JPH0246585B2 - AII77RUINOAMIDOJUDOTAITOSONOIYAKUTEKINIKYOYOSARERUEN - Google Patents

Description

[Detailed description of the invention] The present invention provides an amide derivative of the novel compound AI-77.
Concerning conductors and their pharmaceutically acceptable salts
Ru. This AI-77 amide derivative has the following general formula:
It is indicated by [ ]. (In the formula, Y is NHR_FourOr C and C together with Z
The bond, Z joins H or Y to form a bond between C and C.
Aite, R₁,R₂and R_Fourare independently H, R', -
CH₂R, - represents COR, R₃is H, R or
CH₂Represents R. R is methyl, ethyl, n-pro
pill, n-butyl, n-pentyl, n-hexy
n-heptyl, n-octyl, n-undecile
n-heptadecyl, isopropyl, 2-methylene
Le-propyl, 2-methyl-butyl, 2-propyl
Lepentyl, 4-ethylheptyl, 2.6.10
-trimethyl-tetradecanyl, vinyl, allyl
-1-propenyl, 2-propenyl, 2-butenyl
1,3-butadienyl, 2-pentenyl, 8
-heptadecenyl, 2-methyl-allyl, 2.6
-dimethyl-2,6-heptazinyl, 2,6,9
-trimethyl-2,6,9-tridecatrieni
phenyl, naphthyl, azulenyl, norbol
Nene, norbornane, camphor, adamantoid
cyclopropyl, cyclobutyl, cyclobutyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclobutyl
Lopentyl, cyclohexyl, cycloheptyl
le, cyclooctyl, benzyl, phenethyl,
2-phenylpropyl, naphthylmethyl, naphthi
ruethyl, 2,4-dimethyl-isopropyl-a
Zurenyl, furyl, dihydrofuryl, tetrahydride
lofuryl, pyranyl, dihydropyranyl, thienyl
, tetrazolyl, pyrrolyl, pyrrolidinyl,
noryl, indolyl, indolinyl, piperidi
morpholinyl, pyridyl, oxazolyl,
xazolidinyl, thiazolyl, thiazolidinyl,
and the above hydrocarbons such as chlorine, bromine, fluorine, and
So, carboxyl, hydroxyl, methyl, ethyl
ole, propyl, butyl, pentyl, isopropyl
3-methyl-butyl, isobutylene, propylene
Ren, acetylene, phenyl, naphthyl, azure
nil, tropoyl, cyclopropyl, cyclo
Butyl, cyclopentyl, cyclohexyl,
Cycloheptyl, cyclooctyl, benzy
phenyl, phenethyl, 2-phenylpropyl, naphthi
p-(3-methyl)butylphenyl,
Methoxy, ethoxy, pentoxy, 3-methyl-
Butoxy, 3-methyl-2-butenoxy, methyl
Thio, ethylthio, 3-methyl-butylthio, penylthio
methylthio, methoxycarbonyl, pentoxica
carbonyl, isobutoxycarbonyl, acetyl
xy, propionyloxy, pentanoyloxy
cy, hexanoyloxy, crotonoyloxy,
Acetyl, propionyl, hexanoyl, 3-methane
Chill-butanoyl, furyl, dihydrofuryl, te
trahydrofuryl, pyranyl, dihydropirani
ru, thienyl, tetrazolyl, pyrrolyl, pylori
dinyl, quinolyl, indolyl, indolinyl,
piperidino, morpholino, pyridyl, oxazoli
, oxazolidinyl, thiazolyl, thiazolidinyl
Substituted with one or more groups such as nyl
R′ is a group selected from the group consisting of
As unsaturated carbon or tertiary carbon, the general formula []
Represents a group other than a group directly bonded to O or N.
However, R₁,R₂,R₃and R_Fouris H at the same time
Excludes compounds. ) The present inventors aimed to create a new anti-ulcer agent.
We have carried out intensive research on the
The compound exhibited remarkable anti-ulcer activity in experimental animals.
The present invention was completed based on this discovery. Amide induction of novel compound AI-77 of the present invention
is a compound represented by the above general formula [],
R is as described above, but among these substituents:
As substituents for straight-chain alkyl, halogen,
xo, carboxy, alkoxy, thioalkoxy
Cy, carbalkoxy, acyloxy, monocyclic aliphatic
Included in aliphatic, araliphatic, aromatic, and heterocyclic groups
is preferable, and as a substituent of branched alkyl
is a halogen, alkoxy, thioalkoxy group
Preferably, those included in the substituents of the aromatic group and
is alkyl, alkoxy, thioalkoxy
Oxy, Hydroxy, Acyloxy, Carboal
Those included in Koxy are preferred. Also these
The groups are also preferred as substituents for araliphatic aromatic groups.
Yes. Monocyclic aliphatic substituents include oxo,
carboxyl, alkyl, alkoxyl, carb
What is included in alkoxyl and acyloxyl groups
is preferred. As substituents for heterocycles, alkyl
contained in alkyl, alkoxyl, acyl, and carboxyl groups.
Preferably. In addition, these AI-77 amide derivatives are
Pharmaceutically acceptable salts, such as hydrohalic acids,
Phosphoric acid, sulfuric acid, oxalic acid, maleic acid, dodecyl
It can also be used as a salt of organic sulfonic acids such as sulfuric acid.
can not use. The compound represented by the general formula [] is represented by the following formula:
AI-77-B and AI-77-F shown and that
General formulas [a] and [a] derived from
synthesized from compounds. (In the formula, R₁,R₂,R_Fouris expressed by the general formula []
R₁,R₂,R_Fourrepresents the same group as ) AI-77-B was newly developed by the present inventors.
Strains isolated from Bacillus and Bumilus
AI-77 strain identified as “Agency of Industrial Science and Technology No. 4066”
The culture is carried out aerobically in a medium.
It accumulates in the culture solution, so collect it from the culture solution.
be able to. AI-77-F is based on AI-77-B
can be synthesized chemically. Culture method, synthesis method
Details will be given later. Next, the above AI-77-B and AI-77-F
The physical and chemical properties will be described. 【table】 【table】 AI-77-B mass spectrometry value, ultraviolet absorption value, infrared
The absorption value, NMR, etc. are shown in Table 1, and the solubility is
water, methanol, dimethylformamide, dimethylformamide
Easily soluble in Rusulfoxide and other lower alcohols
Very poorly soluble in dioxane, dioxane, and tetrahydrofuran
So, ethyl acetate, chloroform, ether, hexa
Almost insoluble in chlorine and benzene. Stability
The aqueous solution is unstable to alkali, and gradually becomes unstable even at room temperature.
The hydrolysis of lactone progresses. AI-77-F mass analysis value, ultraviolet absorption value, infrared
The absorption values and NMR are shown in Table 2, and the solubility is shown in Table 2.
Ethyl, chloroform, dimethylformamide, di
Easily soluble in methyl sulfoxide, lower alcohol
dioxane, etc., and is poorly soluble in water, hexane, etc.
It is almost insoluble in benzene. Stability is AI-
Like 77-B, it is unstable in alkalis. For cultivation, general information regarding the cultivation of strains of Bacillus spp.
knowledge is applied. i.e. nitrogen source, carbon source, no
Organic salts, vitamins, amino acids, nucleic acid-related substances, etc.
25-40 in a medium containing the substances necessary for the growth of microorganisms.
It is carried out aerobically at ℃. For large-scale cultivation
It is advantageous to perform an aerated agitation culture. In addition, the AI-77 strain (Agency of Industrial Science and Technology No. 4066)
The scientific properties are as follows. Mycological properties a) Growth status on various media Meat juice: The medium is almost uniformly cloudy and forms a film.
If it doesn't work. Meat juice agar medium; mostly around the colony
It exhibits a smooth type, but especially a rough type.
and spreads flat. Color is opaque or translucent
From ivory color to white to cream color
becomes. No dyes are produced. Glucose gravy agar medium; gravy agar medium
Growth is good and the appearance is the same as on broth agar medium. Gelatin medium; liquefies slowly. Peptone water: Growth is slightly suppressed and the whole
It's getting cloudy. Litmus milk; does not curdle milk. Pe
It doesn't turn into a ton. No discoloration of litmus was observed.
Not possible. Potato medium; grows in pale yellowish brown color
This causes fine wrinkles. Morphological characteristics on glucose broth agar
The shape is short rod-shaped with a size of 0.5-0.9 x 2.0-5.0μ.
and gram-variable, oval to cylindrical spores.
Create. The spores are mostly located in the center,
The difference is not clear. b) Physiological properties Optimal growth conditions: PH5-PH8, 27-35℃ aerobic
sex. Conditions for growth: PH5.0-10.0, 10-55℃. Gram staining; variable. Anti-acidity: None Methylred test; positive Fouges-Broskauer reaction; positive No formation of indole is observed. Almost no hydrogen sulfide formation is observed. No ammonia formation was observed. No reduction of nitrate is observed. Catalase production is vigorous. Slowly liquefy the gelatin. Does not hydrolyze starch. Use citric acid. Grows in 7% saline culture solution. Does not reduce methylene blue. The availability of urea is weak. c) Availability of carbon sources fructose, satucrose, glucose,
Generates acid using mannitrate. Manno
A small amount of trehalose is also used to generate acid.
do. arabinose, xylose, galactose
s, lactose, maltose, raffinose,
Sorbit, Inosit, Glycerol, α-
Methyl glucoside, inulin, dextrin
It does not use starches, starches, or cellulose. either
No gas generation was observed from the carbon source either. The above properties can be expressed as Bergey's manual of
Based on Determinative Bacteriology 7th and 8th edition
When combined, this bacterium produces arabinose and xylose.
It does not produce acids and does not cause peptonization or coagulation of milk.
There are some differences in terms of not being sensitive, etc., but oh
This is consistent with the properties of Bacillus pumilus. death
Therefore, this bacterium was classified as a member of the Bacillus pumilus family.
It was determined to be a bacterial strain, but there is no known identical strain.
Therefore, I named it Bacillus pumilus AI-77.
This strain has been deposited at the Institute of Microbial Technology, Agency of Industrial Science and Technology.
Deposited under No. 4066. The present invention
All about Bacillus pumilus AI-77 strains
Among the natural and artificial mutant strains of AI-77,
Any productive strain can be used. By culturing AI-77-B in the method of the present invention,
The production process and the collection process from the culture are described below.
It is implemented by using the following means. That is,
AI-77-B requires its producing bacteria.
Incubate aerobically in a culture medium containing nutrients for a specified period of time.
AI-
77-Using the physical and chemical properties of B, the culture solution or
They are collected using a combination of various purification methods. Nutrient sources used in fermentation include carbon sources and nitrogen sources.
Raw materials, inorganic salts, and other vitamins as needed
amino acids, and various nutrients necessary for the growth of the bacteria used.
Nutrient factors are used. For example, carbon sources include
lucose, sucrose, fructose, man
Nitholes, organic acids, molasses, starches, glycerin, etc.
Examples of nitrogen sources include corn, stew,
Liquor, soybean flour, Huamamedia, yeast extract,
Meat extract, protein hydrolysis such as peptone and casamino acids
substances, amino acids, ammonium salts, and inorganic salts.
For example, sodium, potassium, calcium
Metal ions such as aluminum, magnesium and iron, ammonia
ion, phosphoric acid, sulfuric acid, chlorine, carboxylic acid, etc.
Salt containing salt is used. Necessary for the growth of production bacteria
Essential nutritional elements must also be included in the medium and
Mins, amino acids, and nucleic acid-related elements as necessary.
added. AI-77-B producing bacteria grow under various conditions.
For example, this microorganism has a wide range of initial PH
Can grow on a variety of media. However, once fermentation starts
The pH of the medium used is 6 to 8, preferably 6 to 7, and
In general, the pH of the culture medium changes somewhat as the microorganisms grow.
move. Culture temperature is 25-40℃ aerobically for 60 hours.
It will run for 96 hours. The AI-77-producing bacteria of the present invention are grown on an agar slant and shaken.
2) In a flask, medium or large fermentation tank
Can be cultured. For mass production, aeration and stirring are recommended.
Fermentation conditions are preferred. Aerobic culture conditions with aeration and agitation
In this case, silicone, polypropylene glycol derivatives
AI-77 Adding antifoaming agents such as conductors to the culture medium
- May be effective in increasing the amount of B component accumulated
be. Production amount of AI-77-B regarding the progress of fermentation
is the increase in ultraviolet absorption at 314 mμ of the culture medium.
It can be tracked by. AI-77-B produced under aerobic fermentation conditions is
Mainly utilizes the physical and chemical properties of each fermentation medium
ion exchange resin, macroreticular resin, gel
Chromatography and solvent extraction using filter agents, adsorbents, etc.
can be isolated in combination. i.e. aerobically
The culture solution cultured for 48 to 96 hours is made into macroreticular resin,
For example, Rohm and Haas Amberly
XAD-2 or XAD-4 or manufactured by Mitsubishi Chemical
Adsorbed to Diaion HP- system, water and organic
Elute using a solvent or a mixture of both.
As an organic solvent, C, which has a particular affinity with water,₁~
C_Fouralcohols, acetone, dioxane, and
Trahydrofuran and the like can be used. example
For example, AI may be caused by water containing 30% or more methanol.
-77-B is detached from the macroreticular resin XAD-2.
When this eluent is concentrated under reduced pressure, the AI
-77-A rough sample of B is obtained. Macro reticular resin
By repeated purification with hot water or
purity by recrystallizing from methanol.
You can obtain crystals of high AI-77-B. Next, general formula [a] and AI-77-F and general
The method for synthesizing the compound of formula [] will be explained. The following ~ is a compound represented by general formula [a]
compound (in the formula, R₁,R₂,R_Fouris the same as above)
It is. R in general formula [a]₁and R₂is H and R_Fourbut
Compound [a-1] which is RCO- is the above-mentioned
AI-77-B is acylated by a general acylation method.
The product is obtained by combining raw materials and raw materials.
Ultraviolet absorption, infrared absorption, NMR, mass of the composition
This can be confirmed by comparing analytical methods. This confirmation method is
It is also used in subsequent synthetic methods. Representative acyl
The conversion method uses acid anhydrides [(RCO)₂O] or acid salt
How to acylate with loride (RCOCl), also
or an acid (RCOOH) and a dehydration condensation agent (e.g.
cyclohexylcarbodiimide, etc.)
Silify. Increase the amount of acylating agent added by 1 to 2 times.
By carrying out the reaction at 0 to 25°C,
R_FourAcyl groups can be introduced with high selectivity into
Wear. In general formula [a], R₁is H and R₂but
RCO-, R_Fouris RCO- [a-
2] is the above [a-1] in a pyridine solvent.
Excess (3 to 20 times mole relative to [a-1]) acid
Anhydrous [(RCO)₂O] and Rui as a catalyst.
By reacting with sulfuric acid at 25-80℃
can get. Using acid chloride as an acylating agent
If so, for [a-1] in pyridine solvent
using 1 to 5 times the molar amount of acid chloride,
Carry out the reaction at room temperature to 40°C. R in general formula [a]₁is RCO-, and R₂is RCO
-So, R_FourCompound [a-3] where is RCO-
is a stronger acylation of the above [a-2]
acylation by a method, i.e., the above-mentioned [a
-2] with pyridine or tertiary amine
1 to 30 times the molar amount of acid in a tonic solvent at 40 to 100℃
Anhydrous [(RCO)₂O] or acid chloride
(RCOCl). A compound of general formula [a] as shown in ~
R of₁,R₂,R_FourIntroducing an acyl group into
The response speed is R_Fouris the largest, followed by R₂,R₁in the order of
Each can be introduced with high selectivity. R in general formula [a]₁is RCO―, and R₂is H,
R_Fouris RCO-, the compound [a-4] is
Preferably, the compound [a-1] is in an inert solvent.
or aprotic polar solvent and pyridine or
Carbobenzooxylic dissolved in tertiary amine
Add 1.5 to 15 moles of loride to room temperature to 80℃
Highly selective and alcoholic by reacting with
Carbon benzoxy group can be introduced into OH group.
Ru. The resulting compounds were subjected to common acylation methods, e.g.
For example, excess (1 to 30 times the mole) of acid anhydride
[(RCO)₂O] with pyridine or tertiary amine
The reaction is carried out at 40-100°C in an aprotic solvent.
Carbon base
Remove the nzoxy group to form compound [a-4]
obtain. R in general formula [a]₁is R′ or -CH₂In R,
R₂is H and R_Fouris RCO- [a-
5] is a case where the above [a-1] is an inert solvent.
Dissolved in a solvent with a small amount of alcohol added.
and excess diazo compound (R′N₂)or
(RCH₂N₂) to form phenolic -OH
Highly selective R′ group or RCH without contacting the group₂basis
can be introduced. The diazo compounds used in the present invention are known from the literature.
Organic functional group
preparations, academic press, New york
and London, 1968P388-407). Also in the present invention
Required R′N₂or RCH₂N₂Other compounds of
can be produced in a similar manner. R in general formula [a]₁is R′ or -CH₂In R,
R₂is RCO, R_Fouris RCO [a-
6] is the compound of [a-2] above with diazo
Compound (R′N₂) in the same manner as above.
Possibly, the above compound [a-5] is
It can be obtained by converting it into a file. R in general formula [a]₁is R′ or -CH₂In R,
R₂is R′ or -CH₂R, R_Fouris an RCO
Compound [a-7] is the compound of [a-5] above.
diazo compound (R′N₂) or RCH₂N₂and
Adding a catalyst (boron fluoride etherate)
By this, an alkyl group is added to the alcoholic -OH group.
Introduce and synthesize. As shown in the above [a-1]
The compound is converted into a diazo compound (R′N₂)or
RCH₂N₂only, the phenolic-OH group is first
Alkyl groups are introduced with high selectivity, and then the catalyst
(Fluorinated hocarium etherate) should be used together.
By adding an alkyl group to the alcoholic -OH group,
can be introduced. General formula [a] is R₁is H,R₂is R′ or
RCH₂,R_Fouris RCO- [a-8]
is described from the compound [a-1] above.
Using phenyldiazomethane,
Benzyl group as a protecting group on phenolic OH group
and alcohol using the reaction shown in
After introducing an alkyl group into the OH group, general contact is performed.
By removing the benzyl group by catalytic reduction method,
can be synthesized. R in general formula [a]₁is RCO―, R₂is R′ also
is RCH₂,R_Fouris RCO- [a-
9] is the reaction of the compound [a-8] above.
Acylate the phenolic OH group in the same way as for
It can be synthesized by R in general formula [a]₁is H,R₂is RCO, R_Fourbut
Compound H [a-10] is synthesized as follows.
It will be done. In other words, AI-77-B is added to 2 to 3 times the molar amount of car
Presence of bobenzooxychloride and tertiary amines
When reacted at room temperature below, R_Fouris Rh-CH₂―
It becomes OOC. This compound is the same as shown in
The alcoholic OH group is acylated in the same manner as R₁
is H, R₂is PCO―, R_Fouris Ph-CH₂-OOC-
Then, by catalytic reduction of this [
a-10]. R in general formula [a]₁is RCO―, R_Fouris RCO
―、R_FourThe compound [a-11] where is H is as follows.
Synthesized by sea urchins. In the reaction above, R₁is H, R₂is RCO―, R_Four
is Ph-CH₂-OOC-
R as shown₁is acylated, then this
It can be obtained by catalytic reduction of this. R in general formula [a]₁G-COR, R₂is H, R_Four
The synthesis method of compound [a-12] where is H is as follows.
It can be synthesized by the following method. That is, the first method is
AI-77-B and 5 to 30 times the molar amount of carbon benzo
Oxychloride in the presence of tertiary amine at room temperature
When reacted at ~80℃, R₂and R_FourToga
[Formula] becomes. This was shown in Similarly R₁is acylated and then catalytically reduced.
It is a target compound. The second method is AI-77-B
5 to 30 times more trichloroacetyl chloride.
react at room temperature to 80°C in the presence of a tertiary amine.
Let me, R₁is H, R₂Ga-COCCl₃,R_Fourbut-
COCCl₃If we obtain a compound of and show this as
Similarly, R₁After converting to -COR, add alkali to
Use an appropriately selected PH range between PH8 and 12.
Hydrolysis is carried out at room temperature for 2 to 24 hours while maintaining
cormorant. Then, the lactonization conditions shown below are applied.
According to this, we acidified and distilled off the solvent.
From this, the compound [a-12] can be synthesized. R in general formula [a]₁is R′ or RCH₂,R₂
is H, R_FourThe compound [a-13] where is H is, for example,
According to the reaction from AI-77-B, R_Fourof-
COCCl₃and according to the reaction in R₁of
R', and the resulting compound is the second compound described above.
Reaction steps alkaline hydrolysis method, lactonization
obtained by reacting according to the method
Ru. R in general formula [a]₁is R′ or RCH₂,R₂
is RCO―, R_FourThe compound [a-14] where is H is,
It can be synthesized using one of the following methods. The first method is to R₂
-COCCl₃and R in the following way₂RCO-
and R in the following way₁R′ or RCH₂year
R obtained by₁is R′ or RCH₂,R₂is RCO-,
R_Fouris Cl₃Synthesize a compound of CCO― and use the same method as above.
Similarly, it undergoes alkaline hydrolysis and lactonization.
target compound. The second method is
R obtained during the reaction of₁is H, R₂is RCO-,
R_Fouris Ph-CH₂-OOC-
R in the way₁R′ or RC₂After contacting
The target compound can be obtained by performing an elimination reaction at
This is a method to R in general formula [a]₁is R′ or RCH₂,F₂but
R′ or RCH₂,R_Fouris H [a-
15] is, for example, a reaction from AI-77-B.
Each other_Four-COCCl₃and for the next reaction
Follow R₁R′ or RCH₂and the anti-
Depending on the R₂R′ or RCH₂and the obtained value
Mix the compound with an alkali at a pH of 8 to 12 as appropriate.
Room for 2-24 hours while maintaining selected PH range
Hydrolysis is carried out at warm temperatures. Then, click the label shown below.
According to the conditions of chthonization, make the solvent acidic and remove the solvent.
Compound [a-15] is obtained by distillation.
It will be done. R in general formula [a]₁is H, R₂is R′ or
RCH₂,R_FourThe compound [a-16] where is H is,
It can be synthesized as follows. first
The method is to add AI-77-B to 2 to 3 times the molar amount of carbs.
In the presence of benzoxychloride and tertiary amine
react at room temperature, R_FourPh―CH₂-OOC-
and then add an excess of phenyldiazomethane to this
Add amount R₁Introducing a benzyl group into
Diazo compound (R′N₂) or (RCH₂N₂)of
Reacted in the presence of boron fluoride etherate
Se, R₂R′ or RCH₂and then catalytic reduction
to separate the benzyl group and carbobenzoxyl group.
The target compound is obtained by removing the compound. The second method is before
R according to the method described₁and R_Fourtogether
lychloroacetylation, then boron fluoride
diazo compound (R′N₂)
or (RCH₂N₂) to react with R₂R'ma
Or RCH₂After that, it is hydrolyzed with alkali and
This is a method to make it a target compound. R in general formula (a)₁is RCO―, R₂is R′ also
is RCH₂,R_FourCompound where is H [a-17]
can be synthesized by the following method. The first method is before
R by the method described below.₁is RCO―, R₂is R′ or
RCH₂,R_FourGa-COCCl₃Synthesize a compound that is
As shown in , it is easily hydrolyzed with alkali.
The target compound can be synthesized by toning.
Ru. The second method is the compound of [a-16] above.
2 to 3 times the mole of carbenzooxychloride
react at room temperature in the presence of a tertiary amine with
R_Fouris a carbobenzooxyl group, and then
R using the method shown in₁is an acyl group, and then
The carbobenzooxyl group is eliminated by catalytic reduction.
The target compound is synthesized. R in general formula [a]₁is H and R₂is H and R_Four
G-CH₂The compound [a-18] which is R is the above-mentioned
It can be synthesized from the compound [a-1]. Dissolve the compound [a-1] in dichloromethane
When dissolved or dispersed, triethyloxonium
Tetrafluoroborate solution in dichloromethane
Add 1 to 2 times the mole of and leave at room temperature for 1 hour to 24 hours.
When reacting for a time, R_FourHighly selective for the amide part of
It is possible to create iminoethers with selectivity.
Wear. Solvent without isolation or isolation
from dichloromethane to dry ethanol
and added triethyloxonium tetraflu
1 to 3 times the mole relative to oroborate, preferably
is 1.5 to 2 times the mole of sodium boron hydride
Add the mineral under ice-cooling and react for 5 to 30 minutes.
Compound [a-18] by acidifying with acid
Can synthesize things. In this reaction, [a-1] and triethyloxo
In the reaction of nium tetrafluoroborate
Despite the presence of two amide groups, the above
Under the conditions - high selectivity for the amide group of NHCOR
It's amazing what can be made to react
That's true. Also, phenolic-OH groups and alkaline
Call property - introduction of protective group for OH group is also required
It turns out that this is not the case. R in general formula [a]_Fouris R-CH₂- then
Other compounds [a-19] to [a-26]
are respectively R₁and R₂is the same as the target compound.
R, R_FourCompound [a-2] where is RCO-
From [a-9], via the same reaction as above
can be synthesized by 【table】 R in general formula [a]₁is H, R₂is H, R_Fourbut
The compound [a-27] which is R′ can be prepared by the following method.
But it can be synthesized. In other words, AI-77-B is a non-prototype.
polar solvents such as dimethylformamide,
Dissolved in dimethylacetamide, etc., 2.5 to 30 times
Mol RW (W means halogen, preferably
means an iodo group) and incubate at 0 to 70℃.
If you do this, you will get [a-27]. R in general formula [a]_FourOther compounds where is R
is synthesized in the same way as . That is, the following compounds [a-28] to [a-
35] are each R₁and R₂is the same as the target compound
and R_FourCompound [a-10] where is H
Synthesized from [a-17]. 【table】 Next, AI-77-B to AI-77-F (applicable)
and a compound represented by general formula [a] [wherein
R₁,R₂is the same as above (〓〓 is applicable)]
I will write it down. AI-77-F is AI-77-B and aluminum halide
Killing is facilitated by heating in polar solvents.
can get. AI-77-B is a polar solvent, for example,
N,N-dimethylformamide, N,N-dimethylformamide
tylacetamide, N-methylpyrrolidone,
Dissolved in hexamethylphosphorotriamide etc.
Suspended and alkyl halides, e.g.
Methyl chloride, ethyl iodide, etc. in excess water, AI-77
-Add 10 to 100 times equivalent to B and heat from room temperature to 70℃
Obtained by overnight reaction. reaction is high
Tracking using fast liquid chromatography, thin layer chromatography, etc.
Wear. After the reaction is completed, it is adsorbed to the macroreticular resin.
After washing thoroughly with water, add a water-compatible organic solvent as appropriate.
For example, methanol, tetrahydrofuran
Obtained by desorption and concentration. 〓〓 In general formula [a], R₁is H and R₂but
Compound [a-1] which is RCO- is AI-77
-R from F using the method shown above₂RCO- and
By doing so, R₁is RCO―, and R₂Compounds where is RCO-
[a-2] is the above from [a-1]
R using the method shown in₁By acylating, R₁is RCO―, and R₂is H [a
-3] is the above synthesis rule from AI-77-F.
Similarly to the reaction in₁to acylate
According to R₁is R′ or RCH₂So, R₂Compound with H
[a-4] is the same reaction as from AI-77-F.
React in the same manner using the reaction route, and R₁R′ or
RCH₂By doing so, R₁is R′ or RCH₂So, R₂is the combination of RCO-
Item [a-5] is the same as the above [a-1].
It reacts with diazo compounds using the same reaction route as
Se, R₁R′ or RCH₂By doing so, R₁is R′ or RCH₂So, R₂is R′ or RCH₂
The compound [a-6] is the above [a-
4] was reacted in the same manner as shown above, and R₂
R′ or RCH₂By doing so, R₁is H and R₂is R′ or RCH₂compound that is
Item [a-7] is from AI-77-F as above.
React as shown, R₂R′ or RCH₂
By doing so, R₁is RCO and R₂is R′ or RCH₂compound that is
Item [a-8] is from [a-7] above.
How to R₁By acylating the respective
can be synthesized. The 5-membered ring in the above general formula [a]
Regarding tons, the general formula [b] is as follows: (In the formula, R₁,R₂,R_Fouris the same as above. ) Mutual conversion can easily occur between the two. That is, general
The compound of formula [a] is a compound of general formula [b]
Organic solvents used to dry things, such as alcohols,
Dissolved in tetrahydrofuran etc. to make it acidic
After that, by distilling off the solvent, the amino acid of [a]
Obtained as salt. Dissolve the salt in an organic solvent
Wash with sodium bicarbonate solution and dry the organic solvent.
is obtained as the free amine of [a].
The compound of general formula [b] is the compound of general formula [a]
Reduce the pH of the compound to 9 or less with a weak alkali in the presence of water.
After maintaining and opening the 5-membered ring lactone, neutralize it.
It is obtained by drying the solvent. Two states [a] in each compound and
Regarding [b], regarding the [a] type compound group,
Roman numerals representing compound groups and B
[a] is added to the [b] type compound group.
In this case, [b] is added. 〓〓 Final reaction obtained by the reactions from above to 〓〓
If you wish to further refine something, please do the following:
Purification methods can be applied. After concentrating the final reaction solution of ~〓〓 reaction, it is diluted with chloride water.
Dry methanol or dry
Dissolve in dry ethanol and concentrate to dryness.
After repeating several times to form the lactone form of general formula a,
Macro reticular resin, such as XAD-2
Adsorb onto the column and use water or water as the elution solvent.
A compatible organic solvent, preferably methanol
alcohol, ethanol, propanol, isopropanol
alcohol, tetrahydrofuran, etc. or water and them.
By performing chromatography using a mixed solvent of
The target product can be purified. Table 3 shows that AI-
Shown by the general formula [] synthesized from 77-B
Amide intermediates [general formulas [a] and [a]]
A typical example is shown below. 【table】 【table】 【table】 【table】 【table】
\

