JPS5946202A - Antifungal agent - Google Patents

Abstract

PURPOSE:An antifungal agent useful as a drug, for agriculture and horticulture, sterilization for external use, etc., having improved antifungal action, comprising (E)-8beta, 17-epoxylabd-12-ene-15,16-dial as an active ingredient. CONSTITUTION:An antifungal agent comprising (E)-8beta, 17-epoxylabd-12-ene-15, 16-dial as an active ingredient shown by the formula I . The compound is known to occur in the seed of afromomum daniellii belonging to the family Zingiber, and obtained by the following process. A compound shown by the formula II is reacted with KCN, etc. to give a compound shown by the formula III, which is reduced, and reacted with ethylene glycol to give a compound shown by the formula IV. This compound is reacted with diisobutylaluminum hydride, treated in the presence of an acid catalyst, reacted further with a compound shown by the formula V to give a compound shown by the formula VI. This compound is reacted with ethylene glycol, made into an alcohol, subjected to lower alkanoyl reaction, epoxidized, hydrolyzed, and finally treated with an oxidizing agent, to give the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to drag agents. For details on the history, the present invention is
(E)-8β. 17-evo 4; Silab 1: -12-en-15. This relates to a fungicide of the group J, which is characterized by containing -15,16-dial as the J component.

The compound in the above formula (1) is Afromonum danieri (ΔrrOblobllil da
nielli) is known to exist in yuzu [8. F.

Kln+l+u. T. N. Njl+ni.
[3. l-,'SontlenOaIl+.

L.J. A. Aklnnlyi, J. D. G
OIlnQllV, J.

CI+en+, Soc. , Perkin T.
rans, 1.

1303 (1070'>Spring 1 (t). The present defenders,
What are the various physiological activities of the compound of formula (1) above? jl
As a result of extensive research, it was discovered that this compound had an excellent anti-drag effect.The present invention was completed based on this knowledge.

The compound of formula (1) above can be prepared, for example, according to the method shown below.

(2) (3) (4) (5) (6) (7) (8) (9) (In)
(11) (12)
(13) [R' and R2 are the same or different and do not represent a lower alkyl group such as methyl, ethyl, butyl, isopropyl, butyl, or tert-butyl group.

R3 is acetyl, propionyl, butyryl, lower alkanoyl of isobutyryl M'J The compound of formula (2) used as a starting material in the invention is a known compound. From the compound of formula (2), formula (
The reaction in which the compound of formula (3) is converted to the compound of formula (2) in a suitable medium is MCN, (14) where N・1 is 1 to an alkali such as lithium or potassium. Accepts metal atoms. ] is performed. ) A wide range of known solvents can be used as long as they are inert solvents, such as water, dimethyl sulfoxide, dimethyl formamide, hexylymethyl phosphoric triamide, and
? 1 to nitrile, atel, etc.) d-line can be mentioned. The compound of formula (2) has the formula ( 1 lI
The use of the compounds listed above is not particularly determined and can be selected from a wide range; however, it is usually preferable to use a smaller amount of the latter with respect to the former. Equimolar to 24r'r mol culm used per stand is J2.

The reaction temperature of the reaction is not limited to 411, but
KO ~ 8 0 'C 19 degrees, the reaction 'h\ progresses suitably at the lowest temperature culm 1σ, and general (this 2~E'
The reaction is complete in about S hours. In addition, to carry out the reaction 1
If the mixture is mixed, ammonium chloride and ruff i are added to the reaction system.
'＋! Preferably, an ammonium salt such as ammonium is present (7) (preferably). In this way, the 11-colored substance of formula (3) is converted to 11 so4!I.

