Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-07-17
2003-05-27
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
Reexamination Certificate
active
06570044
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a technologically improved chemical process for the preparation of 6,6-dimethylhept-1-en-4-yn-3-ol. This compound is an important intermediate for the production of the widely used antifungal drug terbinafine.
PRIOR ART
The synthesis of the antifungal drug terbinafine was described in the chemical literature using various synthetic routes. Out of the processes described in the literature two closely related synthetic routes emerge as very significant processes for the preparation of terbinafine.
European patent EP24,587 describes the following process:
Reacting t-butylacetylene at −20° C. with butyllithium, cooling the reaction mixture to −75° C. and reacting it with acrolein to give 6,6-dimethylhept-1-en-4-yn-3-ol.
Treating the 6,6-dimethylhept-1-en-4-yn-3-ol formed with phosphorous tribromide in hydrobromic acid to give a mixture of Z and E isomers of 1-bromo-6,6-dimethylhept-2-en-4-yne. Usually the isomer ratio obtained is Z:E~1:2 to 1:3.
Treating the bromo compound (isomer mixture) with N-methyl-N-(1-naphthylmethyl)amine to give terbinafine.
The process is given in scheme 1.
The second process is described in Spanish Patent ES550,015 that uses similar building blocks. The process is as follows:
Reacting 1-bromo-6,6-dimethylhept-2-en-4-yne with excess methylamine to form N-methyl-N-(6,6-dimethylhept-2-en-4-ynyl)amine.
Reacting the said amine with 1-chloromethylnaphthalene to form terbinafine
This process is described in scheme 2.
The second process uses the same precursor, namely 6,6-dimethylhept-1-en-4-yn-3-ol, to prepare the required bromo compound.
The synthesis of the chloro analog viz. 1-chloro-6,6-dimethylhept-2-en-4-yne is described in European Patent EP341,048. In this patent the following synthesis is described:
Reacting t-butylacetylene at −40° C. or less with butyllithium, cooling the reaction mixture at −40° C. or less with acrolein further aging the reaction mixture at −50° C. for 30 minutes to give 6,6-dimethylhept-1-en-4-yn-3-ol.
Treating the 6,6-dimethylhept-1-en-4-yn-3-ol formed with thionyl chloride (in the presence of catalytic amount of DMF) to give 1-chloro-6,6-dimethylhept-2-en-4-yne (the ratio of Z and E isomers not specified).
Scheme 3 gives the formulas. This invention is not related to the preparation of terbinafine. It uses the chloro compound for other purposes.
DETAILED DESCRIPTION OF THE INVENTION
As seen from the prior art the preparation of 6,6-dimethylhept-1-en-4-yn-3-ol, which is the key intermediate required for the manufacturing of terbinafine has two characteristics. First, it uses butyllithium for the generation of the t-butylacetylide required for the condensation with acrolein. Second, the condensation is carried out at low temperatures (−75° C. according to one source and −40° C. or less according to another).
Although both requirements can be met in industrial scale production, they cannot be considered as desired ones. Butyllithium is commercially available in large quantities but it is a highly dangerous substance. It is usually manufactured as 15% solution in hexane. However this is a pyrophoric material which ignites spontaneously in air (and the presence of hexane makes the situation even worse), and extremely sensitive to air and moisture. The handling of butyllithium is therefore a difficult and dangerous task. The transportation of this material is also problematic due to strict regulations.
The temperatures cited in the literature for the condensation of t-butylacetylide and acrolein are well below the so-called ordinary temperature range in the chemical industry. Temperatures of 0° C. to −15° C. can be regularly achieved in the chemical industry using conventional technology. Operating at −40° C. or below is possible and the technologies are available. However, special equipment must be constructed, and the current operation is tedious and costly.
Attempts to replace the undesired butyllithium with other reagents in order to generate the t-butylacetylide proved to be a non-trivial issue. We have tried several organometallic compounds and other appropriate agents but found out that these reagents cause rapid polymerization of acrolein. Hardly, if any of the desired product 6,6-dimethylhept-1-en-4-yn-3-ol was formed. Thus, the use of sodamide, lithium diisopropylamide, sodium hydride and calcium hydride was futile. Polymers of acrolein were formed instead. Surprisingly we had found that the reaction between t-butylacetylide and acrolein can be conducted with an acetylide made of t-butylacetylene and an organomagnesium compound of the Grignard type having the formula RMgX wherein R is an alkyl or aryl group and X is a halogen atom chosen from the list of chlorine, bromine and iodine. Especially preferred organomagnesium compound is ethylmagnesium bromide.
Ethylmagnesium bromide prepared in ether or toluene-tetrahydrofuran mixture is reacted with t-butylacetylene. Ethane is evolved and t-butylacetylide is formed. The reaction is carried out at slightly elevated temperature (up to 40° C.) for several hours. The next step was described to take place at low temperatures (at −40° C. or below or at −75° C. To any chemist who is skilled in the art these low temperatures seem to be the correct conditions. On one hand such reactions are usually carried out at such conditions, and on the other hand the aim of lowering the temperature is required in order to avoid polymerization of acrolein. This chemical substance is notorious for its tendency to polymerize under almost any conditions. Commercial acrolein is usually supplied containing a small amount of hydroquinone in it in order to reduce this tendency. It was not surprising that scientists of two large chemical companies (Sandoz as documented in EP24,587 and Sumitomo in EP341,048) chose to work at very low temperatures. To our complete astonishment. we have found out that the reaction between the acetylide formed in the reaction of t-butylacetylene and Grignard reagents, preferably with ethylmagnesium bromide, and acrolein can be equally well done at temperature range of −40° C. to +20° C. preferably at 0° C.-5° C. without significant amount of acrolein polymerization. This leads to a high yield of the desired product -6,6-dimethylhept-1-en-4-yn-3-ol.
The significance of this invention is comprised of two facts. First, it enables one to produce 6,6-dimethylhept-1-en-4-yn-3-ol avoiding the use of the hazardous and difficult to handle butyllithium. Second, this process can be carried out using regular equipment without the need for special, expensive to build and difficult to use dedicated production systems.
Having the above results we had repeated the procedure outlined in EP24,587 but adding the acrolein at about 0° C. instead of −75° C. according to the literature source. To our amazement we found that the reaction between lithium t-butylacetylide and acrolein proceeds well even at the relatively high temperature we used. While literature reported yield of 64% for 6,6-dimethylhept-1-en-4-yn-3-ol we found our procedure to give a similar yield of 60.5% (distilled material). The technological advantage of working at ~0° C. should be emphasized again.
We have also tried to conduct the reaction using metallic lithium to generate the acetylide. It was found that although the reaction of lithium with t-butylacetylene is slow, it can be conducted successfully at temperature range of 20°-60° C. The next step (reaction with acrolein) was conducted at ~0° C. and proceeded smoothly.
While the invention will now be described in connection with certain preferred embodiments in the following examples so that aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the invention as defined by the appended claims. Thus, the following examples which includ
Danon Edna
Friedman Oded
Kaspi Joseph
Chemagis Ltd.
Shippen Michael L.
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