a−1−48 H
H
CHCH₂C.O.

/


CH<sub>3


CH3(CH
2)3CH2COO


\
a−1−49 H
H
CHCH2C.O.


/


CH3
【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】

\
a−5−42 〃
〃
CHCH2C.O.


/


CH3
a−5−43 〃
〃CH
3SCH2C.O.
a−5−44 〃
〃CH
3(CH2)3CH2SCH2C.O.
【table】
\
/
a−5−53 〃
〃
C＝C

/
\

H
C.O.
【table】 【table】
\
／ ＼

C
＝CH

/
\

CH3
H



a−5−66 〃
H







a−5−67 〃
〃




【table】 【table】 【table】 【table】 【table】 ／ ＼
CH3 H
CH3CH2CH(CH2)4CH2
a−5−110 ｜
H
〃
CH3


a−5−111
H
〃




a−5−112
H
〃




a−5−113
H
〃

【table】 \
a−5−121 CH
H CH3
(CH2)2C.O.
/
CH3
【table】
\
a−6−7 CH3CH2
〃
CHCH2C.O.

/

CH3
【table】 【table】 \
a−7−15 CHCH2CH2
CH3
〃
/
CH3
a−7−16 CH3(CH2)2CH2
CH3
CH3C.O.
【table】 【table】
／ ＼

CH3 C.O.
【table】 【table】 【table】 【table】 \
a−13−26 CHCH2CH2
H H
/
CH3
CH3COO
\
a−13−27 CHCH2CH2
H H
/
CH3
【table】 /
CH3
【table】 \
a−13−41 CH
H H
/
CH3
a−14−1 CH3CH2
CH3CO H
a−14−2 〃
(CH3)2CHCO H
a−14−3 〃
CH3(CH2)16C.O.
H

HC(CH2)7CH3
a−14−4 〃
‖H

HC(CH2)7C.O.
【table】 \
a−15−6 CHCH2CH2
〃H
/
CH3


a−15−7
〃H

【table】 /
CH3
a−17−5 CH3CH2C.O.
CH3 H
a−17−6 CCl3C.O.
CH3CH2 H
a−18−1 H
H CH3
CH2
a−18−2 H
H CH3
CH2CH2
a−18−3 H
H CH3
(CH2)2CH2
a−18−4 H
H (CH
3)2CHCH2
a−18−5 H
H (CH
3)2CHCH2CH2
【table】 【table】 【table】 【table】
\

a−18−42 H
H
CHCH2CH2

/


CH3


CH3(CH
2)3CH2COO


\
a−18−43 H
H
CHCH2CH2


/


CH3



a−18−44 H
H




【table】 【table】
/

CH3
【table】 【table】
\
a−19−6 H
〃
CHCH2CH2

/

CH3
【table】 【table】 【table】 【table】 【table】 【table】

\
a−22−44 〃
H
CHCH2CH2


/


CH3



a−22−45 〃
H







a−22−46 〃
H




【table】 【table】

/


｜CH2CH2C＝C
a−22−62 〃
H
／ ＼

CH3
CH2CH2C＝C H

\
／ ＼

C
＝CH

/
\

CH3
H
【table】 【table】 【table】 【table】 /
CH3
CH3COO
\
a−22−100 CHCH2CH2
H
〃
/
CH3
CH3(CH2)3CH2COO
\
a−22−101 CHCH2CH2
H
〃
/
CH3
【table】 /
CH3
CH3

CH3 ｜
CH2CH2CH2
/
｜CH2CH2C＝C
a−22−109 / ＼
H
〃
CH3 CH2CH2C＝C
H
＼／＼
C＝C H
／ ＼
CH3 H
【table】
/

CH3
a−23−3 〃
〃CH
3(CH2)16CH2

HC(CH2)
7CH3
a−23−4 〃
〃
‖

HC(CH2)
7CH2



a−23−5 CH3(CH2)16CH2
〃




【table】 【table】 \
a−24−15 CHCH2CH2
CH3
CH3CH2CH2CH2
/
CH3
a−24−16 CH3(CH2)2CH2
CH3
CH3CH2
【table】 【table】
\
a−28−5 H
CH3(CH2)16C.O.
CH

/

CH3
a−29−1 CH3C.O.
CH3CO CH
3

CH3

\
a−29−2 CH3C.O.
CH3C.O.
CH

/

CH3
a−30−1 CH3C.O.
H CH
3

CH3

\
a−30−2 (CH3)2CHCO
H
CH

/

CH3
【table】 【table】
\
a−35−2 〃
〃
CH

/

CH3
a−1−1 H
CH3C.O.
a−1−2 H
CH3CH2C.O.
a−1−3 H
CH3(CH2)2C.O.
a−1−4 H
(CH3)2CHCO
a−1−5 H
(CH3)2CHCH2C.O.
a−1−6 H
CH3(CH2)3C.O.
a−1−7 H
CH3(CH2)4C.O.
a−1−8 H
CH3(CH2)5C.O.
【table】 【table】 【table】 【table】
\
a−1−42 H
CHCH2C.O.