Reaction 1 is carried out by converting a compound of formula (3) into a compound of formula <lI> o) IL; Used; As a υ primary catalyst,
Widespread use of ordinary reduction catalysts < 11t! A river is made of palladium, for example, 1096-palladium! It can heat a 19-way catalyst of water, Raney nickel, and platinum pi. As for the precipitation of the reduction catalyst, the normal amount of catalyst is J. In addition, as long as the d medium is inert (as a solvent), a wide range of known ilJ media can be used.
Ethers such as TeI-lahydrofuran and the like can be mentioned. Reaction of the reaction) Although the temperature is not limited to 1.r, the reaction normally proceeds suitably at a temperature of about 0 to 50'C, preferably at a seedling drought rate, and is generally 2 to 811. The reaction is completed in about ¥200. Thus, the compound of formula (4) yields +4?
be done.

The reaction of forming the compound of formula (5) from the compound of formula (4) involves reacting the compound of formula (4) with ethylene glycol in the presence of an acid catalyst. Acid catalysts used include, for example, I)-1-l:[sulfonic acid, Ben 1! Sulfonic acids such as ethanesulfone M, ethanesulfonic acid, hydrogen gas, ry? ! h! ! You can use it to spread mineral acid, etc. Regarding the usage ratio of fl-A substance and ethylene glycol in formula (4), it is possible to select 3i!i as appropriate from a wide range of 7i! Equimolar reciprocity, preferably - is 1 to 2
It is best to use twice the molar amount. Further, as a solvent, a wide range of known solvents can be used as long as they are old-fashioned solvents, such as Ben 1! Aromatic carbonized homeols such as
Examples include t. As a reaction preparation for this reaction, especially all l! I+! The boiling point of medium B (usually) is close to f', good #niji < L, L 80~120'
The reaction proceeds suitably at about C, and is generally completed within 1 to 6 cycles. In this way, the compound of formula (5) was obtained +1
be done.

Compound iJr of formula (5) 111 Compound 4 of formula (6)
- The reaction obtained is appropriate 1. The reaction is carried out by reacting the compound of formula (5) with diisobutylaluminum diF, "Zumji1;Su1:" in a KFU medium. The proportion of hX to be used can be appropriately selected from a wide range without any particular limitation. It is possible to use a wide range of well-known a) media as long as they are inactive as Ir media, such as saturated hydrocarbons such as 11-hexadi, cyclobexane, etc. The reaction temperature for this reaction is not particularly limited, but is usually about -70°C to V temperature, preferably -70°C.
~-20℃! ! i! The reaction progresses suitably in about 30 minutes to about 5 hours, and is generally completed in about 30 minutes to 5 minutes. Thus, the formula (6
) is collected (U).

The reaction of converting the compound of formula (7) from the compound of TC(6) (η) is carried out by treating 1L of the compound of formula (6) in a suitable a medium in the presence of a r1! catalyst. Examples of acid catalysts include lower 11tj acids such as acetic acid, trichloro, etc.
nh acid, hydrochloric acid, 1. Mineral acids such as IIi acid can be used. The amount of the acid catalyst to be used is not particularly limited and can be appropriately selected within a wide range.
A wide range of known d-medias can be used, as long as they are inert as d-medias, such as acetic acid, propion, li! 1st place 11 (
Examples include water-containing (water-containing) k1 media such as pine fatty acids, diochirin, ethers such as tetrahydrofuran, and the like. As a reaction skin for MA reaction (although not limited to J waiting time, the reaction normally proceeds suitably at room temperature to 120°C, preferably about 50 to 90°C, and the reaction generally takes about 10 minutes to 2 hours. The compound of formula (7) is thus obtained.

