CN1027693C - Preparation of new type amide compound with xanthic surface - Google Patents

Preparation of new type amide compound with xanthic surface Download PDF

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CN1027693C
CN1027693C CN 90107309 CN90107309A CN1027693C CN 1027693 C CN1027693 C CN 1027693C CN 90107309 CN90107309 CN 90107309 CN 90107309 A CN90107309 A CN 90107309A CN 1027693 C CN1027693 C CN 1027693C
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compound
clausenamide
mouse
liver
kilogram
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CN1049345A (en
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陈延镛
杨明河
黄量
刘耕陶
乌尔里克·本兹
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Institute of Materia Medica of CAMS
Bayer AG
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Bayer AG
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Abstract

A clausenamide compound (9) and a clausenamide compound (0) which have the following structural formulas are obtained by coconut Chinese wampee leaf extraction, separation and purification. The compounds are effective on curing anoxia and amnesia.

Description

Preparation of new type amide compound with xanthic surface
The present invention relates to the preparation of the δ-butyrolactam (being called " Clausenamide " hereinafter) of active phenyl of a kind of novel pharmacology and benzyl replacement; comprise: this compounds separates from Rutaceae Clausena class plant; some derivative of Clausenamide and they are as the application of hypoxia protection agent and anti-forgetful dose, the invention still further relates to the pharmaceutical composition that contains the Clausenamide or derivatives thereof and their preparation method.
Existing report Rutaceae Africa Calusena lansium in a certain area in Africa as herbal medicine people such as (, Planta Medica 32(1) I.Mester 81,1977).Also have the crude extract of report India Calusena lansium effect to be arranged, and isolating two coumarin derivatives clausmarins A and B have spasmolysis (people such as Dhan Prakash, Phytochem.17,1194,1978 from five leaf Calusena lansium to cardiovascular; People such as Aboo Shoeb, J.C.S.Chem.Commun.281,1978).From the Radix clausenae lansii of different genera, stem etc., about 50 kinds of components have been isolated.The great majority of these components are tonka bean camphor, carbazole and terpenic derivative; Up to the present only there are two straight-chain carboxylic acid's acid amides to be present in (people such as S.R.Johns, Aust.J.Chem.20,2795,1967 in the leaf of clausena plant according to reports; People such as Dhan Prakash, Indian J.Chem.Sect.B 19B(12), 1975).
The Clausenamide compound that contains a kind of δ of having-butyrolactam structure in the existing known bulky look Leaf of Chinese Wampee, it contains a phenyl and a benzyl substituent, has the Clausenamide compound (compound (0)) that also contains a kind of structurally very close two ring butyrolactam structures in (" Clausenamide " and compound (9)) bulky look Leaf of Chinese Wampee with two kinds of steric isomers.Find that also Clausenamide and derivative thereof have multiple valuable pharmacological character.Chemical derivatization and spectroscopic data have confirmed the structure of these compounds.
The present invention proposes to have the logical formula I compound of following formula:
Figure 901073091_IMG3
In the formula,
R is a methyl;
R 1Expression hydrogen is perhaps with R 3Represent a chemical bond together;
R 2Expression hydrogen or and R 3Represent oxygen together;
R 3Expression hydroxyl or and R 1Or R 4Represent a chemical bond together, perhaps with R 2Represent oxygen together;
R 4Be hydrogen or and R 3Represent a chemical bond together;
R 5And R 6Each represents hydrogen.
Can be from bulky look Leaf of Chinese Wampee the structural formula of isolated above-claimed cpd as follows:
Figure 901073091_IMG4
(X-ray crystal diffraction has confirmed this stereochemical structure)
The present invention proposes the method for separating compound (0), this method comprises the steps:
A) soak into the leaf of bulky look Calusena lansium with boiling water.
B) in spissated aqueous extract, add diluted acid (for example HCl).
C) make supernatant liquor pass through Zeo-karb, be preferably the resin of H type.
D) use alkali, preferably ammoniacal liquor soaks into resin.
E) use organic solvent, acetic ester or C-C-ketone such as ethers, trichloromethane, methylene dichloride, C-C-alcohol preferably extract this resin with ether.
F) with trichloromethane, methylene dichloride, ether or trichloromethane/carbinol mixture as eluent, separate spissated extract with silicon-dioxide or alumina chromatography.
G) collect and concentrate the corresponding elutriant of its Rf value and compound (0), (silica gel is sorbent material, when chloroform is eluent, Rf=0.8).
The present invention also proposes the method for separating compound (9), and this method is made up of following step:
A) soak into the leaf of bulky look Calusena lansium with boiling water.
B) moisture content in the evaporated extract and in diluted acid (example hydrochloric acid) dissolution residual substance.
C) make supernatant liquor pass through Zeo-karb, preferably the resin of H-type.
D) with alkali for example ammoniacal liquor soak into resin.
E) use organic solvent, extract this resin such as the acetic ester or the C-C-ketone of ethers, trichloromethane, methylene dichloride, C-C-alcohol.
F) on silicon-dioxide or aluminum oxide, spissated extract is carried out chromatographic separation, make eluent with trichloromethane, methylene dichloride, ether or trichloromethane/carbinol mixture.
G) collect and concentrate its Rf value and compound (9) (during with silica gel adsorption and chloroform wash-out, Rf=0.2) elutriant (as: monitoring) accordingly by thin-layer chromatography.
The crude product that obtains with above-mentioned separation method is preferably in recrystallization in the alcohol (for example methyl alcohol or ethanol).
The invention still further relates to and contain logical formula I compound as the pharmaceutical composition and the medicament of effective constituent and prepare these method for compositions.
The compound that the present invention also proposes to lead to formula I is used for the treatment of anoxia and amnesia.
In animal experiment, the compound of logical formula I has big cerebral anoxia of significant protection and anti-forgetful effect, and this effect obviously is better than 2-Pyrrolidone ethanamide (Piracetam).2-Pyrrolidone ethanamide (Piracetam) is structurally the most approaching at the treatment of brain and the allied compound in the nootrpics field.
Figure 901073091_IMG5
2-Pyrrolidone ethanamide (Piracetam)
Even be applied to animal with high dosage, their behavior aspect does not show any material alterations yet.This hypoxia protection effect obviously is not (therefore the latter causes the demand of reduction to oxygen) that causes owing to a kind of non-specific sedative effect.We find: the acute toxicity of formula I compound is very low.
Pharmaceutical composition of the present invention can be made: ointment, colloid, paste, emulsion, sprays (comprising aerosol), lotion, emulsion, solution and emulsion active ingredient, syrup, granule or pulvis in water or non-diluent water.
Said composition preferably make the sterile isotonic aqueous solution or make contain independent or with tablet, capsule, pill and the suppository of the compound of the present invention of mixing diluents.
Can be applied to the thinner that being suitable in the pharmaceutical composition (for example granulate) should form tablet, drageeing, capsule and pill comprises:
(a) filler, for example, starch, sugar, silicic acid;
(b) tackiness agent, for example, derivatived cellulose, alginate, gelatin and polyvinylpyrrolidone;
(c) wetting Agent for Printing Inks, for example, glycerine;
(d) disintegrating agent, for example, agar, lime carbonate and sodium bicarbonate;
(e) absorption enhancer, for example, quarternary ammonium salt compound;
(f) tensio-active agent, for example, hexadecanol;
(g) absorption carrier, for example, kaolin and wilkinite;
(h) lubricant, talcum powder for example, calcium stearate and Magnesium Stearate and solid-state polyethylene glycol.
Tablet, dragee, capsule and the pill made by medicinal compositions of the present invention can have common dressing, wrap and protection matrix, and they can contain opalizer.These medicaments can be made its active ingredient only or more fortunately the privileged site of enteron aisle discharge, and can continue for some time.Dressing, wrap and protection matrix can prepare with polymeric material and paraffin.
The component of medicine also can be made the form of micro-capsule with one or more above-mentioned thinners.
The production of aforementioned pharmaceutical compositions and medicament can be undertaken by any method known to the people on technology.For example, the composition (for example, granulous) that activated combination and mixing diluents are formed a kind of pharmacology (for example: tablet) is made medicament with this composition again.
Pharmaceutical composition of the present invention preferably contains 0.1% to 99.5% effective constituent of total composition weight, and the best is 0.5% to 95%.
The optimal dose that medicament of the present invention is used for the treatment of is 0.001 milligram to 0.2 milligram activeconstituents every day.
With example an explanation is done in this invention below.
Example 1
Separating of compound (0) and compound (9).
