Methods for Separation of Enantiomers

A method of separating a mixture of Compound M-2 and Compound P-2 enantiomers, the method comprising the steps of:

• (a) contacting the mixture with N-Boc-L-phenylalanine to form a mixture of Compound M-2 N-Boc-L-phenylalanine salt and Compound P-2 N-Boc-L-phenylalanine salt;
• (b) filtering the solid phase to obtain a liquid phase enriched with the Compound M-2 N-Boc-L-phenylalanine salt;
• and
• (c) reacting the Compound M-2 N-Boc-L-phenylalanine salt with base to obtain a solid free base Compound M-2.

A method of obtaining substantially pure or enriched Compound M-2 the method comprising the steps of:

• (a) obtaining a mixture of Boc-protected Compound M-2 and Boc-protected Compound P-2;
• (b) chromatographically separating the Boc-protected Compound M-2 from the Boc-protected Compound P-2;
• and
• (c) deprotecting the Boc-protected Compound M-2.

A compound which is

• the N-Boc-D-phenylalanine salt of (2M)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-3,4-dihydronaphthalene-1-carbonitrile;
• the N-Boc-D-phenylalanine salt of (2P)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-3,4-dihydronaphthalene-1-carbonitrile;
• the N-Boc-L-phenylalanine salt of (2M)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-3,4-dihydronaphthalene-1-carbonitrile;
• the N-Boc-L-phenylalanine salt of (2P)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-3,4-dihydronaphthalene-1-carbonitrile;
• the N-Boc-D-phenylalanine salt of (2M)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile;
• the N-Boc-D-phenylalanine salt of (2P)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile;
• the N-Boc-L-phenylalanine salt of (2M)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile;
• or
• the N-Boc-L-phenylalanine salt of (2P)-2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile.

A method of separating a mixture of atropisomers, the method comprising:

• (a) forming a mixture of a solvent, a first atropisomer and a second atropisomer in a crystallization vessel;
• (b) producing a liquid phase and a solid phase by, if necessary, adjusting the temperature of the mixture to a temperature in which the first atropisomer and second atropisomer have different solubilities, where the solid phase contains an enantiomeric excess of the first atropisomer and the liquid phase contains an enantiomeric excess of the second atropisomer;
• (c) removing a portion of the liquid phase;
• (d) subjecting the removed liquid phase portion to conditions sufficient to produce an increased amount of the first atropisomer in the removed liquid phase relative to the amount in the liquid phase in (b);
• (e) returning the removed liquid phase produced in (d) to the crystallization vessel;
• and
• (f) isolating crystals of the first atropisomer.

A method for separating atropisomers comprising

• selectively crystallizing a less soluble atropisomer in a crystallization module;
• and
• epimerizing a more soluble atropisomer in an epimerization module;
• wherein soluble material is continuously or semi-continuously provided from the crystallization module directly or indirectly to the epimerization module, and material from the epimerization module is at least semi-continuously returned to the crystallization module.