Dichloromethane was then distilled off under vacuum and the residue (4 g) was taken up in 2-butanone. After the addition of trimethylchlorosilane/water, 3.8 g of hydrochloride (+21) (98% theoretical) crystallized out. (Ex. 1006 at 32; Ex. XX. ¶ XX.) Based on the foregoing teachings, Dr. Expert2 commenced the synthetic procedure by mixing 300 mg tapentadol HCl (from the research sample) with 4.5 ml freshly prepared saturated aqueous sodium bicarbonate, and then this mixture three times with 3 ml dichloromethane. (Ex. XX. ¶ XX.) He then dried the combined dichloromethane extracts over sodium sulfate, filtered, and evaporated the solvent to give the free base of tapentadol (257 mg, 100% yield) as a in vacuo colorless oil which solidified after storage at 5 °C. (Ex. XX. ¶ XX.) Dr. Expert2 observed that these crystals melted at 86 88 °C. (Ex. XX. ¶ XX.) – Then, Dr. Expert2 followed the disclosure in an attempt to create EP 475 tapentadol HCl (and particularly, Form B) from the tapentadol free base. Because Example 24 did not define the particular reagent:reagent ratio used during the crystallization step, Dr. Expert2 was able to look to other examples in the EP 475’s specification (e.g., Example 1) to obtain specific ratios of 2-butanone : TMSCl/water. (Ex. XX. ¶ XX.). Dr. Expert2’s Example 25 crystallization procedures are set forth below:
Dichloromethane was then distilled off under vacuum and the residue (4 g) was taken up in 2-butanone. After the addition of trimethylchlorosilane/water, 3.8 g of hydrochloride (+21) (98% theoretical) crystallized out. (Ex. 1006 at 32; Ex. XX. ¶ XX.) Based on the foregoing teachings, Dr. Expert2 commenced the synthetic procedure by mixing 300 mg tapentadol HCl (from the research sample) with 4.5 ml freshly prepared saturated aqueous sodium bicarbonate, and then this mixture three times with 3 ml dichloromethane. (Ex. XX. ¶ XX.) He then dried the combined dichloromethane extracts over sodium sulfate, filtered, and evaporated the solvent in vacuo to give the free base of tapentadol (257 mg, 100% yield) as a colorless oil which solidified after storage at 5 °C. (Ex. XX. ¶ XX.) Dr. Expert2 observed that these crystals melted at 86 – 88 °C. (Ex. XX. ¶ XX.) Then, Dr. Expert2 followed the EP 475 disclosure in an attempt to create tapentadol HCl (and particularly, Form B) from the tapentadol free base. Because Example 24 did not define the particular reagent:reagent ratio used during the crystallization step, Dr. Expert2 was able to look to other examples in the EP 475’s specification (e.g., Example 1) to obtain specific ratios of 2-butanone : TMSCl/water. (Ex. XX. ¶ XX.). Dr. Expert2’s Example 25 crystallization procedures are set forth below:
DepoMed-Nucynta-7994364-IPR-draft.docx