Water boil three times of the bulky look Calusena lansium of 80 kilograms exsiccant Skeels (lour) leaf were boiled 4 hours with 800 premium on currency at every turn.This extracting solution is concentrated, obtain 18 kilograms syrup crude product.Use the 0.06NHCl(80 liter) handle this syrupy shape crude product of 16 kilograms, its supernatant liquid is by the cation exchange resin column (the Na-form Zeo-karb by 48 kilograms is converted) of wet H-type.With this resin of deionized water wash, use dry air more then, handle and last (60 liters) extracted with diethyl ether 12 hours of using with 2% ammoniacal liquor (32.2 liters).Then, in a vacuum ether is removed from extract, then residue is dissolved in the chloroform, this chloroformic solution with this residue is concentrated into about 1.5 liters again, therefrom isolates white crystalline solid.Remove the solvent in the filtered liquid and obtain 96.3 gram brown adhesive residue (b) and solid (22.5 gram) is eluent with chloroform and supervises with thin-layer chromatography in silica gel chromatographic column (different ratios was from 100: 1 to 20: 1) processing.Collect and concentrated Rf=0.20(compound (9)) elutriant, obtain 7.22 and digest compound (9) and use twice of recrystallizing methanol again.Obtain the white square crystallization of 3.31 grams, mp205-6 ℃ (compound (9)).Handle residue (b) and use the chloroform wash-out with 1.7 kilograms of silica gel chromatographys.The elutriant of Rf=0.80 is merged, concentrate and obtain 0.52 gram coarse crystallization and this coarse crystallization is carried out recrystallization, obtain 0.18 and restrain white prismatic crystallization, mp164.6 ℃ (compound (0)) with methyl alcohol with methanol wash.Productive rate: compound (9) 0.021%;
Compound (0) 0.001%, (in 16 kilograms of thick starting materials of syrupy shape).
Compound (0):
[α] 24.5 D=-40 ° (0,225 in methyl alcohol)
Ultimate analysis:
Theoretical value (C 18H 17NO 2) experimental value
C 77.42 77.06
H 6.09 6.13
N 5.02 4.76
High resolving power MS:(M 1+ 1)=280,1371
IR γ KBr MaxCm -1: 1690(acid amides-carbonyl), 3080,3060,3010,1600,1500,750,730,705,700
UVλ MeOH maxnm（1gε）：209（4.35），257（2.60）
Table 1: 1H-NMR(is in deuterochloroform): the chemical shift and the ownership of compound (0),
Ppm hydrogen
2.95（s;3H） N-CH 3
3.60（s;1H） C 4-H
4.09（s;1H） C 5-H
4.81（s;1H） C 3-H
5.00（s;1H） C 7-H
7.10-7.50(m, 10H) fragrant H
13The data of C-NMR provide in table 3
Compound (9):
[α] 19 D=0.00(0.29 is in methyl alcohol)
Ultimate analysis:
Theoretical value (C 18H 19NO 3) experimental value
C 77.76 73.00
H 6.45 6.46
N 4.72 4.50
High resolving power MS:(M 1+ 1)=298.1453(C 18H 20NO 3)
IR γ KBr MaxCm -1: 3440,3340(OH), 1600(acid amides-carbonyl), 3060,3030,1600,1490,750, the mono-substituted benzene of 770()
UVλ MeOH maxnm（1gε）：258（2.59）
Table 2: 1H-NMR(is in DMSO); Chemical shift and ownership
Ppm hydrogen
2.90（s;3H） N-CH 3
3.07（t;J＝7;1H） C 4-H
3.89（m;2H） C 3-H;
C 5-H
5.00（dd，J＝5.3;1H） C 7-H
5.53(d, J=7; 1H) C 3-OH; At D 2O adds the back and disappears
5.73(d, J=5; 1H) C 7-OH; At D 2O adds the back and disappears
6.75-6.93(m; 2H) fragrant H
6.95-7.33(m; 8H) fragrant H
13The data of C-NMR provide in following table 9
Table 3: 13C-NMR(is in CDCl); The chemical shift and the ownership of " Clausenamide ", compound (0) and compound (9)
Carbon " Clausenamide (O) (9)
（ppm） （ppm） （ppm）
2 173.6 172.2 172.7
3 68.9 80.3 69.3
4 49.9 50.7 46.7
5 65.3 70.1 68.4
6 30.4 27.3 28.2
7 71.9 82.5 77.3
1′ 136.0 133.3 140.5
2′
1″ 140.5 139.1 141.8
126.3 125.4 125.9 of fragrance
Carbon 128.9 128.5 128.5
Example 2
Compound of the present invention is to the influence of liver function
Adopting body weight in whole experiment is the male Kunming mouse subspecies of 18-22 gram.Compound to be tried is suspended in 5% tween 80, uses the oral gavage administration then, give mouse with control group with identical method the carrier of 5% tween 80 solution.In experiment in vitro, compound dissolution, is directly added in the culturing mixt in the dinethylformamide then at N.
