JPS5850995B2 - Diterpene derivative compounds and their production method - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula: (However, R1 represents hydrogen or a hydroxyl group.

) and its production method.

The compound of the present invention may be derived from a diterpene derivative in which all of the starting materials have an aromatic C ring, as described below;
In particular, it can be derived more easily than l-abietic acid.

L-Abietic acid has the following structural formula and can be easily and inexpensively obtained as the main component of phase detection resins. has been determined, and its total synthesis has also been achieved.

(W, H, 5chuller et al: J,
Am, Chem.

Soc, 83.2563 (1961), E.

Wenkert et al: J, Am, Ch.
em,・Soc, , 86.

2038 (1964)] In addition, examples of compounds that can be easily converted from l-abietic acid (Al) include skin fungi (e.g., Tricophyton + Microsporum).
cinnamoride (C1n), which exhibits antifungal activity against
naolide) [C], dimethyl scyazinonate, which inhibits the growth of silkworm larvae.
5ciadinona-te) CD).

[Collection of abstracts from the 19th Symposium on Flavor, Terpene, and Essential Oil Chemistry, page 149, S. Murakoshie
tal, Agr, Bio, Chem, 39
, 1167.

(1975)) l-Abietic acid (A) can be converted into these compounds by easily converting the aromatic C ring of [A] (dehydroabietic acid CB) in the (a) or (b) direction. Selective cleavage is required.

*On the other hand, levopimaric acid
acid ) (E) into a bicyclic compound [
Although it has been reported that levopimaric acid [E] can be obtained by this method, the raw material levopimaric acid [E] is difficult to obtain and the yield of ozone oxidation is poor.

(S, W, Pelletier et al.
, Chem, Co, mm-un, , 1967
, 96] According to the present invention, when the 12-hydroxy starting material is oxidized with ozone and then treated with various reducing agents, the bicyclic compound is selectively cleaved in the direction (a). are obtained, and these can serve as important synthetic intermediates in the conversion to the above-mentioned physiologically active substances.

The present invention will be described in detail below.

First, the diterpene phenol derivative represented by formula (1), which is the starting material of the present invention, can be easily obtained from l-abietic acid (A) according to the known method as follows.

(R, C, Cambie & R, A, Frani
ch, Au5t, J, Chem, +24.1
17 (1971)] (1): Methyl 12-hydroxy dehydroabietate (Methyl 12-hydroxy dehyetate)
ferruginol (ferruginol), which is also contained as a natural product in pine resin
nol ) (2) can also be used as a raw material.

(2): Ferruginol The thus obtained starting materials, 12-hydroxy compounds (1) and (2), were oxidized with ozone to cleave the aromatic ring, and then reduced using various reducing agents to obtain the desired product. can be obtained.

The ozone oxidation is carried out in a solvent, and the solvent used may be chloroform, methylene chloride, ethyl acetate, etc., but it is particularly advantageous to use CH2Cl2-CH30H (1:1).

The amount of ozone used is preferably in large excess, and the reaction temperature is preferably in the range of 8000 to 0°C.

The reducing agent used is catalytic reduction (10% pdC catalyst).
By selecting a reducing agent using , sodium borohydride, and #sodium sulfate, a compound that meets the purpose can be obtained.

The reaction temperature and reaction time were 0 to 30°C and 30°C, respectively.
Minutes to 12 hours are preferred.

As the solvent, those commonly used for reduction can be used, but CH2CA2-MeOH, EtOH
-H2O, water, acetic acid, etc. are preferably used.

Next, an example of the present invention will be described as follows.

Examples of the compounds obtained according to the present invention are as follows.

The name of the product is labdane (1abdane).
Skeleton (I followed this.

8-dihydroxy-(13→17)-pentazurhabd-900-ene-12,18-dioic acid 18-methyl ester 8α→12-lactone *Ne(8-Dihy
droxy (13→17)-pentanorl
a-bd-9 (1υ-en-12, 18-dioic
acid 18Methyl 8 a-+12-L
actone:)(3), 8α-hydroxy-(13
→17)-Pentaturu Rhabdo-9a1)-Ene-12,
18-dioic acid 18-methyl ester 8α→12-
Lactone [8α-Hydr.

xy (13-+17) pentanor
1abd 9(II)en-12,18-dioic
Ac1d 18-MethylEster 8 a-
+1.2-Lactone) (4), and both are new compounds.

The present invention will be explained below with reference to examples, but the present invention is not limited to these examples.

Example 1 12-OH form (C2+ H2O0g = 330)
(1) 5.0001n9CH2CA2: MeOH(1
:1) in 100 ml) was cooled with dry ice-acetone, blown with ozone for 3 hours, returned to room temperature, and heated to 10% pct.
-CI& is added and subjected to atmospheric pressure catalytic reduction.

Catalytic reduction is carried out until hydrogen is no longer absorbed, and then passed through the mouth.

After concentrating the 0 liquid, ether was added to the residue and the ether layer was diluted with 1
Extract with 0% KOH.

The alkaline layer is acidified with 10% HCl solution and extracted from chloroform.

The chloroform layer and the ether layer were each washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off.

After distilling off the solvent, the chloroform layer is further methylated by adding a diazomecune-ether solution, and then the ether is distilled off.