The reaction for preparing the compound of formula (8) from the compound of formula (7) is carried out by adding the compound of formula (7) in an appropriate solvent to the compound of formula [where R1 and R
Ir1J in front of 2μ. Pl+ does not represent a phenyl group. ]
Line 7J i by reacting the compound represented by
) will be. The ratio of the compound of formula (7) to the compound of formula (15) is not particularly limited and can be appropriately selected from a wide range, but usually, if the latter is less than the former, it is preferably equal to b equimolar. is equimolar to 2 ifs moles to 1 Gishigawa Riruru lJ (J: I. Used) As the U medium, a wide range of known solvents can be used as long as they are inert 111 U medium,
ISl is a mixture of benzene, toluene, etc. V1 ridge 1 water 1
7 knowledge etc. can be mentioned. 'Reaction of nuclear reaction) A degree is not particularly limited, but the reaction normally proceeds suitably at about 50 to 150°C, preferably about 70 to 100'C, and the reaction is generally completed in about 10 to 30 hours. do. A compound of formula (B) is thus obtained.

The reaction to obtain the compound of formula (9) from the compound of formula (8) is
The reaction is carried out under the same reaction conditions of t as the reaction in which the compound of formula (5) is subtracted by 1 from the compound of formula (4).

The reaction of converting the compound of formula (10) from the compound of formula (9) is carried out by reducing the compound of formula (9). The reduction catalyst used may be, for example, lithium aluminum hydride. The reduction catalyst to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually at least equimolar to the compound of formula (9), preferably equimolar to 21Δ
It is best to add about 1 molar amount. In addition, as the 8 medium, the well-known a medium can be widely used as long as it is an inactive t & W.
Examples include ether-'31 such as diethyl ether and tetrahydrofuran. reaction)
! #α is not particularly limited lr (, 1) 10°
0~Fuetsut! i! (preferably seedlings)! f at culm tft
The reaction proceeds suitably and is generally completed within a range of about 1 to 501 times.

In order to obtain the compound of formula (11) from the compound of formula (10), first the compound of formula (10) is subjected to a (I(class) alkanoylation reaction, and then the compound (U) is subjected to a 1112-digit alkanoylation reaction. BJ: I.11 (class alkanolization reaction I
The reaction is carried out by reacting a lower alkanoic acid halide with a compound of formula (1o) in the presence of an In-based compound.
Compound 0) and 11(class alkane 1)
There are no particular restrictions on the level of alkane-brewing halides, and you can choose from within a wide range of r+' i)I, but it is usually about 2 times the molar amount compared to first users, with a small amount of limestone. , preferably for 2 to 5 cultured Mor. culm E stool - Rirunolf
i J: Yes.

The salt compound used is 1'', 1 silicate is 11-
Tertiary amines such as dimethylaminopyridine, pyridine, and triethylamine can be mentioned.

In addition, as long as the solvent is inert, known f
& W can be widely used, for example, pyridine, tertiary amines such as I-ethylamine, aromas such as benzene, toluene, etc. 1■ Hydrocarbon water, geogly! Ethers such as Nan, tetrahydrofuran, etc. can be used as 4'-groups.

As the reaction temperature of nuclear reaction is 1 m, III is not particularly limited, but
Toriya O-・70°C culm, preferably chamber) 1" culm [
The reaction proceeds over 7 times, and the reaction time is generally about 3 to 15 hours, approximately 11 hours. l1f of the compound thus obtained
In the 2-kekyl synthesis reaction, the compound of formula (6) is converted to formula (7).
Four reactions were carried out under similar reaction conditions to those for obtaining the compound.

In order to obtain a compound of formula (12) from a compound of formula (11), first the compound of formula (11) is subjected to an epoxidation reaction, and then the compound of formula The epoxidation reaction can be carried out using the appropriate 'j: :i:
This is carried out by reacting the compound of formula (11) with trimethylsulfonium-r-lide reagent in a medium. Trimethylsulfonium-r 1! 81℃ drug is 1 shi 1 example 1
Helimethylsulfonium a-rodder CF, thorium hydride and dimethylsulfonyl 1: to Ll! Manufactured. 8. (The use of chickens etc. is not particularly restricted and can be varied within a wide range, but the usual method (11)
) is at least equimolecular, preferably
IJ equivalent mole to 21 mole amount of culm (good.J:
As the medium, a wide variety of known solvents can be used as long as they are inert solvents, such as dimethylsulfonate, tetrahydrofuran, etc. The reaction temperature is not particularly limited, but the reaction preferably proceeds at a temperature of 130°C to room temperature (about 1η).
The stroking reaction is complete. So +4? The 11(class) alkanoylation reaction of the compound is expressed by the 11rE formula (1
0) 111-class alkanolization reaction of the compound (
Co1 reaction column 1'1. Do it below J: No. After 1υi, the compound of formula ('+ 2 ) is sipped.

Compound lI of formula (13) from compound Δ of formula (12)! 4 J
i? The reaction is 3U'':h/.'r.Lhs1(
A compound of formula ( 1 2 >) is hydrolyzed in the presence of 1). The substances used include, for example, carbonic acid 1-1, carbonic acid Δ (water-boulium 1-lium,
Basic compounds such as potassium carbonate v/J, etc./metal are used.

The use of such a catalyst may be as follows: -Catalyst M.

As the solvent, a wide variety of known solvents can be used as long as they are inert solvents, such as water and lower alcohols such as methanol and ethanol. reaction + of the reaction
There is no particular limit for p + η and 1, but it is usually extremely thirsty ~ 50
The reaction progresses suitably at about 1°C (1°C, preferably seedlings), and is generally complete in about 1 to 5 hours. i do

A compound of formula (13) is obtained.

The reaction to obtain the compound of formula (1) from the convex substance 11' of formula (13) is carried out using a dimethyl sulfoxide activated reagent as an M stopper.

Such 81 (in medicine, for example) can be combined with an activator such as fluoro61 acid anhydride or oxalyl chloride and dimethyl sulfoxide.

The deactivating agent and dimethyl sulfoxide are treated in an inert medium such as 1-luene or platylated ethynone. l! By doing so, Ayu and Jirko are made. Place 1M! Temperature and treatment time are not particularly controlled, so the temperature should be about -78 to -50°C, and the treatment should be carried out with a stone for about 30 minutes to 2 hours. 1iI made in this way
Adding 110 of the compound of formula (13) to taIi, usually -7
It is good to maintain the culm 1α reaction for 30 minutes to 2 hours at a temperature of about 8 to -50°C. For the compound of formula (13), 1! In II's ′□ as appropriate within a spacious 0 area without oral control + Ul! However, it is possible to use the above-mentioned deactivator and dimethyl sulfoxide (at least 218 mol each (twice, preferably 3 to 51 Δ
The mole Iiii culm degree is J. Then this reaction flk
Add an excess of 1-realkylamine such as 1-lyntylamine or triethylamine to
J: If you react tf& to ili: and maintain the fertility for 30 minutes to 2 hours. In this way, the desired compound of formula (1) is
i! ! Can be built.

The compound of the formula (1) thus obtained can be easily prepared by completing the above-mentioned reaction steps (22 to 1). )
It is possible to obtain d-media Sendeho, Kalamuku [171~Graphie, Steam U, etc.].

The antifungal agent containing the compound of formula (1) as an active ingredient in 4 is used for medicine, agriculture, horticulture, external sterilization, etc.

