JPS6259259A - Intermediate for synthesis of echinocandin and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H or t-butyldimethylsilyl; R<2> is H or tetrahydropyranyl; R<3> is H or t-butyldimethylsilyl; A is OH, pyridinethiol, etc.; B is H, t-butoxycarbonyl, etc.). EXAMPLE:( 2S, 3R )-N-( t-butoxycarbonyl )-2-amino-3-(tetrahydropyranyl)oxy- 4(t-butyldimethylsilyloxyphenyl)-butyroyl-O-(t-butyldimethylsilyl)-thr eonine pyridine thioester. USE:Synthetic intermediate for echinocandin. PREPARATION:The objective compound can be produced by dissolving the threonine derivative of formula II in an organic solvent such as DMF, adding trimethylsilylamidazole to the solution and adding the homotyrosine derivative of formula III thereto.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Field of Application The present invention relates to the general formula (1) (wherein R1 represents a hydrogen atom or a t-butyldimethylsilyl group, R2 represents a hydrogen atom or a tetrahydropyranyl group, and R3 represents hydrogen) It represents an atom or a 1-butyldimethylsilyl group, and A is a hydroxyl group.

Pyridinethiol group or 0NH2 B is a water atom, t-butoxycarbonyl group or D
represents a hydrogen atom, a benzyloxycarbonyl group or a group) t! The present invention relates to an echinocandin synthetic intermediate having L-)=S) and a method for producing the same.

More specifically, the compound having the general formula (1) is a synthetic intermediate of echinocandins having antiyeast and antifungal activities, and has the potential to be widely used as an antibacterial substance in the fields of medicine and agrochemicals. be.

Prior art Echinocandins have been isolated from a few fungi of the Aspergillus genus, have strong anti-yeast and anti-fungal activities, have low toxicity, and have been shown to be useful as pharmaceuticals and agricultural chemicals. It was highly anticipated.

The structure and production method of echinocandins and acreasin are described in Tetrahedron Letters.
etters) pages 4147-4150 (1976)
, Helvetaker Kimika Acta (Helv, Cht
m.

Acta) Vol. 62, p. 1252 (1979) and Japanese Patent Application Laid-open No. 160301/1983.

Cyclic antibiotics such as echinocandins and acreasin are difficult to synthesize by cyclization and by difficulty in synthesizing the abnormal amino acids that form each of the 7 fragments.
Conventionally, it has not been lightly synthesized.

Although the above publication discloses the compound, there is no example of its chemical synthesis, and it is important and desired to synthesize a derivative of the compound and apply it in the fields of medicine and agrochemicals. .

[Problem that the invention seeks to solve]

An object of the present invention is to provide iptide, which is a precursor of echinocandins, and derivatives thereof, by synthesizing constituent amino acids of echinocandins.

Means for Solving the Problems The compound of general formula (1), which is a novel substance of the present invention, can be synthesized by the following method.

That is, 1 formula (3) Dissolve the threonine derivative with an organic solvent.

By adding trimethylsilylimidazole (TMS Im) and then adding a homotyrosine derivative having the formula (2), a peptide bond is formed and the compound of the present invention having the formula (1θ) is obtained.

Any organic solvent may be used in this reaction as long as it does not participate in the reaction, but amide solvents such as methylformamide or dimethylacetamide, and ether solvents such as dioxane and tetrahydrofuran are preferred. Trimethylsilylimidazole used as a condensation reagent is compound (3)
It is best to use 2 parts per volume, but 1 to 2 equivalents may be sufficient.

The reason why 2 equivalents is optimal is considered to be that compound (3) reacts with this trimethylsilylimidazole to produce trimethylsilylamide and trimethylsilyl ester, and this reacts with the active ester to produce a peptide.

For example, when the protecting group of this compound (1θ) is treated with trialkylammonium fluoride, the compound of the present invention having the formula (1f) is obtained, and when this compound (1f) is treated with an acid, the compound having the formula (1g) is obtained. A dipeptide compound of the present invention is obtained.

Examples of acids used here include hydrochloric acid, 1:l-toluenesulfonic acid, camphorsulfonic acid, and hydrobromic acid.

By reacting the compound of formula (1e) with an equivalent amount of triphenylphosphine and an equivalent amount of 42'-dipyridyl disulfide in a hydrocarbon-based or aromatic hydrocarbon-based solvent, a compound having the general formula (1h) can be obtained. A pyridylthioester compound of the invention is obtained. In this reaction, the degree of one reaction source is preferably 50°C to 10°C.

