trans isomer mixture enriched with the/sue isomer 9.0. ! i' (36.7%) is crystallized and this mixture is also subsequently ring-closed to -C. b) Reference l'll] lβ-(2'-Metoya-7carbonyl-ethyl)-iα prepared by d-circulation as shown in 8.
-Nibou-roo 1. ．． 2, 3, 4, 6, 7.12.12b
α-Octahydro-indolo[2,3-al quinolinone 7,0,F (20 mmol) is hydrogenated by 50% in the presence of 1 g of thorium suspension in a nitrogen atmosphere under constant hydrogenation.
3> was boiled for 12 hours in 36 Orll of anhydrous toluene with stirring. After cooling, add this mixture to 2.5 sulfuric acid aqueous solution IQQm/3
Extracted twice. The acid layer was filtered in an alkaline solution with pH=9 by adding concentrated ammonium hydroxide solution in an ice-cooled oven, and the alkaline solution was extracted with dichloromethane for several times. The combined liquid was dried over Magnenaut's earth, filtered, and the liquid was evaporated to dryness in vacuo. The residue was crystallized from methanol.
IJ-, thus the target compound with a melting point of 165-167° C. was obtained in the form of white crystals (literature melting point: 164° C., recrystallized from Nieder, Hungarian Patent Mei 1, No. 1637).
(See No. 69-). Convergence: 5. (1,? (79%) rnsu-=y tor(lr): 1690 (acid-fmido-CO)Q) a Example 1a Crashed due to a month/Sutransx, x chillt7) ([ 1 White 9. Water: 1 Sodium 1 Static solution 13
& ) (G' in 460 ml of anhydrous tolury under i.
Ring closure (-da.obtained) by (2 and 11/11b)
The mixture was also treated (14-Ogin-3α, 17α-
E-homoeprunan and 14-oxo-3β, + fα-
An isomer mixture with E-homoeprunane is produced and this Ii-%) 20 ml of dichloromethane and 3 ml of ether
0ηre 71 was also crystallized from the liquid by 4".
14-Ogin-3α, 17α- of C4,51 (55%)
E-homoeprunan was obtained. The overall yield relative to the starting immonium salt was 428 cm. 14-Okino 3Cχ, 1F α-E-Homoeprunan total weight was 9.5 g. Melting point: 165-167°C (recrystallized from methanol).
Example 2 ]-(2'-Me)oxycarbonyl-ethyl)-1-ethyl-1,2,3,4,6,7-hexahydro-12H-
Indolo[2,3-a]-4 nolinonium chloride 42
& (112 mmol) on charcoal and moranoum catalyst 2.
In the presence of O2, hydrogenation was carried out in 400 ml of water. The consumption of the theoretical hydrogen was completed in 3 hours. The catalyst was filtered, washed with 1!jl of water, and the resulting U liquid was The organic phase was dried, the solvent was removed, and the organic phase was dried and the solvent was removed.
I dt-14-oxo-3α, 17α-E to homoeprunan and dt-1,4-oxo-3β, 17α-
Example 1b
) in 200 ml of anhydrous toluene (t
It was heated in the presence of a 0.6y suspension of sodium sulfur. From this reaction mixture Q, +1 l was treated as described in b), and then -r1. ．． dt of 5.9 (43,4 so)
-14-Oxo-3α,17(χ-E-homoeburnan was obtained. Melting point: 165-167C (from methanol) Reference Example 3 Ethanol 360% in the presence of 3g of lanium with charcoal
ml, 1-(2'-ethynecarbonyl-ethyl)-1-ethyl-1,2,3,4,6,7-hequinahitoO-121(-indo[2,3-ajkinoritsu11 7.0 Ij (18 mmol) of chloride was hydrogenated (~1 h of hydrogen was consumed in about 3 hours, after which the catalyst was filtered and diluted with ethanol to 6βM"I).
Q) Is it liquid? ctY, evaporated to dryness in air. The residue was dissolved in 200 ml of water, the solution was made alkaline with aqueous sodium carbonate solution and extracted several times with dichloromethane. The organic phase of the kernels was dried over magnesium sulfate, the F solution was evaporated to dryness, and the resulting isomer mixture was recrystallized from 10 ml of ethanol. 3.7 g (section 57) of dt-1β-(2'-toxoluponylenal)-1α-ethyl-1,2,3°4.
