JPS6013778A - Production of 8alpha,12-epoxy-13,14,15,16-tetranorlabdane - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as perfumery, from a raw material available in a large quantity at a low cost, by oxidizing and reducing one or more substances selected from the compounds having specific labdane skeleton, and treating the reaction product with a methylation agent and a dehydration agent. CONSTITUTION:One or more substances selected from the compounds of formula I (R is CH2OH, CHO or COOH) or formula II (R1 and R2 are same as R) having labdane skeleton, is treated with an oxidizing agent (e.g. potassium permanganate) and a reducing agent (e.g. aluminum lithium hydride), and the obtained compound of formula III is reacted with a methylation agent and a dehydration agent to obtain the compound of formula IV. The objective 8alpha, 12- epoxy-13,14,15,16-tetranorlabdane can be produced by treating the resultant compound of formula IV with a reducing agent and an oxidizing agent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention involves treating one or more substances selected from the group of compounds having Raglan skeletons represented by the following general formula 11 and general formula 12-Epoxy-1 person 14S1\ 16-Titranorlaggun relates to a manufacturing method.

The above-mentioned 8Q! manufactured by the manufacturing method of the present invention! , 12
-Epoxy-1\14. 1\16-Titranorapdan, a compound called ambrox, is a substance useful as a perfume with an excellent amber aroma. Ambrox is synthesized from manur and scleraol, both of which are compounds extracted from coniferous trees produced in New Sealant, which are expensive and produced in small quantities.

The present inventors have completed various studies on methods of synthesizing ambrox from copal resin, which can be obtained in large quantities at low cost, and have completed the present invention.

Copal resins include Manila copal, Kakuri Kobal,
Congo copal, etc., contains polymeric compounds that are insoluble in solvents and diterpenoid compounds that have a rapgun skeleton (Masayoshi Okiyo, Yoshikazu Ninomiya, et al., Pharmaceutical Journal 9LL 67
2, 1978). An example of a manila copal is shown in the first red.

copal resin), ethyl ether, tetrahydro 7
After soaking in a highly polar solvent such as acetone, methyl alcohol, etc., if a nearly charcoal solvent such as hexane, benzene, or toluene is added, a polymer compound (i.e.
Indicated by B in 4. ) is precipitated. Soluble part ((C) in the same table)
(-J:, in the same table, (1), (2), +31,
+4), (5), +61, and (71), which each contain a compound with a lagdan nucleus. Among these compounds, the compound having the general formula shown in the following ■-1fC wheel, That is, (3), (4), (6), (6),
When the compound shown in (7) is oxidized with an oxidizing agent, compound (8) is obtained. In order to selectively oxidize both double bonds, potassium permanganate is preferred as the oxidizing agent;
The reaction conditions are: when acetone aqueous solution is used as a 7/7 solvent,
-10° to 60°C for 1 to 24 hours is appropriate.

At this time, a phase transfer catalyst such as a crack ether t such as dicyclohexyl-18-kracune 6 or an ammonium salt such as trioctylmethylammonicum chloride is used, and a heterogeneous system of water, benzene, toluene, etc.
Good results can be obtained by using a method of reacting for 5 hours at 0°CXl.

Compound (8) is purified using a solvent such as ethyl ether, tetrahydro7ran, and a peracid, preferably m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perphthalate, etc. at about 15 to 80°c1 for about 6 hours to 5 days [11
When superimposed, Bayer-Villiger oxidation occurs simultaneously with epoxidation of the double bond, yielding compound 9).

Before reducing compound 9), preferably using lithium aluminum hydride, in a solvent, preferably ethyl ether, tetrahydro7ran, etc., at about 0 to 60°C.
．． Compound (10) is obtained by reacting for 5 to 12 hours.

Compound uol was converted to methyl ester to form compound I
ll is obtained. Compound t12) is obtained by dissolving compound +11) in a basic solvent such as pyridine and reacting it with P-toluenesulfonyl chloride or methanesulfonyl 70lide, at a reaction temperature of 15 to 50°C and a reaction time of 6. ~48 hours is preferred.

When the grass compound θ21 is reduced using a reducing agent, the compound +13
), 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 0.
5 to 12 hours is desirable.

Compound I is obtained by oxidizing Compound O with an oxidizing agent, and it is preferable to use a chromic acid-pyridine complex or pyridinium chromate as the oxidizing agent. If a strong oxidizing agent is used, the oxidation will proceed too much and even carboxyl groups will be oxidized, which is not preferable. Suitable reaction conditions are 0 to 30°C and 0.5 to 5 hours.