When used as an antifungal agent for medicine or orchid, it is usually used in the form of a general pharmaceutical preparation. The product All is prepared using commonly used diluents such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, or pjt excipients. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, emulsions, powders, liquids, emulsions, granules, capsules, suppositories, etc.
J agent (liquid agent etc.) Kasa is mentioned. When forming a tablet into a tablet, a wide variety of carriers known in this field can be used, such as lactose, white sugar, kawakasu 1-lium, grape pongee, and I7! Water, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicon, water, ethanol, propatool, simple syrup, grape pongee, starch wave, gelatin solution, carboxymethylcellulose, t'!
Lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, alginium, agar powder, laminaran powder, carbonated water, calcium carbonate, ethylene sorbitan Fat nh h! v esters, lauryl Llt
la 1-rium, stearin late monogly [lido, starch, milk ti! iV disintegrants, white sugar, stearin, cocoa butter, hydrogenated oils, etc. 161 disintegration inhibitors, Part A i
llll ammonia 1 unit, absorption of lauryl sulfate, lithium, etc. (♀ general rule, maintenance of glyc t! phosphorus, starch, etc.) 0 agent, starch, milk clot, power A phosphorus, ben I night, colloidal silicic acid $ 1 stalactite, loaded talc, 1 stearic acid
IA can be shown by Hi-brightening agents such as lubrication, oxidation, polyethylene glycol, etc. Zaraani tablets may be coated with a 1r1N coating as required, such as a coated tablet, geladine cuff tablet, biliary tablet, film-coated tablet, or 1. locked,
It can be called a multilayer tablet. When molding into the emulsion form Tdi, a wide range of conventionally known substances can be used, such as grapes, milk, starch, cacao, etc.
Examples include excipients such as , hydrogenated vegetable oil, kaolin, and talc, disintegrants such as arachia gum powder, tragacanth binder, and laminalan agar. When forming the suppository form fa+, a wide range of conventionally known carriers can be used, such as poly]-dylene glycol, cacao 118, higher alcohols, esters of higher alcohols, gelatin, and semi-containing glycol t2. Rai 1:
I can think of things like. Note 4: When prepared in bulk, the solution is preferably sterilized and isotonic with white oil. All commonly used ones can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, and the like. Jj, in this case the isotonic solution is Xl 1-! A sufficient amount of omega for agricultural purposes, grapes, or glycerin may be added to the national prescription preparation, and conventional solubilizing agents, uu agents, soothing agents, etc. may be added. Furthermore, if necessary, Shichibu agents, preservatives,
Flavorings, flavoring agents, flavoring agents, etc. and other VAaIi products should not be used medically.
It's hard to keep it in your mouth. Base (~, when forming into cream and gel form, use diluents such as white wax, paraffin, glycerin, 1 thick of cellulose, polyethylene glycol, 1 thick of silicone,
Pen 1 to Knight etc. can be used.

The ω of the compound of formula (1) to be contained in the anti-strain agent of the present invention is not particularly limited and may be selected from a wide range (as appropriate); % What to do 11~
J: Yes.

The method of administering the antifungal agent mentioned above is not particularly controlled; it can be administered in one manner according to each (!I!! EJ formulation, desired age, gender, condition of the song, and the patient's level of control). For example, in the case of tablets, emulsions, solutions, emulsions, 1131 grains, and Cabrel's tablets, it is administered by oral route.In the case of 11:r+J tablets, it is administered alone or with regular replenishers such as grapevine, amino acids, etc. etc.) Knead and administer intravenously, and if necessary, administer alone intravenously, intradermally, or subcutaneously. In the case of suppositories, it is administered straight into the mouth, and in the case of soft tablets, it is administered in a line.

The administration date of the above-mentioned National Standards tJ drug is selected as appropriate depending on the usage, age, sex and other conditions of the patient, degree of disease, etc.
jAlfi of the compound of formula (1), which is usually a "component"
I FI t') (411i 1 k(1"i about 0.
2-100nIO Toriruno 7)\Good.

In addition, when used as an antifungal agent for exhibitions, the formula (1
) can be mixed with a carrier known in this field and sprayed.

The antifungal test results, a manufacturing example of the compound of formula (1), and an example of uA are listed below.

Antifungal assay In order to investigate the antifungal effect of the compound of formula (1) on 1!11 bacteria, the minimum growth rate of 111 was determined by the agar dilution plate method [CHEMOTI-IEflAPY. 22.1 1 26
1128 (1974)]. The chestnuts that can be treated with li+ are shown in Table 1.''!J-.

