Process for the production of mixtures of stereoisomers of 8,12-

Details Process for the production of mixtures of stereoisomers of 8,12- Process for the production of mixtures of stereoisomers of 8,12-

1994-01-18

1995-11-28

Dentz, Bernard

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D30792

Patent

active

054709890

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP92/01565 filed on Jul. 10, 1992.


FIELD OF THE INVENTION

This invention relates to a process for the production of stereoisomer mixtures of 8,12-oxido-13,14,15,16-tetranorlabdane by cyclizing dehydration of 8,12-dihydroxy-13,14,15,16-tetranorlabdane in the presence of acid-loaded aluminum oxide.


STATEMENT OF RELATED ART

8.alpha.,12-oxido-13,14,15,16-tetranorlabdane, hereinafter referred to as AMBROXAN.RTM., is a much sought-after fragrance with a pronounced odor of ambergris. Synthetically, AMBROXAN.RTM. can be obtained from sclareol in a multistep synthesis sequence. For example, the odorless diol, 8.alpha.,12-dihydroxy-13,14,15,16-tetranorlabdane, can be prepared by oxidative side-chain degradation of sclareol in accordance with U.S. Pat. No. 3,050,532 and subsequent reduction of the lactone formed. Dehydrating cyclization of this diol gives AMBROXAN.RTM.. Numerous acidic catalysts have been described in the literature for this cyclization. Particular emphasis is placed in this regard on DE 39 12 318 A1 which describes a process for the stereoselective preparation of AMBROXANE.RTM. using acid-loaded aluminum oxide.


STATEMENT OF RELATED ART

However, the preparation of stereoisomers of 8.alpha.,12-oxido-13,14,15,16-tetranorlabdane is not readily possible without losses of yield. Thus, P. F. Vlad and N. D. Ungur have investigated the preparation of the 8-epi and 9-epi isomers with that of AMBROXAN.RTM. by ring closure of the corresponding 1,4-diol intermediates with dimethyl sulfoxide/trimethyl chlorosilane. They found that the cyclization yield is dependent to a large extent on the stereochemistry of the product. Whereas 8.alpha.,12-oxido-13,14,15,16-tetranorlabdane and its 9-epi isomer were obtained in yields of 85% and 90%, respectively, the 8-epi isomer was obtained in a yield of only 46%.
It is also known that mixtures of stereoisomers of 8.alpha.,12-oxido-13,14,15,16-tetranorlabdane have a pronounced ambergris odor. Thus, DE 32 40 054 A1 describes a process for the preparation of a mixture of stereoisomers of 8.alpha.,12-oxido-13,14,15,16-tetranorlabdane. In this process, homofarnesylic acid is cyclized to norambreolide in the presence of titanium tetrachloride and/or certain tin compounds, the norambreolide is then converted into a 1,4-diol and the 1,4-diol is cyclized to 8,12-oxido-13,14,15,16-tetranorlabdane. According to the Example of DE 32 40 054 A1, the yield of the last-mentioned cyclization is only 65%.


DESCRIPTION OF THE INVENTION



Object of the Invention

Accordingly, the problem addressed by the present invention was to provide a process in which stereoisomer mixtures of 8,12-dihydroxy-13,14,15,16-tetranorlabdane could be converted in high yields into a stereoisomer mixture of 8,12-oxido-13, 14,15,16-tetranorlabdane.


SUMMARY OF THE INVENTION

It has now surprisingly been found that stereoisomer mixtures of 8,12-dihydroxy-13,14,15,16-tetranorlabdane can be converted into stereoisomer mixtures of 8,12-oxido-13,14,15,16-tetranorlabdane in yields of at least 95% if the cyclization is carried out in the presence of acid-loaded aluminum oxide.
Accordingly, the present invention relates to a process for the production of stereoisomer mixtures of 8,12-oxido- 13,14,15,16-tetranorlabdane by cyclizing dehydration of stereoisomer mixtures of 8,12-dihydroxy-13,14,15,16-tetranorlabdane with acid-loaded aluminum oxide .


DESCRIPTION OF PREFERRED EMBODIMENTS

The process according to the invention is carried out at temperatures of 120.degree. to 180.degree. C. and preferably at temperatures of 140.degree. to 160.degree. C. The cyclization may be carried out in the absence of solvents, but is preferably carried out in inert solvents, for example toluene, xylene or methyl cyclohexane. Small quantities of water adsorbed onto the acid-loaded aluminum oxide and also the water formed during the cyclization can readily be removed by azeotropic distillation.
The acid-loaded aluminum oxide is used in a quantity of 40 to 100% by weight and preferably in a quantity o

REFERENCES:
patent: 3050532 (1962-08-01), Schumacher et al.
patent: 4503240 (1985-03-01), Staiger et al.
patent: 5274134 (1993-12-01), Bruns et al.

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