Process for preparing terbinafine and HCI salt thereof

Details Process for preparing terbinafine and HCI salt thereof Process for preparing terbinafine and HCI salt thereof

2002-12-27

2004-02-10

Davis, Brian (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S387000, C564S397000

Reexamination Certificate

active

06689913

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing terbinafine and its HCl salt useful as an anti-fungal agent.
2. Description of the Related Art
Terbinafine or its HCl salt is a compound useful as an anti-fungal agent. The chemical name of terbinafine is trans-N-methyl-N-(1-naphthylmethyl)-6,6-dimethylhept-2-en-4-ynyl-1-amine, represented by the following chemical structure.
Conventional processes for preparing terbinafine or its HCl salt are disclosed in European Pat. No. 24,587, U.S. Pat. No. 5,440,049, U.S. Pat. No. 5,817,875
, J. Med. Chem.,
27, 1539 (1984), and Korean Laid-open Pub. No. 2000-65,691.
The process disclosed in European Pat. No. 24,587 may be summarized as following reaction schemes 1 and 2:
In the above process according to the reaction scheme 1, the bromoenyne derivative, intermediate for the preparation of terbinafine, is obtained unfavorably in a mixture form having an E/Z ratio of 3/1. Further, n-butyllithium, which is a strong base difficult to be available for industrial use, is used and the process is completed through so many complicated steps. Accordingly, the process in accordance with the reaction scheme 1 has difficulties to be applied to an industrial-scale mass production.
The process according to the reaction scheme 2 gives a by-product, which decreases the yield of terbinafine. Further, diisobutylaluminum hydride (DIBAL-H), which is a strong reducing agent, is used, which is unfavorable for industrial-scale mass production.
The process disclosed in U.S. Pat. No. 5,440,049 may be summarized as following reaction scheme 3:
The above process employs trans-1,3-dichloropropene, which greatly increases the production cost of the final product. Further, the process is too complicated to be applied to an industrial-scale mass production.
The process disclosed in Korean Laid-open Pub. No. 2000-65,691 may be summarized as following reaction scheme 4:
The above process employs a cis/trans mixture of 1,3-dichloropropene in order to improve the process of U.S. Pat. No. 5,440,049. However, the process may cause an environmental pollution because palladium is used in two steps as a catalyst and is also unfavorably complicated.
The process disclosed in U.S. Pat. No. 5,817,875 may be summarized as the following reaction schemes 5 and 6:
Both reactions in the above employ n-butyl-lithium difficult to be available for industrial use and the procedures are very complicated as shown in the reaction schemes 5 and 6. Further, additional isolation processes are necessary because the above processes produce a by-product.
Accordingly, the conventional processes for preparing terbinafine have many disadvantages as follows: first, strong bases such as n-butyllithium (n-BuLi) and strong reducing agent such as diisobutylaluminum hydride (DIBAL-H) are inappropriate for a mass production; second, heavy metals, such as palladium, copper or zinc, may cause an environmental pollution; third, additional reagents, such as trans-1,3-dichloropropene, raise the cost; fourth, additional purification steps are required in order to isolate (E)-form from the (E)/(Z) mixture.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing terbinafine or its HCl salt which can be performed both under a mild condition and in one pot reaction, using cheap and easily-controllable reagents, so as to be favorably applied to a large-scale mass production.
In one aspect of the present invention, there is provided a process for preparing terbinafine and/or HCl salt thereof, which comprises: (a) reacting a compound of formula 1 with a base; (b) performing a reductive alkylation of the resulting compound obtained in the step (a) with N-methyl-1-naphthalenemethylamine or its HCl salt; and (c) purifying the resulting compound obtained in the step (b):
wherein, R is methyl, phenyl, 4-methylphenyl, 4-methoxyphenyl or 2,4,6-trimethylphenyl.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention, a compound of formula 1 and a base are reacted and a reductive alkylation of the resulting compound is carried out with N-methyl-1-naphthalenemethylamine or its HCl salt. Further, the alkylated resulting compound is purified and isolated to give terbinafine or its HCl salt.
The compound of formula 1, which is a starting material in the process of the present invention, may be prepared by reacting 2-pivaloylfuran with a substituted-sulfonylhydrazide in the presence of a solvent, such as toluene or methanol.
As the base in the step (a) of the present invention, a base widely used for industrial synthesis, such as sodium hydroxide, potassium hydroxide, sodium hydride, or potassium t-butoxide, may be used. Among them, considering an economic aspect, sodium hydroxide is preferable. The amount of the base may be around 1 eq., or a little excess for facilitating the reaction, to 1 eq. of the compound of formula 1. Therefore, the amount of the base may be about 0.8~2.0 eq. to 1 eq. of the compound of formula 1.
Although a reaction temperature of the step (a) may be dependent on a solvent employed, the step (a) is performed preferably at 50° C.~200° C., more preferably at 60° C.~120° C. The step (a) may be completed preferably in about 1~5 hours, more preferably about 2~3 hours.
The step (a) is performed preferably in the presence of an aprotic organic solvent, including benzene, toluene, xylene, decahydronaphthalene, acetonitrile or mixtures thereof. Among them, toluene, which is easily-controllable and cheap, is more preferable.
The reductive alkylation of the step (b) is carried out by adding N-methyl-1-naphthalenemethylamine or its HCl salt to the resulting compound obtained in the step (a). A reducing agent and an alcohol may be added thereto. Although, the eq. ratio of N-methyl-1-naphthalenemethylamine or HCl salt thereof: the compound of formula 1 may be 1:1, when considering an economic aspect, the eq. amount of N-methyl-1-naphthalenemethylamine or its HCl salt may be less than that of the compound of formula 1. Therefore, the amount of N-methyl-1-naphthalenemethylamine or its HCl salt may be about 0.25~1.0 eq. to 1 eq. of the compound of formula 1.
The reducing agent may be selected from the group consisting of sodium borohydride (NaBH
4
), sodium triacetoxyborohydride (NaB(OAc)
3
H), and sodium cyanoborohydride (NaBH
3
CN). Among them, considering an economic aspect, sodium borohydride (NaBH
4
) is more preferable. The amount of the reducing agent may be about 0.5~2.5 eq. to 1 eq. of N-methyl-1-naphthalenemethylamine or its HCl salt, more preferably 0.8~1.0 eq. to 1 eq. of N-methyl-1-naphthalenemethylamine or its HCl salt.
The alcohol includes t-butanol, isopropanol, ethanol, and methanol.
The reductive alkylation of the step (b) may be performed at room temperature or at a temperature of lower than 50° C. Further, considering purity and yield of the product, the reductive alkylation may be performed preferably at −10° C.~10° C., more preferably at −1° C.~3° C.
The purification process of the step (c) may be carried out according to conventional methods, for example, as disclosed in
J. Med. Chem.,
1984, 27, 1539. For example, the trans form of terbinafine or its HCl salt may be isolated by organic solvent/precipitation or column chromatography. For an industrial-scale mass production, it is more preferable to purify and isolate terbinafine or its HCl salt by adding ethyl acetate to the resulting compound obtained in the step (b) and then filtering a solid precipitated thereby.
The steps (a), (b) and (c) may be carried out separately, i.e. in respective separate reactors. However, the steps (a), (b) and (c) are performed preferably in a single reactor.
Without being bound by theory, it is believed that the mechanism of the process of the present invention is as follows:
Upon reacting the compound of formula 1 with a base, the hydrazone bond is decomposed and carbenide is produced. Then, the electron pairs are rearranged and, at the same time, the oxygen-carbon bond of furan is opened, pro

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