Table 1 Sample iMl Minimum j-inhibition depth 1 (l'' - 1) Saccal'ollyces OOI'f3V
ISlae O,' 7 8Scblzos
accl+arolyces p01111N3
Q, 3(1)+1an! ienLIIa an
ou+ala 1, 5 6C
anditla uLllia
1, 5 6Sclero+11a l
lllor mouth ana 3.13 Mucor
mucado 2 5R b
Izopus chlnensis l
2, 5Aperc+illus nlower
1 2, 5 Peniailliu
mcrustosum
6. 25 Production Example (1) Production of compound of formula (3) Potassium cyanide 1.30 and ammonium chloride 800
111CI to water 101 dimethyl small lumamide (Dfv
IF) miV to ULIIlj of 601. lJi 1
Compound 20 of formula (2) was dissolved in a small amount of DMF at room temperature (18°C) in fJ solution. 50 at Doon Mausoleum
．． ! After stirring for 1 day, add 1,201,111 liters of water, and then extract with ether. Wash with saturated saline and rlI! After drying with thorium, concentrate under reduced pressure.

The residue was purified by 1ti1 layer chroma I-graphy (developing solvent ether-f\kizan (v/v) = 1:1) to obtain the formula (
3) compound 2.20 to 1! I. N of the resulting compound
MR spectrum diagram (100Mt-1z, CCI,...
TMS) is shown in FIG.

(2) Production of compound of formula (4) Compound 2501u (1(
1.1 mmol) is dissolved in 81 ml of ethanol. 10
Add 96 palladium on charcoal and 101 O, and heat to 51'1. ¥1itJv! do. The filtrate was concentrated under reduced pressure to obtain compound 254b of formula (4).
NMR spectrum of the resulting compound (100 Ml-1z.

ccl,,TMS) as shown in Figure 2.

(3) Preparation of compound of formula (5) Compound 23711 of formula (4) obtained in step (2)
10 (1.01 mmol), ethyl non-glycol 69
(1) Dehydration of 0 and 11-1 to luenesulfonic acid was carried out in 6 ml of bempine for 3.5 hours. Add 10% carbonated water under water cooling and add 10%
Stir for 1ii11+i minutes. Extract with 50 ml of 1-chill, wash twice each with saturated JM water, 92% with 1-lium sulfate;
NMR-spectrum diagram of the compound (60M IIZCCI 4.T
MS) is shown in Figure 1'43 J0 (4) (1 of equation (6)
Preparation of Compound 1 In the above process, 303 mg of 11-compound of formula (5) was diluted with JB 1112 water,
II) d solution 1'. Step 4: Heat the d solution to -70°C and diisobutylaluminum liquid L'0.60.
Add 2ml and leave at the same temperature for 30 minutes! 1 degree.

Furthermore -45~30℃T'3 II! fliu IR stirring (long, saturated 411 Add ammonium 101 and stir for 20 minutes 1 til IJl. 596 rl Ken'3, 5
Add +++ l and extract with ether. Wash once each with saturated white water and saturated saline, and remove the residue using thin layer chroma 1~graphie (developing medium ether-hexane (V/V) -1:1). Compound 2.851110 of formula (6) is obtained. NMR spectrum of the obtained compound (100M1iz, CCI,.

TM S) is shown in FIG.

(5) The compound of the formula (6), which is 1.0 of the compound of the formula (7);
% M1 acid dissolved in 20 ml under argon atmosphere) 75 h
Heat at ~80'G for 25 minutes. Add the powder to the mixture under water cooling and extract with ether. Rinse thoroughly (5 times with saturated water and once with saturated saline), then dry with 1-lium sulfate and compress. 1W layer chroma 1~graph (
111 solvent ether-hexane (V/V) = 1:
1) and 1! The compound of formula (7) is 1.56! ] to (iIru.