The parameter that liver poison (hepatotoxicity) is adopted comprises: serum transaminase (SGPT), the pathological examination of liver triglyceride level and liver slice.Liver injury is mainly kept the score by inflammation and downright bad degree, and is divided into 0 to 4 grade.
A) effect of protection liver
The test mouse is divided into three groups, feeds control group with carrier.Be spaced apart 8 hours for respectively other two groups take medicine twice (250 milligrams/kilogram) with each compound at every turn.Fed for the second time behind the evolution compound 24 hours, and be dissolved in 0.1% tetracol phenixin in the vegetables oil by 10 milliliters of/kilogram subcutaneous injections, fasting 16 hours, broken end kills then.Measure SGPT and liver fat thing.Be used as liver slice for pathological observation with one.
As shown in the following Table 4, " Clausenamide " and compound (0) both has reduced the level of the SGPT of carbon tetrachloride poisoning mouse significantly.
B) Clausenamide is to the toxic effect of protection tetracol phenixin, thioethanolamine and Paracetamol.
The toxicologic experimental arrangement of anti-tetracol phenixin liver is identical with said process.The dosage of the active compound that is adopted is 125 milligrams/kilogram and 250 milligrams/kilogram.The data of listing in table 5 show, have reduced the rising of the SGPT that causes owing to tetracol phenixin significantly with the Clausenamide of 125 milligrams/kilogram and 250 milligrams/kilogram dosage.With the mouse of 250 milligrams/kilogram compounds for treating, the seriousness of the damage of its liver such as hepatitis and hepatic necrosis is lower than the contrast mouse, and liver fat does not reduce.
In another experiment, at first every other day to three 10 milligrams of/kilogram 0.15% tetracol phenixin in vegetables oil of mouse injection.After for the first time injecting tetrachloroization, treat mouse every day since second day to the 5th day with Clausenamide (250 milligrams/kilogram).Carried out the mensuration of SGPT and the pathological examination of liver slice at the 7th day that tests.Gained is the result show: this compound has the effect that SGPT is reduced, but constantly influences liver injury (seeing Table 6).
In thioacetamide liver toxicological experiment, according to the programmed treatment mouse of testing for the first time, but use is thioacetamide (50 milligrams/kilogram) rather than tetracol phenixin.We find that Clausenamide has obviously reduced SGPT level (table 7).
Resist-the toxicologic experiment of Paracetamol liver with following method, gave and same dosage for twice Clausenamide of mouse (250 milligrams/kilogram) in subsequent second day in first day.After the last administration 6 hours, give mouse subcutaneous injection Paracetamol by 150 milligrams of/kilogram dosage.Behind the injection Paracetamol 20 hours, to measure SGPT and also detect hepatic tissue, Clausenamide has obviously reduced the level of SGPT and has alleviated liver injury (seeing Table 8).
C) to the influence of the serum and the liver transaminase (GPT) of normal mice.
The Clausenamide of feeding carrier or 250 milligrams/kilogram for respectively two groups of mouse, once a day, continuous seven days.Twenty four hours behind the last medicine feed is measured serum and liver GPT.As shown in table 9, the SGPT of a little higher than contrast of the SGPT level of the mouse for the treatment of with Clausenamide mouse, but difference is not obvious.To liver GPT, also obtained similar results.
D) to hepatomicrosome cytochrome p-450 inducing action
In the detoxification processes of (Xenobitics) of heteroplasia, the hepatomicrosome cytochrome p-450 plays a key effect.Give and test the Clausenamide that mouse feeds 250 milligrams/kilogram, once a day, for three days on end.The contrast mouse is then accepted carrier.Overnight fasting kills the test mouse.The preparation hepatomicrosome.Measure microsomal monoxygenase then.
Data are shown in table 10.Liver cell pigment p-450, cytochrome b, NADPH-cytochrome C-reductase, pyramidon piptonychia enzyme and benzopyrene hydroxylase activity obviously improve.
