JPS5823852B2 - Sesquiterpene derivatives and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel sesquiterpene derivative and a method for producing the same.

Compounds of the invention have the formula It is a sesquiterpene derivative represented by

The compound of the present invention is a novel compound that has not been described in any literature and has the physical properties described in the Examples below.

The compound of the present invention is a known substance barburganal (war).
Barbaganal is an important intermediate in the total synthesis of Barbaganal, and the final synthetic substance, Barbaganal, is a natural product derived from the East African plant Barbagia.
burgia), its structural formula has also been determined, and its physiological activity is similar to that of the night robber moth (Arm.
A strong antifeedant against y worms.
It is known as a useful substance that acts as a feedant (Chem, Comm 1, p.

1013 (1976)].

The compound of the present invention is useful as an important intermediate in the next step in the total synthesis of barbarganal.

In the above step, the starting material 7-oxoisodrimenin (7-oxoisodrimenin) is already isolated as a natural product.
odrimenine) (J, Chem, Soc
1, p.

4685 (1960)] with an oxidizing agent, especially chromic acid (HoH,
Appel, etal: J, C9S, 4685
(1960)], and the raw material indolimenin has already been completely synthesized by the present inventor as a sesquiterpene derivative derived from ■-abietic acid, and is easily available [Japanese Patent Application No. 52-38628 No. (Japanese Unexamined Patent Publication No. 124256/1983)].

In addition, easily available β-ionone (β-1onone)
The present inventor has also succeeded in synthesizing indolimenin in an extremely short process from
Specification No. 59).

To explain the above process, the starting material 7-oxoindomenine is first induced into a ketal form, and then a ketone form, a diacetate form, an epoxy form, a triol form, a silyl form, a carbonate form, an alcohol form, an aldehyde form, a ketal form. , the aforementioned barburganal can be synthesized by converting it into a diol form and an aldehyde form, respectively.

To explain this according to the steps, first, the starting material 7 to oxoisotrimenine (2) is treated with a dialcohol and an organic acid and refluxed to obtain the ketal compound (3) in high yield.

The obtained ketal body (3) can be reacted with a reducing reagent in an organic solvent to lead to the ketone body (4) in high yield.

The diacetate (5) can be obtained in high yield by reacting the obtained ketone (4) with an acetylating agent in a solvent.

The epoxy compound (6) is obtained in high yield by treating the obtained diacetate compound (5) with a peroxide in the presence of an aqueous alkali solution.

The obtained epoxy compound (6) is reacted with hydrazine hydrate to introduce a double bond to obtain the compound of the present invention, a triol compound (7).

The obtained triol body (7) is reacted with imidazole and trialkylsilyl chloride to obtain a silyl body (8), which is a compound in which the aryl group and the hydroxyl group are protected.

The obtained silyl compound (8) is refluxed with phosgene or carbonylimidazole to obtain a carbonate compound (9) in which glycol is protected with carbonate in a high yield.

By treating the obtained carbonate form (9) with an organic acid, the silyl is returned to alcohol, and the alcohol form (9) is converted into an alcohol form.
10) can be obtained quantitatively.

When the obtained alcohol compound (10) is reacted with an oxidizing agent, an aldehyde compound (1υ) is obtained in high yield.

In order to further protect the obtained aldehyde 0υ with acetal, it is treated with a dialcohol and an organic acid to produce a ketal (12)') which is stable in alkali! - Obtained.

By treating the obtained ketal compound (12) with an alkali, diol compound 03) can be obtained in high yield.

The obtained diol (I3) is reacted with an oxidizing agent under basic or neutral conditions to obtain an aldehyde (I4).

When the aldehyde 04) thus obtained is reacted with an organic acid, the above-mentioned barburganal (15) is obtained.

Barberganal 05) synthesized in this way is
It completely matches the physical properties of the natural product Barbaganal.

The compound of the present invention can be produced by the following method.

That is, the ketal (3) can be obtained in high yield by treating the 7-oxoindomenine (2) with a dialcohol and an organic acid and refluxing.

In this case, organic acids such as p-1 luenesulfonic acid and cannur sulfonic acid are used, aromatic hydrocarbons such as benzene and toluene are used as solvents, and ethylene glycol,・3-propanediol etc. can be used, especially in benzene solution, p
-) It is preferable to use luenesulfonic acid or ethylene glycol.

The reaction temperature and reaction time at this time are not particularly limited, but
80-150°C and 4-12 hours are suitable, respectively.