(6) Production of compound (R'-1t2-methyl) of formula (8) Compound 10 of formula (7) and formula (15
3.90 of the compound (RI = 11”-methyl) of ) was dissolved in anhydrous bempine 201), then 2 d in a stream of argon.
0 hour'rW flow - Re'. After 6 acupuncture incisions, column chromatography 1J1 (power 1J - ether (V/V) = 3:
2) Compound of formula (8) (Ill-112-methyl) E396h+oti-1. NMR spectrum of the compound subjected to ltI (100tvlHz, CC
I 4 , TMS) are not shown in FIG.

(7) Production of compound 'IIJ of formula (0) (R' = 11'' methyl) 806 mg of the compound (R1-R2-methyl) of formula (8) 1iI above, 108 mO of ethyl non-glycol
And p-1 ~ Ruensulfon 椴0011Io bent t!
Dehydration is carried out for 3.5 hours in a tank 30b+1. IJ under ice cold! Add the powder and stir for 10 minutes. Extract with ether 501,
Wash twice each with saturated water and saturated warm water, then brew 1-
The compound of formula (9) (R' = i12-methyl) is obtained by drying with sodium hydroxide and concentrating under reduced pressure. N M r<spectrum diagram of the compound to be lidded (100 MHz,
CCI,, TMS) is shown in FIG.
Lithium aluminum hydride 7118Ill under stirring! 1
was added and reacted for 20 minutes at a variable temperature for 311'1.Next, it was extracted with ether, and the extract was poured into a filtrate using the formula (10).
The compound is obtained. The compound is used as is in the next reaction.

(9) Compound of formula ('+ 1 ) (R3-aretyl)
Compound 8 of formula (10) obtained by Me1zo'2, pyridine 10b
+I and anhydrous vinegar l11121Pjζ After cooling down at night,
The JIJ medium was distilled off under reduced pressure, and then water was added and extracted with ether. ? After washing with lS river acid, washing with water + 'fi, the ether notification is applied to the deep 1+il C1, and it is converted into a (?del) 1.:
Compound 1>).

Then, the 11-compound was added to 1d1 of 50% vinegar (to 3r++1).
i) F MV, 25 at 75-80°G in argon flow
Heat for a minute. Under ice-cooling, the 117-so powder was added with λ and extracted with ether. Wash thoroughly with saturated water 5 times and saturated saline, then dry with thorium.
1+1f-Iiru. (remaining) 1 1 Δ ri I] 7 tographie (1 jil iB medium ether hekylin (■, ′
Obtain the compound (R3-a(gochino) 8!'s 2n+g) of formula (11) by observing the iN with a Sifu 1:1).The spectrum diagram ( 100
Ml-1z.

CCI, Wang MS) is shown in Figure 1'17.

(10) Compound 4>J (It ” =' of formula (12)
71= ri r'r freezing of 11-storium 22 b+ (J and U dimethyl sulfoxy i' (1) MSO) 1, zl mountain l'27j
Heat to 70-80'C in a stream of -C for 30 minutes. Add all 1 product of the Iah hair (restored twice, 'Tsume 1-1 Niji Tan 6n11. Then add the 11y hair to -10 ~
--2(')' Cold D to C, trimethylsul'J 4 nIQ'D D MSo 1, 4 1+
Add fk 'k 3 min Ni' L -C to lI. After stirring for 5 minutes, add 144 mo of dimethoxyethane 2.5 b + l solution of formula (11) (tI) in 30 seconds.
After stirring for 10 minutes at 8 degrees, remove the water bath and stir for 1β for 50 minutes. Add water-cooled sewage 301 and extract with ether. Washed three times with saturated saline solution) - dried over sodium sulfate and concentrated under reduced pressure. Dissolve the residue in pyridine 31 and transfer to anhydrous Y
Add 0.7 ml of acid, stir the reaction mixture for 6 hours, concentrate, and then extract with ether. Add 1 dilute salt to the ether layer
1! ! , After washing with water, columnar [1
71・Separation (hekilyne-ether (v/v)-4:1
) and the compound of formula (12) (R3-acetyl) 4 1
11IO to 1#I.