Compound I is reacted with a thiol using an acid catalyst to perform thioketalization to obtain compound lll51. Suitable acid catalysts include P-toluenesulfonic acid, trifutukahokuron ether complex salt, etc., and the preferred reaction conditions are 10
~50°C for 1 to 24 hours.

The compound is subjected to desulfurization reduction using Raney nickel, for example, to obtain compound .l[9. Reaction conditions are 60-90℃
, 1 to 24 hours is preferred.

The strained compound 04) can also be subjected to a Wolff-Kissiner reaction to obtain a compound Vl odor. That is, the aldehyde is converted into a hydrazone or semicarbazone, and the compound ++d is obtained by heating in the presence of a strong base such as an alkali metal alkoxide.

Hereinafter, the invention will be explained in detail with reference to Examples, but the invention is not limited to just one example.

Examples (Please refer to Table 1) (1) Manila copal < tj , ljl (A) 1
10 gf ethyl ether 30 (1 mg) was dissolved with heating in M. After adding 500 ml of benzene to this, it was heated to remove the ethyl ether. After cooling and standing still, the viscous polymer portion (B) precipitated. The above liquid was decompressed and TRf L
64 g of a yellow transparent resinous substance (0) was obtained. This substance (C) contains compounds having a labdane skeleton, such as cabresic acid and tolurosol.

(2) 3.3 g of the above resinous substance (C) was mixed with 100 g of benzene.
I bathed it in m1. In addition, 4.5% potassium permanganate
g and trioctylmethylammonicum chloride 1.5g
A solution of C6 dissolved in 30 ml of water was added to the mixture. Although an exotherm occurred, stirring was continued for 1 hour at room temperature. The reaction solution was transferred to a separatory funnel, the benzene layer was dehydrated with sodium sulfate, concentrated under reduced pressure with H4, and then separated using a silica gel column chromatograph (benzene: ethyl acetate 10:1).
Target compound (8) (The number in parentheses indicates the compound with the same number as above.) 1.0 g? 4) It was. Compound 18
) (is a pale yellow oily substance, 018H2803 (molecular species 29
2), Engineering R: 1720am -1 (::CO), t69
0-” (-cooH), 13cm NMR: 209.2p
pm(', ::co), 183.6ppm (-C:
0OH), 106.3 ppm (:=caz), 147
．． 4ppmC==C:).

(3) Compound t818.3g was added to chloroform L30+
nl! Further, 15 g of m-chloroperbenzoic acid was added and dissolved. After standing at room temperature for 4-0 hours, it was heated to 40°C for 4 hours. After cooling, the reaction solution was washed with an aqueous solution of sodium iodine, an aqueous solution of thiosulfuric acid, an aqueous solution of sodium bicarbonate, and brine in this order, and dehydrated with sodium sulfate. After that, the solvent was removed, and the crude product 10 of compound (9) was
°Ig was obtained. In an atmosphere of 4 argon atmospheres, a solution of 10.1 g of compound 1911 in somg of tetrahydrofuran was added to a suspension of lyticum aluminum hydride 3.5B in 20 mf of tetrahydrofuran while cooling with water for 4 t4, and stirring was continued for 3 hours. Furthermore, 1 phase of sodium sulfate solution was added, the white precipitate was filtered out, 7 tons were removed, and the pressure was reduced to 15 units, and ethyl needle was added.
White crystals formed. Count the crystals, compound +o;2.
1p; obtained 0 Compound (to): white crystal mp 191, J'
C% yield (counter compound 131) 26%, C16H28
04 (molecular weight 284), Engineering R: 3400 am” (
-OH), 1680 cm-1 (C!001();1
9C-NMR: 178.7 ppm (-COOH), 6
3.2ppm(-CI(20H), 71.4ppm(-
C-OH).

(4) Dissolve 111.4 g of compound +1F in tetrahydrofuran and add 1diazomethane ether mWi,
Concentration under reduced pressure yielded compound (11). Add this to 10ml of pyridine! 1.66 iJ] of P-toluenesulfonyl chloride was added to the mixture, and the mixture was stirred and allowed to stand at room temperature for 24 hours. Add 100 m/k of ethyl needle to this reaction solution.
After that, the ether layer was pre-cleaned with dilute hydrochloric acid and brine, dehydrated with sodium sulfate, and further evaporated under reduced pressure i71 to obtain 0 to 0.8 g of the compound by silica gel column chromatography (chloroform).