The obtained ketal body (3) can be reacted with a reducing reagent in an organic solvent to lead to the ketone body (4) in high yield.

In the above reaction, lithium aluminum hydride is suitably used as the reducing reagent, and ethers such as ether, dioxane, and tetrahydrofuran are used as the solvent. In particular, when lithium aluminum hydride is used in anhydrous ether, suitable.

The reaction temperature and reaction time are not particularly limited, and room temperature and 2 to 12 hours are suitable, respectively.

The diacetate (5) can be obtained in high yield by reacting the obtained ketone (4) with an acetylating agent in a solvent.

As the acetylating agent in this case, acetic anhydride-pyridine, acetyl chloride-pyridine, etc. can be used, but especially excellent results are obtained in the case of acetic anhydride-pyridine.

In the above reaction, the reaction temperature and reaction time are not particularly limited, and particularly suitable results are obtained at room temperature for 4 to 12 hours.

The epoxy compound (6) is obtained in high yield by treating the obtained diacetate compound (5) with a peroxide in the presence of an aqueous alkali solution.

As the alkali in this case, an aqueous solution of sodium hydroxide, potassium hydroxide, etc. is used, as the peroxide, hydrogen peroxide, t-butyl hydroperoxide, etc. are used, and as the solvent, alcohols, ether, etc. are used. However, it is particularly preferred to use hydrogen peroxide in methanol solvent in the presence of sodium hydroxide.

Although the reaction temperature and reaction time are not particularly limited, a temperature around 0°C and a time of 1 to 4 hours is suitable.

The obtained epoxy compound (6) is reacted with hydrazine hydrate to introduce a double bond to obtain the compound of the present invention, a triol compound (7).

As the hydrazine, 100% hydrazine hydrate is suitable, and a solvent is not particularly required, and the reaction proceeds advantageously even in the absence of a solvent.

Reaction temperature and reaction time are not particularly limited, but 120°C
It is preferable to leave it in the vicinity (room temperature is also possible) and for 10 to 30 minutes.

The obtained triol body (7) can be reacted with imidazole and trialkylsilyl chloride to obtain a silyl body (8) in which the hydroxyl group of the aryl group is protected.

In this reaction, dimethyl t-butylsilyl chloride gives suitable results as the trialkylsilyl chloride.

Solvent: DMF (dimethylformamide), DMSO
(An organic solvent such as dimethyl sulfoxide or acetate ester can be used as appropriate, and DMF is particularly suitable.

The reaction temperature and reaction time are not particularly limited, but especially -1
00-0°C and 10-60 minutes are preferred.

Furthermore, the obtained silyl compound (8) is refluxed with phosgene or carbonylimidanol to obtain a carbonate compound (9) in which the carbonate is protected with glycol in a high yield.

In this reaction, phosgene can be used, but N.N'-carbonylimidazole is preferably used because it is a dangerous gaseous substance.

As the solvent, organic solvents such as benzene and chloroform are used.

Further, the reaction temperature and reaction time are not particularly limited, but a temperature around 90° C. and 30 to 60 minutes is particularly suitable.

The obtained carbonate-1 compound (9) is treated with an organic acid to convert the silyl back into alcohol, and the alcohol compound (10) is quantitatively obtained.

As the organic acid used in this reaction, organic acids such as camphorsulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and acetic acid are used, and alcohols, ethers, etc. can be used as the solvent, and in particular, in methanol, It is preferable to use camphorsulfonic acid.

The reaction temperature and reaction time at this time are not particularly limited, but
Particularly good results are obtained at room temperature for 3 to 5 hours.

When the obtained alcohol compound (10) is reacted with an oxidizing agent, aldehyde compound 0υ is obtained in high yield.

The oxidizing agent in this oxidation reaction is Jones (Jones).
nes) reagent (chromic anhydride in dilute sulfuric acid) is preferably used, acetone is particularly effectively used as the solvent, and the reaction temperature and reaction time are not particularly limited, but each -
The reaction proceeds at 10° to 0°C and in a short period of about 5 to 30 minutes.

By treating the obtained aldehyde (1υ) with a dialcohol and an organic acid to further protect it with an acetal, an alkali-stable ketal (1) is obtained.

In this case, organic acids such as p-)luenesulfonic acid and camphorsulfonic acid are used, and aromatic hydrocarbons such as benzene and toluene are used as the solvent.
Examples of dialcohols include ethylene glycol, ■・3-
Propanediol and the like can be used, and it is particularly preferable to use p-toluenesulfonic acid and 1,3-propanediol in a benzene solution.