6,7.12.12bα-octahydro-indolo[2
゜3-a] Quinolinone was precipitated. Melting point: l3 (i-138C (recrystallized from ethanol) IR spectrometer (K13r): 3400 (Indole Nd I) 1730 (1) (C02C2H5)
NMIζS4ctor(CI)C43)2δ=8.12
ppm l H, S (indole-NH), 7.
48-6.99 (411, m, aromatic proton), 4.
00(2H, J=7.3cps, C00CII2C
I(3), 1.27-], 04 (611,2t,
J==7.3 cps, C0DCH2CH3 and Cl
l2CH3) Analysis for C22I(3oN202: Molecule 1'i=
354.48 calculation f+i'j: C74, 53 section H8,
Fi3 section N 7.90 section Actual value: C74, so section)
I8.47chi N7.65 mooring 1if, 0.60
．． 9(96I)) lβ-(2'-Etquincal+1?
Nyl-ethyl 1,2,3,4,6,7.1 2,1 2bβ-octahydro-indolo[2.3-a)]-quiquinoline was precipitated from the mother liquor. Melting point: 1 0 5 - 1 0 7 C (recrystallized from 1 tanol) IR temperature (KBr): 3
3 2 0 (indole-Nl+)1 7 1 2I
m (CO2C2ars) NMIts subject/re.
(CDCl2) 'δ = 8.7 8 ppm:
(I H + s + Indore NH), 7
．． 46 - 6.90 (4H. ml aromatic protons, 4.16 (2H, d
, J=7.3cpg. COO[-H2CH3), 1. 3 3 (3H
, t, J-7. 3C P9. CH2Cl13), 0.66(3T1.t,
J-7. 3epR. C00CI-I2Cl13) Analysis for C22■■3oN20: Molecule ii=54
3.48 Calculated value: C74.53 section H8.53% N7
．． 90% actual value: C74.12chi H8.44% N7
．． Section 72 - 3.7 g (1
0.4 mmol) Nodi 1β-(2/-ethoxycarbonyl-ethyl)-iα-ethyl-1,2,3
,4,6,7.12,12bα-octahydro-indolo[2.3-a]quinolinone was ring-closed in 170 ml of anhydrous l.luene as described in the previous example. This reaction produced 2.4 g (74.5 units) of the target compound. Melting point: 165-167℃ (from methanol) Reference 1 silicate 4 charcoal ill have radium 2.0,? In the presence of water 5
In 00 ml, C 6.0 & (15.4 mmol) of 1-(2'-1-goxycarbonyl-ethyl)-
1-ethyl-1. 2,3,4,6.7-hegizahydro-12■I-indolo [2. 3-a] Gynolidinium chloride was hydrogenated. Old 31. Each batch of hydrogen was consumed in about 2 hours, after which time the catalyst was filtered and washed with water. This F solution was made alkaline (pl (=9)) by adding 5% thorium carbonate aqueous solution and extracted several times with dichloromethane. The organic phase was dried over magnesium sulfate, the solvent was removed, and the obtained The isomer mixture 5.5I was ring-closed as described in the previous example in 250 ml of anhydrous toluene under a 0.8.P suspension of sodium hydride.The resulting isomer mixture was tIr was crystallized from a mixture of sochloromethane and needle or methanol, and in this way 2
．． 9. ! The target compound i' (61qA) was obtained. 1.i! l! Point: 165-167°C (recrystallized from methanol) Reference example 5 (anhydrous) /L, F4 (5.8g in l ml)
18.8 mmol) of dt-14-oxo-3α, 1 f-α-E-homoeprunane was suspended. This suspension K
Potassium tert-gutylate 4.0 in 40 ml anhydrous toluene by adding 12 ml tert-puglunitrile
,? (35.4 mmol) of Shu solution was added to this mixture for 1 hour while stirring continuously under a nitrogen atmosphere.
