Crystalline forms of a hepatitis b antiviral agent
A form, crystal technology, applied in the field of crystal form of hepatitis B antiviral agent, can solve the problems of reducing purity, instability and the like
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Embodiment 1
[0235] Embodiment 1: the synthesis of compound (1)
[0236] I. Published Synthesis :
[0237] The following syntheses are disclosed in PCT Publication WO / 2013 / 096744, which is hereby incorporated by reference in its entirety.
[0238] Reaction scheme :
[0239]
[0240]
[0241] Step 1: Preparation of compound 2
[0242] Compound 1a (10.0 g, 42.0 mmol) was dissolved in SOCl 2 (60 mL) was heated to reflux overnight. The mixture was concentrated in vacuo. The residue was dissolved with toluene (30 mL) and concentrated in vacuo to give the crude product which was used directly in the next step.
[0243] Step 2: Preparation of compound 3
[0244]To a boiling solution of crude compound 2 (42 mmol) in toluene (100 mL) was slowly added a suspension of aniline (6.17 g, 42 mmol) in toluene (40 mL) and refluxed for 2 hours. The mixture was concentrated in vacuo to obtain a solid which was used directly in the next step.
[0245] Step 3: Preparation of compound ...
Embodiment 2
[0269] Example 2: Anhydrous Form I of Compound (1)
[0270] I. Process for Forming Anhydrous Form I of Compound (1) :
[0271] The following procedure was developed for the preparation of Form I of compound (1).
[0272] Acetone (5.3V) was added to compound (1) at 45°C. Water was then added, and the solution was filtered at 45°C to remove mechanical impurities. Then, the solution was cooled to 20°C and poured into water (2.5V) as quickly as possible. Agglomeration occurs during this process, ie crystallization in the form of acetone. The solution was further cooled to 10°C, thereby consuming supersaturation. Then, it was slurried with a mixture of acetone and water (50 / 50) at 10° C. at 3 V, and then washed with a solution of the mixture. Filtration and drying under vacuum at about 50°C yields Form III of compound (1).
[0273] A slurry was formed from the resulting Form III of compound (1) mixed with methyl tert-butyl ether (MTBE) at 25°C for at least 4 hours. This ...
Embodiment 3
[0292] Example 3: Formation and Characterization of Anhydrous Crystal Form of Compound (1) (Form XVI)
[0293] I. Process for Forming Form XVI of Compound (1) :
[0294]Acetone (7V) was added to compound (1) at 45°C. Water (3V) was added, and the solution was filtered to remove mechanical impurities. The solution was then cooled to 20° C., and the solution was seeded with 0.7% of Form III of compound (1 ) to form Form III. Additional water (4V) was added to achieve a 50 / 50 ratio of acetone to water. The solution was then cooled to 10°C over 20 minutes to consume supersaturation. Then, it was slurried with a mixture of acetone and water (50 / 50) at 10° C. at 4 V, and then washed with a solution of the mixture. Filtration and drying at about 50°C under nitrogen saturated with acetone yielded Form III of compound (1). Further filtration and drying under nitrogen at about 50°C yields "dry" Form III of compound (1).
[0295] A slurry was formed from the resulting dry form ...
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