/

CH3
【table】 【table】 【table】
/

｜CH2CH2C＝C
a−1−67 H
／ ＼

CH3 CH2CH2C＝C H

＼／＼

C＝C H

／ ＼

CH3 H
【table】 【table】
｜

CH3
a−2−1 CH3C.O.
CH3C.O.
a−2−2 CH3CH2C.O.
〃
【table】 ／ ＼
CH3 C.O.


a−3−15
H

【table】 【table】 【table】 /
CH3
CH3COO
\
a−4−27 CHCH2CH2
H
/
CH3
CH3(CH2)3CH2COO
\
a−4−28 CHCH2CH2
H
/
CH3
【table】 /
CH3
CH3

CH3 ｜
CH2CH2CH2
/
｜CH2CH2C＝C
a−4−36 / ＼
H
CH3 CH2CH2C＝C
H
＼／＼
C＝C H
／ ＼
CH3 H
【table】 【table】 Compounds of general formula [a] represented in Table 3
Using as a raw material, prepare a compound of the general formula [] below.
[R in the formula1,R2,R3,RFouris the same as above)
We will explain how to do this. 〓〓 Compound of general formula [a] and ammonia or
is a dry primary amine (NH2R3) is used as raw material.
1.5 to 100 times for free amines and 2.5 times for salts
In order to react ~100 times the mole, amines are
In the case of solutions, the reagent is used as a solvent, and gas or solid
In the case of a body, a non-containing
Protic solvents and alcohols in some cases.
By stirring for 1 to 72 hours at 0 to 30℃ using
General reaction of amines to 5-membered ring lactone
A compound of formula [] is obtained. 〓〓 Under the same reaction conditions as 〓〓, an aprotic solvent is used as the solvent.
A polar solvent such as dimethylformamide,
Using dimethyl sulfoxide etc.
The compound of general formula [] is obtained from the compound of a]
It will be done. Compounds of general formulas [] and [] are combined with a weak alkali.
Hydrolysis of a 6-membered ring lactone in a solution of
Compounds can also be obtained. A group of compounds obtained by the above reaction 〓〓〓〓
and their corresponding raw material groups are shown below. 【table】 【table】 【table】 【table】 Table 4 shows compounds synthesized by the method described above.
Representative examples are shown below, but as mentioned above, these compounds
shows remarkable medicinal efficacy. According to the method described below in Table 4.
The ulcer-inhibiting effects of the representative compounds tested are listed below.
Ru. The drug efficacy test was conducted as follows. 1 Anti-ulcer test Rat (Wistar, male, weight around 150g)
The subjects were fasted for 24 hours before the start of the test. physiological food
A given concentration of test compound using saline as a solvent.
Prepare a solution or suspension of
administered. One hour after drug administration, the rats were placed in a wire mesh cage.
Fix the body and place it in a water tank at 21℃ up to the xiphoid bone.
Soaked for an hour. Animals were sacrificed by cervical vertebrae
After that, the stomach is removed and an incision is made along the greater bay to expose the inner wall of the stomach.
An autopsy was performed. Almost no ulcers are observed.
0.5, 1, depending on the degree of ulcer occurrence.
I scored 2 and 3. Ulcer suppression from the formula below
The rate was calculated. Ulcer control rate (%) = 100 - total scores of drug-administered animal groups
Sum/sum of scores of drug-free animal groups x 100 Table 4 shows each compound at 25mg/Kg and 50mg/Kg.
This shows the ulcer suppression rate when administered intraperitoneally. 【table】 【table】 【table】
\