The reaction temperature and reaction time at this time are not particularly limited, but
Each reacts well at 80 to 150°C and in a short time of about 10 to 30 minutes.

By treating the obtained ketal (12) with an alkali, the diol (13) can be obtained in high yield.

As the alkali at this time, an aqueous solution of sodium hydroxide, potassium hydroxide, etc. is used, and as the solvent *ether,
Ethers such as dioxane and tetrahydrofuran can be used, but it is particularly preferable to use sodium hydroxide in a dioxane solution.

The reaction temperature and reaction time are not particularly limited, but at room temperature
~3 hours is preferred.

EXAMPLES Below, the method for producing the compound of the present invention will be specifically explained with reference to Examples.

Reference Example 1 (1)-Isotrimenine (1) 400~ of chromic acid is added to 30 TL of an acetic acid solution of 318Tn9 and stirred at 50°C for 4 hours.

After the reaction, water was added and extracted with ether, and the ether layer was extracted with water and
After washing with saturated sodium bicarbonate water and saturated saline, dry with sodium chloride.

The solvent is then distilled off to obtain 301m9 of an oil.

This was subjected to silica gel column chromatography (Loba
r column; Hexane: Ezo acetate/l/
=3:1), 7-oxoindomenine (2)2
Obtain 39m9.

This is further recrystallized from n-hexane-ether to obtain colorless prism crystals.

(physical properties) Melting point: 107-109℃ Two-element analysis value: (calculated value) C172,55H2S.

12 (actual value) C172,41H18,12 Infrared absorption spectrum (IR) (CCI4) Rainbow maX1
770.1680C:1TL-1 Nuclear magnetic resonance spectrum (NMR) (CDCl2): 0.93 (Me) OJ7 (Me) 1.28 (Me) 1 4.81 (S; -C-0-CH2) Example 1 7-Okituisodorimenine (2) obtained in Reference Example 1 2
To 54 m9 of a benzene solution (20 ral), 2 ml of ethylene glycol and 30 to toluenesulfonic acid were added, and the mixture was refluxed overnight in a Dean-Stark apparatus.

After the reaction, the benzene layer was washed with 10% aqueous sodium carbonate and saturated brine, and then dried over magnesium sulfate.

After evaporation of the solvent, a silica gel column (L
(obar column; hexane:acetic ether (3:1)) to obtain ketal compound (3) 281Tv.

When this is further recrystallized from n-hexane-ether,
Obtain colorless prismatic crystals.

(Physical properties) Melting point: 88.5-89.5℃ Elemental analysis value: (calculated value) C169,84H2S, 27(
Actual measurement value) C, 69, 82H, 8, 27 IR (CCI4) Niji max 1760cm 'NM
R(CDCl2): 0.88 (Me)o, c+2(
Me) 116 (4Vfe) Ca 3.8~4.2 (m, -〇Cdan,,CH,,O
-)1 4.68 (S; C-0CH2) Example 2 Ketal compound (3) obtained in Example 1 3.3? Anhydrous.

Two portions of lithium aluminum hydride were added to 100 ml of the ether solution, and the mixture was stirred at room temperature for 2 hours and 30 minutes.

After the reaction, water and 10% HCI were added, followed by ether extraction, and the ether layer was washed with saturated brine and dried over magnesium sulfate.

When the solvent is distilled off, ketone body (4) 2.9602 is obtained.

(Physical properties) Mass spectrometry: m/e: 234
(M+-: H2O) (High resolution mass spectrum) ■R (CC14) Rainbow maX3400.1665IrL
-1 NMR (CDCIs): 0.88 (Me) 0.
92 (Me) 1.15 (Me) Example 3 Ketone body (4) obtained in Example 2 2.960? Add 10 ml of acetic anhydride to 10 ml of pyridine solution of
Leave it for a while.

After the reaction, water is added under cooling to perform ether extraction, and the ether layer is washed with 10% HCI, 10% l'Ja2cO3, and saturated brine, and then dried over magnesium sulfate.

After distilling off the solvent, it was subjected to silica gel chromatography (hexane:ether-1:1) to obtain diacetate (5) 2
．． Get 5509.

When this is further recrystallized from n-hexane-ether,
Colorless needle-shaped crystals are obtained.

(Physical properties) Melting point: 87-88℃ Elemental analysis value: (calculated value) C167,83H2S, 39 (
Measured value) C167,89H2S, 36 I R (cci4) Rainbow maX1745.16801
'NMR (CDCl2): 0.91 (Me)0.9
4 (Me) 1,,18 (Me) 2.00 (OAc) 2.05 (OAc) Example 4 Diacetate obtained in Example 3 (5J1.060V
5ml of 30% hydrogen peroxide in 30ml of methanol solution
1 and then 2.5 ml of 10% sodium hydroxide and stirred at 0°C for 1 hour.