In other experiment, give the Clausenamide of 250 milligrams/kilogram of test mouse.After obeying this compound, carried out subcutaneous injection vetanarcol (50 milligrams/kilogram) in back 1 hour and 24 hours taking medicine.The length of one's sleep is estimated in disappearance and recovery by the record regular reflection at interval.Data are listed in table 16.Advance Clausenamide at preceding 24 hours clothes of injection Sodital, obviously shorten the length of one's sleep of mouse, otherwise took this compound in last hour in the Sodital injection, and obviously prolong rather than shorten the length of one's sleep of mouse.Yet obeying this compound did not in advance influence by veronal inductive mouse length of one's sleep.Because veronal is not by liver metabolism.The prolongation of the Sodital length of one's sleep of this explanation due to Clausenamide is by having suppressed hepatic drug metabolizing enzyme.So this compound has the two-phase effect to the hepatomicrosome cytochrome p-450, that is: suppress afterwards to induce earlier.
E) acute poisoning experiment
10 mouse are pressed the single oral dose administration of 3 gram/kilogram Clausenamides, do not have in 7 days to cause death.
Table 4: the influence (every group 9 mouse) of carbon tetrachloride poisoning mouse on the SGPT level
The % P of SGPT unit
X±SE
Control group 1678 ± 261＜0.01
Compound (0) 391 ± 94
" Clausenamide " 617 ± 323＜0.01
The protective effect of the test mouse liver poisoning due to the table 5 pair tetracol phenixin
The liver injury of the % of group SGPT unit liver lipoid
The downright bad rank of X ± SE mg/g liver inflammation rank
X±SE
Contrast 3016 ± 23 21.0 ± 4.2 1.70 2.33
Clausenamide 21.6 ± 4.4
125 milligrams/kilogram * 2 2365 ± 245*--
250 milligrams/kilogram * 2 1900 ± 257** 13.4 ± 3.0 0.38 1.33
Every group of 9 mouse
＊p＜0.05;＊＊＜0.01
The therapeutic action of the test mouse liver poisoning due to the table 6 pair tetracol phenixin
The % P of number of elements SGPT unit of group mouse
X±SE
Contrast 8 2695 ± 110
Clausenamide
(250 milligrams/kg/day * 4) 8 17118 ± 224＜0.01
The provide protection of the test mouse liver poisoning due to the table 7 pair thioacetamide
The % of group SGPT unit liver lipoid (milligram/gram)
X±SE X×SE
Contrast 1696 ± 231 61 ± 11.7
Clausenamide 718 ± 229* 39 ± 3.9
(250 milligrams/kilogram * 2)
Every group of 9 mouse
＊p＜0.01
Test due to table 8 acetylaminobenzene (acetaminophen)
The provide protection of mouse liver poisoning
Parameter contrast Clausenamide
250 milligrams/kilogram * 3
The % of SGPT unit 2778 ± 270 697 ± 163**
Liver lipoid 79 82 ± 17
Milligram/kilogram
Liver inflammation (rank) 0.5 0.1
Hepatic necrosis (rank) 1.4 0
Every group of 9 mouse
＊＊P＜0.01
The serum of table 9 pair normal mice and the influence of liver transaminase
% LGPT unit of group SGPT unit/100 milligrams
X×SE X×SE
Contrast 217 ± 17.5 260 ± 11.6
Clausenamide 252 ± 22.1 292 ± 8.0*
(250 milligrams/kg/day * 7)
Every group of 8 mouse
＊P＞0.05
The inducing action of table 10 pair test mouse hepatomicrosome cytochrome P-450
The contrast Clausenamide
250 milligrams/kg/day * 3
Liver weight in grams % 4.0 ± 0.2 5.4 ± 0.2**
Microsomal protein matter 6.3 ± 0.3 9.1 ± 0.6**
(milligram/gram liver)
Cytochrome P-450 0.87 ± 0.07 1.14 ± 0.07**
(mmole/milligram protein)
NADPH-cytochrome C-reductase 103 ± 2.5 117 ± 2.5**
(mmole reductive pigment C/ minute
/ mg protein)
Cytochrome b 0.15 ± 0.01 0.19 ± 0.01
(mmole/milligram protein)
Pyramidon demethylase 81 ± 6.3 126 ± 5.2**
(mmole formaldehyde/minute protein)
AHH
Mmole/minute/milligram protein 2.6 ± 0.4 5.7 ± 0.76**
＊＊P0.01
The influence of test mouse length of one's sleep due to the table 11 pair barbiturate(s)
The barbiturate(s) group is with compound and use the length of one's sleep
Barbiturate(s) it (minute)
Between interval X ± SE
Sodital contrast 71 ± 7
50 milligrams of/kilogram Clausenamide 1h 152 ± 15＜0.01
(250 milligrams/kilogram)
Clausenamide 24h 46 ± 6＜0.01
(250 milligrams/kilogram)
Veronal contrast 197 ± 27
200 milligrams of/kilogram Clausenamide 1h 172 ± 13＞0.05
250 milligrams/kilogram
Example 3
The raising of anoxic tolerance (mouse) due to the Clausenamide
A group male mice (body weight 20 grams) is placed in the plastic box that is divided into two Room (volume of case is 15 * 28 * 40 centimetres, and being equivalent to its capacity is every bos1.68 liter).20 mouse of each indoor placement.Charge into the mixed gas that contains 3.5% oxygen and 96.5% nitrogen in the case.The volume that charges into is 4 liters/minute.Experimentizing oral test material and carrier preceding 30 minutes.
Charge into the anoxic gas mixture and began the back about 7 minutes, the animal hypoxia death.When three animals of chamber, the left side (control animal group) only respiratory symptom occurs, stop experiment.Open chest and calculate the number that a treated animal after treatment still lives then.
According to Fisher and Yates(1963) X test evaluation difference between the surviving animals in two groups of proposing such as (Thomann people, 1975).
Table 12
Dosage contrast Clausenamide effectiveness
(milligram/kilogram is oral) (survival number/total number of animals) (%)
10 9/60 19/60 19.6
30 9/60 31/60 41.1
100 9/60 40/60 58.8
P＝0.05
Table 12 shows, can significantly improve the anoxybiotic tolerance with Clausenamide, only uses oral 100 milligrams/kilogram of few material (barbiturates), and survival rate just can improve 59%.
Example 4
Clausenamide is to the influence of hypomnesis (rat) under anoxia condition
Device (39 cm long, 21 centimetres are high, 21 centimetres are wide) form by two Room.Make (29 centimetres in length) by translucent plastic and another blacking (long 10 centimetres) for one.This device has at the bottom of the metal grid mesh, and aperture plate is connected with the stimulating apparatus that 20 seconds 1.6mA electric currents can be provided.
Connected by door between two Room, door can be closed.
With male rat (body weight 100-120 gram) be placed on big between, allow rat to check two Room three minutes of this device then.
Then, rat is placed into little (blacking), close the connection door, carry out end vibration, afterwards rat is put into sealed chamber, charge into the mixed gas that contains 3.8% oxygen and 96.2% nitrogen in this sealed chamber.Animal is placed this kind anaerobic environment, up to show show be about to occur the panting of respiratory insufficiency till (the longest is 15 minutes).
After 24 hours, again rat is put back to device bright.Be 3 minutes observing time.
In three groups of 15 rats, once test:
The A group: control group, without undergoing anaerobic environment.
The B group: control group, accepting anaerobic environment after the training for the first time.
The C group: the group of taking medicine, accepting anaerobic environment after the training for the first time.
Assessment: animal enters the required time of inner room with calculating second.
Regard the time difference between two control groups as 100%(A-B=100%).
Calculate control group B and the time difference of taking medicine between the group C with percentage ratio (C-B=X%), X is that material to be tested resists the tolerance of forgeing effect.
Clausenamide X
(milligram/kilogram is oral) (%)
3 47
10 65
30 100

Claims (1)

1, separate Clausenamide compound (0) and/or Clausenamide compound (9) method,
This method comprises following step:
A) leaf of the bulky look Calusena lansium of usefulness boiling water treating,
B) diluted acid is added in the spissated extraction liquid,
C) supernatant liquid is passed through Zeo-karb,
D) use the alkaline purification resin,
E) use the organic solvent extraction resin,
F) concentrate this organic solvent extraction liquid, filter to isolate crystalline solid, the solvent of removing in the filtrate obtains residue, with crystalline solid and residue respectively with silicon-dioxide or aluminum oxide chromatography, and carry out wash-out as eluent with trichloromethane, methylene dichloride, ether or trichloromethane/carbinol mixture
G) for first part's crystalline solid, collect and concentrate its R value and be 0.2 elutriant, with obtaining compound (9) after the recrystallizing methanol,
For the residue of second section, then collect and concentrate its R value and be 0.80 elutriant and obtain compound (0) after with recrystallizing methanol
CN 90107309 1985-09-17 1990-08-24 Preparation of new type amide compound with xanthic surface Expired - Lifetime CN1027693C (en)

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