−1−25 H H
H CHCH2CH2
94

/


CH3


CH3(CH2)4
O

\

−1−26 H H
H CHCH
2CH2 89

/


CH3

【table】 【table】
\

−1−41 H H
H CH
94

/


CH3

【table】 \ /
−2−3 H C=C
H H
78
／ ＼


H CO


【table】 【table】 \
−9−5 CHCH2CH2
〃H H
78
/


CH3


−10−1 H H
CH3CH2CH2
H
94
【table】 【table】
\

−15−2 CH3CH2
〃 CHCH2CH2
H
50

/


CH3




−15−3 CH3CH2C
H2CO CH3CH2CH2CH2
H
50



−15−4 CH3 CH3CH2C.O.
CH3CH2 CH
3CH2 44

【table】
/

CH3



−19−3 H H
〃

66



−20−1 H CH3C.O.
CH3
H
89
【table】
\

−22−2 (CH3)2CHCO H
CH H
66

/


CH3

−23−1 CH3CH2 H
CH3
H
89
−23−2 〃H
〃
CH2(CH2)2CH2 66




−23−3 〃H
〃
66



【table】
\

−25−2 〃 CH3(CH2
)2CH CH H
56

/


CH3

−25−3 CH3(CH2)2CH2 CH3(CH2)
2CH2 CH3
H
56
−26−1 H CH3
CH3
H
89

CH3


\

−26−2 H CH3
(CH2)17 CH
H56


/


CH3

【table】 【table】 ／ ＼

H CO

【table】 Preferred compounds of the present invention in terms of anti-ulcer properties
is the general formula [-1], [-10], [-19]
This is the group of compounds shown. Examples of the present invention will be described below. Example 1 Bacillus pumilus AI-77 on plain agar slope
The cells were inoculated and cultured at 30°C for 1 day to serve as a seed culture. 500ml
Pour 100 ml of the following nutrient medium into a shoulder shake flask.
I did. Inoculate this with the above inoculum and leave it at 30℃ for 1 day.
Cultured with repeated shaking. This cultured bacterial cell was prepared in the following example.
It was used as an inoculum in 2. Glucose 1.0% Polypeptone 1.0 Meat extract 0.5 NaCl 0.5 Antifoaming agent KF-96 (manufactured by Shin-Etsu Chemical Co., Ltd.) 0.1 Example 2 Example 1 for a jar furnace with a capacity of 20
Prepare 10 of the used culture medium and incubate with the inoculum from Example 1.
500ml inoculation, aeration rate 0.5V/V/m, stirring number
The cells were cultured at 30°C for 1 day at 300 rpm. Inoculum this 7
A volume of 200 cells containing 125 medium of the same composition was prepared.
Inoculate the fermentation tank, air permeability 0.5V/V/m, stir.
The cells were cultured at 30°C for 18 hours at a stirring speed of 300 rpm.
Using this as a seed culture, a medium with the same composition as in Example 3
2.5m³Contents: 5m³Seeds are placed in the fermentation tank of
The entire amount of bacteria was inoculated. Air flow rate 0.5V/V/m, stirring
The cells were cultured at 30° C. for 4 days with a stirring speed of 170 rpm. Cultivation
After culturing, the culture solution is packed with hollow fiber ultrafiltration.
It was made into a liquid using a vacuum cleaner and filled with 130
The first column was run down. 2.6m³10% methanol
After washing the column with an aqueous solution of 30% methanol,
Aqueous solution 2.6m³was allowed to flow down to elute component B. detachment
Continuously mix an equal amount of water with the liquid,
2 Flow down the second column packed with 80 to form B.
was adsorbed onto the column again. 20% methanol water
solution 1.6m³After washing with 100% methanol
Component B was eluted at 180 ml. methanol eluate
Upon concentration, 650 g of the tetrahydrate salt of component B was obtained.
The specimen obtained here was analyzed using high performance liquid chromatography.
Purity test showed 98% purity. This crystal is
It was washed with setonitrile and air dried. further this
Dry over phosphorous pentoxide under reduced pressure at 60°C for 6 hours.
showed the physical and chemical properties mentioned above. Example 3 Put 30g of AI-77-B into a glass pressure-resistant container,
Dissolve in 150ml of DMF. Add 300ml of methyl iodide,
Shake overnight at 50°C. DMF and excess iodination
After distilling off the methyl under reduced pressure, add 50ml of methanol and water.
Dissolve Amberlite XAD in 50ml of mixed solvent.
Flow down a column packed with 2-2. column
After thoroughly washing with 50% methanol and 50% water,
% methanol-water (containing 10% 1N-hydrochloric acid)
When eluted and concentrated, 20g of AI-77-F was obtained as a white solid.
Obtained as a crystalline precipitate. P this2OFiveAbove 50℃
If dried under reduced pressure overnight, the above-mentioned AI-77
- Showed the physical and chemical properties of F. Example 4 8.48 g of thoroughly dried AI-77-B 20 mmol
Dissolved in 36 ml of pyridine and 40 ml of acetic anhydride at room temperature.
Add 4.08 g of mole dropwise and stir for 3 hours. reaction is weak
Layer chromatography (e.g. Merck & Co.
TLC5714 developing solvent chloroform: methanol =
10:1). Pyridine was distilled off under reduced pressure.
Afterwards, wash the residue twice with 50 ml of water, for a total of 100 ml of water.
do. This residual sorcery is dissolved in water-methanol solvent (water 50%).
Dissolved in methanol 50%), Amberlite
Flow down a column packed with one layer of XAD-2.
After washing the column with 5 parts water, methanol 85% water 15 parts
% solvent system was collected, concentrated and dried.
Then, 7.5 g of the target product a-1 was obtained. IR, UV,
From NMR spectrum and Mass spectrum, purpose
It was identified as a compound. In the following examples, the same method was used to identify
Ta. Example 5 Pipulate 30 g of thoroughly dried AI-77-B71 mmol.
142 mmol of caprylic anhydride dissolved in 500 ml of lysine
Add 38.2g of water at room temperature. Stir at room temperature for 3 hours.
After that, pyridine is distilled off under reduced pressure. This dry matter
Dissolved in 400ml of methanol and saturated methanol with hydrochloric acid
Set the pH to 1. This is concentrated to dryness under reduced pressure. difference
Furthermore, dissolve this in 200ml of methanol and dilute to 1N.
Bring the pH to 5 with sodium hydroxide solution. This solution
Leave it at -20℃ overnight and separate the formed precipitate.
Ru. The separated precipitate was mixed with water-methanol solvent (water 50%
%, methanol 50%), amber light
Flow down a column filled with three times XAD-2.
After washing the column with 15% water, methanol 85% water 15%
% solvent system, collect the effluent fraction, concentrate and dry.
Then, 29, 78 g of the target product a-1-9 was obtained. Example 6 2.1 g of thoroughly dried AI-77-B4.95 mmol
Stearic anhydride dissolved in 25 ml of pyridine at room temperature
Add 3.3 g of 6 mmol and stir at room temperature for 4 hours.
After distilling off the pyridine under reduced pressure, add 100 ml of water.
Separate the resulting precipitate and dry thoroughly. This solid
Wash the item with 150ml of hexane three times, totaling 450ml.
Ru. Dissolve this in 150ml of chloroform and
Add 330 mg of luenesulfonic acid and stir for 2 hours.
Add 100ml of water to this, separate the liquids, and remove the chloroform layer.
Take it out, dry it with mirabilite, separate the mirabilite, and dry it with chlorine.
Concentrate the loform layer to obtain the target a-1-11, 2.29
I got g. Example 7 Thoroughly dried AI-77-B18.9 mmol 8.01g
Dissolve in 30 ml of pyridine and add isobutyric anhydride at room temperature.
Add 37.8 mmol 5.97 g and stir at room temperature for 3 hours.
Ru. After distilling off the pyridine under reduced pressure, add 400ml of water.
I can do it. Separate the resulting precipitate and dry thoroughly. child
Dissolve this in 80 ml of tetrahydrofuran and cool at room temperature.
-Add 900mg of toluenesulfonic acid and stir for 1 hour and 30 minutes.
Stir. The solvent was removed under reduced pressure and the residue
Dissolve in 200ml of form, add 300ml of water and separate.
Remove the chloroform layer, dry it with Glauber's salt,
Separate and concentrate the chloroform layer to obtain the target product a.
-1-4, 8.52g was obtained. Example 8 5g of thoroughly dried AI-77-B11.8 mmol
Dissolve trichloroacetyl in 20ml of pyridine and cool on ice.
Add 2.19 g of 12 mmol of chloride and cool on ice for 4 hours.
Stir for an hour. After distilling off the pyridine under reduced pressure,
Dissolve in 2 ml of tanol and add this to 100 ml of ice water.
A powder is formed. After this, add 30ml of water.
Wash twice with a total of 60ml of water, dry and remove the object a-
1-12, 4.54g was obtained. Example 9 a-1-1.2 mmol synthesized in Example 4
into 4 ml of pyridine and add 30 ml of propionic anhydride.
Add limol. Add 20 mg of zinc chloride to this and
Stir at warm temperature for 2 hours. This reaction solution was poured into a large amount of ice water.
and separate the formed precipitate. Add 5ml of this
Wash twice with 10 ml of water. This precipitate
Water, tetrahydrofuran solvent (50% water, tetra
Amberlite suspended in hydrofuran 50%)
Flow down a column packed with 100 ml of XAD-2.
After washing the column with 500ml of water, add tetrahydrofura
Collect the spilled fraction with a solvent system of 70% water and 30% water.
Concentration yielded 700 mg of a-2-10. Example 10 a-1-12, 2 mmol synthesized in Example 8
into 5 ml of pyridine, add trichloroacetyl
Add 10 mmol of loride and stir at room temperature for 1 hour and 30 minutes.
Stir. Pour this reaction solution into a large amount of ice water to generate
Separate the precipitate. Add this twice with 10 ml of water.
Wash with 20ml of water. This precipitate is mixed with water and tetrahydrogen.
Dorofuran-based solvent (50% water, tetrahydrofuran
50%) and suspend Amberlite XAD-2 in
Flow down a column packed with 100 ml. 500 columns
After washing with ml water, 70% tetrahydrofuran, 30% water
% of the solvent system was collected and concentrated to a
-2-1,680 mg was obtained. Example 11 a-2-10, 1.5 mm synthesized in Example 9
Dissolve the solution in 4 ml of pyridine and add 20 ml of isobutyric anhydride.
Add moles dropwise and stir at 50°C for 4 hours. pyridine
After distilling off under reduced pressure, pour the residue into a large amount of ice water.
Ru. Wash this three times with 10ml of water, totaling 30ml of water.
and dilute the residue with water and tetrahydrofuran solvent (water 40%
%, tetrahydrofuran 60%), and
Flow through a column packed with 100ml of Burlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Area spilled with a solvent system of 70% hydrofuran and 30% water
The fractions were collected and concentrated to obtain a-3-2, 712 mg. Example 12 a-2-1, 1.5 mm synthesized in Example 10
Dissolve 20 mmol of acetic anhydride in 4 ml of pyridine.
was added dropwise and stirred at 5°C for 4 hours. Reduce pyridine
After distillation under pressure, the residue is poured into a large amount of ice water.
Wash this with 10 ml of water three times, a total of 30 ml of water, and
The residue was mixed with water, tetrahydrofuran solvent (40% water, tetrahydrofuran)
Suspended in trahydrofuran (60%), Amberla
Flow down a column filled with 100 ml of ItoXAD-2.
Ru. After washing the column with 500ml of water,
Collect the spilled sections with a solvent system of 70% furan and 30% water.
The mixture was concentrated to obtain 670 mg of a-3-10. Example 13 a-3-2,1 mmol synthesized in Example 11
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Excess sodium borohydride in gas-saturated ethanol
Decompose um. After drying this under reduced pressure, water,
Tetrahydrofuran solvent (40% water, tetrahydrofuran)
Amberlite suspended in Lofuran 60%)
Flow down a column filled with 70 ml of XAD-2.
After washing the column with 500ml of water, add tetrahydrofura
- The content of tetrahydrofuran was reduced to 10 in an aqueous solvent.
%, increase sequentially to 20%, and elute at 60%.
were collected and concentrated to obtain 150 mg of a-20-2. Example 14 a-2-10, 1.5 mm synthesized in Example 9
of diazomethane was dissolved in 10 ml of methylene chloride.
Add 15 mmol of ether solution and stir overnight at room temperature.
Ru. Excess diazomethane was removed with acetic acid, and the reaction solution was
Dry under reduced pressure. Dissolve the residue in water and tetrahydrofuran.
suspended in a solvent system (40% water, 60% tetrahydrofuran).
Make it cloudy and fill it with 100ml of Amberlight XAD-2.
flow down the column. Wash the column with 500ml of water.
After cleaning, remove tetrahydrofuran with a tetrahydrofuran-water solvent.
The content of hydrofuran was gradually increased to 10% and 20%.
Collect the fraction eluting at 60%, concentrate and a-
6-12,630mg was obtained. Example 15 a-6-12, 1 mmol synthesized in Example 14
was dissolved in 10 ml of methylene chloride under an argon atmosphere.
triethyloxonium fluoroborate 1.5
Add mmol and stir at room temperature for 4 hours. Methyl chloride
After distilling off the tyrene under reduced pressure, add 10 ml of absolute ethanol.
Add 2 mmol of sodium borohydride under ice cooling.
After stirring for 10 minutes, add hydrogen chloride gas saturated
Decompose excess sodium borohydride with tanol
do. After drying this under reduced pressure, water and tetrahydrohydride were added.
Lofuran solvent (40% water, 60% tetrahydrofuran
%) and suspended Amberlite XAD-2 in 60%
Flow down the column packed with ml. 300ml column
After washing with water, remove from tetrahydrofuran-water solvent.
The content of tetrahydrofuran was sequentially increased to 10% and 20%.
The fraction eluting at 60% was collected and concentrated.
85 mg of a-23-11 was obtained. Example 16 a-2-10, 1.5 mm synthesized in Example 9
Dissolve the solution in 10 ml of methylene chloride immediately after distillation, and
Triethyloxonium fluoro
Add 1.5 mmol of borate and stir at room temperature for 4 hours.
do. After removing methylene chloride under reduced pressure,
Add 10ml of alcohol and add sodium borohydride under ice cooling.
After stirring for 10 minutes, add 2 mmol of chloride water.
Excess sodium borohydride in saturated ethanol
decomposes lium. After drying this under reduced pressure,
Water, tetrahydrofuran solvent (40% water, tetra
Amberlite suspended in hydrofuran (60%)
Flow down a column filled with 70 ml of XAD-2.
After washing the column with 500ml of water, add tetrahydrofura
- A water-based solvent with a low tetrahydrofuran content.
Increase the concentration sequentially to 10% and 20%, and the area that elutes at 50%
The fractions were collected and concentrated to obtain 325 mg of a-19-9. Example 17 a-1-1.3 mmol synthesized in Example 4
Dissolve in 50ml of methanol and add diazobutane at room temperature.
Add 30 mmol of ether solution and stir overnight.
Ru. Excess diazobutane was removed with acetic acid, and after the reaction
Dry under reduced pressure. Add this to 5ml of methanol
Merck TLCPSC-Fertigplatten
KIESELGEL60F―254 (Art5717) 20cm×20cm×
Spot on 24 pieces of 2mm, methanol:chloroform
Developed in a 10:1 solvent system, Rf0.52 part (ultraviolet
(absorption, no fluorescence) is scraped off and collected to produce methane.
Add the mixture and stir for 30 minutes. separated from silica gel
After that, concentrate the methanol to a-5-3,800mg
I got it. Example 18 a-1-12.5 mmol synthesized in Example 8
A mixed solvent of 20 ml of methanol and 80 ml of chloroform
Dissolve with. Ether solution of diazoethane at room temperature
Add 30 mmol and stir for 1 hour. excess diazo
Ethane was removed with acetic acid and the solvent was evaporated under reduced pressure to leave a residue.
Transfer the residue to water-methanol solvent (50% water, methanol)
50%) and 300% of Amberlite XAD-2.
Flow down the column packed with ml. column 1
After washing with water, use a solvent system of 90% methanol and 10% water.
Collect the eluted portion, concentrate and dry, target product a
-5-13, 2.72g was obtained. Example 19 a-5-3.1 mmol synthesized in Example 17
Dissolve in 15 ml of methylene chloride and evaporate with diazomethane.
Add 1.2 mmol of ether solution and add 1.2 mmol of
Lifted boron ether complex (Wako Pure Chemical Industries) 0.5ml
Add and stir overnight. Remove excess diazomethane with vinegar
After removing with acid, pour the reaction solution into a large amount of ice water.
Separate the resulting precipitate. Do this twice with 5 ml of water.
Wash with a total of 10 ml of water, and dissolve the residue in water-tetrahydrof.
Lan-based solvent (40% water, 60% tetrahydrofuran)
Suspended in and filled with 70ml of Amberlite XAD-2.
flow down the column. Fill the column with 500ml of water.
After washing, dilute with tetrahydrofuran-water solvent.
Rahydrofuran content was gradually increased to 10% and 20%.
Collect the fraction eluting at 65%, concentrate and a
-7-16,632mg was obtained. Example 20 a-5-13, 1 mmol synthesized in Example 18
Dissolve diazopropane in 15 ml of methylene chloride and
Add 1.2 mmol of ether solution and immediately after distillation
Boron trifluoride ether complex (Wako Pure Chemical Industries) 0.5
ml and stir overnight. excess diazopropane
After removing with acetic acid, the reaction solution was placed in a large amount of ice water.
and separate the formed precipitate. Add this with 5ml of water.
Wash twice with a total of 10 ml of water, and remove the residue with water-tetrahydride.
Lofuran solvent (40% water, 60% tetrahydrofuran
%) and 70ml of Amberlite XAD-2.
Flow down the packed column. 500ml column
After washing with water, use a tetrahydrofuran-water solvent.
The content of tetrahydrofuran was increased sequentially to 10% and 20%.
The fraction eluting at 65% was collected and concentrated.
A-7-17, 670 mg was obtained. Example 21 a-7-16, 1 mmol synthesized in Example 19
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Gas saturated ethanol with excess sodium borohydride
decomposes lium. After drying this under reduced pressure,
Water, tetrahydrofuran solvent (40% water, tetra
Amberlite suspended in hydrofuran (60%)
Flow down a column filled with 70 ml of XAD-2.
After washing the column with 500ml of water, add tetrahydrofura
- A water-based solvent with a low tetrahydrofuran content.
Increase the concentration sequentially to 10% and 20%, and the area that elutes at 70%
The fractions were collected and concentrated to obtain 230 mg of a-24-16. Example 22 a-5- synthesized by the same method as Example 17
Add 5.4 mmol to 40 ml of freshly distilled methylene chloride.
Dissolve triethyloxoni under argon atmosphere
Add 6 mmol of fluoroborate and leave at room temperature.
Stir for 4 hours. Methylene chloride was distilled off under reduced pressure.
After that, add 40ml of absolute ethanol and heat the hydrogenated fluoride under ice cooling.
Add 2 mmol of sodium urethane and stir for 10 minutes.
After that, remove excess hydrogen with hydrogen chloride gas-saturated ethanol.
Decomposes sodium boronate. Dry this under reduced pressure.
After solidifying, water, methanol solvent (80% water, meth)
Amberlite XAD2 dissolved in (20%)
flow down a column filled with 200 ml of column
After washing with water in step 2, with methanol-water solvent,
The methanol content was gradually increased to 10% and 20%.
Collect the fraction eluting at 40%, concentrate and a-
22-5,500 mg was obtained. Example 23 a-5-3.1 mmol synthesized in Example 17
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Excess sodium borohydride in gas-saturated ethanol
Decompose um. After drying this under reduced pressure, water,
In methanol solvent (80% water, 20% methanol)
Suspend and fill with 70ml of Amberlite XAD-2.
flow down the column. Fill the column with 500ml of water.
After washing, remove methanol using a methanol-water solvent.
The content of
Collect the sections to be released, concentrate and a-22-3, 103
I got mg. Example 24 a-1-1, 10 mmol synthesized in Example 4
Dissolve in 200 ml of methanol and add phenyl dichloride at room temperature.
Add 20 mmol of azomethane and stir for 3 hours.
Excess phenyldiazomethane is dissolved in benzene acetate with acetic acid.
to The reaction solution was dried under reduced pressure, and the residue was poured into 20 ml of evaporator.
Wash with water. Dry this residue thoroughly and
Dissolve this in 200 ml of methylene chloride. Gia to this
Add 50 mmol of ethereal solution of zomethane and
Boron trifluoride ether complex (Wako Pure Chemical Industries) 5
ml and stir overnight at room temperature. excess diazome
After removing the chlorine with acetic acid, remove the solvent under reduced pressure.
Ru. Place the residue in a large amount of ice water and remove the resulting precipitate.
Separate. Do this twice with 50ml of water, for a total of 100ml of water.
Wash and thoroughly dry the residue. Add this to methanol
Dissolve in 30ml of Pd-C (10%) and add 500mg of Pd-C (10%).
Shake with hydrogen gas at 1 atm and room temperature. Reacts in 20 minutes
After the Pd-C was removed, the solvent was removed under reduced pressure.
To leave. The residue was dissolved in water-methanol solvent (water 40%
%, methanol 60%) suspended in Amberlite
Flow down a column filled with 300 ml of XAD-2.
Methanol - methanol content 10 in water-based solvent
%, increase sequentially to 20%, and elute at 50%.
was collected and concentrated to obtain 820 mg of a-8-9. Example 25 a-8-9, 1 mmol synthesized in Example 24
Dissolve in 5 ml of pyridine and add 20 mmol of isobutyric anhydride.
dropwise and stir at 50°C for 4 hours. Pyridine
After distilling off under reduced pressure, pour the residue into a large amount of ice water.
Ru. Wash this three times with 10ml of water, totaling 30ml of water.
and dilute the residue with water and tetrahydrofuran solvent (water 40%
%, tetrahydrofuran 60%), and
Flow through a column packed with 100ml of Burlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Area spilled with a solvent system of 70% hydrofuran and 30% water
The fractions were collected and concentrated to obtain 420 mg of a-9-9. Example 26 a-9-9, 0.7 mm synthesized in Example 25
Dissolve the alcohol in 7 ml of methylene chloride immediately after distillation, and
Triethyloxonium fluoro
Add 1 mmol of borate and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 7 ml of the solution and add sodium borohydride under ice cooling.
Add 1.4 mmol of chloride water and stir for 10 minutes.
Excess sodium borohydride in saturated ethanol
decomposes lium. After drying this under reduced pressure,
Water, tetrahydrofuran solvent (40% water, tetra
Amberlite suspended in hydrofuran (60%)
Flow down a column filled with 50 ml of XAD-2.
After washing the column with 400ml of water, add tetrahydrofura
- The content of tetrahydrofuran was reduced to 10 in an aqueous solvent.
%, increase sequentially by 20%, and elute at 60%.
were collected and concentrated to obtain 120 mg of a-26-9. Example 27 a-8-9, 1 mmol synthesized in Example 24
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10 ml of the solution and add 2 ml of sodium borohydride under ice cooling.
After stirring for 10 minutes, add hydrogen chloride gas.
Excess sodium borohydride in saturated ethanol
disassemble the system. After drying this under reduced pressure, water and
Trihydrofuran solvent (40% water, tetrahydrofuran)
Amberlite XAD suspended in Furan 60%)
Flow down a column filled with 70 ml of -2. column
After washing with 500ml of water, tetrahydrofuran-water
The content of tetrahydrofuran in the system solvent is 10%, 20
% and collect the segment that elutes at 40%.
180 mg of a-25-9 was obtained. Example 28 a-1-1, 10 mmol synthesized in Example 4
into 30 ml of pyridine, add benzyloxycarbo
Add 20 mmol of nil chloride. 1 hour at room temperature
Stir for 30 minutes. Place this reaction solution in a large amount of ice water.
and separate the formed precipitate. Add this with 50ml of water
Wash twice with a total of 100 ml of water. more ether
Wash with 50ml. After drying thoroughly, pyridine
Dissolve 100 mmol of propionic anhydride in 40 ml of
Add dropwise and stir at 50°C for 4 hours. Depressurize pyridine
After evaporation, the residue is placed in a large amount of ice water. child
Rinse it three times with 100ml of water for a total of 300ml, and then fill it.
Dry for a minute. Dissolve this in 30ml of methanol,
Add 550 mg of Pd-C (10%), 1 atm, room temperature sewage
Shake with raw gas. The reaction was completed in 1 hour, and Pd
After removing -C, the solvent is distilled off under reduced pressure. residue
water-tetrahydrofuran solvent (40% water, tetrahydrofuran)
Suspended in 60% lahydrofuran),
Flow down a column filled with 300 ml of XAD-2.
Ru. Tetrahydrofuran - Tetrahydrofuran in an aqueous solvent
The content of Dorofuran was gradually increased to 10% and 20%.
Collect the fraction eluting at 40%, concentrate and a-
4-1, 2.3g was obtained. Example 29 a-1-12.5 mmol synthesized in Example 8
into 15 ml of pyridine, add benzyloxycarbo
Add 10 mmol of nil chloride. 2 o'clock at room temperature
Stir for a while. Place this reaction solution in a large amount of ice water,
Separate the formed precipitate. Add this with 30ml of water 2
Wash twice with a total of 60 ml of water. Plus 30ml of ether
Wash with After thoroughly drying, add 25ml of pyridine.
Dissolve 50 mmol of trichloroacetyl chloride
dropwise and stir at 50°C for 4 hours. Pyridine
After distilling off under reduced pressure, place the residue in a large amount of ice water.
Ru. Wash this with 50ml of water three times, totaling 150ml of water.
and dry thoroughly. Dissolve this in 15ml of methanol
Then, add 300 mg of Pd-C (10%) and heat at 1 atm and room temperature.
Under hydrogen gas and shake. The reaction was completed in 1 hour,
After removing Pd--C, the solvent is distilled off under reduced pressure.
Dissolve the residue in 50 ml of chloroform and add diazomethane.
Add 20 mmol of ether solution of
Add 2 ml of boron tsunide ether complex (Wako Pure Chemical Industries).
Then, stir at room temperature overnight. excess diazomethane
After removal with acetic acid, the solvent is removed under reduced pressure. residue
suspended in a mixed solvent of 10 ml of methanol and 20 ml of water.
Add a 1N sodium hydroxide solution to a pH of 12.
Add until completely combined. Stirring at room temperature lowers the pH, so
Add the above alkali until the pH reaches 12.
If the pH does not drop below 12, adjust the pH with 1N hydrochloric acid.
Adjust to 7 and use Amberlight XAD-2.
Flow down a column packed with 150 ml. with 500ml water
After washing, remove methanol using a methanol-water solvent.
The content of 10% and 20% was gradually increased, and at 50%,
Collect and concentrate the eluted fractions. Add this to hydrogen chloride
Dissolve in 10ml of Japanese methanol and stir under ice cooling for 30 minutes.
Ru. The solvent was distilled off under reduced pressure, thoroughly dried, and a-
16-1,920 mg was obtained. Example 30 a-1-1,1 mmol synthesized in Example 4
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Excess sodium borohydride in gas-saturated ethanol
Decompose um. After drying this under reduced pressure, water,
Amberlite dissolved in methanol solvent
Flow down a column packed with 70 ml of XAD-2.
After washing the column with 500ml of water, methanol-water system
(Water contains 10% of 1N hydrochloric acid)
The content of the oil was gradually increased to 10%, 20%, and 45%.
Collect the eluted fraction and concentrate it to a-18-1,
Obtained 220 mg. Example 31 a-1-2 synthesized in the same manner as in Example 4,
Dissolve 1 mmol in 10 ml of freshly distilled methylene chloride.