) and continued stirring at room temperature for 1 hour. A homogeneous solution was produced. The reaction was followed by layer chromatography (KG-G-benzene:methanol=14:3, Rf value of starting material higher than Rf value of target compound). After completion of this reaction L5, the reaction mixture obtained was 121! of ammonium chloride! The aqueous layer was extracted twice with 3Qme of toluene. The combined toluene layers were dried over magnesium sulfate, filtered, and the p-liquid was washed l□m/! in vacuo. Concentrated into The precipitated ocimum was filtered and washed with cold toluene. Yield M: 4.4 g (69th grade) Melting point: 258°C (Melting point in literature: 260°C, Yield: 60
% (see Hungarian Patent No. 163769)
1705 (lactam CO), 1640 crn' (C=N) Example 1 Anhydrous methanol 4()m in the presence of 1.175' (21,6 mlJ mol) sodium methylate under anhydrous conditions
dt-14-oxo-15-hydroxy/imino-3α,17α-E-homoeglunan prepared as in Reference Example 5 in 3.2. P (9.5 mmol) was heated for 1 hour. After cooling, the sodium mebulate was decomposed with acetic acid and the solution was evaporated to dryness in an IT vacuum.
child. Add 30 ml of water to this residue and adjust the Pll to 1:1.
slowly by addition of aqueous aluminum hydroxide solution of 8
(C8 times), and this alkaline solution was extracted three times with dichloromethane.
filtrate, evaporate this liquid, and evaporate the residue/if
Recrystallization was carried out from 20 ml of iT methanol. Yield 4J4°: Target compound 2.42F (69%), melting point:
179C (methanol) HtS4R Lb: (Kr3r): 3420 (N
Il, 0TI). 1710rtn(Co2CH3) NMR spectrum (C1)C43): δ=8.05
ppm (IN, NH,), 7.6-7.0 (4H
1m, aromatic r glycodon): 3.5 (3ri, !l
, (-02(-It3) 1.1.1 (3II,
t, CH2CH mass quictor: m7'e 70
eVM'-= Analysis of 369 formula C21■■27N303: Molecular experiment = 369.44i1''W, (+R:
c68. z7% rx7. , +6% N1138%
Actual value: C6858CH TI7.29% Nl 1.
．． The Itf-value of this starting material was much higher than the target %'>1 (KG-G, benzene-methanol-14.3). Below is a blank space Example 2 dL-14-oxo- produced as described in Reference Example 5
0.5 g (1.5 mmol) of 15-hydroxyimino-3α-17α-t]-homoeburnan was heated in 2 oml of absolute ethanol under anhydrous conditions in the presence of 0.19 g of sodium ethylene for 1.5 hours. 7. Excess sodium ethylate was destroyed with acetic acid and the solvent was removed in vacuo. To this residual IRE was added 20 ml of water, and to this mixture was then slowly added a J:1 dilute aqueous ammonium hydroxide solution to make it alkaline (pjl = 8) KL, and the alkaline solution was extracted several times with dichloromethane. . The combined organic layers were dried over magnesylanosulfate, filtered, and evaporated to dryness, and the residue was recrystallized from ethanol. Yield: 0. 28.9 (49,3%) Melting point 2 156-158℃ (from ethanol) IR spectrum (KBr): 3400 (NH,011). 1700c7n (C02C2H5) NMIt spectrum (CDC13): ' 8.
3 Pp” (IH, NH), 4.0 (2H, q
, J = 7.3Cp! l ,C0(JCH2Q(,
). 1.18 (3H,t, J=7.3cps C00CH
2CH,,). ], l 8 (3H, t, J-7, 3Q P!l
C00CH2CH3)C22F■2. Analytical molecular weight for N03 = 383.47 Total blue value C68, 90%
H7,62% N 1.0.95% Seed 1111+ f Direct C68,6c + Chi H745% N10.65% Reference Example 6 dL-Adevinonomine Seed Mli t/II dt- produced as described in 1
14-methoxycarvinyl-14-hydroxyamino-
3α, 16α-epurnan 20g (5.42 mmol)
was heated in a water bath for 1 hour in a mixture of 37.5 ml of methanol and 1.3.5 ml 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 nochloromethane solutions were dried over magnesium sulfate, Y-filtered, the p solution was evaporated to dryness, and the residue was recrystallized from 5M methanol. Section J: Target compound 1.32. S' (7,25%
) Ile・p point: 133-135℃ (methanol 0) 1R sectol (Kllr): I 735 (
CO2C113,). 163.5 (C=C), 1610 tan-1 (aromatic) NM
R Skull Tor I) C13) δ = 7.2-70 (4J
1. m. Good! group proton), 6.1 (]] H, s, vinyl 11 less 4.1 (IH, 31 S, 3.9 (3H, S
, C02CJI3). 1.0 (:', II, t, J=70.
