Processes of making 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile and polymorphs thereof

A process of preparing an amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile)-benzonitrile, wherein the amine is:

• (i) NHR1R2 where (1) R1 is hydrogen and R2 is C2-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C1-6 alkyl;
• (2) R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C1-6 alkyl and R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C1-6 alkyl;
• or (3) R1 and R2 together with the nitrogen atom to which they are attached form cyclylamine;
• or
• (ii) R3R4N—(CH2)n—NR5R6 where n is an integer selected from 1 to 6 and R3, R4, R5, and R6 are independently H, C1-C6 alkyl or C3-C7 cycloalkyl, comprising:
• (a1) contacting 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile with the amine NHR1R2 or R3R4—N—(CH2)n—R5R6 where R1 and R2 are as defined in (i), and R3, R4, R5, R6, and n are as defined in (ii), in the presence or absence of one or more suitable organic solvents to provide a mixture containing the amine solvate;
• (b1) optionally adding (i) one or more anti-solvent and/or (ii) a solid crystalline seed of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or a solid crystalline seed of the amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or a combination thereof, to the mixture of Step (a1) to precipitate the amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;
• and
• (c1) isolating the precipitate of Step (b1) to obtain a solid amine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile.

A process of preparing crystalline Form B polymorph of a diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile having an X-ray powder diffraction pattern comprising peaks at angular positions 13.8 and 21.3, wherein the angular positions may vary by +/−0.2° 2θ as measured by X-ray powder diffraction at ambient temperature using (Cu Kα) an X-ray wavelength of 1.5406 Å, comprising:

• (a2) contacting 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile with diethylamine, in the presence or absence of one or more suitable organic solvents to provide a mixture containing diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;
• (b2) adding (i) one or more anti-solvent and/or (ii) a crystalline seed of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or a solid crystalline seed of the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile, or a combination thereof, to the mixture of Step (a2) to precipitate the crystalline Form B polymorph of the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile;
• and
• (c2) isolating the crystalline Form B polymorph of the diethylamine solvate of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile.