JPH05320148A - Synthesis of cyclic depsipeptide pf1022 substance - Google Patents

Abstract

PURPOSE:To obtain a cyclic depsipeptide PF1022 substance useful as an anthelmintic drug from phenyllactic acid, lactic acid and leucine. CONSTITUTION:The objective compound of formula can be produced by cyclizing the compound of the formula L-N-CH3.Leu-D-lac-L-N-CH3-Leu-D-phe.lac-L-N- CH3.Leu-D-lac-L-CH3-Leu-D-phe.lac-OH (lac is lactic acid; N-CH3-Leu is N- methylleucine; phe-lac is phenyllactic acid; Leu is leucine). The cyclization is carried out by dicyclohexylcarbodiimide (DCC) process or water-soluble DCC+ additive (e.g. N-hydroxysuccinimide) process in a solvent (e.g. THF-DMF) at 0-50 deg.C.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for synthesizing a cyclic depsipeptide PF1022 substance represented by the following formula (I).

[0002]

[Chemical 1]

[0003]

2. Description of the Related Art The PF1022 substance has an anthelmintic action and is expected to be applied to the fields of medicine, veterinary medicine and the like, and it is known that it can be produced by a fermentation method (JP-A-3-35796). ). Japanese Patent Application No. 3-163085 is known as a related substance obtained by a fermentation method. However, the fermentation method cannot be said to be effective as a method for obtaining derivatives in a wide range and screening for useful substances.

[0004]

The disease called parasitic disease causes a great deal of damage to human and animal health and agriculture. From such a background, finding an advantageous method for producing anthelmintic active substances and finding new and useful anthelmintic active substances are always demanded. The present inventors have paid attention to the above points, and have aimed to provide a novel method for producing a PF1022 substance and a method for producing a large number of novel substances using the PF1022 substance as a lead compound. ..

[0005]

The present inventors succeeded in synthesizing according to the flow shown below in order to solve the above problems.

[0006]

[Chemical 2]

Various investigations have been made on various methods for synthesizing PF1022 substance. First, (I) and (II) are condensed with an ester bond to give (IV), and (II) and (III) are condensed with an ester bond ( V), then (IV) and (V) are condensed with an amide bond to form (VI), (VI) and (VI) are combined by amide condensation to form (VII), and (VII) is closed. The present invention has been completed by finding that PF1022 substance can be synthesized.

The method of ester bond of (I) and (II) or (II) and (III) in the present invention is (I) or (II).
When I) is the D form, the DCC + additive (N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc.) method is used, and when (I) or (III) is the L form, (I), (III)
Although the method of condensing while inverting the conformation of the hydroxyl group of is used, the method by the Mitsunobu reaction is preferable because it does not accompany racemization.

In order to sequentially condense (I), (II) and (III) according to the above flow, the carboxyl groups of (I) and (III) are protected and the amino group of (II) is protected. And protecting groups (I) and (III) and (II)
It is necessary that the protecting groups of can be selectively removed.
Examples of the protecting group of (I) and (III) include a protecting group such as t-butyl, benzyl, p-methoxybenzyl, benzhydryl and trityl group which can be removed under acid hydrolysis or reducing conditions.

Examples of the protecting group (II) include a protecting group such as a benzyloxycarbonyl group, a t-butyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group and a formyl group which can be removed under acid hydrolysis or reducing conditions. ..
In addition, since it is necessary to selectively remove the protecting groups for the carboxyl group and amino group, if the carboxyl group is a protecting group that is removed under reducing conditions, the protecting group for amino groups is removed under acid hydrolysis conditions. It is only necessary to select a protecting group that can be used, and vice versa. As a method for removing the protecting group, a trifluoroacetic acid method, a methanesulfonic acid method, a trifluoromethanesulfonic acid method, or the like is applied under the acid hydrolysis condition, but the trifluoroacetic acid method is preferable. In the case of reducing conditions, the catalytic reduction method using a palladium catalyst is preferable.

In the condensation of (IV) and (V), the amino group of (IV) and the carboxyl group of (V) or the carboxyl group of (IV) and the amino group of (V) are condensed by an amide bond. It is possible to In the condensates (IV) and (VII), two cases are possible, in which the carboxylic acid terminal is lactic acid and phenyllactic acid.

