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A process for the synthesis of terbinafine and derivatives thereof

A compound, straight-chain technology, applied in the field of synthesis of terbinafine and its derivatives, can solve the problems of final drug price impact, unsuitability for industrial production, social consequences, etc.

Inactive Publication Date: 2007-07-04
F I S FAB ILTALIANA SINTETICI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But on the other hand, due to the use of tributylacetylene (5), this reactant is not suitable for industrial production due to its high price, and palladium complexes and (or) salts (such as tetrakis (triphenylphosphine) palladium (0) or dichloro-bis(triphenylphosphine)palladium(II)) these catalysts are also very expensive
This has a large impact on the price of the final drug, with obvious social consequences

Method used

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  • A process for the synthesis of terbinafine and derivatives thereof
  • A process for the synthesis of terbinafine and derivatives thereof
  • A process for the synthesis of terbinafine and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Example 1: 1,1-dichloro-3,3-dimethylbutene

[0090] Add FeCl to a reactor filled with inert gas 3 50.0 g (0.3 mol) and 350 ml of dichloromethane. At a temperature of 20-25°C, a mixture containing 478ml (407g; 4.39mol) of tri-butyl chloride and 380ml (426g; 4.39mol) of vinylidene chloride was added dropwise to the aforementioned suspension, and three Hour. The half-quantity method is to add 20g (0.123mol) FeCl 3 solution, and finally an additional 5 g (0.07 mol) was added. After the reaction mixture was stirred for 2 hours, the suspension was poured into a reactor containing 500 ml of water. The two phases were separated and the organic phase was washed with 250 ml of water followed by 250 ml of an aqueous solution of NaHCO3 (5% w / w).

[0091] The organic phase was distilled under vacuum conditions to obtain 395g (2.58mol-58% yield) of 1,1-dichloro-3,3-dimethylbutene (the component peak of the fraction was P=140mbar; T=65°C ), the purity is 95.1% GC (A%)-(the perce...

Embodiment 2

[0092] Example 2: 1,1-dichloro-3,3-dimethylbutene

[0093] Add FeCl to a reactor filled with inert gas 3 50.0 g (0.3 mol) and 350 ml of 1,2,4-trichlorobenzene. At a temperature of 20-25°C, a solution containing 478ml (407g; 4.39mol) of tri-butyl chloride and 380ml (426g; 4.39mol) of vinylidene chloride was added dropwise to the aforementioned suspension, and 4 After stirring the reaction mixture for 16 hours, the suspension was poured into a reactor containing 500 ml of water. The two phases were separated and the organic phase was washed with 250 ml of water followed by 250 ml of an aqueous solution of NaHCO3 (5% w / w).

[0094] The organic phase was distilled to obtain 387 g (2.53 mol-57.6% yield) of 1,1-dichloro-3,3-dimethylbutene (composition peak value of the fraction was P=100 mbar; T=65° C.), purity It was 93.0% GC (A%).

Embodiment 3

[0095] Example 3: 1,1-dichloro-3,3-dimethylbutene

[0096] Add FeCl to a reactor filled with inert gas 3 25.0 g (0.15 mol) and 175 ml of nitrobenzene.

[0097] At a temperature of 20-25°C, a mixture containing 239ml (204g; 2.2mol) of tri-butyl chloride and 190ml (213g; 2.2mol) of vinylidene chloride was added dropwise to the aforementioned solution for 2 hours , and the reaction mixture was stirred for 2 hours.

[0098] The mixture was distilled under vacuum to give 150 g (0.98 mol-41% yield) of 1,1-dichloro-3,3-dimethylbutene (composition peak of the fraction at P=140 mbar; T=65° C.) , with a purity of 94.4% GC (A%).

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Abstract

The present invention relates to a synthetic method for terbinafine and analogues thereof using metal catalysts, preferably Ni (II) salts and / or complexes.

Description

technical field [0001] The invention relates to a synthetic method of terbinafine and its derivatives. Background technique [0002] The chemical name of terbinafine (terbinafine) is (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthylmethylamine, which has The chemical structure shown in (1), is a topical and oral antifungal drug. [0003] [0004] Initially, in European patent EP0 024 587, a synthetic route to this compound under laboratory conditions was described, involving the reaction of the lithium salt of tributylacetylene with acrolein, followed by an atomic rearrangement under the action of allyl bromide to generate the intermediate The product (E+Z) - 1-bromo-6,6-dimethyl-hepten-4-yne, which is then concentrated under (1-naphthylmethyl)methanamine to yield (E+Z) A mixture of -N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthylmethylamine, which was then isolated as the hydrochloride salt of structure (1 ) of terbinafine, if this synthetic route is used ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/10C07C209/68C07C211/30
CPCC07C211/30C07C209/68C07F7/10
Inventor 费得里科·德拉·内拉科里斯天奥·哥兰地尼马里诺·斯帝瓦雷罗
Owner F I S FAB ILTALIANA SINTETICI SPA
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