By treating this compound (1h) with 4-methyl-3-hydroxyprolinamide in an organic solvent in the presence or absence of a base, a 6-putide bond is formed and the formula (
11) The compound of the present invention having the following formula is obtained. The base used in this reaction is preferably a trialkylamine, and the solvent is preferably an amide type solvent, but there are no particular limitations as long as the solvent does not participate in the reaction.

The protecting groups for the hydroxyl group and abano group of this compound (11) can be removed with a weak acid. For example, the formula (1j
] An echinocandin synthetic intermediate, which is the peptide 9 of the present invention having OH 2 , is obtained.

This compound has 4-hydroxyproline and general formula (4
) can be synthesized from formula (1k ) The echinocandin synthesis intermediate of the present invention having OH is obtained.

The benzyloxycarbonyl group of this compound (1k) is removed under general deprotection conditions using noradium-carbon and hydrogen gas to obtain the compound of the present invention having the formula (11).

By treating this compound (1k) and the 4-hyPOxyglutamic acid derivative (6) with the above-mentioned condensing agent, the compound of the present invention having the formula (1m) is obtained.

Next, a method for producing the amino acid used in the present invention will be described.

Some of these compounds were approved by the Tohoku Branch of the Pharmaceutical Society of Japan in 1982.
One of the inventors of the present invention made a presentation at the 107th annual general meeting (February 16, 1985).

First, β-hydroxyhomotyrosine represented by formula (2a) can be obtained by the following synthetic route.

αη+ A compound having this compound (2a) can be obtained by using the above-mentioned dipyridyl disulfide and triphenylphosphine.

4-Methyl-3-human 90xyproline is a known compound (
H, NA, GAOKA et al. Tetrahedron 37
Volume 3873 (1981)) is obtained from a compound of the formula (force) by the following synthetic route.

This (28,3S,48)-4-methyl-3-hydroxyproline is [α)D-27,0° (H20).

The melting point was 260°C.

(28,4R)-4-hydroxyproline used in the present invention is described in Journal Ono Organic Chemistry, Vol. 42, 3440 Sada (1977). Furthermore, the synthesis route for the 4-hydroxyglutamic acid salt conductor (6) is shown below.

NHcOC□7H3□3) Protection The thus obtained (28,4R)-N-lylyl-2-amino-4-(t-butyldimethylsilyl)-oxy-55-:)methoxyR-ntanoic acid methyl ester is as follows: It has the following properties.

Properties: Oily substance [α) D knee 8.3° (C-0,7,CHC/3) Engineering R
Spectrum (film, cm): 3280°175
0.1650 square meters (m/Z): 551 (M +
-CH30H) NMR spectrum (CDC13, δ):
0.06 (6H=S Lo, 88(9H,S)
, 0.88 (3H, b days).

i, io-1,60 (16H, mL 1.80-2.
30 (6H, m), 2.76 (2H, m)t3
．． 38 (3H, e), 3.40 (3H, s).

3.70 (3H, S), 3.80 (IH, da.

J-5t 10 H2), 4.16 (I Hlm
).

4, 82 (I Hy m ) y 5-12-5.5
0 (4H.

m), 6.36 (IH, d, , T-8H2) Examples Example 1 (2S, 3R)-N-(t-butoxycarbonyl)-2
-Abano-3-(tetrahibilobin2nyl)oxy-4(
t-Butyldimethylsilyloxyphenyl)-phthyroyl-0-(t-buF-rudimethylsilyl)-threonine pyridine thioester 0-(t-butyldimethylsilyl)-threonine (0.15 mmol) was dissolved in anhydrous N , N-dimethylmethylmuamide α3auKw! A cloudy,
Add 44 μA (0.30 mmol) of trimethylsilylimidazole and stir for 1 hour at room temperature under a nitrogen stream.
After making a colorless and transparent solution, (28,3R)-4- to -butyldimethylsilyloxyphenyl)-3-(2-tetrahydropyranyl)oxy-2-N- to -butoxycarbonylaminobutyric acid-2-pyridylthiol Ester45.
Add a solution of 5 μm (0,076 mmol) of anhydrous N,N-dimethylmethimabad (0,7111 μmole) and add 15 μm (0,076 mmol) at room temperature.
Stir for hours. Water was added to the reaction solution, the pH was adjusted to 4 with IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to obtain an oil.