Ether layer (neutral part) Oil 1,754.9 GLC:4A 1.5% 0v-17 Simalite (S
himalite) I supported, temperature 200°C tR = 2.45.2.3m1n and many others, I tried to purify it by silica gel chromatography, but it was not purified.Chloroform layer (acidic part) Oily substance 3.368g Column chromatography was performed using 100 g of silica gel, and oil (5) 1,051.9 (22%) was obtained from the eluate of petroleum ether: ether = 2:1. Crystals (3) 6181n9 (14 %).

(5): Recrystallized from n-hexane 835m9 colorless prism crystal mp: 945-958C elemental analysis (Cl70
260! i) Theoretical value: C65,78H844 Actual value: C65,83H8,37 Br IR: ν 1740.1725,1715I'a
X NMFj(CO(J?3) δ0.74 S 3H
(1,0-Me)1.18 S 3H(,4-Me) 362) ゎReiiゎ8.3゜3.68 (4-COOMe.

9 CH2COOCH2 C0O Recrystallized from ethyl acetate-〇-hexane Colorless needle crystals mp: 187-190°C Elemental analysis (CIOH22
o5) Theoretical value C65,29M7.53 Actual value C65,51H7,61 Br IR rainbow 3400,1750,1716°aX 1645 cyrr-' MMR (COCl2) δ1.23 S 3H (4-
Me) 1.33 8 3H (10-Me) 3.67 S 3H (COOMe) 4.63-4. ．． 83(4,73)br,S.

IHWh/=5Hz (9-OH) 5.58 S IH(11-H) Uv: λ”OHOH209nε=12348) aX Note): (5) is levopimaric acid (levopimaric acid)
icacid) to pelletizer (pelletie)
There was no melting point drop even when mixed with the standard product synthesized according to method G of et al. (mixed melting point: 94-95°C),
GLC and NMR were completely consistent.

Example 2 Hydroxy lactone
) (3) 150 ml (50% (V/V) E
tOHH205ml! ) to NaBH4200111?
50% (V/V) EtOH-H20 solution in the presence of (
Dissolve the mixture, add Na BH4 while stirring under water cooling, and stir for 30 minutes.

Then add water and extract from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na2SO4, the solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane to obtain 119m9 of colorless prism crystals (4).

(4): mp: 153.5-155°C elemental analysis (as C1a H2204) Theoretical value: C69,0,4H7,97 Actual value: C69,0,4) 1787, KBr IR, ν 1750, 1720, 1640cIIL
-1aX NMR (CDC13): δ], 20S3H(4-Me)1.25
S3H(10-Me) 3.62 S3H(COOMe) 4.85 (octet J:=1,5.

7, 2, 9, 6Hz II-4 (8-H) 5.49d J=1.5Hz LH (11-H) NOE (100MHz): 10-Me→8-Hlo, 4
% increase Uv: λEtOH aX 209 nm (ε 12427) Example 12-OH compound (1) 1.0009 (CH2CA2:
Ozone was bubbled into 20 ml of MeOH (1:1) for 2 hours under cooling with dry ice and acetone, and the mixture was returned to room temperature.
After adding 40 mO of the mixture and stirring at room temperature for 12 hours, the mixture was acidified with 10% HC7 and extracted from chloroform.

The chloroform layer was washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off.

The residue (962) * was subjected to column chromatography using 30 g of silica gel, and the ether eluate was purified with acetic ether.
Recrystallized from n-hexane to give colorless needle-like crystals (3) 180■
(20%).

Even when mixed with the standard product (mixed melting point: 186-190°C), there is no drop in the melting point, and it is IR.

NMR was completely consistent.

Example 4 12-OH compound (1) 1,000! 9(CH2CA2
:MeOH (1:1) in 20 ml) was cooled with dry ice-acetone, ozone was blown in for 1 hour, the temperature was returned to room temperature, and NaBH4 (800 m9) 50% (V/V
) Add EtOH-H2O (10 yd) solution and stir for 30 minutes.

Then add water and extract from ether.

The ether layer was washed with saturated brine, dehydrated and dried over Na2SO4, and the solvent was distilled off.

The residue (808 .mu.) was recrystallized from ethyl acetate-n-hexane to obtain 546 .mu. (65%) of colorless prism crystals (4).

There is no drop in the melting point even when mixed with the standard product (mixed melting mp: 152-154°C), and also in IR, NMR, and GLC.

Totally agreed.

Claims (1)

[Claims] 1. A diterpene derivative compound represented by the general formula: (wherein R1 represents hydrogen or a hydroxyl group). The compound according to claim 1, which is represented by: 3. A compound according to claim 1, which is represented by the formula: 4 A diterpene phenol derivative (1) represented by the formula: is oxidized with ozone to cleave the aromatic ring, and then treated with sodium borohydride to obtain a compound represented by the formula: Method for producing pen-based derivatives. 5 The diterpene phenol derivative (1) represented by the formula: is oxidized with ozone to cleave the aromatic ring, and then treated with catalytic reduction or sodium sulfate to obtain the compound represented by the formula: A method for producing a diterpene derivative, which comprises further treating with sodium borohydride to obtain a compound represented by the formula: