JPH0472833B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is directed to one compound selected from the group of compounds having a Labranian skeleton represented by the following general formula and general formula.
The present invention relates to a method for producing 8α,12-epoxy-13,14,15,16-tetranorhabdane represented by the following general formula by processing the above substances. The above 8α produced by the production method of the present invention,
12-Epoxy-13,14,15,16-tetranorhabdane, a compound called ambrox, is a substance useful as a perfume with an excellent amber odor. Ambrochus is synthesized from manur and scleraol, both of which are compounds extracted from coniferous trees grown in New Zealand, and are expensive and produced in small quantities. The present inventors conducted various studies on a method of synthesizing ambrox from copal resin, which can be obtained in large quantities at low cost, and finally completed the present invention. Copal resins include Manila copal, cauli copal, and Congo copal, and they contain polymer compounds that are insoluble in solvents and diterpenoid compounds that have a labdan skeleton (Masayoshi Okikawa, Yoshikazu Ninomiya, et al., Pharmaceutical Journal Vol. 98, 672 pages, 1978). An example of the composition of Manila copal is shown in Table 1. After dissolving copal resin (A) in a highly polar solvent such as ethyl ether, tetrahydrofuran, acetone, or methyl alcohol, adding a nearly non-polar solvent such as hexane, benzene, or toluene results in a polymer compound (see Table 1). ) is precipitated. Soluble parts (in (C) in the same table,
Contains compounds with labdane nuclei shown in (1), (2), (3), (4), (5), (6), and (7), respectively. Among these compounds, compounds having the general formula shown in () or () below, i.e., (3), (4),
Compounds (5), (6), and (7) are oxidized with an oxidizing agent to yield compound (8). In order to selectively oxidize both double bonds, potassium permanganate is preferred as the oxidizing agent, and the reaction conditions are -10° to 60°C for 1 to 24 hours when acetone aqueous solution is used as the solvent. It is. In this case, a phase transfer catalyst such as dicyclohexyl
Using a crown ether such as 18-crown 6 or an ammonium salt such as trioctylmethylammonium chloride, water and benzene. Good results can be obtained by using a method of reacting in a heterogeneous system such as toluene at 0 to 100°C for 1 to 5 hours. Compound (8) is treated with a peracid, preferably m
- Using chloroperbenzoic acid, perbenzoic acid, peracetic acid, perphthalic acid, etc., at about 15 to 80°C for about 6 hours to 5 hours.
When the reaction is allowed to proceed for several days, epoxidation of the double bond and Baeyer-Villiger oxidation occur simultaneously, yielding compound (9). Compound (9) is reduced using a reducing agent, preferably lithium aluminum hydride, in a solvent, preferably ethyl ether, tetrahydrofuran, etc.
Compound (10) is obtained by reacting at ~60°C for about 0.5 to 12 hours. Compound (10) is methyl esterified to form compound (11)
is obtained. Compound (12) is obtained by dissolving compound (11) in a basic solvent such as pyridine and reacting it with P-toluenesulfonyl chloride or methanesulfonyl chloride.
℃ and reaction time of 6 to 48 hours is preferable. When compound (12) is reduced using a reducing agent, the compound
(13) is obtained, the reducing agent is preferably lithium aluminum hydride, the solvent is ethyl ether or tetrafuran, the reaction temperature is 15-50°C,
The reaction time is preferably 0.5 to 12 hours. When compound (13) is oxidized using an oxidizing agent, the compound
(14) is obtained, but it is preferable to use a chromic acid-pyridine complex or pyridinium chromate as the oxidizing agent. It is not preferable to use a strong oxidizing agent because the oxidation progresses too much and even carboxyl groups are oxidized. Reaction conditions include 0 to 30°C;
0.5 to 5 hours is appropriate. Compound (14) is reacted with thiol using an acid catalyst to form a thioketal to obtain compound (15). Suitable acid catalysts include P-toluenesulfonic acid and trifuscaboron ether complex, and preferred reaction conditions are 10 to 50°C and 1 to 24 hours. Compound (15) is subjected to desulfurization reduction using, for example, Raney nickel to obtain compound (16). Reaction conditions are 60~
Preferably, the temperature is 90°C for 1 to 24 hours. In addition, compound (14) was added to Polf. Oxygen reduction,
Compound (16) can also be obtained. That is, compound (16) is obtained by converting aldehyde into hydrazone or semicarbazone and heating in the presence of a strong base such as an alkali metal alkoxide. The present invention will be explained in detail below with reference to Examples, but the present invention is not limited thereto. Examples (See Table 1) (1) 110 g of Manila Kobal resin (A) was dissolved in 300 ml of ethyl ether under heating. Add this to 500ml of benzene
was added and then heated to distill off the ethyl ether. Upon cooling and standing, a viscous polymer portion (B) precipitated. The supernatant liquid was concentrated under reduced pressure to obtain 64 g of a pale yellow transparent resinous substance (C). This substance (C) contains compounds with a labdane skeleton such as capresic acid and tolurosol. (2) 3.3 g of the above resinous substance (C) was dissolved in 100 ml of benzene. Add to this 4.5g of potassium permanganate.
and trioctylmethylammonium chloride
A solution of 1.5g and 30ml of water was added. Although heat generation occurred, stirring was continued for 1 hour at room temperature. The reaction solution was transferred to a separating funnel, the benzene layer was dehydrated with sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (benzene: ethyl acetate 10:1) to obtain the target compound.
(8) (The numbers in brackets indicate the compounds with the same numbers as above.) 1.0 g was obtained. Compound (8) is a pale yellow oil, C ₁₈ H ₂₈ O ₃ (molecular weight 292), IR: 1720 cm ^-1
(CO), 1690 ^-1 (−COOH), ^13C −NMR:
209.2ppm (CO), 183.6ppm (−COOH),
106.3ppm (CH ₂ ), 147.4ppm (=C=). (3) 8.3 g of compound (8) was dissolved in 130 ml of chloroform, and 15 g of m-chloroperbenzoic acid was added and dissolved. After standing at room temperature for 40 hours, it was heated to 40°C for 4 hours. After cooling, the reaction solution was washed with an aqueous sodium iodide solution, an aqueous sodium thiosulfate solution, an aqueous sodium bicarbonate solution, and brine in this order, and then dehydrated over sodium sulfate. Then remove the solvent and
10.1 g of crude compound (9) was obtained. In an argon atmosphere, 10.1 g of compound (9) and 50 ml of tetrahydrofuran were added to a suspension of 3.5 g of lithium aluminum hydride in 20 ml of tetrahydrofuran while cooling on ice.
The solution was added and stirring continued for 3 hours. Further saturated sodium sulfate solution was added and the white precipitate was filtered off. After concentrating the liquid under reduced pressure, ethyl ether was added to produce white crystals. The crystals were collected to obtain 2.1 g of compound (10). Compound (10): white crystal mp 191.3°C, yield (compared to compound (8)) 26%, C ₁₆ H ₂₈ O ₄ (molecular weight 284), IR:
3400cm ^-1 (-OH), 1680cm ^-1 (COOH); ¹³ C-
NMR: 178.7ppm (-COOH), 63.2ppm (-
_CH2OH ),

[Formula] (4) 1.4 g of compound (10) was dissolved in tetrahydrofuran, an ether solution of diazomethane was added, and the mixture was concentrated under reduced pressure to obtain compound (11). Add this to pyridine 10
ml, 1.6 g of P-toluenesulfonyl chloride was added, dissolved, and allowed to stand at room temperature for 24 hours. After adding 100 ml of ethyl ether to this reaction solution, the ether layer was washed with dilute hydrochloric acid and brine,
After dehydration over sodium sulfate and further concentration under reduced pressure, 0.8 g of compound (12) was obtained by silica gel column chromatography (chloroform). Compound (12): pale yellow oil, C ₁₇ H ₂₈ O ₃ (molecular weight
280), yield (relative to compound (10)) 58%; IR:
1730cm ^-1 (-COOMe); ^13C -NMR: 51.0ppm
(−OCCH ₃ ), 64.7ppm (−CH ₂ O−), 79.5ppm
(-C-O-), 177.2ppm (-COO-) (5) In an argon gas atmosphere, a solution of 570 mg of compound (12) in 2 ml of tetrahydrofuran was added to a suspension of 160 mg of lithium aluminum hydride in 5 ml of tetrahydrofuran at room temperature. The mixture was added dropwise with stirring, and then refluxed for 30 minutes. After cooling, a saturated aqueous sodium sulfate solution was added to remove a white precipitate.
The liquid was concentrated under reduced pressure to obtain 460 mg of white crystals of compound (13). 460 mg of this compound (13) was dissolved in 30 ml of methylene chloride, 550 mg of pyridium chloromate was added while cooling with ice, and the mixture was stirred for 2 hours. The reaction solution was diluted with ethyl ether and passed through a short column of Florisil. The eluate was washed with dilute hydrochloric acid and aqueous sodium chloride solution, and then dehydrated with anhydrous sodium sulfate. The residue obtained by further concentration under reduced pressure was subjected to column chromatography (hexane: ethyl ether 3:2) using silica gel, and the compound
(14) 433 mg was obtained. Compound (14): pale yellow oil C ₁₆ H ₂₆ O ₂ (molecular weight
250), yield (counter compound (12)) 85.1%, IR1720cm ^-1
(-CHC), ^1H -NMR9.76ppm(S) (-CHO),
3.90 pmm(t) (-O-CH ₂ -) (6) Dissolve 1.23 g of compound (14) in 2 ml of methylene chloride, add 0.5 ml of ethane sitiol and 100 mg of p-toluenesulfonic acid, and reflux for 2 hours. did.
After releasing the pressure, the reaction solution was subjected to silica gel column chromatography (hexane: ethyl ether 20:
1) to obtain 1.20 g of compound (15). Compound (15) White crystal C ₁₈ H ₃₀ OS ₂ (molecular weight 326) Yield (counter compound (13)) 74.8% ¹ H-NMR 3.15 ppm (-
SCH ₂ -), 3.88ppm (-O-CH ₂ -), 5.15ppm

[Formula] (7) 1.20 g of compound (15) was added to Raney Nickel W-2 (prepared from 24 g of Raney alloy) prepared in advance, and further 50 ml of ethyl alcohol was added and the mixture was stirred under reduced pressure for 14 hours. After the reaction, the contents were filtered and the liquid was concentrated under reduced pressure to obtain compound (16)0.84
I got g. Compound (16) White crystal mp 73-74°C (methyl alcohol recrystallization) C ₁₆ H ₂₈ O (molecular weight 236) Yield (counter compound (15)) 96.7% ¹³ C-NMR 21.1 ppm (4-CH ₃ , 8- _CH3 )
33.6ppm (4- _CH3 ), 15.0ppm (10- _CH3 )

【table】

Claims (1)

[Claims] 1. One or more substances selected from the group of compounds having a labdane-type skeleton represented by the following general formula are treated with an oxidizing agent and a reducing agent to form a compound represented by the following general formula. , which is treated with a methylating agent and a dehydrating agent to form a compound represented by the following general formula, which is then treated with a reducing agent and an oxidizing agent to further reduce the compound represented by the following general formula. 8α, 12-epoxy-13, 14,
15, 16-Method for producing tetranorlabdane.