Compound: pale yellow oil, C17H2803 (molecular weight 280), yield (relative to compound 110)) 5&%; Engineering R: 1730cJn-1 (-cooMe); 13
cm) 11JR: st, oppm (-QCCH3), 6
4.7ppm (-cg2o=), 79, 5ppm
(-C-0-), 177.2ppy, (-coo-)(
5) In an argon gas atmosphere, 70 mg of compound + f21570 mg of tetrahydrofuran 2me @ solution was added dropwise at room temperature to a 7% suspension of 160 mg of lyticum aluminum hydride in 5 mJ of TetrahyF Roalane with stirring, and then for 30 min.
Refluxed for minutes. After cooling, a saturated aqueous solution of sodium chloride was added, and 7 white precipitates were lost. Concentrate the f solution under reduced pressure,
460 mg of white crystals of the compound were obtained. This compound t1
3) Add 460mg to methylene chloride 30m/f4,
550 mg of pyridinicum chlorochromate was added while cooling with water, and the mixture was stirred for 2 hours. Diluted with anti-HHM & ethyl ether and jetted a rectangular column of Florisil. /zo￥
The l:lj solution was washed with dilute acid and sodium chloride solution in water, and then diluted with dilute sodium chloride solution.

Furthermore, the cuttings 1 which had been subjected to a pressure of 1, p (,,; I bowed my head.

Compound, 1 illusion: light yellow 1)'! tt<si C16p
2602 (molecule; '+j,' 250), yield (total compound 1 ka) 8', >, 1%, lR17kQ-1 (-
CHo),'TJ NMR9,76ppm (s)
(CHO), 3.90ppm Ct) (-0-CH2
-) (6) Compound J'! 11.23g of methylene chloride 2mi
i6 j'; (L/1 ethanedithiol 0.5 mff
To the mixture was added 9100 mg of p-)luensulfon, and the mixture was refluxed for 2 hours. After pressure reforming, the reaction solution was subjected to 11 silica gel column chromatography (hexane: ethyl ether 2
0:l) to obtain 511.20 g of compound u.

Compound t151 white crystal 018H300S2 (/1+
Kono 326) Yield (counter compound g41) 74.8%"H
-1nAn 3.15ppm (-scu2-), 3.8
8ppm (-0-0) (2-), 5.15ppm (-
CH<cloudy) (7) 1.20 g of compound t+m was mixed with Ranini Soglu W-2 (Rani Alloy 24 [E
In addition to the mixture (prepared from (prepared from )), ethyl alcohol was further added and the mixture was reduced and stirred for 14 hours. After incubation, the contents were filtered, and the p liquid was stored in a vacuum chamber to obtain 0.84 g of compound 11υ white crystals mp 73-74'C (methyl alfur vs. biological compound Vl) 96.7% "O-NMR 21.1 ppm (4-OH3, 8-C
H3) 33, 6 ppm (4-OH3), 15.
0ppm (1(1-CI'T3)R1=CH20I
L CH Su Mata jlcOOH (1) R2 CH 20 HXCI Mi again! zuCQ○H (11〕 (110 θ翫゛) Procedural amendment 1982, February 2nd, 1981 Commissioner of the Japan Patent Office Indication of Kazu Inu Wakasugi case Name of invention of patent application No. 120689 of 1982
8CM, 12-1-Hoxy 13.14.15.16-
Person who amends the manufacturing method of Chitranorlapdan: Grandson of the town '4 Patent applicant (residence) 671-4 Mizuashi, Noro-cho, Kakogawa-shi, Hyogo Prefecture Name ('8'8) Representative of Harima Kasei Kogyo Co., Ltd. Rijinhaga 13 Date Month, Showa 1 Subject of spontaneous amendment Contents of amendments to the specification and detailed explanation of the invention As attached, the structural formula +91.021 and H of the compound on page 5 of the specification are changed to the following: I will correct it accordingly.

Claims (1)

[Claims] One or more substances selected from the group of compounds having a dibutane type skeleton represented by the following general formulas I and II are treated with an oxidizing agent and a reducing agent to form a compound represented by the following general formula (■). A compound is treated with a methylating agent and a dehydrating agent to obtain a compound represented by the following general formula (1), which is further treated with a reducing agent and an oxidizing agent to obtain the following general formula (2). 8Q expressed as! , 12-epoxy-1 person 14.
1\16-Production method of titranorrapgun. R is CH20H.
H (I) (11) tl[) 01')