249296-44-4

Usage

Uses

Used in Smoking Cessation:
Varenicline is used as a selective nicotinic receptor modulator for smoking cessation. It helps to reduce the craving and withdrawal symptoms associated with quitting smoking by acting as a partial agonist on the α4β2 neuronal nicotinic acetylcholine receptors (nAChRs), which are involved in the addictive properties of nicotine.
Used in Pharmaceutical Industry:
Varenicline is used as an organic heterotetracyclic compound that acts as a partial agonist for nicotinic cholinergic receptors in the form of its tartrate salt. It is an aid to giving up smoking and is marketed under the brand name Chantix by Pfizer.

Clinical Use

Aid to smoking cessation

Synthesis

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).

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

Varenicline undergoes minimal metabolism with less than 10% excreted as metabolites. About 92% of a dose is excreted unchanged in the urine. Minor metabolites in urine include varenicline N-carbamoylglucuronide, N-glucosylvarenicline and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug-related material.

references

[1] garrison gd, dugan se. varenicline: a first-line treatment option for smoking cessation. clin ther. 2009 mar;31(3):463-91.

InChI:InChI=1/C13H13N3/c1-2-16-13-5-11-9-3-8(6-14-7-9)10(11)4-12(13)15-1/h1-2,4-5,8-9,14H,3,6-7H2

Synthetic route

5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11).3.5,7,9-pentaene tosylate (1197286-22-8) → varenicline (249296-44-4)

Conditions	Yield
With ammonia In water at 20 - 30℃; pH=9 - 10; Product distribution / selectivity;	95.06%

1-(5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11).3.5,7,9-pentaene)-2,2,2-trifluoro-ethanone → varenicline (249296-44-4)

Conditions	Yield
With sodium carbonate In methanol	95%
With sodium carbonate In methanol; water at 65 - 70℃; for 3h; Product distribution / selectivity;	87.2%
With water; sodium carbonate In methanol at 25 - 70℃; Product distribution / selectivity;

5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,7,9-pentaene sulfate (1333145-92-8) → varenicline (249296-44-4)

Conditions	Yield
With sodium hydroxide In water at 20 - 30℃; for 0.5h; pH=12.5 - 13.5;	83%

varenicline tartrate → varenicline (249296-44-4)

Conditions	Yield
With sodium hydroxide In water; toluene at 38℃; for 1.5h; Product distribution / selectivity;	80%

5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,7,9-pentaene mesylate (1333146-06-7) → varenicline (249296-44-4)

Conditions	Yield
With sodium hydroxide In water at 20 - 30℃; for 0.5h; pH=12.5 - 13.5;	70%

C21H21N3O (1206484-38-9) → varenicline (249296-44-4)

Conditions	Yield
With palladium 10% on activated carbon; ammonium formate In methanol for 0.5h; Reflux;	64%

5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,7,9-pentaene fumarate (1186072-37-6) → varenicline (249296-44-4)

Conditions	Yield
With sodium hydroxide In water at 20 - 30℃; for 0.5h; pH=12.5 - 13.5;	59.4%

1-(5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11).3.5,7,9-pentaene)-2,2,2-trifluoro-ethanone + 1-(4-amino-10-aza-tricyclo[6.3.1.02,7]dodeca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (230615-56-2) → varenicline (249296-44-4)

Conditions	Yield
With sodium hydroxide; water In toluene at 37 - 40℃;

7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine L-tartrate → varenicline (249296-44-4)

Conditions	Yield
With sodium hydroxide In water for 0.0333333h;

1-(5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,9-pentaene)-2,2,2-trifluoro-ethanone → varenicline (249296-44-4)

Conditions	Yield
With water; sodium hydroxide In methanol at 0 - 30℃; for 1h; Product distribution / selectivity;

10-(trifluoroacetyl)-10-azatricyclo[6.3.1.02,7]dodeca-2,4,6-triene-4,5-diamine → varenicline (249296-44-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: Amberlite IRA 67 / water; tetrahydrofuran / 0 - 30 °C 2: potassium carbonate / water; methanol / 4 h / 50 - 55 °C View Scheme
Multi-step reaction with 2 steps 1: lead(II) oxide / water; dimethyl sulfoxide / 55 - 60 °C 2: sodium hydroxide; water / methanol / 1 h / 40 - 45 °C View Scheme

varenicline (249296-44-4) + benzenesulfonic acid (98-11-3) → 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepin benzenesulfonate

