ChemicalBook CAS DataBase List Varenicline

Varenicline synthesis

5synthesis methods

Product Name:Varenicline
CAS Number:249296-44-4
Molecular formula:C13H13N3
Molecular Weight:211.26

Several modifications to the original synthesis have been reported in the literature, including an improved process scale synthesis of the last few steps.The Grignard reaction was initiated on a small scale by addition of 2-bromo fluorobenzene 113 to a slurry of Magnesium turnings and catalytic 1,2-dibromoethane in THF and heating the mixture until refluxing in maintained. To this refluxing mixture was added a mixture of the 2-bromo fluorobenzene 113 and cyclopentadiene 114 over a period of 1.5 h. After complete addition, the reaction was allowed to reflux for additional 1.5 h to give the Diels- Alder product 115 in 64% yield. Dihydroxylation of the olefin 115 by reacting with catalytic osmium tetraoxide in the presence of N-methylmorpholine N-oxide (NMO) in acetone: water mixture at room temperature provided the diol 116 in 89% yield. Oxidative cleavage of diol 116 with sodium periodate in biphasic mixture of water: DCE at 10oC provided di-aldehyde 117 which was immediately reacted with benzyl amine in the presence of sodium acetoxyborohydride to give benzyl amine 118 in 85.7% yield. The removal of the benzyl group was effected by hydrogenation of the HCl salt in 40-50 psi hydrogen pressure with 20% Pd(OH)2 in methanol to give amine hydrochloride 119 in 88% yield. Treatment of amine 119 with trifluoroacetic anhydride and pyridine in dichloromethane at 0oC gave trifluoroacetamide 120 in 94% yield. Dinitro compound 121 was prepared by addition of trifluoroacetamide 120 to a mixture of trifluoromethane sulfonic acid and nitric acid, which was premixed, in dichloromethane at 0oC. Reduction of the dinitro compound 121 by hydrogenation at 40-50 psi hydrogen in the presence of catalytic 5%Pd/C in isopropanol:water mixture provided the diamine intermediate 122 which was quickly reacted with glyoxal in water at room temperature for 18h to give compound 123 in 85% overall yield. The trifluoroacetamide 123 was then hydrolyzed with 2 M sodium hydroxide in toluene at 37-40oC for 2-3h followed by preparation of tartrate salt in methanol to furnish varenicline tartrate (XV).

Ethanamine, N-[(3,5-dichlorophenyl)methylene]-2,2-diethoxy-

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249296-44-4
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Yield: 95.06%

Reaction Conditions:

with ammonia in water; pH=9 - 10 at 20 - 30;Product distribution / selectivity;

Steps:

16
In a 250 ml 4 neck round bottom flask equipped with mechanical stirrer, Thermo pocket were charged DM water (30 ml) and 5,8,14-Triazatetracyclo [10.3.1.02,11.04,9]hexadeca-2(ll),3,5,7,9-pentaene Tosylate salt (10 g, having atotal purity of 99.42% obtained in example 4). The above suspension was stirred for 30 minutes at 25-30°C. To this was added 25 % aqueous ammonia solution (5 ml) to adjust the pH to 9.0-10 at 25-30°C, and MDC (30 ml) was added to this solution. The resulting mixture was stirred for 30 minutes at 20-25⁰C. The organic layer was separated, and the aqueous layer was extracted with MDC (4x30 ml). The combined organic layer was washed with DM water (30 ml). The organic layer was treated with activated carbon (1.0 g), and stirred for 30 minutes at 25-30⁰C. The resulting solution filtered through celite. Concentration afforded a solid product, i.e. 5,8,14- Triazatetracyclo[ 10.3.1.02, 11.04,9]hexadeca-2(ll),3,5,7,9-pentaene. (Yield-5 g (95.06 % (relative to VRN-Tosylate)), HPLC purity- 99.43 %).

References:

TEVA PHARMACEUTICAL INDUSTRIES LTD.;TEVA PHARMACEUTICALS USA, INC. WO2009/143347, 2009, A2 Location in patent:Page/Page column 25

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249296-44-4
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References

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249296-44-4
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References

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249296-44-4
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References

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