and triethyloxonium under argon atmosphere.
Add 1.5 mmol of fluoroborate and incubate at room temperature for 4 hours.
Stir for an hour. After removing methylene chloride under reduced pressure,
Add 10ml of absolute ethanol and add borohydride under ice cooling.
Added 2 mmol of sodium and stirred for 10 minutes.
After that, excess hydrogenation with hydrogen chloride gas saturated ethanol
Decomposes sodium boron. This was dried under reduced pressure.
After that, dissolve in water or methanol solvent, and
-Flow down a column filled with 70ml of Light XAD-2
let After washing the column with 500ml of water, methanol
- water-based solvent (water contains 10% of 1N hydrochloric acid)
) Increase the methanol content sequentially to 10% and 20%.
Collect the fraction eluting at 50%, concentrate and a
-18-2,210mg was obtained. Example 32 a-1-6 synthesized in the same manner as in Example 4,
Dissolve 1 mmol in 10 ml of freshly distilled methylene chloride.
and triethyloxonium under argon atmosphere.
Add 1.5 mmol of fluoroborate and incubate at room temperature for 4 hours.
Stir for an hour. After removing methylene chloride under reduced pressure,
Add 10ml of absolute ethanol and add borohydride under ice cooling.
Added 2 mmol of sodium and stirred for 10 minutes.
After that, excess hydrogenation with hydrogen chloride gas saturated ethanol
Decomposes sodium boron. This was dried under reduced pressure.
After that, dissolve in water or methanol solvent, and
-Flow down a column filled with 70ml of Light XAD-2
let After washing the column with 500ml of water, methanol
Ru-aqueous solvent (water contains 10% of 1N hydrochloric acid)
) Increase the methanol content sequentially to 10% and 20%.
Collect the fraction eluting at 55%, concentrate and a
-18-6,215 mg was obtained. Example 33 a-1-9,1 mmol synthesized in Example 5
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Excess sodium borohydride in gas-saturated ethanol
Decompose um. After drying this under reduced pressure, water,
Amberlite dissolved in methanol solvent
Flow down a column filled with 70 ml of XAD-2.
After washing the column with 500ml of water, methanol-water system
(Water contains 10% of 1N hydrochloric acid)
Gradually increase the content of alcohol to 10%, 20%, and then 70%.
Collect the fraction eluted with and concentrate it to a-18-9,
Obtained 250mg. Example 34 a-1-11, 1 mmol synthesized in Example 6
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Excess borohydride in gas-saturated ethanol
Decomposes basic sodium. This was dried under reduced pressure.
After that, dissolve it in water or methanol solvent, and make it amber.
Flow down a column filled with 70 ml of ItoXAD-2.
Ru. After washing the column with 500ml of water,
Furan-water based solvent (10% 1N hydrochloric acid in water)
) Tetrahydrofuran content is 10%, 20% and
Gradually increase the concentration, collect the fraction that elutes at 50%, and
This was concentrated to obtain 230 mg of a-18-11. Example 35 a-7-17, 1 mmol synthesized in Example 20
suspended in a mixed solvent of 2 ml of methanol and 4 ml of water.
Add a 1N sodium hydroxide solution to a pH of 12.
Add until completely combined. Stirring at room temperature lowers the pH, so
Add the above alkali until the pH reaches 12.
If the pH does not drop below 12, adjust the pH with 1N hydrochloric acid.
Adjust to 7 and use Amberlight XAD-2.
Flow down a column packed with 30 ml. with 100ml water
After washing, remove methanol using a methanol-water solvent.
The content of 10% and then 20% was gradually increased, and at 70%,
Collect and concentrate the eluted fractions. Add this to hydrogen chloride
Dissolve in 2 ml of Japanese methanol and stir under ice cooling for 30 minutes.
Ru. The solvent was distilled off under reduced pressure, thoroughly dried, and a-
15-8,370 mg was obtained. Example 36 a-5-13.5 mmol synthesized in Example 18
suspended in a mixed solvent of 10 ml of methanol and 20 ml of water.
Add a 1N sodium hydroxide solution to a pH of 12.
Add until completely combined. Stirring at room temperature lowers the pH, so
Add the above alkali until the pH reaches 12.
If the pH does not drop below 12, adjust the pH with 1N hydrochloric acid.
Adjust to 7 and use Amberlight XAD-2.
Flow down a column packed with 150 ml. with 500ml water
After washing, remove methanol using a methanol-water solvent.
The content of 10% and 20% was gradually increased, and at 60%,
The eluted fractions were collected and concentrated. Add this to hydrogen chloride
Dissolve in 10ml of Japanese methanol and stir under ice cooling for 30 minutes.
Ru. The solvent was distilled off under reduced pressure, thoroughly dried, and a-
13-2, 1.89g was obtained. Example 37 a-6-13 synthesized in the same manner as Example 14,
1 mmol was reacted in the same manner as in Example 39.
and detrichloroacetylation is performed. purification
was carried out in the same manner as in Example 39, and the methanol content was 70
Collect and concentrate the fractions eluting at %. Add this to chlorinated water
Dissolve in 2 ml of saturated methanol and stir under ice cooling for 30 minutes.
do. The solvent was distilled off under reduced pressure, thoroughly dried,
320 mg of a-14-9 was obtained. Example 38 a-1-12.5 mmol synthesized in Example 8
Dissolve in 100 ml of methanol and add phenyl dichloride at room temperature.
Add 10 mmol of azomethane and stir for 3 hours.
Excess phenyldiazomethane is dissolved in benzene acetate with acetic acid.
to The reaction solution was dried under reduced pressure, and the residue was poured into 15 ml of evaporator.
Wash with water. Dry this residue thoroughly and
Dissolve this in 100 ml of methylene chloride. Gia to this
Add 25 mmol of ethereal solution of zomethane and
Boron trifluoride ether complex (Wako Pure Chemical Industries)
Add 2.5 ml and stir overnight at room temperature. excess zia
After removing zomethane with acetic acid, remove the solvent under reduced pressure.
do. Place the residue in a large amount of ice water and remove the resulting precipitate.
Separate. Do this twice with 25ml of water, for a total of 50ml of water.
Wash and thoroughly dry the precipitate. Add this to methanol
Dissolve in 15 ml of Pd-C (10%) and add 250 mg of Pd-C (10%).
Shake with hydrogen gas at 1 atm and room temperature. Reacts in 20 minutes
After the Pd-C was removed, the solvent was removed under reduced pressure.
To leave. After thoroughly drying the residue, add 15 ml of pyridine.
and dropwise add 100 mmol of propionic anhydride.
and stir at 50°C for 4 hours. Distill pyridine under reduced pressure
After removing, place the residue in a large amount of ice water. this
Wash with 150 ml of water three times, totaling 450 ml of water. this
suspended in a mixed solvent of 10 ml of methanol and 20 ml of water.
Add a 1N sodium hydroxide solution to a pH of 12.
Add until completely combined. Stirring at room temperature lowers the pH, so
Add the above alkali until the pH reaches 12.
If the pH does not drop below 12, adjust the pH with 1N hydrochloric acid.
Adjust to 7 and use Amberlight XAD-2.
Flow down a column packed with 150 ml. with 500ml water
After washing, remove methanol using a methanol-water solvent.
The content of 10% and then 20% was gradually increased, and at 70%,
Collect and concentrate the eluted fractions. Add this to hydrogen chloride
Dissolve in 10ml of Japanese methanol and stir under ice cooling for 30 minutes.
Ru. The solvent was distilled off under reduced pressure, thoroughly dried, and a-
17-5,830mg was obtained. Example 39 a-2-1,1 mmol synthesized in Example 12
suspended in a mixed solvent of 2 ml of methanol and 4 ml of water.
Add a 1N sodium hydroxide solution to a pH of 12.
Add until completely combined. Stirring at room temperature lowers the pH, so
Add the above alkali until the pH reaches 12.
If the pH does not drop below 12, adjust the pH with 1N hydrochloric acid.
Adjust to 7 and use Amberlight XAD-2.
Flow down a column packed with 150 ml. with 500ml water
After washing, remove methanol using a methanol-water solvent.
Gradually increase the content of 10%, 20%, and at 50%
Collect and concentrate the eluted fractions. Add this to hydrogen chloride
Dissolve in 2 ml of Japanese methanol and stir under ice cooling for 30 minutes.
Ru. The solvent was distilled off under reduced pressure, thoroughly dried, and a-
12-1,400 mg was obtained. Example 40 Pyridine 5 mmol of thoroughly dried AI-77-B.
Dissolve benzyloxycarbonylchloride in 10ml of
10 mmol of Ride was added and stirred at room temperature for 3 hours.
After that, benzyloxycarbonyl chloride 20ml
mol and further stirred at room temperature for 1 hour and 30 minutes.
This reaction solution was placed in a large amount of ice water, and the precipitate formed
Separate. Add this twice with 50ml of water, for a total of 100ml.
Wash with water. Further wash with 50 ml of ether.
After thoroughly drying, dissolve in 40ml of pyridine and add
Add 50 mmol of chloroacetyl chloride, 50
Stir at ℃ for 4 hours. Pyridine was distilled off under reduced pressure.
Then, place the residue in a large amount of ice water. Add 50ml of this
Wash with water three times, a total of 150 ml of water, and dry thoroughly.
Dissolve this in 15 ml of methanol and make Pd-C (10%)
Add 280mg of and shake with hydrogen gas at 1 atm and room temperature.
Ru. The reaction was completed in 2 hours and the Pd-C was removed.
Afterwards, the solvent is distilled off under reduced pressure. The residue is water-tetrahy
Dorofuran-based solvent (40% water, tetrahydrofuran
60%) and suspend Amberlite XAD-2 in
Flow down a column packed with 150 ml. Tetrahydrofuran - Tetrahydride in aqueous solvent
The content of Lofuran was gradually increased to 10% and 20%,
Collect the fraction eluting at 30%, concentrate and a-12-
9, 1.02g was obtained. Example 41 Pyridine 5 mmol of thoroughly dried AI-77-B.
Dissolve benzyloxycarbonylchloride in 10ml of
Add 10 mmol of Ride and stir at room temperature for 3 hours.
Ru. After pyridine was distilled off under reduced pressure, the residue was dissolved in 10 ml of
Wash twice with 20 ml of water. More ete
Wash with 30ml of water. After thoroughly drying, methanol
Dissolve phenyldiazomethane in 100 ml of Phenyldiazomethane at room temperature.
Add 10 mmol and stir for 3 hours. Hue in excess
Convert nyldiazomethane to benzyl vinegar with acetic acid.
The reaction solution was dried under reduced pressure, and the residue was washed with 10 ml of ether.
Purify. Dry this residue thoroughly and add methylene chloride.
Dissolve in 100ml. Add to this the ether of diazoethane.
Add 10 mmol of the trifluoride solution and
Add 2.5 ml of elementary ether complex (Wako Pure Chemical Industries) and bring to room temperature.
Stir overnight. Remove excess diazoethane with acetic acid.
After removing the solvent, remove the solvent under reduced pressure. a large amount of residue
Place in ice water and separate the resulting precipitate. This is 25
Wash twice with 50 ml of water to thoroughly remove the residue.
to dry. Dissolve this in 15 ml of methanol, Pd-C (10
%) and shaken with hydrogen gas at 1 atm and room temperature.
To do so. The reaction was completed in 2 hours and the Pd-C was removed.
After that, the solvent is distilled off under reduced pressure. Water the residue - Tet
Lahydrofuran solvent (40% water, tetrahydrofuran
Amberlite XAD-
Flow down a column filled with 150 ml of 2. Tetra
Hydrofuran - Tetrahydrofuran in an aqueous solvent
The content of
Collect the sections to be released, concentrate and a-16-7, 1.21
I got g. Example 42 a-16-7.1 mmol synthesized in Example 41
into 4 ml of pyridine and add benzyloxycarbonate.
Add 2 mmol of chloride and stir at room temperature for 3 hours.
Stir. After pyridine was distilled off under reduced pressure, the residue was
Wash twice with 4 ml of water. Further
Wash with 6 ml of water. After drying thoroughly, remove
Add trichloroacetyl chloride to 4 ml of gin.
Add 10 mmol of chloride and stir at 50°C for 4 hours. Pi
After lysine was distilled off under reduced pressure, the residue was poured into a large amount of ice water.
Put it in. Do this three times with 10ml of water, a total of 30ml of water.
Wash and dry thoroughly. Add this to 3ml of methanol
Dissolve, add 50 mg of Pd-C (10%), and heat to 1 atm, room temperature.
Shake with warm hydrogen gas. Reaction completed in 1 hour
After removing Pd-C, the solvent is distilled off under reduced pressure.
Ru. The residue was dissolved in water-tetrahydrofuran solvent (water 40%
%, tetrahydrofuran 60%), and
Flow through a column packed with 30ml of Barlite XAD-2.
Let it go down. Tetrahydrofuran-water solvent
Gradually increase the content of trahydrofuran to 10% and 20%
Collect the fraction eluting at 40% and concentrate.
210 mg of a-17-6 was obtained. Example 43 Pyridine 1 mmol of thoroughly dried AI-77-B.
Dissolve in 4 ml of benzyloxycarbonylchloride.
Add 2 mmol of Ride and stir at room temperature for 3 hours.
Ru. After pyridine was distilled off under reduced pressure, 2 ml of the residue was
Wash twice with water, totaling 4 ml of water. More ete
Wash with 6 ml of water. After thoroughly drying, pyridine
4 ml and add 15 mmol of acetic anhydride. child
Add 10 mg of zinc chloride to the mixture and stir at room temperature for 2 hours.
Ru. This reaction solution was poured into a large amount of ice water to produce
Separate the precipitate. Add this twice with 2 ml of water, totaling 4 ml.
Wash with water. Dissolve this in 3 ml of methanol, Pd-C (10
%) and shaken with hydrogen gas at 1 atm and room temperature.
do. The reaction was completed in 1 hour and the Pd-C was removed.
After that, the solvent is distilled off under reduced pressure. Residue in water-tetra
Hydrofuran-based solvent (40% water, tetrahydrofuran
Amberlite XAD-2
flow down a column filled with 30 ml of Tetrahydride
Lofuran - A hydrogen solvent containing tetrahydrofuran.
Increase the amount sequentially to 10% and 20%, and elute at 30%.
Collect the fractions and concentrate to obtain a-10-1,230 mg.
Obtained. Example 44 Pyridine 1 mmol of thoroughly dried AI-77-B.
Dissolve in 4 ml of benzyloxycarbonylchloride.
Add 2 mmol of Ride and stir at room temperature for 3 hours.
Ru. After pyridine was distilled off under reduced pressure, 2 ml of the residue was
Wash twice with water, totaling 4 ml of water. More ete
Wash with 6 ml of water. After thoroughly drying, pyridine
4 ml and add 15 mmol of acetic anhydride. child
Add 10 mg of zinc chloride to the mixture and stir at room temperature for 2 hours.
Ru. This reaction solution was poured into a large amount of ice water to produce
Separate the precipitate. Add this twice with 2 ml of water, totaling 4 ml.
Wash with water. After thoroughly drying, add pyridine 4
ml, add 10 mmol of butyric anhydride, and incubate at 50℃.
Stir for 4 hours. After distilling off the pyridine under reduced pressure,
Place the residue in a large amount of ice water. Add this with 10ml of water
Wash three times with a total of 30 ml of water and dry thoroughly. Dissolve this in 3 ml of methanol, Pd-C (10
%) and shaken with hydrogen gas at 1 atm and room temperature.
do. The reaction was completed in 1 hour and the Pd-C was removed.
After that, the solvent was distilled off under reduced pressure.
Dorofuran-based solvent (40% water, tetrahydrofuran
60%) and suspend Amberlite XAD-2 in
Flow down a column packed with 30 ml. Tetrahydro
Content of tetrahydrofuran in furan-aqueous solvents
Increase the concentration sequentially to 10% and 20%, and elute at 40%.
Collect the fractions and concentrate to obtain a-11-6, 270 mg.
Ta. Example 45 Pyridine 1 mmol of thoroughly dried AI-77-B.
Dissolve in 4 ml of benzyloxycarbonylchloride.
Add 2 mmol of Ride and stir at room temperature for 3 hours.
Ru. After pyridine was distilled off under reduced pressure, 2 ml of the residue was
Wash twice with water, totaling 4 ml of water. More ete
Wash with 6 ml of water. After thoroughly drying, pyridine
4 ml and add 15 mmol of acetic anhydride. child
Add 10 mg of zinc chloride to the mixture and stir at room temperature for 2 hours.
Ru. This reaction solution was poured into a large amount of ice water to produce
Separate the precipitate. Add this twice with 2 ml of water, totaling 4 ml.
Wash with water. After thoroughly drying, methanol 4
ml and 16 ml of chloroform. room
Add 6 mmol of a warm ethereal solution of diazoethane.
Then, stir for 1 hour. Excess diazoethane with acetic acid
and evaporate the solvent under reduced pressure. Dissolve this in 3 ml of ethanol, Pd-C (10
%) and shaken with hydrogen gas at 1 atm and room temperature.
do. The reaction was completed in 1 hour and the Pd-C was removed.
After that, the solvent is distilled off under reduced pressure. Residue in water-tetra
Hydrofuran-based solvent (40% water, tetrahydrofuran
Amberlite XAD-2
flow down a column filled with 30 ml of Tetrahydride
Lofuran - An aqueous solvent for tetrahydrofuran.
Increase the content sequentially to 10% and 20%, and elute at 50%.
Collect the fractions and concentrate to obtain a-14-1,273mg
I got it. Example 46 Thoroughly dried AI in a 50ml glass pressure container
-77- Add 848 mg of B2 mmol and add N,N-dimethylene.
Dissolve in 10ml of formamide. Methyl iodide 10mg
Add Rimol, seal tightly and shake vigorously for 1 hour at room temperature.
To do so. Furthermore, add 10 mmol of methyl iodide,
Carry out the same reaction as above. 10 ml of methyl iodide again
After adding RIMOLE and shaking vigorously for a day and night, remove the solvent.
of N,N-dimethylformamide and the final reaction of
Methyl iodide is distilled off under reduced pressure. Convert residue to methanol
Mix to 2 ml, Merck TLCPSC-
Fertigplatten KIESELGEL 60F―254
(Art.5717) 20cm x 20cm x 2mm Spot on 20 sheets
and developed in a solvent system of methanol:chloroform:10.
Open, Rf value 0.38 part (with ultraviolet absorption, ninhydride)
Scrape off the phosphorus (red-purple color), collect it, and add it to methanol.
Add 200ml and stir for 30 minutes. Separate the silica gel
After that, concentrate the methanol to obtain 72 mg of a-27-1.
I got it. Example 47 Thoroughly dried AI-77-B 1.2 mmol was added to N,
Dissolve in 5 ml of N-dimethylformamide and iodide.
Add 3 mmol of ethyl and stir at room temperature for 2 hours.
Ru. Add 3 mmol of ethyl iodide at 1 hour intervals.
Add 4 times each. Dissolve the reaction solution as is under reduced pressure.
The solvent and excess ethyl iodide are distilled off. residue
Dissolve in 2 ml of methanol, Merck TLCPSC-
Ferti-gplatten KIESELGEL60F-254
(Art.5717) Spotted on 10 pieces of 20cm x 20cm x 2mm,
Developed with methanol:chloroform:10 solvent system
and the part with an Rf value of 0.40 (with ultraviolet absorption,
Scrape off the reddish-purple color, collect it, and add 100 ml of methanol.
ml and stir for 30 minutes. separated from silica gel
After that, concentrate the methanol to obtain 70mg of a-18-1.
Obtained. Example 48 Pipet 778 mg of thoroughly dried AI-77-F2 mmol.
Dissolve in 4 ml of lysine and add 40 mmol of acetic anhydride.
Ru. Add 20mg of zinc chloride to this and stir at room temperature for 2 hours.
Stir. Pour this reaction solution into a large amount of ice water to generate
Separate the precipitate. Add this twice with 5 ml of water.
Wash with 10ml of water. Dissolve in 2 ml of methanol,
Merck & Co. TLCPSC-Fertigplatten
KIESELGEL60F―254 (Art.5717) 20cm×20cm×
Spotted on 15 pieces of 2mm, chloroform:methanol
Developed in a solvent system with a ratio of Rf0.70 (UV).
(absorbed), collect and add 100ml of methanol.
and stir for 20 minutes. After separating the silica gel,
Concentrate methanol to obtain a-1-1, 520 mg.
Ta. Example 49 In place of acetic anhydride used in Example 48,
Example 52 Using Lichloroacetyl Chloride
2 mmol of a-1-12 synthesized in the same manner as
Dissolve in 4 ml of pyridine and add 26 mmol of acetic anhydride.
Add and stir at 50°C for 3 hours. Pyridine distilled under reduced pressure
After removing it, pour the residue into a small amount of ice water. this
After washing three times with 10 ml of water for a total of 30 ml of water,
Suspend in a mixed solvent of 4 ml of alcohol and 8 ml of water, and
Add constant sodium hydroxide solution until pH is 12.
Ru. Stirring at room temperature will lower the pH, so the pH will further increase to 12.
Add the above alkali until PH from 12
If it doesn't go down, adjust the pH to 7 with 1N hydrochloric acid.
Fill this with 60ml of Amberlight XAD-2.
flow down the column. Washed with 200ml water
After that, use a tetrahydrofuran-water solvent to remove the tetrahydrofuran.
Collect the fraction eluting at 50% hydrofuran content
Concentrate. Add this to 4 ml of methanol saturated with hydrogen chloride.
Melt and stir under ice cooling for 30 minutes. Distill the solvent under reduced pressure
This was thoroughly dried to obtain 530 mg of a-3-1. Example 50 a-1-1, 1 mmol synthesized in Example 48
Dissolve in 2 ml of pyridine and add 13 ml of propionic anhydride.
Add Rimol and stir at 50°C for 3 hours. pyridine
After distilling off under reduced pressure, dissolve in 1 ml of methanol,
Merck & Co. TLCPSC-Fertigplatten
KIESELGEL60F―254 (Art.5717) 20cm×20cm×
Spot on 10 pieces of 2mm, chloroform:methanol
Developed in a 50:1 solvent system, and Rf0.60 part (UV
(absorbed), collect it and add 50ml of methanol.
Add and stir for 20 minutes. After separating the silica gel,
Tanol was concentrated to obtain 305 mg of a-2-2. Example 51 a-1-1, 1 mmol synthesized in Example 48
Dissolve in 5 ml of chloroform and add diazometha at room temperature.
Add 10 mmol of an ether solution of
Ru. Excess diazomethane was removed with acetic acid, and the reaction solution was
Dry under reduced pressure. Dissolve in 1 ml of methanol and dissolve
KIESELGEL60F
-254 (Art.5717) 20cm x 20cm x 2mm 10 pieces with spots
and chloroform:methanol 50:1 solvent system
Expand it and scratch the Rf0.60 part (with ultraviolet absorption).
Add 50ml of methanol and stir for 20 minutes.
Ru. After separating the silica gel, concentrate the methanol
270 mg of a-5-1 was obtained. Example 52 Crush 778 mg of thoroughly dried AI-77-F2 mmol.
Dissolve diazoethane in 10ml of loloform at room temperature.
Add 15 mmol of ether solution and stir for 1 hour.
Remove excess diazoethane with acetic acid and reduce the reaction solution.
Press dry. Dissolved in 2 ml of methanol, Merck
TLCPSC―Fertigplatten KIESELGEL60F―254
(Art.5717) Spotted on 15 pieces of 20cm x 20cm x 2mm,
Developed with a solvent system of chloroform:methanol 40:1
Then scrape off the Rf0.70 part (with ultraviolet absorption),
Collect, add 100ml of methanol, and stir for 20 minutes. S
After separating the licagel, concentrate the methanol and
A-4-2, 680 mg was obtained. Example 53 a-4-2, 1 mmol synthesized in Example 52
Dissolve in 10ml of methylene chloride and add diazobuta to this.
Add 5 mmol of the ether solution of
Boron fluoride ether complex (Wako Pure Chemical Industries) 0.5ml
Add and stir overnight at room temperature. Remove excess diazobuta with vinegar
After removal with acid, the reaction solution is dried under reduced pressure. methano
Dissolve in 1 ml of Merck TLCPSC-Fertig
―Platten KIESELGEL60F―254 (Art.5717) 20
Spot on 10 sheets of cm x 20 cm x 2 mm, and
Developed with a solvent system of methanol: 50:1, Rf0.70
Scrape off the part (with ultraviolet absorption), collect it and use meta
Add 50ml of alcohol and stir for 20 minutes. silica gel
After separating, methanol is concentrated and a-6-5,
Obtained 290 mg. Example 54 a-6-4 synthesized in the same manner as Example 53,
Dissolve 2 mmol in 10 ml of methanol, Pd-C
Add 100 mg of (10%) and mix with hydrogen gas at 1 atm and room temperature.
Shake. The reaction was completed in 20 minutes and the Pd-C was removed.
After that, add 2 ml of methanol and remove the solvent under reduced pressure.
Melted, Merck & Co. TLCPSC-Fertigplatten
KIESELGEL60F―254 (Art.5717) 20cm×20cm×
Spotted on 15 pieces of 2mm, chloroform:methanol
Developed in a 30:1 solvent system, and the Rf0.65 part (UV
(absorbed), collect and add 100ml of methanol.
and stir for 20 minutes. After separating the silica gel,
Concentrate methanol to obtain a-7-8, 520 mg.
Ta. Example 55 a-7-8, 1 mmol synthesized in Example 54
Dissolve in 4 ml of pyridine and add 10 mmol of acetic anhydride.
Add and stir at 50°C for 3 hours. Pyridine under reduced pressure
After distilling off, dissolve in 2 ml of methanol and
TLCPSC―Fertigplatten KIESELGEL60F―254
(Art.5717) Spotted on 10 pieces of 20cm x 20cm x 2mm,
Developed with a solvent system of chloroform:methanol 50:1
Then scrape off the Rf0.70 part (with ultraviolet absorption),
Collect, add 50ml of methanol, and stir for 20 minutes. Siri
After separating the gel, methanol is concentrated and a
-8-5, 240 mg was obtained. Example 56 a-18-1.2 mmol synthesized in Example 30
Dissolve in a mixed solvent of 2 ml of methanol and 5 ml of water,
1N - Sodium hydroxide aqueous solution until pH10
Add. As the PH decreases as it is stirred, the PH further increases.
Add until it reaches 10. PH no longer drops below 10
If so, adjust the pH to 7 with 1N-HCl, and add this solution to the anhydrous solution.
Purify with Burlite XAD-2 resin. Fill with water
After washing for minutes, use a solvent based on 50% methanol and 50% water.
Elute (ring opening of γ-lactone). Concentrate this
Then, 820 mg of a-18-1 was obtained. Add the above to a mixed solution of 2 ml of methanol and 5 ml of water.
Dissolve in medium and adjust the pH of 1N sodium hydroxide aqueous solution.
Add until it reaches 12. The pH drops as you stir.
Then, add more until the pH reaches 12. PH is below 12
If it stops, adjust the pH to 7 with 1N-HCl,
This solution was purified and eluted with XAD-2 in the same manner as above.
Elute with 30% alcohol and 70% water and concentrate.
c-18-1,810mg was obtained. b-18-1.1 mmol to 5 ml of methanol
Dissolve, add 1 ml of hydrogen chloride saturated methanol solution,
After stirring for 1 hour under ice cooling, the solvent was distilled off and a-
18-1,400mg was obtained. Also c-18-1,1 mi
Using remol, do the same operation and a-18-1,
Obtained 380mg. Example 57 a-4-1.1 mmol synthesized in Example 28
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Excess sodium borohydride in gas-saturated ethanol
Decompose um. After drying this under reduced pressure, water,
Tetrahydrofuran solvent (40% water, tetrahydrofuran)
Amberlite suspended in Lofuran 60%)
Flow down a column filled with 70 ml of XAD-2.
After washing the column with 500ml of water, add tetrahydrofura
- The content of tetrahydrofuran was reduced to 10 in an aqueous solvent.
%, increase sequentially to 20%, and elute at 60%.
were collected and concentrated to obtain 160 mg of a-21-9. Example 58 Place thoroughly dried fruit in a 50ml glass pressure-resistant container.
Add 2 mmol of a-10-1 synthesized in Example 43.
Dissolved in 10ml of N,N-dimethylformamide.
vinegar. Add 10 mmol of methyl iodide, seal and store in the room.