Without purifying this oil, use anhydrous dichloromethane.
5t/combined, triphenylphosphine 23.8■ (
0,091 mmol) and dipyridyl disulfite”
16.71 FW (0,076 #remol) was added, and the mixture was stirred at room temperature under a nitrogen stream for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting oil was subjected to silica gel column chromatography [eluent: ethyl ether-n-hexane (1:1
)) to obtain the title compound 38.91+11i1.

(Yield 63%) Properties: Oil NMR spectrum (CDC13, δ): 0.01. 0
．． 05 (3He B each), 0.16 (6Hs s L
o, 88. 0.90 (8 each. 9H in total).

0.95 (9H, s), 1.14, 1.20 (each a,
J-5Hz, aH)t 1.48 (brst9
H), 6.72, 6.73 (each a, IIT=8H2゜2HL 7.09 (2H, d, J-8Hz).

7, 16-7.80 (3H, m)e 8.59
(IH.

tl, J-5Hz) Example 2 (28,3R)-Nt-nodoxycarbonyl-2-amino-3-tetrahydropyranyl-4(4-t-butyldimethylsilyloxyphenyl)-phthyroyl-0- (
t-Butyldimethylsilyl)-threonyl(28,3
8,4S)-3-hydroxy-4-methyl]-2-pyrrolidinecarboxamide 52.5 mg (0,064 mmol) of the compound obtained in Example 1 in anhydrous N,N-:,>methylformamide (C15
-) solution of the compound 20 (0,139
A solution (0.5d) of the same solvent (mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour under a nitrogen stream. The reaction solution was concentrated under reduced pressure, and the resulting oil was subjected to silica gel chromatography, pyridinethiol was eluted with ethyl ether, and the title compound was eluted with ethyl acetate, and concentrated under reduced pressure to give 43.5 mm.
I got it.

(Yield: 80 cm) Properties: Amorphous crystal IR spectrum (chloroform, σ): 3530-3
020.1695 751. ((M1H)+-t-butquine carbonyl) NMR spectrum (CDCA'a, J): 0.
05-0.20 (12H, m), 0.89 and 0.90 (
each 8°9H), 0.96 (9H,s)t 1.0
3 and 1.06 (each d, 3H, J-6H2) t 1.
20 and 1.23 (each d, 3H, J-6H2), 1
．． 46 and 1.48 (each brs, 9H), 6.73
(brd.

2H, J=8Hz), 7.04 and 7.06 (brd.

2H, J-8H2) Example 3 (2S,3R)-2-amino-3-human 90x-4(
4-hydroxyphenyl)-phthyroyl-threonyl-(2'S, 3'8. 4/S) -3/-hydroxy-4'-methylpyrrolidine-2'-carboxamide 9
Compound 68 Tng (0,0841
After 0.5 ml of trifluoroacetic acid was added and stirred at room temperature for 1 hour, the reaction solution was distilled off under reduced pressure. The obtained oil was dissolved in 05 resistant tetrahydrone, and 1 rag of 05 N hydrochloric acid was added.
was added and stirred at room temperature for 4.5 hours. Wash the reaction solution with ethyl ether, separate the aqueous layer, and apply DOWEX 50WK4 resin (DOW13X 50W X 4) as it is.
was adsorbed to. After washing the resin with water, it was eluted with IN aqueous ammonia and concentrated under reduced pressure to obtain the title compound 35rIK/
I got it. (Yield 100%) Properties: Amorphous crystal [α) D knee 36.9° (C-1,86, CH30H)
Engineering R spectrum (film, cm-”): 336
0゜1.690,1638 Mass quictor (m/z): 439 (M+H)+NM
R spectrum (D20.δ): 1.02 (3H, d,
, T=7Hz), 1.25 (3H,d, J
-6,5Hz).

2.40-2.52 (IH, m), 2.66 (IH.

dd, Jl=9.5. '14) f), 2.83 (iH.

da, J-3,5,14H2), 3.50 (I
H.

t, J=10Hz), 3.875 (IH, a.

, T-6H2), 3.96 (IH, d4.,
T=8°10H2), 4.07(IH, d+i4.,
T-3,5,6,9H2), 4.15 (IH,q
, J=6H2), 4.27(IH, da,
J-2,4H2), 4.335(IH,a,,T=2H
2).