3 cps, C112CH,). Analysis for C21H24N202: Molecule 1. 'r,
= :(:< 6.42 total 4n11ii!', :
C74,94chi f17.28% N8.31 fruit 1
11Hi6. :C74,77% f(7,20%
N8.28%8 Example 7 ++ 1- A+l? Hincamic acid ethyl ester Example 2

To d,/,-14-ethoxy-calyI prepared as described in [; The reaction mixture was poured into ice water and made alkaline (rf (=9)) by adding a concentrated ammonium hydroxide bath solution, and then the alkaline bath solution was heated for 40 minutes. The combined nochloromethane solution was mixed with sulfuric acid (・β-magnesilla j・
Dry on soil, pour into a container, evaporate all of this P solution, and crystallize this residue using 5 ml of ethanol. Purified white matter 1.5g (82%) Melting point: l22'C (9I It from ethanol
7 A9 Ri I. Ru (KHr): 1 7 3 5 (
CO,,C2H5),]638(C τ+U) r
I 6 1 5/1n-1(fFh'j)NMIlsc'ector. '(CDC4=,)δ=7,f.
i-7. 11 pp, n(4F■,rn +
>, fragrant) 0 roton) (5) 2 (I II, S
, vinyl-H), 4.45 (2N, q, J=7.3CI
)! l, COOCIIjDI, ), 4
．． 1 5 (1) 1, 3 F
I), 1.40 (3H. t, J = 7., E cpq, CH2(Ij,,
), 1.02 (, IH, t, J = 7.3c
p s + '-(JO(-112O1, s)
-C22ξI2 6N2. ”3 (Analysis of tricks,
Molecular end = 350.34ffH'? :IJ:C7
, 5.3 9% H 7.47% N 7.9i actual measurement 1st shift: C75.40% H 7.42% N
7.75% total white reference example 8 dj-vincamine and dA-apovincamine implementation f series 1
dt-14-7 toxiccarinyl-14-human Iff gynoamino 3α, 16α prepared as described in 11
~0.44 g (1.19 mmol) of Egluone was dissolved in 1.6 M glacial acetic acid with gentle heating, 16 me 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 ammonium hydroxide aqueous solution, and the resulting arunonoritic solution was extracted three times with dichloromethane. The combined liquid was dried over magnesium sulfate, filtered, and the solvent was extracted from the solution with 9% filtrate. Removed by evaporation. To the residue K containing dL-vincamine, d5-' apovincamine and starting material was added 5 ml of anhydrous methanol and 9 (l) of sodium chloride. The starting hydroxyamino compound remained in solution. The precipitated pure Nad
Filter the t-vincamine and wash with methanol.
? I did it. Yield 2 dt-vincamine 0.181.42% Melting point: 234°C (chlorobenzene) The mass 7-gluctol and engineering R spectra of this product are identical to that of dt-vincamine produced according to Hungarian Patent Specification No. 163143. A solution of sulfuric acid in methanol (37 ml of methanol and 13 ml of concentrated sulfuric acid) was added to this solution F containing sodium methylate.
) was added and the solution was heated for 1.5 hours. This mixture was then poured into ice water, made alkaline with concentrated aqueous ammonium hydroxide solution, and extracted several times with methane. The combined solution was dried over magnetogram sulfate, the p-liquid was evaporated and the residual tM was crystallized from 2 ml of methanol. Yield: 0.13 g (32%) This product matched the dt-apovincamine described in Example 8 in all physical and chemical characteristics. Reference Example 9 Five moxibustion f The method of Reference Example 8 was repeated. However, the mother liquor containing sodium J. methylate obtained after passing through the dt-binnopan was neutralized with 11 parts of whole vinegar, the solvent was removed in air, and the remaining solution was heated with sulfuric acid in ethanol for 1 hour. did. After treatment of this mixture according to Example 10 and crystallization in ethanol, dt-apovincamic acid ethyl ester old Og (23) was obtained. melting point 2122
°C Reference Example] 0 dt-14-O VNO15 produced as described in Example 5
-Hydroxyimino-3α, 1G (Y-E-homoeburnan 2.0 g (5,93 mmol) sulfuric acid in methanol (372 ml of methanol and θ゛1 t of sulfuric acid)
The mixture was heated for 2 and a half hours in 135 ml of liquid a, 60 rnJ. Pour this reaction mixture onto ice water, add all the concentrated ammonium hydroxide aqueous solution to make it alkaline, and make it alkaline.