Shake vigorously for 1 hour at warm temperature. Furthermore, methioiodide
Add 10 mmol of chlorine and carry out the same reaction as above.
Added 10 mmol of methyl iodide again and left it bald for a day and night.
After shaking thoroughly, remove the solvent N,N-dimethylform.
Amide and unreacted methyl iodide are distilled off under reduced pressure.
do. Dissolve the residue in 2 ml of methanol,
TLCPSC―Fertigplatten KIESELGEL60F―254
(Art.5717) 20 cm x 20 cm x 2 mm 20 pieces,
Developed with a solvent system of methanol:chloroform 1:10
The part with an Rf value of 0.40 (with ultraviolet absorption,
Scrape off the reddish-purple color, collect it, and add 200 ml of methanol.
ml and stir for 30 minutes. separated from silica gel
After that, concentrate the methanol to obtain 80 mg of a-28-1.
Obtained. Example 59 In a 50 ml glass pressure-resistant container, as in Example 44.
Add 1.2 mmol of a-11- synthesized by
Dissolve in 10ml of N,N-dimethylformamide. Yo
Add 10 mmol of methyl uride, seal and leave at room temperature for 1 hour.
Shake vigorously for an hour. In addition, 10 mi of methyl iodide
Add rimole and carry out the same reaction as above. Yo again
Add 10 mmol of methyl uride and shake vigorously overnight.
After shaking, the solvent N,N-dimethylformamide
and unreacted methyl iodide are distilled off under reduced pressure.
Dissolve the residue in 2 ml of methanol,
TLCPSC―Fertigplatten KIESELGEL60F―254
(Art.5717) 20 cm x 20 cm x 2 mm 20 pieces,
Developed with a solvent system of methanol:chloroform 1:20
and the part with an Rf value of 0.50 (with ultraviolet absorption,
Scrape off the reddish-purple color, collect it, and add 200 ml of methanol.
ml and stir for 30 minutes. separated from silica gel
After that, methanol was concentrated to obtain 92 mg of a-29-1.
Obtained. Example 60 In a 50 ml glass pressure-resistant container, synthesized in Example 39.
Add 1.2 mmol of a-12- and N,N-di
Dissolve in 10ml of methylformamide. Methyl iodide
Add 10 mmol, close tightly and leave at room temperature for 1 hour.
Shake well. Furthermore, add 10 mmol of methyl iodide.
Well, do the same reaction as above. Methyl iodide again
After adding 10 mmol and shaking vigorously for a day and night,
Solvent N,N-dimethylformamide and unreacted
The corresponding methyl iodide is distilled off under reduced pressure. metabolize the residue
Dissolve in 2 ml of Nord, Merck TLCPSC-
Fertigplatten KIESELGEL60F―254 (Art.5717)
Spotted on 20 pieces of 20cm x 20cm x 2mm, methanol
Developed in a solvent system of 1:10 chloroform and Rf
Portion with value 0.38 (with ultraviolet absorption, nindolin coloring red)
Scrape off the purple), collect it and add 200ml of methanol.
Stir for 30 minutes. After separating the silica gel, methane
The filtrate was concentrated to obtain 76 mg of a-30-1. Example 61 In a 50 ml glass pressure-resistant container, synthesized in Example 36.
Add 2.2 mmol of a-13- and N,N-di
Dissolve in 10ml of methylformamide. Methyl iodide
Add 10 mmol, close tightly and leave at room temperature for 1 hour.
Shake well. Furthermore, add 10 mmol of methyl iodide.
Well, do the same reaction as above. Methyl iodide again
After adding 10 mmol and shaking vigorously for a day and night,
Solvent N,N-dimethylformamide and unreacted
The corresponding methyl iodide is distilled off under reduced pressure. metabolize the residue
Dissolve in 2 ml of Nord, Merck TLCPSC-
Fertigplatten KIESELGEL60F―254 (Art.5717)
Spotted on 20 pieces of 20cm x 20cm x 2mm, methanol
Developed in a solvent system of 1:10 chloroform and Rf
Part with value 0.52 (with ultraviolet absorption, ninhydrin coloring)
Scrape off the reddish purple), collect it and add 200ml of methanol.
Stir for 30 minutes. After separating the licagel, methano
The mixture was concentrated to obtain 85 mg of a-31-2. Example 62 In a 50 ml glass pressure-resistant container, as in Example 37.
Add 1.2 mmol of a-14- synthesized by
Dissolve in 10ml of N,N-dimethylformamide. Yo
Add 10 mmol of methyl uride, seal and leave at room temperature for 1 hour.
Shake vigorously for an hour. In addition, 10 mi of methyl iodide
Add rimole and carry out the same reaction as above. Yo again
Add 10 mmol of methyl uride and shake vigorously overnight.
After shaking, the solvent N,N-dimethylformamide
and unreacted methyl iodide are distilled off under reduced pressure.
Dissolve the residue in 2 ml of methanol,
TLCPSC―Fertigplatten KIESELGEL60F―254
(Art.5717) 20 cm x 20 cm x 2 mm 20 pieces,
Developed with a solvent system of methanol:chloroform 1:30
0.60 part of Rf value (with ultraviolet absorption, ninhydride)
Scrape off the phosphorus (red-purple color), collect it, and add it to methanol.
Add 200ml and stir for 30 minutes. Separate the silica gel
After that, concentrate the methanol to obtain 98 mg of a-32-1.
I got it. Example 63 In a 50 ml glass pressure-resistant container, as in Example 35.
Add 1.2 mmol of a-15- synthesized by
Dissolve in 10ml of N,N-dimethylformamide. Yo
Add 10 mmol of methyl uride, seal and leave at room temperature for 1 hour.
Shake vigorously for an hour. In addition, 10 mi of methyl iodide
Add rimole and carry out the same reaction as above. Yo again
Add 10 mmol of methyl uride and shake vigorously overnight.
After shaking, the solvent N,N-dimethylformamide
and unreacted methyl iodide are distilled off under reduced pressure.
Dissolve the residue in 2 ml of methanol,
TLCPSC―Fertigplatten KIESELGEL60F―254
(Art.5717) Spotted on 20 pieces of 20cm x 20cm x 2mm,
Developed with a solvent system of methanol:chloroform 1:30
and the part with Rf value 0.50 (with ultraviolet absorption,
Scrape off the reddish-purple color, collect it, and add 200 ml of methanol.
ml and stir for 30 minutes. separated from silica gel
After that, concentrate the methanol to obtain 95 mg of a-33-1.
Obtained. Example 64 In a 50 ml glass pressure-resistant container, as in Example 41.
Add 1.2 mmol of a-16- synthesized by
Dissolve in 10ml of N,N-dimethylformamide. Yo
Add 10 mmol of methyl uride, seal and leave at room temperature for 1 hour.
Shake vigorously for an hour. In addition, 10 mi of methyl iodide
Add rimole and carry out the same reaction as above. Add 10 mmol of methyl iodide again and leave it for a day and night.
After vigorous shaking, remove the solvent N,N-dimethylform.
Muamide and unreacted methyl iodide are distilled off under reduced pressure.
leave Dissolve the residue in 2 ml of methanol and
CompanyTLCPSC―Fertigplatten KIESELGEL60F―
254 (Art.5717) 20cm x 20cm x 2mm Spot on 20 pieces
and in a solvent system of methanol:chloroform 1:10.
Expand the part with Rf value 0.40 (with ultraviolet absorption,
Scrape off the reddish-purple color, collect it, and add it to methanol.
Add 200ml and stir for 30 minutes. Separate the silica gel
After that, concentrate the methanol to 70mg of a-34-1.
I got it. Example 65 In a 50 ml glass pressure-resistant container, as in Example 38.
Add 1.2 mmol of a-17- synthesized by
Dissolve in 10ml of N,N-dimethylformamide. Add 10 mmol of methyl iodide, seal and leave at room temperature.
Shake vigorously for the next 1 hour. Furthermore, methyl iodide
Add 10 mmol and carry out the same reaction as above. Re
Add 10 mmol of methyl iodide and leave it for a day and night.
After shaking, remove the solvent N,N-dimethylforma.
Mido and unreacted methyl iodide are distilled off under reduced pressure.
Ru. Dissolve the residue in 2 ml of methanol,
TLCPSC―Fertigplatten KIESELGEL60F―254
(Art.5717) 20 cm x 20 cm x 2 mm 20 pieces,
Developed with a solvent system of methanol:chloroform 1:20
The part with an Rf value of 0.40 (with ultraviolet absorption,
Scrape off the reddish-purple color, collect it, and add 200 ml of methanol.
ml and stir for 30 minutes. separated from silica gel
After that, concentrate the methanol to obtain 90mg of a-35-1.
Obtained. Example 66 2.1 g of thoroughly dried AI-77-B4.95 mmol
Dissolve oleic anhydride 6 in 25 ml of pyridine at room temperature.
Add mmol and stir at room temperature for 4 hours. under reduced pressure
After distilling off the pyridine, add 100 ml of water. arising
Separate the precipitate and dry thoroughly. This solid substance
Wash three times with 150 ml of hexane for a total of 450 ml. child
Dissolve this in 150ml of chloroform and add P-toluene.
Add 330 mg of sulfonic acid and stir for 2 hours. to this
Add 100ml of water, separate the liquids, and remove the chloroform layer.
Dried and dried with mirabilite, separated from mirabilite and soaked in chloroform.
Concentrate the layer to obtain 2.10 g of the target product a-1-13.
Ta. Example 67 Pipulate 3 g of thoroughly dried AI-77-B71 mmol.
Dissolve 14 mmol of benzoic anhydride in 50 ml of lysine.
Add at room temperature. After stirring at room temperature for 3 hours, pyridine
The ion was distilled off under reduced pressure. This dry matter was mixed with methanol 40
ml and adjust the pH to 1 with methanol saturated with hydrochloric acid.
Ru. This is concentrated to dryness under reduced pressure. Furthermore, this
Dissolve in 20ml of methanol and add 1N sodium hydroxide.
Adjust the pH to 5 with a solution. This solution was heated to -20℃.
Leave to stand day and night and separate the resulting precipitate. separated sink
Water-methanol solvent (50% water, methanol)
50%) and suspend Amberlite XAD-2 in
Flow down a column packed with 300 ml. column 1.5
After washing with water, the solvent was 85% methanol and 15% water.
The fraction that flows out of the system is collected, concentrated, dried, and used for the purpose
2.51 g of product a-1-14 was obtained. Example 68 Add 2 mmol of thoroughly dried AI-77-B to chlorine.
Suspend in 1 ml of form and add 4-cyclohexylbutyric acid 10
Add mmol. Furthermore, dicyclohexylcal
Add 8 mmol of bodiimide and stir at room temperature for 4 hours.
do. After distilling off the solvent under reduced pressure, the residue was dissolved in methanol.
Dissolve in 2 ml of Merck's TLCPSC-
Fertigplatten KIESELGEL60F―254 (Art.5717)
Spotted on 20 pieces of 20cm x 20cm x 2mm, methanol
Developed in a solvent system of 1:10 chloroform and Rf
Scrape off and collect the part with a value of 0.65 (with ultraviolet absorption)
Add 200ml of methanol and stir for 30 minutes. silica
After separating the gel, concentrate the methanol to 730 mg.
I got a-1-19. Example 69 Add 2 mmol of thoroughly dried AI-77-B to chlorine.
Suspend in 10 ml of form and add N-thyl-tetrazolka.
Add 10 mmol of rubonic acid. Further to dicyclo
Add 8 mmol of xylcarbodiimide and leave at room temperature.
Stir for 4 hours. After distilling off the solvent under reduced pressure, the residue
Dissolved in 2 ml of methanol, Merck TLCPSC
―Fertigplatten KIESELGEL60F―254
(Art.5717) 20 cm x 20 cm x 2 mm 20 pieces,
Developed with a solvent system of methanol:chloroform 1:10
Then remove the part with an Rf value of 0.51 (with ultraviolet absorption).
Collect the mixture, add 200ml of methanol, and stir for 30 minutes.
After separating the silica gel, concentrate the methanol and
520 mg of a-1-27 was obtained. Example 70 Add 2 mmol of thoroughly dried AI-77-B to chlorine.
Suspend in 10ml of form and add cyclohexanone-2-carbonate.
Add 10 mmol of rubonic acid. Further to dicyclo
Add 8 mmol of xylcarbodiimide and leave at room temperature.
Stir for 4 hours. After distilling off the solvent under reduced pressure, the residue
Dissolved in 2 ml of methanol, Merck TLCPSC
―Fertigplatten KIESELGEL60F―254
(Art.5717) 20 cm x 20 cm x 2 mm 20 pieces,
Developed with a solvent system of methanol:chloroform 1:1
Then remove the part with an Rf value of 0.70 (with ultraviolet absorption).
Collect the mixture, add 200ml of methanol, and stir for 30 minutes.
After separating the silica gel, concentrate the methanol and
510 mg of a-1-33 was obtained. Example 71 Add 2 mmol of thoroughly dried AI-77-B to chlorine.
Suspend in 110 ml of form and add 4-methylthiobenzoic acid.
Add 10 mmol. Furthermore, dicyclohexylca
Add 8 mmol of rubodiimide and stir at room temperature for 4 hours.
Stir. After distilling off the solvent under reduced pressure, the residue was
Dissolve in 2 ml of liquid, Merck TLCPSC-
Fetigplatten KIESELGEL60F―254 (Art.5717)
Spotted on 20 pieces of 20cm x 20cm x 2mm, methanol
Developed in a 1:30 solvent system of chloroform and Rf value
Scrape off the 0.40 part (with ultraviolet absorption) and collect it.
Add 200ml of methanol and stir for 30 minutes. Shirikage
After separating the methanol, concentrate the methanol to 700 mg.
I got a-1-46. Example 72 a-1-131 mmol synthesized in Example 66
Dissolved in 10 ml of methylene chloride immediately after distillation and heated with argon.
Under atmosphere, triethyloxonium fluorobore
Add 1.5 mmol of salt and stir at room temperature for 4 hours.
After removing methylene chloride under reduced pressure, add absolute ethanol.
Add 10 ml of sodium borohydride and add 2 ml of sodium borohydride under ice cooling.
Add RIMOLE and stir for 10 minutes, then add hydrogen chloride gas.
Excess sodium borohydride in saturated ethanol
Disassemble. After drying this under reduced pressure, water and tetra
Lahydrofuran solvent (40% water, tetrahydrofuran
Amberlite XAD-
Flow down a column filled with 70 ml of 2. column
After washing with 500ml of water, use tetrahydrofuran-water system.
The content of tetrahydrofuran in the solvent is 10%, 20%
Raise the concentration one by one, collect the fraction that elutes at 50%,
Concentration gave 210 mg of a-18-13. Example 73 a-1-14, 1 mmol synthesized in Example 67
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Excess sodium borohydride in gas-saturated ethanol
Decompose um. After drying this under reduced pressure, water,
Tetrahydrofuran solvent (40% water, tetrahydrofuran)
Amberlite suspended in Lofuran 60%)
Flow down a column filled with 70 ml of XAD-2.
After washing the column with 500ml of water, add tetrahydrofura
- The content of tetrahydrofuran was reduced to 10 in an aqueous solvent.
%, increase sequentially to 20%, and elute at 40%.
were collected and concentrated to obtain 250 mg of a-18-14. Example 74 a-1-19, 1 mmol synthesized in Example 68
was dissolved in 10 ml of methylene chloride immediately after distillation, and the
triethyloxonium fluorocarbon under
Add 1.5 mmol of chloride and stir at room temperature for 4 hours.
Ru. After removing methylene chloride under reduced pressure, anhydrous ethanol
Add 10ml of the solution and add sodium borohydride under ice cooling.
After adding 2 mmol and stirring for 10 minutes, hydrogen chloride
Excess sodium borohydride in gas-saturated ethanol
Decompose um. After drying this under reduced pressure, water,
Tetrahydrofuran solvent (40% water, tetrahydrofuran)
Amberlite suspended in Lofuran 60%)
Flow down a column filled with 70 ml of XAD-2.
After washing the column with 500ml of water, add tetrahydrofura
- The content of tetrahydrofuran was reduced to 10 in an aqueous solvent.
%, increase sequentially to 20%, and elute at 60%.
was collected and concentrated to obtain 170 mg of a-18-19. Example 75 a-1-59 synthesized in the same manner as Example 68,
Dissolve 1 mmol in 10 ml of freshly distilled methylene chloride.
and triethyloxonium under argon atmosphere.
Add 1.5 mmol of fluoroborate and incubate at room temperature for 4 hours.
Stir for an hour. After removing methylene chloride under reduced pressure,
Add 10ml of absolute ethanol and add borohydride under ice cooling.
Added 2 mmol of sodium and stirred for 10 minutes.
After that, excess hydrogenation with hydrogen chloride gas saturated ethanol
Decomposes sodium boron. This was dried under reduced pressure.
After that, water, tetrahydrofuran-based solvent (water 40
%, tetrahydrofuran 60%), and
Flow through a column packed with 70ml of Barlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Hydrofuran - Tetrahydrofuran in an aqueous solvent
The content of
Collect the sections to be released, concentrate and a-18-53, 190
I got mg. Example 76 a-1-16 synthesized in the same manner as Example 66,
Dissolve 1 mmol in 10 ml of freshly distilled methylene chloride.
Under an argon atmosphere, triethyloxonitrile
Add 1.3 mmol of mufluoroborate and leave at room temperature.
Stir for 4 hours. Methylene chloride was distilled off under reduced pressure.
After that, add 10ml of absolute ethanol and boil hydrogen under ice cooling.
Added 2 mmol of sodium chloride and stirred for 10 minutes.
After that, excess hydrogenation with hydrogen chloride gas saturated ethanol
Decomposes sodium boron. This was dried under reduced pressure.
After that, water, tetrahydrofuran-based solvent (water 40
%, tetrahydrofuran 60%), and
Flow through a column packed with 70ml of Barlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Hydrofuran - Tetrahydrofuran in an aqueous solvent
The content of
Collect the sections to be released, concentrate and a-18-16, 210
I got mg. Example 77 a-1-38 synthesized in the same manner as Example 67,
Dissolve 1 mmol in 10 ml of freshly distilled methylene chloride.
and triethyloxonium under argon atmosphere.
Add 1.5 mmol of fluoroborate and incubate at room temperature for 4 hours.
Stir for an hour. After removing methylene chloride under reduced pressure,
Add 10ml of absolute ethanol and add borohydride under ice cooling.
Added 2 mmol of sodium and stirred for 10 minutes.
After that, excess hydrogenation with hydrogen chloride gas saturated ethanol
Decomposes sodium boron. This was dried under reduced pressure.
After that, water, tetrahydrofuran-based solvent (water 40
%, tetrahydrofuran 60%), and
Flow through a column packed with 70ml of Barlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Hydrofuran - Tetrahydrofuran in an aqueous solvent
The content of
Collect the sections to be released, concentrate and a-18-32,260
I got mg. Example 78 Synthesized by the same method as Example 17 a-5-14,1
Dissolve mmol in 10 ml of freshly distilled methylene chloride.
and triethyloxonium under argon atmosphere.
Add 1.5 mmol of fluoroborate and incubate at room temperature for 4 hours.
Stir for an hour. After removing methylene chloride under reduced pressure,
Add 10ml of absolute ethanol and add borohydride under ice cooling.
Added 2 mmol of sodium and stirred for 10 minutes.
After that, excess hydrogenation with hydrogen chloride gas saturated ethanol
Decomposes sodium boron. This was dried under reduced pressure.
After that, water, tetrahydrofuran-based solvent (water 40
%, tetrahydrofuran 60%), and
Flow through a column packed with 70ml of Barlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Hydrofuran - Tetrahydrofuran in an aqueous solvent
The content of
Collect the sections to be released, concentrate and a-22-14, 220
I got mg. Example 79 a-5- synthesized by the same method as Example 17
16.1 mmol into 10 ml of methylene chloride immediately after distillation
Dissolve triethyloxoni under argon atmosphere
Add 1.5 mmol of fluoroborate and bring to room temperature.
Stir for 4 hours. Methylene chloride was distilled off under reduced pressure.
After that, add 1 ml of absolute ethanol and add hydrogenated fluoride under ice cooling.
Add 2 mmol of sodium urethane and stir for 10 minutes.
After that, remove excess hydrogen with hydrogen chloride gas-saturated ethanol.
Decomposes sodium boronate. Dry this under reduced pressure.
After solidifying, water, tetrahydrofuran solvent (water 40
%, tetrahydrofuran 60%), and
Flow through a column packed with 70ml of Barlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Hydrofuran - Tetrahydrofuran in an aqueous solvent
Increase the content of 10% and 20% sequentially and elute at 50%.
Collect the fractions and concentrate to obtain a-22-15, 240mg
I got it. Example 80 a-5- synthesized by the same method as Example 17
23.1 mmol into 10 ml of freshly distilled methylene chloride
Dissolve triethyloxoni under argon atmosphere
Add 1.5 mmol of fluoroborate and bring to room temperature.
Stir for 4 hours. Methylene chloride was distilled off under reduced pressure.
After that, add 10 ml of absolute ethanol and heat the hydrogenated fluoride under ice cooling.
Add 2 mmol of sodium urethane and stir for 10 minutes.
After that, remove excess hydrogen with hydrogen chloride gas-saturated ethanol.
Decomposes sodium boronate. Dry this under reduced pressure.
After solidifying, water, tetrahydrofuran solvent (water 40
%, tetrahydrofuran 60%), and
Flow through a column packed with 70ml of Barlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Hydrofuran - Tetrahydrofuran in an aqueous solvent
Increase the content of 10% and 20% sequentially and elute at 50%.
Collect the fractions and concentrate to a-22-22, 200mg
I got it. Example 81 a-5- synthesized in the same manner as Example 17
19.1 mmol into 10 ml of methylene chloride immediately after distillation
Dissolve triethyloxoni under argon atmosphere
Add 1.5 mmol of fluoroborate and bring to room temperature.
Stir for 4 hours. Methylene chloride was distilled off under reduced pressure.
After that, add 10ml of absolute ethanol and boil hydrogen under ice cooling.
Added 2 mmol of sodium chloride and stirred for 10 minutes.
After that, excess hydrogenation with hydrogen chloride gas saturated ethanol
Decomposes sodium boron. This was dried under reduced pressure.
After that, water, tetrahydrofuran-based solvent (water 40
%, tetrahydrofuran 60%), and
Flow through a column packed with 70ml of Barlite XAD-2.
Let it go down. After washing the column with 500ml of water,
Hydrofuran - Tetrahydrofuran in an aqueous solvent
The content of
Collect the sections to be released, concentrate and a-22-18, 190
I got mg. Example 82 a-5-123 synthesized in the same manner as Example 18
1 mmol in a mixed solvent of 2 ml of methanol and 4 ml of water
1 N sodium hydroxide aqueous solution to pH
Add until it becomes 12. Stirring at room temperature lowers the pH.
Therefore, add the above alkali until the pH reaches 12.
Add. If the pH does not fall below 12, the first rule applies.
Adjust the pH to 7 with hydrochloric acid and add it to Amberlite.
Flow down a column filled with 30 ml of XAD-2.
After washing with 500 ml of water, add a methanol-water solution.
The methanol content was gradually increased to 10% and 20% using a medium.
Collect and concentrate the fraction eluting at 80%. this
Dissolve in 10 ml of methanol saturated with hydrogen chloride and cool on ice.
Stir for 30 minutes. Distill the solvent under reduced pressure and dry thoroughly.
380 mg of a-13-8 was obtained. Example 83 a-5-7 synthesized by the same method as Example 18
1 mmol in a mixed solution of 2 ml of methanol and 4 ml of water.
Suspend in medium and add 1N aqueous sodium hydroxide solution.
Add until the pH reaches 12. When stirred at room temperature, the pH changes.
Since the pH drops further, use the above alkali until the pH reaches 12.
Add. If the PH does not fall below 12, it is 1st period.
Adjust the pH to 7 with constant hydrochloric acid and add Amberlite.
Flow down a column filled with 30 ml of XAD-2.
After washing with 500 ml of water, add a methanol-water solution.
The methanol content was gradually increased to 10% and 20% using a medium.
Collect and concentrate the fraction eluting at 50%. this
Dissolve in 10 ml of methanol saturated with hydrogen chloride and cool on ice.
Stir for 30 minutes. Distill the solvent under reduced pressure and dry thoroughly.
350 mg of a-13-1 was obtained. Example 84 a-5- synthesized by the same method as Example 18
124 Mix 1 mmol with 2 ml of methanol and 4 ml of water
Suspend in a solvent and add 1N aqueous sodium hydroxide solution.
Add until the pH becomes 12. PH when stirred at room temperature
As the pH decreases, the above Alka
Add li. 1 if the pH does not fall below 12
Adjust the pH to 7 with normal hydrochloric acid and add it to Amberlite.
Flow down a column filled with 30 ml of XAD-2.
After washing with 500 ml of water, add a methanol-water solution.
The methanol content was gradually increased to 10% and 20% using a medium.
Collect and concentrate the fraction eluting at 60%. this
Dissolve in 10 ml of methanol saturated with hydrogen chloride and cool on ice.
Stir for 30 minutes. Distill the solvent under reduced pressure and dry thoroughly.
300 mg of a-13-33 was obtained. Example 85 a-5-125 synthesized in Example 18 1 mmol
suspended in a mixed solvent of 2 ml of methanol and 4 ml of water.
Add a 1N sodium hydroxide solution to a pH of 12.
Add until completely combined. Stirring at room temperature lowers the pH, so
Add the above alkali until the pH reaches 12.
If the pH does not drop below 12, adjust the pH with 1N hydrochloric acid.
Adjust this to 7 and add this to Amberlight XAD-2.
flow down a column filled with 30 ml of 500ml water
After washing with methanol and water, methanol
Gradually increase the content of alcohol to 10%, 20%, and then 60%.
Collect and concentrate the eluted fraction. This is hydrogen chloride
Dissolve in 10 ml of saturated methanol and stir under ice cooling for 30 minutes.
Ru. The solvent was distilled off under reduced pressure, thoroughly dried, and a-
13-20, 280mg was obtained. Example 86 Synthesized in Example 83 in a 50 ml glass pressure-resistant container.
Add 1.2 mmol of a-13- and N,N-di
Dissolve in 10ml of methylformamide. Methyl iodide
Add 10 mmol, close tightly and leave at room temperature for 1 hour.
Shake well. Furthermore, add 10 mmol of methyl iodide.
Well, do the same reaction as above. Methyl iodide again
After adding 10 mmol and shaking vigorously for a day and night,
Solvent N,N-dimethylformamide and unreacted
The corresponding methyl iodide is distilled off under reduced pressure. metabolize the residue
Dissolve in 2 ml of Nord, Merck TLCPSC-
Fertigplatten KIESELGEL60F―254 (Art.5717)
Spotted on 20 pieces of 20cm x 20cm x 2mm, methanol
Developed in a solvent system of 1:15 chloroform and Rf
Portion with value 0.40 (with ultraviolet absorption, ninhydrin color development)
Scrape off the red-purple color, collect it, and add 200 ml of methanol.
Stir for 30 minutes. After separating the silica gel,
Nol was concentrated to obtain a-31-1, 70 mg. Example 87 Synthesized in Example 82 in a 50ml glass pressure-resistant container
Add 8.2 mmol of a-13-N,N-dimethyl
Dissolve in 10ml of chillformamide. Methyl iodide 10
Add mmol, close tightly and heat vigorously at room temperature for 1 hour.
Shake. Furthermore, add 10 mmol of methyl iodide.
Well, do the same reaction as above. Methyl iodide again
After adding 10 mmol and shaking vigorously for a day and night,
Solvent N,N-dimethylformamide and unreacted
The corresponding methyl iodide is distilled off under reduced pressure. metabolize the residue
Dissolve in 2 ml of Nord, Merck TLCPSC-
Fertigplatten KIESELGEL60F―254 (Art.5717)
Spotted on 20 pieces of 20cm x 20cm x 2mm, methanol
Developed in a solvent system of 1:10 chloroform and Rf
Part with value 0.52 (with ultraviolet absorption, ninhydrin coloring)
Scrape off the reddish purple), collect it and add 200ml of methanol.
Stir for 30 minutes. After separating the silica gel, meta