After the reaction, the solvent is distilled off and extracted with ether. The ether layer is washed with saturated brine and dried over magnesium sulfate.

The solvent was distilled off to obtain 835 mg of crystals of epoxy compound (6).

When this is further recrystallized from ether-hexane, colorless needle crystals are obtained.

(Physical properties) ; Melting point: 117-118°C Elemental analysis value: (calculated value) C167,13H1O,02(
Actual measurement value) C167,11H1O,08 IR (CHCI3): 'max 3590.3
46011695bo-1 NMR (CDCl2): δ0.84 (Me)0.8
6 (Me) 1.13 (Me) Example 5 Epoxy body (6) obtained in Example 4 10 in 835 m9
Add 12 ml of 0% NH2NH2.H2O and heat at 120°C for 15 minutes.

After the reaction, the mixture is extracted with ether, and the ether layer is washed with saturated brine and dried over magnesium sulfate.

When the solvent is distilled off, 720m9 of triol compound (7) is obtained.

After being subjected to partial preparative thin-layer chromatography (silica gel: ethyl acetate), it is recrystallized from ether to give colorless prism crystals.

(Physical properties) Melting point: 137-138°C Mass: m/e: 223 (M-CH2O
H)? ■R (CuCl2) Niji maX3470CrrL
-1NMR (CDCl2): 0.80 (Me)o
, 9o(Me) 0.92 (Me) 5.86 (broad, 7-H) Reference Example 2 Triol compound (7) obtained in Example 5 1067729
Add imidazole 851n9 to 27711 of a dimethylformamide solution, then add 1rfl of a dimethylformamide solution of 63m9 of dimethyl t-butylsilyl chloride.
1 and stirred for 20 minutes under water cooling.

After the reaction, the mixture is extracted with ether, and the ether layer is washed with saturated brine and dried over magnesium sulfate.

After evaporating the solvent, it was subjected to preparative thin layer chromatography (silica gel: heptahexane: ether - 1:1) to obtain the silyl compound (8) 841rlI? get.

) (Physical properties) Mass: m/e: 337 (M+-CH
2OH) IR (CuCl2) Niji maX3420-1N
MR (CDCl2): 5.81 (broad:
7-H) Reference Example 3 To 15 ml of a benzene solution of the silyl compound (8) 1941n9 obtained in Reference Example 2, N-N'-carbonyldiimidazole 342~ is added and refluxed for 30 minutes.

Next, after adding ether and washing with saturated brine, drying over magnesium sulfate and distilling off the solvent, carbonate 1 (
9) 2247/l& is obtained.

When recrystallized from n-hexane, fine colorless needle crystals are obtained.

(Physical properties) Melting point: 59-60℃ Elemental analysis value: (calculated value) C166,96H2O,71(
Measured value) C, 67, 26H2O, 73 IR (CuCl3) Rainbow max 1785 (z IN
MR (CDCl2): 4.17 (S; -Cu
2-08i) 4.32 (d, J=9, II CH-0-C~) +1 4.75 (d, J=9, CH-0-C-) 6.05
(broad, 7-H) Reference Example 4 To 61 rL of a methanol solution of carbonate (9) 63 obtained in Reference Example 3, 15 to 15 camphorsulfonic acid was added, and the mixture was stirred at room temperature for 3 hours.

After the reaction, remove the solvent. Distilled off, extracted with ether methylene chloride,
The ether-methylene chloride solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over magnesium sulfate.

After evaporation of the solvent, crystallization was performed from n-hexane-ether.

Then, alcohol compound (1,0) 45~ is obtained.

Recrystallization from n-hexane-benzene gives colorless needle-like crystals.

(Physical properties) Melting point: 146-149℃ Elemental analysis value: (calculated value) C168,54H2S, 63(
Actual measurement value) C168, 98H2S, 80%); I R (C
HCI3): νmax” 600.3400178
5bo-1' NMR (CDC13): 0.82 (Me)0,
90 (Me) 0.92 (Me) 4.19 (S; 2H, CH2-0H) 1 4.36 (d, J = 9, -CH-QC-) 1 4.71 (d, J = 9, -CH-OC~)6.15 (
dd.
) After adding 6 drops of reagent, stir for 5 minutes.

After the reaction, ingropanol was added, the solvent was distilled off, water was added, ether-methylene chloride extraction was carried out, and the ether-methylene chloride solution was washed with saturated brine, saturated sodium bicarbonate, and saturated brine, followed by sulfuric acid. Dry with magnesium.

When the solvent is distilled off, the aldehyde compound 0υ69~ is obtained.

Recrystallization from benzene-n-hexane gives colorless needle-like crystals.

(Physical properties) Melting point: 133-135℃ Elemental analysis value: (calculated value) C169,04H17,97 (
Actual measurement value) C168,97H2S, 13 IR (CHCl3) Rainbow max 1790.1695
CTL-1 NMR (CDCl2): δ0.83 (Me)0.9
4 (Me) 0.96 (Me) ((4,34(d, J=9, CH2-O-C-O)1 4.62 (d, J=9, CH2-QC-0)7-2
1 (d, d, J=5.2;7-H)9.40(S;C
HO) Reference Example 6 1,3-propanediol L5y was added to 4077Il of the benzene solution of the aldehyde αυ308~ obtained in Reference Example 5.
A small amount of p-toluene phosphoric acid was added and the mixture was heated in a Dean-Stark apparatus for 1 hour.
Reflux for 5 minutes.

After the reaction, ether is added, and the ether layer is washed with a 10% aqueous sodium carbonate solution and saturated brine, and then dried over magnesium sulfate.

After evaporation of the solvent, crystallization with ether-hexane results in
360 m9 of ketal (12) is obtained.

Recrystallization from ether-hexane gives colorless needle-shaped crystals.

(Physical properties) Melting point: 167-168℃ Elemental analysis value: (calculated value) C167,83H2S, 39(
Actual measurement) C167,92H2S, 42 I R (CHCl5): Max 1780cm
'NMR (CDCl2): δ0.80 (Me)
0.88 (Me) 0.91 (Me) 1 4°30 (d, J=9; CH2-QC-0)5.

4 (S; 401>)); 5.12 (d, J=9; CH2-QC-0)6.
31 (d, d,, J=5.2; 7-H) Reference Example 7 10 ml of dioxane solution of 200 ~ ketal compound (12) obtained in Reference Example 6 1K 3 ml of 10% sodium hydroxide solution
1 and 5 TL of water, and stirred at room temperature for 1 hour and 30 minutes.

After the reaction, the mixture is extracted with ether, and the ether layer is washed with saturated brine and then dried over magnesium sulfate.

After distilling off the solvent, the diol (1,3) was analyzed using silica gel chromatography (hexane:ether-1:4).
181~ is obtained.

Recrystallization from ether-hexane gives colorless columnar crystals.

(Physical properties) Melting point: 9'9-100℃ Elemental analysis value: (calculated value) C169,64H2O,74(
Actual measurement value) C169,77H2O,75 IR (CHCL3) Niji max 3500cIfL'N
MR (CDCl, ): 0.87 (Me)0.
91 (2X Me) 5.14 (S; SeH>) 6.23 (broad, 7-H)

Claims (1)

[Claims] 1 A compound represented by the formula: 2. A method for producing a compound represented by the formula: , which comprises reacting the compound represented by the formula with hydrazine hydrate. 3. A method for producing a compound represented by the formula: which is characterized by treating the compound represented by the formula with a peroxide in the presence of an alkaline solution, thereby reacting the compound represented by the formula with hydrazine/-idlate. . 4 A compound represented by the formula: is reacted with an acetylating agent to obtain a compound represented by the formula: The compound represented by the formula: is treated with a peroxide in the presence of an alkaline solution to convert the compound represented by the formula into hydrazine. A method for producing a compound represented by the formula: characterized by reacting it with no-idrut. 5 A compound represented by the formula: is reacted with lithium aluminum hydride to obtain a compound represented by the formula: This compound is reacted with an acetylating agent to obtain a compound represented by the formula: The compound is made alkaline. A method for producing a compound represented by the formula: which comprises reacting the compound represented by the formula with hydrazine hytre 1. by treating with a peroxide in the presence of a solution. 6: A compound represented by formula: is reacted with a dialcohol and an organic acid to obtain a compound represented by formula: This compound is reacted with lithium aluminum hydride to obtain a compound represented by formula: The compound represented by the formula: is reacted with a hydrazine hydrate by reacting the compound with a hydrazine hydrate to obtain a compound represented by the formula: and treating the compound with a peroxide in the presence of an alkaline solution. method of manufacturing the compound represented by the patent.