The ring-closing method includes DCC or water-soluble DCC + additive (N-hydroxysuccinimide, 1
-Hydroxybenzotriazole etc.) method is used.
As the solvent, ether solvents such as ether, tetrahydrofuran and dioxane and aprotic solvents such as N, N-dimethylformamide, acetonitrile and chloroform can be used, preferably tetrahydrofuran and N, N.
A mixed solvent of dimethylformamide. The reaction is 0
It can be carried out at 50 ° C, preferably at 20-30 ° C.

The abbreviations used in this specification have the following meanings. Bn: benzyl Boc: t-butoxycarbonyl BH: benzhydryl lac: lactic N-CH ₃ · Leu: N- methylleucine phe · lac: phenyl acid Leu: Leucine HOBt: 1-hydroxybenzotriazole DCC: dicyclohexylcarbodiimide EDCI: 1- (3-Dimethylaminopropyl) -3-
Ethylcarbodiimide Water-Soluble DCC The present invention will be described in more detail with reference to the following examples.

[0014]

EXAMPLES Example 1 Synthesis of D-phe.lac-OBn 1.652 g of commercially available D-phenylalanine was added to 10 m of water.
It was dissolved in a mixed solution of 10 ml of acetic acid and 2 ml of 1,4-dioxane at room temperature and then cooled to about 5 ° C. NaNO ₂
2.068 g was gradually added, and the mixture was stirred at room temperature for 3.5 hours. After adding 30 ml of saturated saline solution and extracting three times with 50 ml of ethyl acetate, the organic layer was dried over anhydrous Na ₂ SO ₄ . Na ₂ SO
₄ was filtered off, and the filtrate was concentrated under reduced pressure. Approximately 5 toluene in the residue
By adding 0 ml and concentrating under reduced pressure, a trace amount of acetic acid was removed.

12 ml of water and 1.63 g of cesium carbonate were added to the residue.
Was added and dissolved, and the mixture was concentrated to dryness under reduced pressure. After thoroughly drying under reduced pressure, the residue was dissolved in 20 ml of DMF, and PhC was added.
1.3 ml of H ₂ Br was added, and the mixture was stirred at room temperature for 17 hours.
The reaction mixture was directly concentrated under reduced pressure, 60 ml of ethyl acetate was added, and the mixture was washed with 30 ml of water and 30 ml of saturated saline. The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered, and the residue obtained by concentrating the filtrate was subjected to silica gel column chromatography (Wakogel C-200, 90 g, ethyl acetate / cyclohexane 1/13 500 ml → 1 / 10 750
The target product was obtained as a pale yellow oil.

Yield 1.057 g (41%) NMR (CDCl ₃ , δ, TMS) 270 MHz 2.78 (d, J = 6.4 Hz; -OH), 2.97
(Dd, J = 6.41,13.92; β -C H 2 -P
h), 3.11 (dd, J = 4.77, 13.92; β
_{-C H 2 -Ph), 4.48 (} 1H, dd, J = 4.
8,6.4; α-CH), 5.17 (S, 2H; -CO
_{2 C H 2 -Ph), 7.12~7.38} (m, 10H;
-Ph x 2)

Example 2 Synthesis of L-Boc-N-Me-Leu Commercially available N-Boc-L-leucine monohydrate 20.268
g was dissolved in 100 ml of DMF and concentrated under reduced pressure. After thoroughly drying under reduced pressure, dissolve in 240 ml of THF and cool with ice.
20 ml (0.32 ml) of I was added, and 9.61 g of NaH was gradually added.
Stir for 5 hours. The solvent was directly concentrated under reduced pressure to about 100 ml, and 100 ml of ethyl acetate was added. While stirring under ice cooling, 5% saline solution 150 ml, 10% KHSO ₄ 100 m
47 ml of 1,2N-HCl was gradually added to adjust the pH to 3.25. 200 ml of ethyl acetate was added and the aqueous layer was removed. The organic layer was washed twice with 100 ml of 5% Na ₂ S ₂ O ₃ and saturated saline solution 1 times.
It was washed with 00 ml and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated and dried under reduced pressure at room temperature for 8 hours. n-
Add 250 ml of hexane and put it in the freezer (-10 ℃) for 2
The result obtained after standing for one day was collected by filtration. It was dried for 1 day under reduced pressure to obtain the desired product as white needle crystals.