Nol was concentrated to obtain a-3-13, 82 mg. Example 88 Add 10 mmol of thoroughly dried AI-77-B to ice.
Dissolve in 100 ml of 1N HCl-ethanol on the bath.
Ta. Immediately remove the solvent under reduced pressure (bath temperature 20-30
°C) and then thoroughly remove the residue using a vacuum pump.
Dry. Then add 50 ml of 0.5 mole heavy carbon to this residue.
Add sodium acid solution and 600ml of ethyl acetate.
Extraction was performed using Add ethyl acetate layer to saturated brine
After washing with water, Glauber's salt was added and left overnight. Glauber's salt
Separately, ethyl acetate was removed under reduced pressure, resulting in 3.98g
(yield 98%) of AI-77-B-γ-lactone (AI-
77-Ba) was obtained. Example 89 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
It was dissolved in ru. Monomethylamine (40% aqueous solution)
Dry N to 70ml2Mosquitoes were forced out by blowing gas into them.
Nomethylamine was cooled on dry ice.
I caught it with a tup. The obtained monomethylamine was dissolved in water.
Vaporize over the bath (10-20℃) and use a caustic soda tube.
After drying, add methanol solution of AI-77-Ba.
It was blown into the air. The reaction was carried out on a water bath (10-15℃) for 3 hours.
After a while, the reaction solution was dried under reduced pressure. residue
Dissolve in 20ml of chloroform and fill with chloroform.
Place 500ml on a packed silica gel column (100g)
After washing the column with chloroform,
Fractionate the product with methanol = 4:1 (2)
Then, when concentrated to dryness under reduced pressure, 1.3g of the target product -
I got 1-2. Example 90 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
Add 50 mmol n-butylamine.
Then, cover it tightly on a water bath (10-15℃) and stir for 5 hours.
Ta. After the reaction is complete, remove the solvent and n-butylamine.
It was concentrated to dryness under reduced pressure. Pour the resulting residue into 10ml
Silica dissolved in chloroform and filled with chloroform
Place 200ml of chlorofluorocarbon on Kagel column (100g).
After washing the column with chloroform:methano
The product was fractionated using a ratio of 7:1 (2.5) and concentrated under reduced pressure.
When the mixture was condensed to dryness, 1.2 g of the target product-1-4 was obtained. Example 91 AI-77-Ba5 mmol in 100 ml of anhydrous ethanol
Dissolve 50 mmol of octadecylamine in
Add it, seal it, and let it react for 20 hours with stirring at room temperature.
Ta. After the reaction, remove the solvent under reduced pressure and dry the reaction product.
Ta. Dissolve the obtained residue in 50 ml of chloroform,
Silica gel column packed with chloroform (300
g), chloroform:methanol = 50:1
When the product is fractionated and concentrated to dryness in (4),
0.45g of target product-1-6 was obtained. Example 92 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
Dissolve 50 mmol of tetrahydrofulfate in
Add Rylamine, tightly stopper and stir at room temperature for 15 hours.
Ta. After that, remove the solvent under reduced pressure, and then
Tetrahydrofurfuryl atom
Min was removed. The obtained residue was dissolved in chloroform.
Silica gel color dissolved and filled with chloroform
(100g) and color with 200ml of chloroform.
After washing the membrane, chloroform: methanol = 9:
When the product is fractionated and concentrated to dryness in step 1 (2),
Target-1-15 0.63g was obtained. Example 93 AI-77-Ba5 mmol in 100 ml of anhydrous ethanol
Add 50 mmol of oleylamine.
The mixture was sealed tightly and allowed to react at room temperature for 20 hours with stirring.
After the reaction, the solvent was removed under reduced pressure and the reaction product was dried.
Dissolve the obtained residue in 50 ml of chloroform and chromate.
Silica gel column (300g) packed with Roform
Chloroform:methanol = 50:1 (5
) and concentrated to dryness, yielding 0.38g of
Objective object-1-8 was obtained. Example 94 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
Add 50 mmol of benzylamine.
The mixture was sealed and stirred at room temperature for 10 hours. Then dissolve under reduced pressure.
After removing the medium, further remove the medium using a high vacuum pump.
ndylamine was removed. The resulting residue is chloro
Silica dissolved in form and filled with chloroform
Place it on a gel column (100g) and add 200ml of chloroform.
After washing the column with chloroform:methanol
Fractionate the product with 15:1 (2) and concentrate to dryness.
As a result, 71 g of the target object-1-1 was obtained. Example 95 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
Add 60 mmol of furfurylamine.
The mixture was then tightly stoppered and stirred at room temperature for 16 hours. Then under reduced pressure
After removing the solvent, further using a high vacuum pump
Furfurylamine was removed. The resulting residual black
Silica dissolved in chloroform and filled with chloroform
Place on Kagel column (100g) and add 200ml of chlorofluorocarbon.
After washing the column with chloroform:methano
Fractionate the product with a ratio of 12:1 (2) and concentrate to dryness.
Then, 0.55 g of the target product-14 was obtained. Example 96 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
50 mmol of 2-aminoethyltetate dissolved in
Add lahydropyran and stir at room temperature for 13 hours.
Stirred. Then remove the solvent under reduced pressure, then high vacuum
Add 2-aminoethyltetrachloride using a pump.
Hydropyran was removed. The resulting residue is chloro
Silica dissolved in form and filled with chloroform
Place it on a gel column (100g) and add 200ml of chloroform.
After washing the column with chloroform:methanol
Fractionate the product using 9:1 (2) and concentrate to dryness.
And, 0.67g of target product-1-16 was obtained. Example 97 AI-77-Ba5 mmol in 100 ml of anhydrous ethanol
50 mmol of 2-naphthalenemethyl dissolved in
Add amine and react for 48 hours with stirring at room temperature in a sealed cap.
I let it happen. After the reaction, remove the solvent under reduced pressure and dry the reactant.
Hardened. Dissolve the obtained residue in 50 ml of chloroform.
silica gel column packed with chloroform
(300g), chloroform:methanol=
When the product is fractionated at 60:1 (7) and concentrated to dryness,
1.08g of target product-1-18 was obtained. Example 98 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
Dissolve 50 mmol of 3-methoxybutyl alcohol in
The mixture was stirred for 12 hours at room temperature with the mixture sealed. the
After removing the solvent under reduced pressure, use a high vacuum pump.
3-methoxybutylamine was further removed.
Dissolve the obtained residue in chloroform and chloroform.
Into a silica gel column (100g) packed with form.
After washing the column with 200ml of chloroform,
Raw with chloroform: methanol = 8:1 (2)
When the components are fractionated and concentrated to dryness, the target product -1-
26, 1.14g was obtained. Example 99 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
Add 50 mmol of geranylamine.
The mixture was sealed and stirred at room temperature for 20 hours. Then dissolve under reduced pressure.
After removing the medium, the gel is further removed using a high vacuum pump.
Ranylamine was removed. The resulting residue is chloro
Silica dissolved in form and filled with chloroform
Place it on a gel column (100g) and add 200ml of chloroform.
After washing the column with chloroform:methanol
Fractionate the product with 30:1 (2) and concentrate to dryness.
Then, 0.58 g of the target product-1-30 was obtained. Example 100 AI-77-Ba5 mmol in 100 ml of anhydrous ethanol
Add 50 mmol of P-toluidine.
The reaction was allowed to proceed for 48 hours with stirring at room temperature with a sealed stopper. reaction
Afterwards, the solvent was removed under reduced pressure and the reaction product was dried. Obtained
Dissolve the residue in 50 ml of chloroform and add chloroform.
A silica gel column (300g) packed with
Se, chloroform:methanol = 20:1 (5)
When the product was fractionated and concentrated to dryness, 1.03 g of
Obtained target-1-43. Example 101 AI-77-Ba5 mmol in 100 ml of anhydrous methanol
Dissolve 50 mmol of N-(2-aminoethyl
) - Add piperidine and stir at room temperature for 15 hours.
Stirred. Then remove the solvent under reduced pressure, then high vacuum
Further N-(2-aminoethyl) using a pump
- Piperidine was removed. The resulting residue is chloro
Silica dissolved in form and filled with chloroform
Place it on a gel column (100g) and add 200ml of chloroform.
After washing the column with chloroform:methanol
Fractionate the product with 12:1 (2) and concentrate to dryness.
As a result, 0.53 g of target product-1-46 was obtained. Example 102 a-10-1 synthesized in Example 43 5 mmol
Dissolve in 50 ml of dry dimethylformamide and add water.
6.5 ml of dry ammonia gas above the bath (10-15℃)
Dissolve to mol, seal tightly, and react for 48 hours.
Ta. The solvent was immediately removed under reduced pressure and the mixture was dried. Obtained
Dissolve the residue in 10 ml of chloroform, and
Into a silica gel column (100g) packed with form.
Wash the column with 300 ml of chloroform.
After that, chloroform:methanol = 10:1 (2)
The product was fractionated and concentrated to dryness under reduced pressure to yield 0.19
The target product-2-1 of g was obtained. Example 103 a-11-6.5 mmol synthesized in Example 44
Dissolve in 30 ml of dry dimethylformamide and add water.
7.0 ml of dry ammonia gas above the bath (10-15℃)
Dissolve to mol, seal tightly, and react for 48 hours.
Ta. The solvent was immediately removed under reduced pressure and the mixture was dried. Obtained
Dissolve the residue in 10 ml of chloroform, and
Into a silica gel column (100g) packed with form.
Wash the column with 300 ml of chloroform.
After that, chloroform:methanol = 15:1 (2)
When the product was fractionated and concentrated to dryness under reduced pressure, 0.27g
Objective-3-2 was obtained. Example 104 a-12-1.5 mmol synthesized in Example 39
Dissolve in 30 ml of dry dimethylformamide and add water.
7.0 ml of dry ammonia gas above the bath (10-15℃)
Dissolve to mol, seal tightly, and react for 48 hours.
Ta. The solvent was immediately removed under reduced pressure and the mixture was dried. Obtained
Dissolve the residue in 10 ml of chloroform, and
Into a silica gel column (100g) packed with form.
Wash the column with 300 ml of chloroform.
After that, chloroform:methanol = 10:1 (2)
When the product was fractionated and concentrated to dryness under reduced pressure, 0.26g
Objective-4-1 was obtained. Example 105 30 mmol of a-13-2.5 mmol obtained in Example 36
50 mmol butylene dissolved in ml absolute methanol
Add Ruamine, tightly stopper it, and place it on a water bath (10-16℃) for 5 minutes.
Stir for hours. After the reaction, remove the solvent and amine under reduced pressure.
The resulting residue was dissolved in chloroform (10ml).
Silica gel column packed with chloroform
(100g) and dry with 150ml of chloroform.
After washing the membrane, chloroform: methanol = 30:
When the product is fractionated and concentrated to dryness in step 1 (2),
Target-5-3 was obtained (1.41 g). Example 106 5 ml of a-13-2 (hydrochloride) obtained in Example 36
Add 100ml of 0.5M sodium bicarbonate solution to the mole.
The mixture was then extracted three times with 300 ml of ethyl acetate.
After washing the ethyl acetate layer with saturated saline, add sodium sulfate.
After drying, remove the mirabilite and remove the ethyl acetate under reduced pressure.
When removed, 2.3g of a-13-2 (hydrochloric acid free) is released.
Obtained. Dissolve this residue in 100ml of anhydrous methanol.
Then add 50 mmol of P-toluidine and cap tightly.
The residue remained at room temperature for three days. Then remove the solvent under reduced pressure.
After that, dissolve the residue in 50 ml of chloroform and chromatize.
Silica gel column (400g) packed with Roform
Chloroform: methanol = 30:1 (5
) to concentrate the product to dryness under reduced pressure.
1.4 g of target product-5-4 was obtained. Example 107 a-14-9.5 mmol synthesized in Example 37
Dissolve in 30 ml of dry dimethylformamide and add water.
6ml of dry ammonia gas above the bath (10~15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform:methanol=30:1(2)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.31 g of
Obtained target-6-3. Example 108 a-15-8.5 mmol obtained in Example 35
Dissolved in 100 ml of absolute methanol, 50 mmol of
Add butylamine, seal and place on a water bath (10-16℃)
The mixture was stirred for 5 hours. After the reaction, remove the solvent and amine under reduced pressure.
and the resulting residue was dissolved in chloroform (10ml).
Silica gel color dissolved and filled with chloroform
(100g) and color with 150ml of chloroform.
After washing the membrane, chloroform: methanol = 25:
The product is fractionated in step 1 (3) and concentrated to dryness to achieve the purpose.
Product-7-4 was obtained (1.58 g). Example 109 a-16-1.5 mmol synthesized in Example 29
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 30 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed tightly, and reacted for 2 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 10:1 (2)
When concentrated to dryness under reduced pressure, 1.11g of the target product-8
I got -1. Example 110 a-18-2.5 mmol synthesized in Example 31
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed tightly, and reacted for 2 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 15:1 (2)
When concentrated to dryness under reduced pressure, 1.18g of the target substance -10
-I got 1. Example 111 a-18-6.5 mmol synthesized in Example 32
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed, and reacted for 3 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 20:1 (3)
When concentrated to dryness under reduced pressure, 1.21g of the target substance -10
-I got 2. Example 112 a-18-6.5 mmol obtained in Example 32
Dissolved in 100 ml of absolute methanol, 50 mmol of
Add butylamine, seal tightly and place on a water bath (10-16
℃) for 3 hours. After the reaction, remove the solvent and aqueous solution under reduced pressure.
The residue obtained by removing the amine was dissolved in chloroform (10
ml) and filled with chloroform.
Place it on a column (100g) and add 150ml of chloroform.
After washing the column with chloroform:methanol
Fractionate the product using 30:1 (3) and concentrate to dryness.
Then, the target object-10-4 was obtained (1.39 g). Example 113 a-20-2.5 mmol synthesized in Example 13
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 30:1 (3)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.29 g of
Obtained at Target-12-1. Example 114 a-21-9.5 mmol synthesized in Example 57
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 15:1 (2)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.18 g of
Obtained target-13-3. Example 115 a-22-5.5 mmol synthesized in Example 22
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed, and reacted for 3 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 15:1 (2)
When concentrated to dryness under reduced pressure, 1.36g of the target substance -14
-I got 2. Example 116 a-22-15.5 mmol synthesized in Example 76
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed, and reacted for 3 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 20:1 (3)
When concentrated to dryness under reduced pressure, 1.38g of the target substance -14
-I got a 5. Example 117 30 mmol of a-23-11.5 mmol obtained in Example 15
ml of dry dimethylformamide. mono
Dry N in 30 ml of ethylamine (70% aqueous solution)2gas
to remove the expelled monoethylamine.
It was captured in a trap cooled with lye ice. profit
The obtained monoethylamine was heated in a hot bath (20-30℃).
After vaporization and drying with a caustic soda tube, up to 7 mmol
Blow into the dimethylformamide solution and seal tightly.
The mixture was stoppered and stirred for 48 hours. Then remove the solvent under reduced pressure.
and dissolve the resulting residue in 30 ml of chloroform.
silica gel column packed with chloroform
(100g), chloroform:methanol=
When the product is fractionated at 20:1 (3) and concentrated to dryness,
0.35g of target product-15-4 was obtained. Example 118 a-24-16.5 mmol obtained in Example 21
Dissolved in 100 ml of absolute methanol. monoethyl
Dry N in 30 ml of amine (70% aqueous solution)2blow gas
The monoethylamine that is mixed in and expelled is removed by dryer.
It was captured in a trap cooled in a chair. obtained
Monoethylamine was vaporized on a hot bath (20-30 °C).
After drying with a caustic soda tube,
Blow into methanol solution, seal tightly and stir for 3 hours.
did. The solvent was then removed under reduced pressure and the resulting residue
Dissolve the residue in 30 ml of chloroform and add chloroform to
Place it on a packed silica gel column (100g) and
Produced with loloform: methanol = 30:1 (3)
When the substance is fractionated and concentrated to dryness, 1.51g of the target substance -
I got 16-4. Example 119 a-25-9.5 mmol synthesized in Example 27
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas (~15 °C)
The mixture was dissolved, sealed tightly, and reacted for 2 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 15:1 (2)
When concentrated to dryness under reduced pressure, 1.25g of the target substance -17
-I got 3. Example 120 a-26-9.5 mmol synthesized in Example 26
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 20:1 (3)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.22 g of
Obtained target-18-3. Example 121 a-27-1.5 mmol synthesized in Example 46
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed tightly, and reacted for 2 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 10:1 (2)
When concentrated to dryness under reduced pressure, 1.57g of the target substance -19
-I got 1. Example 122 a-28-1.5 mmol synthesized in Example 58
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed tightly, and reacted for 40 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 12:1 (2)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.9 g of
Obtained target-20-1. Example 123 a-29-1.5 mmol synthesized in Example 59
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 15:1 (3)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.23 g of
Obtained target-21-1. Example 124 a-30-1.5 mmol synthesized in Example 60
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 15:1 (2)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.18 g of
Obtained target-22-1. Example 125 a-31-2.5 mmol obtained in Example 61
Dissolved in 100 ml of absolute methanol, 50 mmol of
Add butylamine, seal tightly and place on a water bath (10-16
℃) for 3 hours. After the reaction, remove the solvent and aqueous solution under reduced pressure.
The resulting residue was dissolved in chloroform (10
ml) and filled with chloroform.
Place it on a column (100g) and add 150ml of chloroform.
After washing the column with chloroform:methanol
Fractionate the product with 20:1 (4) and concentrate to dryness.
As a result, the target object-23-2 was obtained (1.48 g). Example 126 a-31-1.5 mmol synthesized in Example 86
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed tightly, and reacted for 2 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 10:1 (2)
When concentrated to dryness under reduced pressure, 1.29g of the target substance -23
-I got a 5. Example 127 a-32-1.5 mmol synthesized in Example 62
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 15:1 (3)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.30 g of
Obtained target-24-1. Example 128 a-33-1.5 mmol synthesized in Example 63
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed tightly, and reacted for 2 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 20:1 (3)
When concentrated to dryness under reduced pressure, 1.27g of the target substance -25
-I got 1. Example 129 a-34-1.5 mmol synthesized in Example 64
Dissolve in 100 ml of absolute methanol and place on a water bath (10
up to 50 mmol of dry ammonia gas at ~15 °C)
The mixture was dissolved, sealed tightly, and reacted for 2 hours. Immediately
The solvent was removed under reduced pressure and dried. The resulting residue was 10
Dissolve in ml of chloroform and fill with chloroform
Place it on a silica gel column (100g) and add 300ml.
After washing the column with chloroform,
Fractionate the product with methanol = 9:1 (2)
When concentrated to dryness under reduced pressure, 1.11g of the target substance -26
-I got 1. Example 130 a-35-1.5 mmol synthesized in Example 65
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 15:1 (2)
When the product was fractionated and concentrated to dryness under reduced pressure, 0.16 g of
Obtained target-27-1. Example 131 a-1-4.5 mmol synthesized in Example 7
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
A silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 15:1 (3)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.34 g of
Obtained target-28-2. Example 132 a-1-11.5 mmol obtained in Example 6
Dissolved in 100ml of absolute ethanol. monoethyl
Dry N in 30 ml of amine (70% aqueous solution)2blow gas
The monoethylamine that is mixed in and expelled is removed by dryer.
It was captured in a trap cooled in a chair. obtained
Monoethylamine was vaporized on a hot bath (20-30 °C).
After drying with a caustic soda tube, a-1-11 ethanol
The solution was blown into the solution, sealed tightly, and stirred for 3 hours.
Then, remove the solvent under reduced pressure and clean the resulting residue.
Dissolve in 30ml of loloform and fill with chloroform.
Place it on a silica gel column (100g),
Separate the product using lume: methanol = 50:1 (3).
After drawing and concentrating to dryness, 0.9g of target substance-28-4
I got it. Example 133 30 mmol of a-2-10.5 mmol obtained in Example 9
ml of dry dimethylformamide. mono
Methylamine (40% aqueous solution) 30ml dry N2gas
The expelled monomethylamine is removed by blowing
It was captured in a trap cooled with lye ice. profit
The obtained monomethylamine was heated in a hot bath (20-30℃).
After vaporization and drying with a caustic soda tube, up to 7 mmol
Blow into the dimethylformamide solution and seal tightly.
The mixture was stoppered and stirred for 49 hours. Then remove the solvent under reduced pressure.
and dissolve the resulting residue in 30 ml of chloroform.
silica gel column packed with chloroform
(100g), chloroform:methanol=
When the product is fractionated at 20:1 (3) and concentrated to dryness,
0.35g of target product-29-2 was obtained. Example 134 a-4-1.5 mmol synthesized in Example 28
Dissolve in 30 ml of dry dimethylformamide and add water.
Add 7 mmol of dry ammonia over the bath (10-15℃)
The mixture was dissolved until the volume reached 100ml, sealed tightly, and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing with 300ml of chloroform,
Separate the product using lume:methanol = 15:1 (3).
When concentrated to dryness under reduced pressure, 0.17g of the target product was obtained.
I got 31-1. Example 135 a-5-3.5 mmol obtained in Example 17
Dissolved in 100 ml of absolute methanol. monoethyl
Dry N in 30 ml of amine (70% aqueous solution)2blow gas
The monoethylamine that is trapped and expelled is removed by dryer.
It was captured in a trap cooled in a chair. obtained
Monoethylamine was vaporized on a hot bath (20-30 °C).
After drying with a caustic soda tube, remove the meth from a-5-3.
Blow into the nol solution, seal and stir for 3 hours.
Ta. Then, remove the solvent under reduced pressure and the resulting residue
Dissolve in 20ml of chloroform and fill with chloroform.
Place it on a packed silica gel column (100g) and chromatize.
Product with roform:methanol=8:1(2)
When fractionated and concentrated to dryness, 1.1g of the target product -32
-I got 1. Example 136 a-6-12.5 mmol synthesized in Example 14
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 20:1 (3)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.26 g of
Obtained target -33-1. Example 137 a-7-16, 5 mmol synthesized in Example 19
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 20:1 (3)
The product was fractionated and concentrated to dryness under reduced pressure, resulting in 0.28 g of
Obtained target -34-1. Example 138 30 mmol of a-8-9.5 mmol obtained in Example 24
ml of dry dimethylformamide. mono
Dry N in 30 ml of ethylamine (70% aqueous solution)2gas
to remove the expelled monoethylamine.
It was captured in a trap cooled with lye ice. profit
The obtained monoethylamine was heated in a hot bath (20-30℃).
After vaporization and drying with a caustic soda tube, up to 7 mmol
Blow into the dimethylformamide solution and seal tightly.
The mixture was stoppered and stirred for 48 hours. Then remove the solvent under reduced pressure
The resulting residue was dissolved in 30 ml of chloroform,
Silica gel column packed with chloroform (100
g), chloroform:methanol = 15:1
When the product is fractionated and concentrated to dryness in (3), 0.24
The target product-35-1 of g was obtained. Example 139 a-9-9.5 mmol synthesized in Example 25
Dissolve in 30 ml of dry dimethylformamide and add water.
7ml of dry ammonia gas above the bath (10-15℃)
The mixture was dissolved to a molar level, sealed and reacted for 48 hours.
The solvent was immediately removed under reduced pressure and the mixture was dried. obtained
Dissolve the residue in 10 ml of chloroform and add chloroform.
Place it on a silica gel column (100g) packed with
After washing the column with 300 ml of chloroform,
Raw with chloroform: methanol = 20:1 (3)
When the product was fractionated and concentrated to dryness under reduced pressure, 0.33 g of
Obtained target -36-1. Example 140 Thoroughly dried AI-77-F (Example 3) 5 mm
Dissolve the solution in 100 ml of dry dimethylformamide,
Add 7.5 mmol of pentylamine and cap tightly.
The mixture was stirred at room temperature for three days. After the reaction, remove the solvent and amine under reduced pressure.
The resulting residue was dissolved in chloroform (20
ml) and filled with chloroform.
Place 100 ml of chloroform on a column (100 g) and add 100 ml of chloroform.
After washing the column with chloroform:methanol
Fractionate the product using a ratio of 7:1 (2.5) and concentrate under reduced pressure.
After drying, 0.32 g of the target product V-1-2 was obtained. Example 141 30 mmol of a-3-2.5 mmol obtained in Example 11
ml of dry dimethylformamide,
Add 7.5 mmol of benzylamine and cap tightly.
Stir on a water bath (10-16°C) for two days. After reaction, decrease
The solvent and amine were removed under pressure and the resulting residue was chromatographed.
Dissolve in chloroform (10ml) and fill with chloroform
Place it on a silica gel column (100g) and add 150ml.
After washing the column with chloroform,
Fractionate the product with methanol = 30:1 (2)
After concentrating and drying, the target product-30-1 was obtained.
(0.27g).</sub>