Conditions	Yield
In isopropyl alcohol at 50 - 55℃; Solvent;	94%

varenicline (249296-44-4) + acetic acid (64-19-7) → varenicline acetate

Conditions	Yield
In methanol at 25℃; for 1h; Product distribution / selectivity;	87.5%

varenicline (249296-44-4) + citric acid (77-92-9) → varenicline citrate (536696-70-5)

Conditions	Yield
In water; isopropyl alcohol at 50 - 55℃; for 1.25h;	87%

varenicline (249296-44-4) + L-Tartaric acid (87-69-4) → varenicline L-tartarate (375815-87-5)

Conditions	Yield
In methanol	84%
In methanol at 20 - 25℃; for 1h; Product distribution / selectivity;	66.1%
In methanol

varenicline (249296-44-4) → varenicline hydrobromide

Conditions	Yield
With hydrogen bromide In ethanol at 25℃; for 2h; Product distribution / selectivity;	84%

varenicline (249296-44-4) + toluene-4-sulfonic acid (104-15-4) → 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11).3.5,7,9-pentaene tosylate (1197286-22-8)

Conditions	Yield
In isopropyl alcohol at 0 - 75℃; for 1.25h; Product distribution / selectivity;	81.84%

varenicline (249296-44-4) + toluene-4-sulfonic acid (104-15-4) → varenicline tosylate

Conditions	Yield
In methanol at 25 - 70℃;	64.41%

varenicline (249296-44-4) + p-trifluoromethyl-phenylisocyanate (1548-13-6) → N-(4-(trifluoromethyl)phenyl)-6,7,9,10-tetrahydro-8H-6,10-methanoazepino[4,5-g]quinoxaline-8-carboxamide

Conditions	Yield
In dichloromethane at 20 - 23℃; for 2h;	55%

varenicline (249296-44-4) + methanesulfonic acid (75-75-2) → 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,7,9-pentaene mesylate (1333146-06-7)

Conditions	Yield
In acetone at 20 - 30℃; Product distribution / selectivity;	1.43%

varenicline (249296-44-4) + L-Lactic acid (79-33-4) → varenicline hemi-L-lactate

Conditions	Yield
In tert-butyl methyl ether at 40℃; for 1h;

varenicline (249296-44-4) + Adipic acid (124-04-9) → varenicline hemiadipate

Conditions	Yield
In isopropyl alcohol at 40℃; for 1h;

varenicline (249296-44-4) + sodium 1,2-ethanedisulphonate (5325-43-9) → varenicline hemi-1,2-ethanedisulfonate

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 40℃; for 1h;

varenicline (249296-44-4) + malic acid (617-48-1) → varenicline L-malate

Conditions	Yield
In isopropyl alcohol at 40℃; for 1h;

varenicline (249296-44-4) → 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine hydrochloride

Conditions	Yield
With hydrogenchloride In tert-butyl methyl ether; water at 20℃; for 3h; Product distribution / selectivity;
With hydrogenchloride In methanol; ethyl acetate at 20℃; for 0.166667h;

varenicline (249296-44-4) + (2E)-but-2-enedioic acid (110-17-8) → 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,7,9-pentaene fumarate (1186072-37-6)

Conditions	Yield
In water at 20 - 70℃; for 2h; Product distribution / selectivity;

varenicline (249296-44-4) → 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2(11),3,5,7,9-pentaene sulfate (1333145-92-8)

Conditions	Yield
With sulfuric acid In water at 0 - 5℃; Product distribution / selectivity;

varenicline (249296-44-4) → varenicline sulfate

Conditions	Yield
With sulfuric acid In ethanol; water at 5 - 25℃; for 4h; Product distribution / selectivity; Cooling; Heating;

Upstream product

• 1197286-22-8 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2⁽¹¹⁾.3.5,7,9-pentaene tosylate 
• 1206484-38-9 C₂₁H₂₁N₃O 
• 230615-59-5 1-(7,8-dinitro-4,5-dihydro-1H-1,5-methanobenzo[d]azepin-3(2H)-yl)-2,2,2-trifluoroethanone 
• 230615-69-7 1-(7,8-diamino-4,5-dihydro-1H-1,5-methanobenzo[d]azepin-3(2H)-yl)-2,2,2-trifluoroethanone 
• 1333145-92-8 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2⁽¹¹⁾,3,5,7,9-pentaene sulfate 
• 1333146-06-7 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2⁽¹¹⁾,3,5,7,9-pentaene mesylate 
• 1186072-37-6 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2⁽¹¹⁾,3,5,7,9-pentaene fumarate 
• 230615-70-0 1-(9,10-dihydro-6H-6,10-methanoazepino[4,5-g]quinoxaline-8(7H)-yl)-2,2,2,-trifluoroethanone 
• 230615-56-2 1-(4-amino-10-aza-tricyclo[6.3.1.0^2,7]dodeca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone 