Extracted several times with lomethane. The solution was removed by drying over magnesium sulfate, the residue was filtered and the p-liquid was removed and the resulting residue was crystallized from 5M methanol. Yield: dt-apovincamine 1,2j9(6t)ti). Melting point: 133-135°C Reference example 11 d, /, -7 Tipinkamine n branch ethyl ester □ -
□□□□□□□□−−−□□−□→□−１□□−１□□
-□- □-□□--←--Reference example For reference, 190 ximino-
;3α116α-E-71su7-eprunan 20g (5
, 93 mmol) in a water bath - 1 - 37 ml of absolute ethanol
The mixture was heated for 3 hours in a mixture of and 13 m/ml of concentrated sulfuric acid. Next, pour this mixture into ice water, and 2. Make alkaline (P'l-9) with +15 ammonium hydroxide aqueous solution,
And this alkali fl: M solution with nochloromethane 3
Extracted twice. The combined organic solution was dried over magnesium sulfate and filtered, and the p solution was evaporated in vacuo. This residue was crystallized from 5 ml of ethanol. Yield: d t −f yj? Vincamic acid knee f-
Le: r-sf Le 1.3. (625%) Melting point: 122℃ and) 41c] 2 dt-14- manufactured by Ji14 by S1&1J5
Megiso 15-hydroxyimino-3α,17α-E-
Homoieburnan] O(lIII!i/(0.29 mmol)) was heated on a water bath in dilute sulfuric acid in ethanol (37 rni of ethanol and 1.3 ηtl of 1 pitch of concentrated sulfur). After heating the reaction mixture for 10 minutes, Pour 3 ml of sample into ice water, add 1N am/monium hydroxide aqueous solution of I to make φ, adjust P++ of C?L to 8, and add this alkaline solution. Methane
C was extracted. This dried dichloromethane fδfi1
．． 7-71-Graphy (KG-” F2
54+3661 (14.3 mixture of ben-V and methanol) was poured with carbon. , (starting dt-, +4-oxo1
5-Hydroxy f-mino-3α, 17α-E-homoepurnan 1e1jfe4, is dt-1,4-methoxy-carbogol-14-hydroxy-1mino-3α,1
It is higher than the Rfl direct of 7α-egrunan or 9. Elution was done with dichloromethane in ether. ) After elution from the adsorbent, d/=-14-methoxy-carbonyl-14-
Hydroxyamino-3α,16α-ebrunan 10m7
(melting point 179°C) and unchanged dt-14-, dxo-1,5-hydrogi/imino-3α,17α-E-pomoieburnan (melting point 258°C) 3 o my could be isolated. Half of this reaction mixture was heated for 6 hours. After processing this mixture in a conventional manner, dt-apovincamine 25r%
'(I got 5 (Jji). b'Nl! Point 2 133135 ℃Nhi-
Example 13 In the presence of 1.8 g of 50% hydrogenated WE, (-)-1β-(:2'-methoxycarbonyl)- in anhydrous toluene 45Qn/i with constant stirring Ethyl-1-ethyl-1,2,3,4,6,
7,12゜12(1-y! Kutahide Droin o[2,
3-al-quinolidino 9.8 g (28.8 mmol)
was added for 5 hours.) After cooling, this solution total 2.5%
A sulfuric acid aqueous solution 11i was shaken 3 times at 120 mt, and while this aqueous layer was completely cooled, an aqueous 16' ammonium hydroxide solution was added to make -rtolulyl: 4g (+・ll=g), and this solution 1 [Extracted several times with nochloromec/. This extract was dried over sulfuric acid, filtered, the solvent ω was removed with JC nitrogen, and the residue was crystallized from methanol.ノ１also f”(: 5.:ko y (60%
), melting point: 1.52-1!54℃ (minute angle '7)
[(χJD=;+325° (CH2Ct2
, C-= 1.3 5) Reference Example J4 In 712 ml of anhydrous TOL and 4.8 ml of tart-pudylnitrile (14-Ox: 3α, 10α)
-E-homoeprunan2. l O,9 (all 6.8 millimeters)゛I f ~ So, -zo- to this suspension,
Anhydrous tonneau L-n 12m1 t (2 W static 7'!'J =
S) lium tert-fiber plate 1. ! ”13
g (] 3i mmol) was added under a nitrogen atmosphere with constant stirring. This mixture was stirred at room temperature for 1 hour,
Afterwards, 4.2% am7nium chloride in 80m of water, F