[Brief explanation of drawings]

Figure 1 shows AI in deuterated methanol.
^1H nuclear magnetic resonance spectrum of 77-B, Figure 2 is
Infrared absorption spectrum of AI-77-B with KBr tablets, Figure 3 shows ¹ H nuclear magnetic resonance spectrum of AI-77-F in deuterated dimethyl sulfoxide, Figure 4 shows AI- with KBr tablets. The infrared absorption spectrum of 77-F is shown.

Claims (1)

[Scope of Claims] 1. Amide derivatives of the AI-77 class represented by the following general formula [] and pharmaceutically acceptable salts thereof. (In the formula, Y is the bond between C and C when combined with NHR ₄ or Z, Z is the bond between C and C when combined with H or Y, and R ₁ , R ₂ and R ₄ are Each independently H, R′, -
CH ₂ R, - represents COR, R ₃ is H, R or CH ₂ R
represents. R is methyl, ethyl, n-propyl, n
-Butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-undecyl, n-heptadecyl, isopropyl, 2-methyl-propyl, 2-methyl-butyl, 2-propyl-pentyl, 4-ethyl -heptyl, 2,6,10-trimethyl-tetradecanyl, vinyl, allyl-1-propenyl, 2-propenyl, 2-butenyl, 1.
3-butadienyl, 2-pentenyl, 8-heptadecenyl, 2-methyl-aryl, 2,6-dimethyl-2,6-heptazinyl, 2,6,9-trimethyl-2,6,9-tridecatrienyl, phenyl, Naphthyl, azulenyl, norbornene, norbornane, camphor, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl, phenethyl, 2-phenylpropyl, naphthylmethyl, naphthylethyl, 2.4 -dimethyl-isopropyl-azulenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyranyl, dihydropyranyl, thienyl, tetrazolyl, pyrrolyl, pyrrolidinyl, quinolyl, indolyl, indolinyl, piperidyl, morpholinyl, pyridyl, oxazolyl, oxazolidinyl, thiazolyl, thiazolidinyl, and The above hydrocarbons include chlorine, bromine, fluorine, oxo, carboxyl, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, isopropyl, 3-
Methyl-butyl, isobutylene, propylene, acetylene, phenyl, naphthyl, azulenyl, tropoyl, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, benzyl, phenethyl, 2-phenylpropyl, naphthylmethyl,
p-(3-methyl)butylphenyl, methoxy,
ethoxy, pentoxy, 3-methyl-butoxy,
3-methyl-2-butenoxy, methylthio, ethylthio, 3-methyl-butylthio, pentylthio, methoxycarbonyl, pentoxycarbonyl, isobutoxycarbonyl, acetyloxy,
Propionyloxy, pentanoyloxy, hexanoyloxy, crotonoyloxy, acetyl, propionyl, hexanoyl, 3-methyl-
butanoyl, furyl, dihydrofuryl, tetrahydrofuryl, pyranyl, dihydropyranyl, thienyl, tetrazolyl, pyrrolyl, pyrrolidinyl,
R' is a group selected from the group consisting of those substituted with one or more groups of quinolyl, indolyl, indolinyl, piperidino, morpholino, pyridyl, oxazolyl, oxazolidinyl, thiazolyl, and thiazolidinyl; Represents a group other than the group directly bonded to O or N in the general formula [] as a saturated carbon or tertiary carbon. )however,
Compounds in which R ₁ , R ₂ , R ₃ and R ₄ are simultaneously H are excluded.