4.655 (IH, eL, J-6H2), 6
．． 835 (2Hs d-J-s, 5 H2) -7
135 (2H-a, J-3,5Hz) Example 4 )-3-Hydroxy]Homothyrone Ruthreonyl C(38,4S)-3-Hydroxy-
4-Methyl]prolinamide Compound 59 obtained in Example 3
．． 71 ng (0.14 mmol) and the compound 654 (0.14 < mol) obtained in Reference Example 6 were dissolved in 1.2 ng (0.14 mmol) of anhydrous N,N-dimethylmethamide, and 32.5 μJ of diphenylphosphoric azide was added at 0°C. (0.15 mmol) and triethylaneξ21 μ71! (0,15<limole) were added one after another, and the mixture was stirred at 0°C for 2.5 hours and at 26° to 29°C for 38 hours under a nitrogen stream. 20 d of ethyl acetate was added to the reaction solution, followed by 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and
After washing with a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was subjected to silica gel column chromatography, eluted with methanol-chloroform (1:9), and the solvent was distilled off under reduced pressure to obtain the title compound 71.9. (Yield 59cm) Properties: Amorphous crystal [α) D knee 75.7° (C-tss CH30) 1
) Engineering R spectrum (film p cm): 33
68 T1687.1634 -qsusubek)/l/(m/z):901 (M+H)
+NMR spectrum (DMSO-a 6.δ): 0.
02. 0.06 (3H, s each), 0.82 (9H, 5
)tO,93(3H,d, J-5,0Hz), 1
07 (3H, eL, J-5,0Hz), 1.20
(3H.

d, J-4,5Hz), 1.91 (cldd,
IH.

J-5, 8, 14H2), ZI O~Z25 (IH
#m), 2. ．． 56 (IH, da, J-6, 13
,5H2), 2.71 (IH, (1(1,J-8
, 5, 13, 5 Hz), 3.18 (LH, t.

J-10,0,10,0H2), 3.70 (IH.

brd, J-11H2), 3.76 (IH,,d
d+J-4, 11Hz), 3.88-4.12 (6H,
m)+4.18(IH,be), 4.26(IH,(
1 (1°, T-8, 5, 9, 0Hz), 4.37 (
IH, be).

4.59 (IH, t, J-8Hz), 4.61 (
IH, 'brt, J-8&), 5.05 (2H.

8) #5.06 (I Ht de J-5Hz
) +5.10 (IH, d, J-5H2),
5゜16 (tHs d, J-4,0H2), 5.2
0(ddd.

IH, J-5,0,11,0,11,0Hz)+6.5
8(2H, (1,, T-8, 5H2), 6.99(
2H, d, J-8, 5Hz), 6.99 (IH.

d* J-8,0&), 7.14 (IH,a, J
-8-5Hz ) * 724 (I Hed *
J to 8-5 H2) +7.28-7.40 (IH,
m), 7.47 (IH.

d, J""'9.5H2), 8.28 (I H,
d, J-9,0Hz), 9.08(IH,s).

Example 5 (28,4R)N-lyluyl-2-amino-4-O-(
t-butyldimethylsilyl)-5-:)methoxypentanoyl-〇-t-butyldimethylsilyl-threonyl-((4R)-4-hydroxy]furoyl-((3R)
-Hydroxy] homotyrosylthreonyl-((38,
48) -3-Human90xy-4-methyl]prolinamide Compound obtained in Example 4
mol) was dissolved in 0.4 wLl of ethanol, 8 cm of 10% palladium on carbon was added, and the mixture was stirred at room temperature under a hydrogen stream for 16 hours. The catalyst was removed by filtration, and the P solution was concentrated under reduced pressure to obtain 23.43Iv of an oil.

This oil and Compound A (below) 24.4■ (0,043
mmol) total anhydrous N. Dissolve in 0.35 id of N-dimethylformamide, ’) phenyl phosphate a:)) 9.5 μ7 (
0,044 mmol) and 60 μl of triethylamine (
0104349 mol) was added at 0°C. 0 under nitrogen flow
After stirring for 1.5 hours at ℃, the mixture was stirred for 18 hours at 25℃. 10 d of ethyl acetate was added to the reaction mixture, which was washed successively with a 5% aqueous tartaric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained oil was subjected to silica gel chromatography.

Elution was carried out with methanol-chloroform (13:87), and the solvent was distilled off under reduced pressure to obtain the title compound 19.4. (Yield 48%) Properties: Amorphous crystal NMR spectrum (CD30D, δ): 0.10
(3H, B).