Yield 15.894 g (80%) Melting point 57.5-58.0 ° C. NMR (CDCl ₃ , δ, TMS, 270 MHz) 0.94 (d, 3H, J = 6.3; δ-CH ₃ ) , 0.
96 (d, 3H, J = 6.3; δ-CH ₃ ), 1.46.
(S, 9H, t-Bu), 1.5 to 1.76 (m, 3
H, β-CH ₂ , δ-CH), 2.80 (s, 3H; N
_{-CH 3), 4.62 (dd,} 0.5H, J = 4.3,
10.3; α-CH), 4.82 (t, 0.5H, J =
7.5; α-CH) NMR (DMSO-d ⁶ , δ, TMS, 270 MH ₂ ) 0.85 (d, 3H, J = 6.4; δ-CH ₃ ), 0.
90 (d, 3H, J = 6.4; δ-CH ₃ ), 1.36
And 1.39 (s × 2, 9H; t-Bu), 1.49-
1.67 (m, 3H, β-CH ₂ and γ-CH), 2.6
8 (s, 3H; N- CH 3), 4.40 (dd, 0.5
H, J = 4.3, 10.9; α-CH), 4.61 (d
d, 0.5H, J = 4.3, 10.9; α-CH), 1
2.60 (s, 1H; -COO H )

Example 3 Synthesis of L-Boc-Me.Leu-D-Lac-OBH N₂PPh in the atmosphere₃1.313 g (5.00 mmol),
L-Lac-OBH 1.538 g anhydrous Et₂O6 ml melt
1.227 g of L-Boc-Me.leu in the liquid, diet
Luazodicarboxylate 0.78 ml anhydrous Et₂O5
The ml solution was added dropwise at room temperature over 15 minutes. After stirring for 23 hours
The precipitate formed was filtered off and Et₂Washed with 12 ml O. Filtrate
And the washings are combined and concentrated, and the residue is taken up in 100 ml of ethyl acetate.
Melt and saturate NaNCO₃Wash with 50 ml of water and 50 ml of saline
Clean The organic layer is anhydrous Na₂SO_FourAfter drying with, filter and filter
The residue obtained by concentrating the liquid was applied to a silica gel column,
(Wako gel C-200, 100 g, CHCl₃20
0 ml, chloroform / Ethyl acetate = 50/1 710
The target compound was obtained as a colorless oil.

Yield 2.276 g (94%)¹ H-NMR (CDCl₃, Δ, TMS, 270MH
z) 0.92 (d, 3H, J = 6.2; δ-CH₃(Mel
eu)), 0.93 (d, 3H, J = 6.2; δ-CH
₃(Meleu)), 1.43 and 1.45 (s × 2, 9
H; t-Bu), 1.51 (d, 3H, J = 6.96;
β-CH₃(Lac)), 1.50 to 1.67 (m, 3
H; p-CH₂, Γ-CH (Meleu)), 2.71.
And 2.73 (s × 2,3H; NCH₃), 4.73 (d
d, 0.5H, J = 5.2, 10.1; α-CH (La
c)), 4.98 (dd, 0.5H, J = 5.8, 1
0.0; α-CH (Me · leu), 5.21 (q,
1H, J = 6.96; α-CH (Lac)), 6.89
(S, 1H; COOCHPh ₂), 7.25 to 7.37
(M, 10H; Ph × 2)

Example 4 L-Boc-Me.leu-D-Phe.lac-OB
Synthesis of n 1-hydroxybenzotriazole monohydrate 695 mg D
After dissolving in 10 ml of MF, it was concentrated to dryness. Dried sufficiently under reduced pressure, D-Phe lac-OBn 1.057g,
L-Boc / Me / leu 1.011 g, pyridine 10
ml was added, and the mixture was stirred under ice cooling. A solution of 852 mg of DCC in 2 ml of pyridine was added, and the mixture was stirred at 5 ° C. for 17 hours and then DCC20.
1 mg was added and the mixture was stirred for 24 hours. The precipitate formed was filtered off and washed with 8 ml of ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate and ice-cooled 5% KHSO ₄ water 50 ml, saturated NaHCO ₃ water 50 m.
1, washed successively with 50 ml of 5% saline, dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified twice with a silica gel column.