N M R subvec 1 - UA (1
00MI-1. z , CCI t , TMS) as the eighth
As shown in the figure.

(11) Production of compound of formula (13) Compound (113-a[
Dell) 4 I nlft Charcoal N 7J IJ 6 0
mg, 4.5+nl of 1 nor and 611+1 of water and stirred for 3 minutes at 30°C. Next, it is neutralized with dilute maric acid and extracted with ether. The ether Its was washed with water, and the solvent a) was distilled off to obtain the compound of formula (13). The compound was subjected to the following hexagonalization treatment after 92 bombardments with MOLE 4: URASIBE.

(12) Production of the chemical compound of formula (1) DMSO3 1 , 4 + aliJfJM mef l//
('1.1ml IC, iu dissolved, cooled to -50°0 711-!I'. 1-' for the run) Full: 41
-17a (7J<hVh16 3 , 5moe 1
Divide into 0 and add. 100il JP Mu, 1 mlidR of methionone chloride of the compound of formula (13) obtained by
Add the shiitake for 10 minutes. After stirring at the same temperature for 30 minutes,
O,'I5mlσ) l-ly2ethylamine was added over 3 minutes and then stirred 1iX for 40 minutes at room temperature. Add saturated mv1 water to the water-cooled mixture and perform ether extraction.

(twice with saturated saline) 81, sulfuric acid! b. 1 pressure) Mu persimmon 1jn, :i spear 1. ,J'A Hekirien-Etheno I
J (V/V)=11) for 1 h to obtain compound 14 of formula (1).
Obtain m□. NMR spectrum diagram of the obtained compound (100Mtlz, GDCIg, TMS)
Please refer to Figure 9.

Formulation example 1 Compound of formula (1) 100g Abishel (trade name, Asahi Kasei (14) 14) 40 (1
Cornstarch 300° Magnesium Stearate 207O-51
0゜ (Product name, Shin-Etsu Chemical Co., Ltd. (1), Human [1-xypropyl methylcellulose) polyethylene glycol-600030 Himashiura
400 methanol
4O.

Take the compound of formula (1), Abishel, starch and magnesium stearate and 111! Combined rJI IFr
Compress the tablets with a Uj Choi R10111bl machine. TO-5, polyethylene glycol-600
A film coated tablet of the above 111 J was prepared by coating with a film coating agent consisting of castor oil and methanol.

Formulation Example 2 Compound 8 of formula (1) 21Jin
Lanolin 5° coarse beeswax 5° white petrolatum
Add 88゜υ lassi beeswax
(LA 1)), then the compound of formula (1),
Add purified lanolin and white walnut and heat until it becomes liquid (h) Stir until it begins to solidify, then add 1 cup of the above 4ml composition soft mouth preparation.

[Brief explanation of the drawing]

FIG. 1 is a N NII R spectrum diagram of the compound of formula (3,). Figure 2 shows that N M r< of the compound of formula (4)
It is a block diagram. Koma 3 diagram shows N of the compound of formula (5)
FIG. 1 is a diagram of MRS vectors. Figure 4 is an NMR spectrum diagram of the compound of formula (6). Figure 5 shows the formula (
8) N lv of chemical compound 8 (RI = r12-methyl)
It is an lR spectrum diagram. Figure h'16 is here: (9)
It is an NMR spectrum diagram of the compound (R1-112-methyl). FIG. 7 shows the NN/IR spectrum of the compound (R3-acetyl) of formula (1'l). Figure 118 shows the NMR of the compound (R3-aretyl) of formula (12).
It is a spectrum diagram. Figure 9 shows the N of the compound of formula (1).
It is an MR spectrum diagram. (Above) Attorney °1-3 1. ′! Eiji.

Claims (1)

[Claims] (E)-13β, 17. -: A group J fungicide characterized by containing r-boxyrabdo-12--V and c-15.16-dial as active ingredients.