Downstream Products

• 375815-87-5 varenicline L-tartarate 
• 1197286-22-8 5,8,14-triazatetracyclo[10.3.1.0(2,11).0(4,9)]hexadeca-2⁽¹¹⁾.3.5,7,9-pentaene tosylate 

Relevant academic research and scientific papers

Varenicline synthesis method

The present invention relates to a process for the preparation of varenicline or a pharmaceutically acceptable salt thereof. The invention also relates to an intermediate compound useful in the process and the preparation of such intermediate compound.

Cocrystal of varenicline and oxalic acid, pharmaceutical composition thereof, and methods of use thereof

Provided is a cocrystal of varenicline and oxalic acid. In particular, provided is a cocrystal of varenicline and oxalic acid of formula (I) having a molar ratio of varenicline to oxalic acid of 1:1.5. Also provided is a process for preparing the cocrystal, a pharmaceutical composition containing the cocrystal and a method of using the cocrystal and pharmaceutical composition, such as for reducing nicotine addiction or tobacco use.

IMPROVED PROCESS FOR THE PREPARATION OF SUBSTITUTED QUINOXALINES

The present invention is directed to an improved process for the preparation of substituted quinoxalines by cyclization of the corresponding dianiline in the presence of ion exchange resin.

HIGHLY PURE VARENICLINE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF SUBSTANTIALLY FREE OF METHYLVARENICLINE IMPURITY

Provided herein is an impurity of varenicline, 6-methyl-5,8,14-triazatetracyclo[l 0.3.1.02'n,04'9]hexadeca-2(l l),3,5,7,9-pentaene (methylvarenicline) impurity, and a process for the preparation and isolation thereof. Provided further herein is a highly pure varenicline or a pharmaceutically acceptable salt thereof substantially free of methylvarenicline impurity, a process for the preparation thereof, and pharmaceutical compositions comprising highly pure varenicline or a pharmaceutically acceptable salt thereof substantially free of methylvarenicline impurity.

SOLID STATES FORMS OF VARENICLINE SALTS AND PROCESSES FOR PREPARATION THEREOF

Salts and crystalline forms of several salts of Varenicline, i.e., Varenicline sulfate, Varenicline mesylate, and Varenicline fumarate, methods of preparing the solid states of Varenicline sulfate, Varenicline mesylate, and Varenicline fumarate, and processes for preparing Varenicline base from those Varenicline salts are provided.

An efficient synthesis of varenicline

Synthesis of varenicline the antismoking drug has been achieved in six steps with 10% overall yield. A Diels-Alder reaction, oxidative cleavage of an olefin and reductive amination remain as key steps in the synthesis.

PROCESS FOR PREPARING VARENICLINE, VARENICLINE INTERMEDIATES, AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

Provided herein is an improved, convenient, commercially viable and environmentally friendly process for the preparation of varenicline or a pharmaceutically acceptable salt thereof comprising reacting l-(4,5-diamino-10-aza-tricyclo[6.3.1.02 7]dodeca-2(7),3,5-trien- 10-yl)-2,2,2-trifluoro-ethanone with chloroacetaldehyde in the pressence of an oxygen source. Provided further herein is an improved and industrially advantageous process for the preparation of l-(4,5-diamino-10-aza-tricyclo[6.3.1.02 7]dodeca-2(7),3,5-trien-10-yl)-2,2,2- trifluoro-ethanone.

VARENICLINE TOSYLATE, AN INTERMEDIATE IN THE PREPARATION PROCESS OF VARENICLINE L-TARTRATE

Crystalline forms of Varenicline Tosylate, processes for preparing those crystalline forms of Varenicline Tosylate, and processes for obtaining high purity Varenicline base using Varenicline Tosylate are provided.

A NEW POLYMORPHIC FORM OF A PYRAZINO[2,3-h][3] BENZAZEPINE DERIVATIVE

The invention relates generally to a crystalline polymorphic form of 7, 8, 9, 10-tetrahydro-6, 10-methano-6H-pyrazino[2, 3-h][3] benzazepine, varenicline base, i.e. a hydrate of varenicline base, designated herein as Form II, and to a method for preparing and obtaining the same.

PROCESSES FOR THE PREPARATION OF VARENICLINE AND INTERMEDIATES THEREOF

The invention provides an improved process for the preparation and purification of Varenicline and intermediates for the preparation of Varenicline.