First time: C-200, 100 g, chloroform 400 ml → chloroform / Ethyl acetate = 80/1
800 ml → chloroform / Ethyl acetate = 50/1
250 ml, 2nd time: C-200, 100 g, chloroform 200m
l → chloroform / Ethyl acetate = 50/1 1 liter Yield 1.187 g (59.6%) ¹ H-NMR (δ.ppm.TMS, CDCl ₃ ) 270M
Hz 0.89 (d, 6H, J = 6.41; δ-CH ₃ (Me
-Lac)), 1.43 and 1.49 (s x 2, 9H; t
-Bu), 1.42 to 1.61 (m, 3H; β-C
H ₂ , γ-CH (Me · lac)), 2.60 and 2.6
5 (s × 2,3H; N- CH 3), 3.11 (dd, 1
H, J = 7.9, 14.5; β-CH ₂ (Phe · la
c), 3.18 (dd, 1H, J = 4.6, 14.5;
β-CH ₂ (Phe · lac)), 4.70 (dd,
0.5H, J = 6.2, 10.3; α-CH (Me · l
eu)), 5.00 (dd, 0.5H, J = 5.0,
9.9; α-CH (Me · leu)), 5.07 to 5.
18 (m, 2H; OC H ₂ Ph), 5.27 (dd, 1
H, J = 4.6, 7.9; d-CH (Phe · la
c), 7.13 to 7.35 (m, 10H; -Ph x 2)

Example 5 Synthesis of L-Boc-Me.leu-D-lac-OH L-Boc-Meleu-Lac-OBH 2.241
g was dissolved in 25 ml of methanol and 0.05 ml of acetic acid under N ₂ atmosphere, 240 mg of 10% Pd / C was added, and then the system was replaced with H ₂ (normal pressure). The mixture was stirred at room temperature for 2 hr, the catalyst was filtered using Hyflo, and the filtrate was concentrated, and the silica gel column (35 g, ethyl acetate / n-hexane = 1/3) was concentrated.
140 ml, ethyl acetate / toluene = 1/1 140 m
l, ethyl acetate / toluene = 2/1 105 ml) to give the desired product as a colorless oil. 1.465g
(Yield 99.6%)

¹ H-NMR (δ.ppm.TMS, CDCl
₃ ) 0.93 (d, 3H, J = 6.3; δ-CH ₃ (Me ·
leu)), 0.96 (d, 3H, J = 6.3; δ-C
H ₃ (Me ・ leu), 1.46 and 1.47 (s ×
2,9H; t-Bu), 1.53 (d, 3H, J = 6.
9; β-CH ₃ (Lac)), 1.52 to 1.77.
(M, 3H; β-CH ₂ γ-CH (Me · leu)),
2.82 (s, 3H; N- CH 3), 4.74 (dd,
0.5H, J = 3.8, 10.4; α-H (Me · le
u)), 4.89 (dd, 0.5H, J = 6.9, 9.
1; α-CH (Me · leu), 5.11 (q, 1)
H, J = 7.1; α-CH (Lac)), 10.47
(S, 1H; COO H)

Example 6 Synthesis of L-Me.leu-D-Phe.lac-OBn L-Boc-Me.leu-D-Phe.lac-OB
1.156 g of n was dissolved in 5 ml of trifluoroacetic acid at room temperature, stirred for 20 minutes at room temperature and then concentrated as it was. Dissolve in 50 ml of ethyl acetate and wash with 30 ml of NaHCO ₃ water Na ₂ S
After drying with O ₄ , it was filtered. The filtrate was concentrated and used as it was in the next reaction.

Example 7 L-Boc-Me.leu-D-Lac-L-Me.l
Synthesis of en-D-Phe.lac-OBn L-Boc-Me.leu-Lac-OH 703 mg,
H-Me ・ leu-Phe ・ lac-OBn869mg,
330 mg (2.443 mmol) of HOBt was added to 10 ml of THF,
Dissolve in a mixed solvent of 1 ml of pyridine, and under ice cooling, DCC550
mg (2.666 mmol) was added, and the mixture was stirred at 5 ° C for 3 days.

The precipitate formed was filtered off and the filtrate was concentrated. Dissolve the residue in 80 ml of ethyl acetate and add 40% 5% KHSO ₄
ml, saturated NaHCO ₃ water 40 ml, and brine 40 ml, washed successively, dried over Na ₂ SO ₄ , and then filtered. After concentrating the filtrate, silica gel column 50 g chloroform (ethyl acetate = 30
/ 1 500 ml, 20/1 310 ml 10/1 33
(0 ml) to give the desired product as a colorless oil.