0.12 (3H, θ), 0.15 (3H, θ).

0.18 (3H, Sun), 0.88 and 0.90 (5I9 each)
H) + 0.92 (9H,s), 1.05(
3H, d, J-7,0Hz), 5.25-5.40 (4
H, m), 6.67 (2H, a.

A2B2 type, J-8,0Hz), 7.08 (2
H.

a, A2B2 type, J-8,0Hz) Reference example 1 (23,3s, 48)-3-hydroquine-4-methyl-
Pyrrolidine-2-carpoabad(28,38,48)-Nt-nodoxycarbonyl-
3-Human 90x-4-methylproline methyl ester (182 µm (0.7 mmol)) was dissolved in 1 d of ty dichlorothane, 11 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure and the residue was diluted with methanol 10
1 and add 10 d of liquid ammonia to 48 ml at room temperature.
Stir for hours.

The reaction solution was distilled off under reduced pressure, and the residue was dissolved in 3-3ml of water.
) After adding the resin and allowing it to stand for 10 minutes, it was separated from the furnace at normal pressure. After washing the resin with water, the product was eluted with 1N aqueous ammonia and concentrated to obtain 101 ml of the title compound (yield: 100%).

Properties: Two oily substances (α) D: -28,6° (C-16, meta, /-l)
IH couture (film, cm-”): 337
0°Mass spectrum (m/z): 114-5 (+H)”
, 10100N spectrum (D20. δ): 0.5
2 (3H, d.

J-7H2), 1.60-2.02 (I H, m
L2.59 (IH, d, d, J-12, 12Hz)
.

3.10 (IH, da, J-8, 12H2).

3.86 (I H, d, J-I H2), 3
．． 96 (IH, dd, J-1,4Hz) Reference Example 2 (28,3R)-4-(4-t-methyldimethylsilyloxyphenyl)-3-(2-te)lahydrobilanyl)oxy-2-N- t-butoxycarbonylaminobutyric acid-2
-pyridylthiol ester (28,3R)-4-(4
-t-butyldimethylsilyloxyphenyl)-3-(2
-Tetrahydropyranyl)oxy-2-N-butoxycarbonylaminobutyric acid (1.03,9 (2-02 mmol)) was removed with 10 tdK of anhydrous dichloromethane, trinoenylphosphine (954 mmol) (3,64 mmol), cypyridyl Disulfite 9712-(3.24 mmol) was added, and the mixture was stirred at 40° C. for 8.5 hours and at room temperature for 14 hours under a nitrogen stream. The reaction solution was distilled off under reduced pressure and subjected to silica gel chromatography [elution solvent n-hexane-ethyl ether (1
:1)) to give 846 wg (yield 69%) of the title compound.
I got it.

Properties: Oil substance engineering R structle (film, crrL-”): 345
0゜72O NMRx (CDOA! as JGo, 16)
(6H# 8) 10.96 (9H, e), 1.54 (9
H,s).

6.74 and 706 (each 2H, A2B2 Noreen, d
, J-gHz), 7.24 (IH, m).

7.44-7.80 (2H, m), 8.52 (IH) Reference Example 3 N-(-?silyloxycarbonyl)-0-(t-butyldimethylsilyl)-threonine imidazole 2.42.9( 35,6 mmol) in anhydrous N,N-9 methylformamide (3 mA') solution.

N-(benzyloxycarbonyl)-threonine 3.9
(11949 mol) of anhydrous N, N-dimethylformamyl (7 m4) solution, and t-butyldimethylsilyl chloride 5.38 N (35,6 mmol) of anhydrous N,
A solution of ``N-dimethylformamide'' (101! Ll) was added thereto, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into 20 Od of water and extracted with ethyl ether.

The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain an oil. Add 24% of this oil to tetrahydrofuran.
111! 0.5N potassium hydroxide aqueous solution 24
d (12 mmol) was added and stirred at 0°C for 4 hours. The reaction solution was extracted with ethyl ether, and the aqueous layer was separated. The aqueous layer was adjusted to pH 2-3 with IN hydrochloric acid and extracted with ethyl ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.88 g (10.5 mmol) of the title compound. (Yield 89%
) Properties: White scaly crystals Melting point: 150.5°C to 152.5°C [α]D nide 13,2° (C-to, CHC/3)I
R-! :Cuttle (CHCJ3.cfn):3480
, 1740 mass spectrum/Iz (m/z): 367 (M
”), 31ONMR spectrum (CD (J3.
δ): 0.06. 0.08 (3H-' each) w O,
86 (9H, s).