Add fc and then stir with IHJ for 15 minutes. The toluene layer was separated and the aqueous phase was decanted twice with toluene. The combined toluene solutions were dried over magnesium sulfate, and the powder was evaporated to dryness in vacuo. This residue i1.9.9 was obtained by dissolving it in 8 ml of methanol, and the solution was adjusted to 5 t ml by adding salt in methanol. was filtered and washed with methanol. Yield: [A hydrochloride salt L40.@(55 ＼) was obtained. Melting point: 254-257°C (methanol 7)) I
R Skrittle (KBr): l 730 (Co),
l 635(m-'(C=N) this salt)l! u4, from the hydrochloride of the Ll-like compound, bathe it in 5% aqueous sodium carbonate solution, extract the bath with dichloromethane, dry the extract, filter, and evaporate the lIj solution. It was dried and solidified. The base of the target compound was removed as an oily residue. [αJ n-+61° (c = i, cII2cz
,,,) Reference Example 15 (+)-A7]? Ethyl vincamate anhydrous ethanol 5.57171! and concentrated sulfur f'tt1.95mJ
0.30jj (0.8 mmol) of (-4-) r 14-oxo-15-hydroxyimino-3α,17α-E-homoegrunane salt e kff, f in a water bath for 4 and a half hours in a mixture of did. The solution was then poured into ice water, and the mixture was made alkaline (pH=9) by adding concentrated aqueous ammonium hydroxide solution under water cooling, and the alkaline solution was extracted four times with nochloromethane. The combined organic layers were all dried over magnesium sulfate to remove the drying powder, and the solvent was evaporated from the solution in a vacuum. The remaining 0.26 g of oil was crystallized from 0.5 ml of ethanol.
, 6ch) Melting point: 148-151℃ (from ethanol) IR irradiation target KBr): l 740 (C
O2C2TI5). 1640crn (C-C) [α]0-→-147° (CHCL3.C: 1.1
) Patent Applicant Riditer Careme/G1 Noeszetei Noyar El, Chi. 1 o'clock W [Applicant's Patent Attorney Roben Yoiki 17ij (2 Patent Attorney Kazuyuki Yotate Yama "1 Akira Continuation of 1st page @l! Interchanger Ienone Farkas Budapest, Hungary XXI Magyar ° Utsza 11 0 shots Inventor: András Nemes Hungarian State of Hungarian Budapest II Hankosy Utsza 11 0 Inventor Hedwig Belsky Hungarian State of Budapest 1-XI Moskotarii Utsza 37 0 Inventor Tarif Rakuzna Hungarian Budapest V. M Utsutua 7 Procedural amendment (method) % formula % Showa 5) 341 '+ is f Permission No. 120149 2
, Name of the invention (7'1, Hydroxamino-eburnane derivative and method for producing the same 3
, Relationship with the person making the amendment ['1 Patent applicant 4, agent (2 others) 5 Date of amendment order November 29, 1980 (shipment date) 6. Specification subject to amendment 7, Amendment Copy of autopsy with detailed contents (no change in content) 8. Inventory of attached documents 1 copy 889-

Claims (1)

[Claims] 1. Represented by the general formula C,, ll5 (wherein, [E is a C1-4 argyl group]); 1) Racemized or optically active salts obtained from xoaminoepurnan 1.θ and the like. 2. General If racemized IJ of the formula (Ill), the optically active 14-okino-15-hydroxyimino-3α,17α-E-homoeglunan is converted into a compound with the general formula R'OH (wherein RlU', C4
-4 alkyl group) and the salt -1. If desired, the resulting general formula (IV) 2115 (where Il'tfJ is the above-defined or converting the racemized or optically active hydroxiaminoleglunan derivative represented by Rahimization, which is expressed by the general formula ■), is also characterized by the IU splitting of the derivative. ! , (+ 廿 or medicinally acceptable,
A method for producing acid I/J7JII salt by Suso L et al.