1.378 g (yield 91%) ¹ H-NMR (δ.ppm.TMS, CDCl ₃ ) 270
NHz 0.84 to 0.95 (d × 4, 12H; δ-CH ₃ (M
e · leu) × 4), 1.22 (d, 1.5H, J =
6.8; β-CH ₃ (Lac)), 1.24 (d, 1.
5H, J = 6.8; β-CH ₃ (Lac)), 1.28.
˜1.95 (m, 6H; β-CH ₂ , γ-CH (Me.
leu) × 2), 1.43 and 1.45 (s × 2, 9H;
t-Bu), 2.75, 2.82, 2.83, 2.85.
(S × 4, 6H, N—CH ₃ × 2), 3.03 to 3.2
9 (dd × 2, d, 2H; J = 9.5, 14.1 and J =
4.6, 14.1 and 6.0), 4.40 (dd, 0.5
H, J = 5.7, 8.5; α-CH (Me · le
u)), 4.76 (dd, 0.5H, J = 4.7, 1)
1.2; α-CH (Me · leu), 4.95 (t,
0.5H, J = 6.7; α-CH (Me · leu)),
5.14-5.41 (m, 2.5H, α-CH (Me ・
leu), α-CH (Lac), α-CH (Phe · l
ac)), 7.12 to 7.39 (m, 10H; Phx
2), 5.08 (d, 1H, J = 12.0; -OCH ₂
Ph), 5.15 (d, 1H , J = 12.0; -OC H
₂ Ph)

Example 8 L-Boc-Me.leu-D-Lac-Me.leu
Synthesis of -D-Phe-lac-OH Boc-Me-leu-Lac-Me-leu-Phe
-Lac-OBn 578 mg, 10% Pd / C 59 mg N
₂Dissolve in 6 ml of methanol under an atmosphere and add H ₂Replace with
After (normal pressure), the mixture was stirred at room temperature for 4 hours. Hyflo is used as a catalyst
After filtration, the filtrate was concentrated and used as it was in the next reaction.

Example 9 L-Me.leu-D-Lac-L-Meleu-D-
Synthesis of Phe-lac-OBn Boc-Me-leu-Lac-Me-leu-Phe
· The lac-OBn 602 mg was dissolved in CH ₂ Cl ₂ 3ml, it was added under ice-cooling TFA3ml. After stirring at 5 ° C for 20 minutes, the reaction solution was concentrated as it was. The residue was dissolved in 30 ml of ethyl acetate, washed with 15 ml of NaHCO ₃ water, dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and used as it was in the next reaction.

Example 10 L-Boc-Me.leu-D-Lac-Me.leu
-D-Phe / lac-L-Me / leu-D-Lac
Synthesis of -L-Me-leu-D-Phe-lac-OBn Boc-Me-leu-Lac-Me-leu-Phe
-Lac-OH 500mg, H-Me-leu-Lac
-Me-leu-Phe-lac-OBn 513 mg,
HOBt (126 mg) and NEt _{3 (} 0.12 ml) were dissolved in THF (8 ml), DCC (213 mg) was added under ice cooling, and the mixture was stirred at 5 ° C. for 4 days. The resulting precipitate was filtered off and the filtrate was concentrated. The residue was dissolved in 60 ml of ethyl acetate, 30 ml of 5% KHSO ₄ water,
Wash with 30 ml of NaHCO ₃ water and 30 ml of brine and wash with Na ₂ S
After drying with O ₄ , it was filtered. After concentrating the filtrate, 30 g of silica gel column, chloroform 60 ml, chloroform / Ethyl acetate = 10/1 550 ml, chloroform / Ethyl acetate / methanol = 200/20/2 220 ml)
And purified to obtain the desired product as a colorless solid.

689 mg (71% yield) ¹ H-NMR (δ.ppm.TMS, CDCl ₃ ) 270
MHz 0.81 to 0.91 (d × 8, J = 6.4; δ-CH ₃
(Me · leu)), 1.44 (s, 9H, tBu),
1.25 to 1.80 (m × 18H; β-CH ₂ , γ-C
H (Me · leu × 4) β-CH ₃ (Lac × 2)),
2.72~3.30 (m, 16H; N- CH 3 × 4, β
-CH ₂ (Phe · lac × 2)), 4.35 to 5.5
5 (m, 10H, α-CH (Me · leu × 4), α-
CH (Lac × 2), α-CH (Phe · lac × 2)
_{-OCH 2 Ph), 7.14~7.35 (m} , 15H,
-Ph x 3)

Example 11 Synthesis of PF1022 Substance 673 mg of the product of Example 10 was CH.₂Cl₂Dissolved in 4 ml
Then, add 2 ml of trifluoroacetic acid under ice cooling and stir at 5 ° C for 40 minutes.
I stirred. The reaction mixture is concentrated as it is and dissolved in 5 ml of toluene.
After that, it was concentrated again. Dissolve the residue in 50 ml of ethyl acetate,
Saturated NaHCO ₃Wash with 30 ml of water and 30 ml of saturated saline,
Na₂SO_FourDried in. After filtration, the filtrate is concentrated and the residue
Was dissolved in 6 ml of methanol, and 65 mg of 10% Pd-C was added.
, And reduced at room temperature for 2 hours. After removing the catalyst by filtration, the solvent was
It was distilled off under reduced pressure.

