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Polymorphs of 7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine acetate

IP.com Disclosure Number: IPCOM000198755D
Publication Date: 2010-Aug-15
Document File: 5 page(s) / 46K

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Polymorphs of 7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine acetate

7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine(2R, 3R )-2,3- dihydroxybutanedioate (1:1) having the following structure:

is indicated for smoking cessation, acting as a partial agonist selective for certain subtypes of nicotinic receptors.

Provided are polymorphs of the acetate salt of 7,8,9,10-tetrahydro-6,10-methano-6H - pyrazino[2,3-h][3]benzazepine.

Preparation of 7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine acetate form I

7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine base (2 g,
9.47 mmol) was dissolved at 25ºC in methanol (4.2 mL, 2.1V). Glacial acetic acid (0.57 g, 9.47 mmol, 1 eq) was added to the solution with stirring. After 1 hour no precipitation was observed. The methanol was evaporated to dryness under reduced pressure. The

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resulting residue was dried in a vacuum oven (35 mbar) at 40 ºC for 16 hours to give 7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine acetate form I
(2.25 g, 87.5% yield, Assay = 98.4%, KF = 2.3%) as an off-white solid.

Preparation of 7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine acetate form I

7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine base (1 g,
4.73 mmol) was dissolved at 25ºC in toluene (23 mL) resulting in a clear yellow solution. To the stirred solution was added a mixture of acetic acid/toluene (25:75 w/w) (1.14 g,
4.73 mmol, 1 eq). Precipitation was observed after about 5 minutes, and stirring was continued for 16 hours. The mixture was then cooled to 5ºC. The solid was isolated by filtration and washed with cold (5ºC) toluene (2x7.5 mL). Drying of the solid in a vacuum oven (35 mbar) at 60ºC for 68 hours afforded 7,8,9,10-tetrahydro-6,10-methano- 6H -pyrazino[2,3-h][3]benzazepine acetate form I (1.03 g, 80.5% yield).

Preparation of 7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine acetate form I

7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine base (1 g,
4.73 mmol) was dissolved at room temperature in ethyl-acetate (36 mL) resulting in a clear yellow solution. To the stirred solution was added a mixture of acetic acid/ethyl- acetate (25:75 w/w) (1.14 g, 4.73 mmol, 1 eq). Precipitation was observed after about 5 minutes, and stirring was continued for 16 hours. The mixture was then cooled to 5ºC, the solid was isolated through filtration and washed with cold (5ºC) EtOAc (2x7.5 mL). Drying of the solid in a vacuum oven (35 mbar) at 60ºC for 68 hours afforded 7,8,9,10- tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine acetate form I as an off- white solid (0.92 g, 71.9% yield).

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FIGURE 1- Form I

                     Degrees 2 theta
Preparation of 7,8,9,10-tetrahydro-6,10-methano-6H -pyrazino[2,3-h][3]benzazepine acetate form II

7,8,9,10-tetrahydro-6,10-methano-6H -pyrazi...