1.20 (3H, d, J-8H2), 4.24
-4.60 (2H, m), 5.13 (2H, 8).

5.70 (I H, a, =-T-8H2), 7.3
5(5H,s) Reference Example 4 O-(t-butyldimethylsilyl)-threonine N-(-jsilyloxycarbonyl)-0-(t-butyldimethylsilyl)-threonine 500η (1,36 mol) Dissolve in 20 d of ethanol.

Add 50 μl of 10-cynoradium carbon, and under a hydrogen stream,
Stirred at room temperature for 14 hours. The catalyst was removed by filtration, and the filtrate was distilled off under reduced pressure to obtain the title compound 317 (1.36 mmol).
I got it. (Yield 100%) Properties: White powder crystal Melting point: 152° to 169°C (decomposed) [α)D: 28.7° (C-t, o, cH3oH)
IR Suiktor (nujol, m): 2300~
3600.1720 Mass spectrum (m/z): 234 (M+H)”-17
6N M R s ODs J)
: 0.10-0.11 (3H, e each), 0.89 (
9H,')tL28(3H,d, J-6,5H2),
4.54 (IHt dq, , T-2,6,5H2
).

Reference Example 5 N-(benzyloxycarbonyl),0-(1-butyldimethylsilyl)-threonine-pyridylthiol ester 839111 g (2.29 mmol) of the compound obtained in Reference Example 3 was dissolved in dichloromethane 9-, and triphenylphosphine was added. 718 .mu. (2.74 mmol) and dipyridyl disulfide 566 .mu. (2.57 mmol) were added, and the mixture was stirred at room temperature for 16 hours under a nitrogen stream. The reaction solution was concentrated under reduced pressure, and the resulting oil was subjected to silica column chromatography, eluted with ethyl ether-n-hexane (2:3), and the solvent was distilled off under reduced pressure to obtain the title compound 969■. Ta.

(Yield 92%) Properties: Oil Reference Example 6 N-(benzyloxycarbonyl)-〇-(1-butyldimethylsilyl)-threonyl-((48)-4-hyproxy)proline pH 4-hydroxy- 44.1 μl (0.34 mmol) of L-proline was suspended in anhydrous N,N-dimethylformamide 1-, 98 μl (0.34 mmol) of trimethylsilylibadazole, and 28 μl (0.20 mmol) of triethylamine.
The mixture was stirred at room temperature under a nitrogen atmosphere for 2-5 hours to form a clear solution. A solution of 103.2 ml (0.22 mmol) of the compound obtained in Reference Example 5 in the same solvent (2 times) was added to this, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, the pH was adjusted to 3 with IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained oil was subjected to silica gel column chromatography, and methanol-chloroform (1:
4), and the solvent was distilled off under reduced pressure to obtain the title compound 72.
I got 2 ■. (Yield: 67 cm) Properties: Amorphous crystal [α) D: -49,5 (C = 3.07. CH30H
) engineering R spectrum (chloroform, cm): 345
2゜Mass spectrum (m/z): 481 (M”H)+
NMR spectrum (CDC13, δ): 0.06 (6H
,s).

0.86 (9H,s), 1.20 (3)(,
d-J=7), 2.20-2.40 (2H, rn).

5.07 (2H, s), 5.60 (IH, a.

J = 7H2, ), 7.32 (5H, s) Effects of the Invention The echinocandin synthetic mesomorph, which is a compound provided by the present invention, is a peptide having exactly the same three-dimensional structure as echinocandin C, and is similar to echinocandin. antifungal and
It is expected to have anti-yeast effects.

(5 other people)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 represents a hydrogen atom or a t-butyldimethylsilyl group, R^2 represents a hydrogen atom or a tetrahydropyranyl group, and R^ 3 represents a hydrogen atom or a t-butyldimethylsilyl group, A represents a hydroxyl group, a pyridinethiol group, or a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ B represents a hydrogen atom, a t-butoxycarbonyl group or a group ▲Mathical formula , chemical formula, table, etc.▼ (where D represents a hydrogen atom, benzyloxycarbonyl group, or group ▲numerical formula, chemical formula, table, etc.▼)] An echinocandin synthetic intermediate having the following.