Lithium chloride 247 mg, common salt 339 mg, potassium chloride 433 mg, cesium chloride 976 mg, EDCI
While stirring a solution of 1.1 g of THF (500 ml) and DMF (150 ml) at room temperature, a solution of the previously obtained deprotected compound and 1-hydroxybenzotriazole (393 mg) in THF (80 ml) was added, and the mixture was stirred at room temperature for 1 week. The solvent was distilled off under reduced pressure, 160 ml of ethyl acetate and 80 ml of water were added, and the aqueous layer was separated. The organic layer was mixed with 80 ml of NaHCO ₃ water and 80 m of 5% KHSO ₄ water.
1, washed with 80 ml of brine and dried over Na ₂ SO ₄ . After filtration and concentration, the resulting residue was purified by silica gel column chromatography (50 g, chloroform). 100 ml, chloroform
/ Methanol = 100/1 to 50/1) and then purified again by silica gel column chromatography (25 g, ethyl acetate / toluene = 1/3) and then recrystallized from methanol / water to give 271.5 mg of the desired product ( Yield 49%) was obtained.

[Α]²⁰ _D-99 ° (C = 0.2, CH₃
OH) melting point 136-138 [deg.] C. FAB-MS [m / z] 949¹ H-NMR (δ.ppm.CD₃OD) 500 MHz 0.78 to 1.05 (d × 9, 27H, J = 6.4 to
7.0; δ-CH₃× 8 (Me ・ leu), β-CH₃
(Lac)), 1.38 (d, 3H, J = 7.0; β-
CH₃(Lac)), 1.3 to 1.4 (m, 4H; γ-
CH × 4 (Me · leu)), 1.47 to 1.87
(M, 8H; β-CH₂× 4 (Me · leu), 2.
81, 2.88, 2.90, 2.99 (s × 4, 12
H, N-CH₃× 4), 3.087 (dd, 1H, J =
8.0, 13.2; β-CH₂(Phe lac)),
3.090 (dd, 1H, J = 7.8, 13.2; β-
CH₂(Phe lac)), 3.168 (dd, 1)
H, J = 7.3, 13.2; β-CH ₂(Phe ・ la
c)), 3.177 (dd, 1H, J = 7.2, 13.
2; β-CH₂(Phe lac)), 4.76 (d
d, 1H, J = 4.0, 11.3; α-CH (Me · l
eu)), 5.17 (q, 1H, J = 6.8; α-CH
(Lac)), 5.22 (dd, 1H, J = 4.6, 1
1.3; α-CH (Me · leu), 5.39 (d
d, 1H, J = 4.6, 11.6; α-CH (Me · l
eu)), 5.43 (dd, 1H, J = 4.6, 11.
6; α-CH (Me · leu), 5.53 (q, 1)
H, J = 6.9; α-CH (Lac)), 5.73
(T, 1H, J = 7.6; α-CH (Phe · la
c)), 5.81 (t, 1H, J = 7.6; α-CH
(Phe · lac)), 7.23 to 7.34 (m, 10)
H, -ph x 2).

The synthetic product is PF1 having the above properties obtained by fermentation.
It was confirmed that the synthetic product has the same structure as the PF1022 substance, since it is identical to the 022 substance and has the same anthelmintic activity.

[0037]

INDUSTRIAL APPLICABILITY The method for synthesizing the PF1022 substance according to the present invention can be expected to be used as a method for screening and producing a more useful anthelmintic agent than the PF1022 substance.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tadaaki Okada 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery Co., Ltd.

Claims (1)

[Claims] 1. A _{L-N-CH 3 · Leu} -D-lac-
_{L-N-CH 3 · Leu} -D-phe · lac-L-N
_{-CH 3 · Leu-D-lac} -L-N-CH 3 · Leu
Cyclic depsipeptide PF1022, characterized by ring-closing the compound represented by -D-phe-lac-OH
Method of synthesizing substances.