Disclosed herein are processes for preparing certain intermediates useful in the synthesis 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 pharmaceutically acceptable salt thereof.

Disclosed herein are processes for preparing certain intermediates useful in the synthesis 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 pharmaceutically acceptable salt thereof.

Disclosed herein are processes for preparing certain intermediates useful in the synthesis 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 pharmaceutically acceptable salt thereof.

Disclosed herein are processes for preparing certain intermediates useful in the synthesis 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 pharmaceutically acceptable salt thereof.

Disclosed herein are processes for preparing certain intermediates useful in the synthesis 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 pharmaceutically acceptable salt thereof.

Disclosed herein are processes for preparing certain intermediates useful in the synthesis 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 pharmaceutically acceptable salt thereof.

The invention belongs to the pharmaceutical manufacturing field, which relates to a novel process for the preparation of substituted phenylacetic acids derivatives, especially relates to the preparation of 2-(4-(2-oxocyclopentyl)phenyl)propanoic acid. The process for the preparation of the precursor form of loxoprofen which use 1,4-di-halobenzyl compounds or disubstituted benzyl compounds as starting material, is through the substitution reaction of cyclopentanone groups or its precursor compounds.

##STR00001##

Wherein X is halogen, L.sub.1 is a suitable leaving group selected from halogen, OH, OMs, OTs, OTf and the like; L.sub.2 is a suitable leaving group selected from halogen, CN, OH, CH.sub.2OH, CHO, CH.sub.3NO.sub.2, ester group, NR.sub.4R.sub.5, OTf, OTs, OMs, CCR.sub.6, CCR.sub.7 and the like, wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7 are short chain alkyl groups; Z is cyclopentanone group and its precursor form selected from

##STR00002##

and the like; R.sub.3 is short chain alkyl groups. L.sub.3 is a suitable leaving group selected from halogen, OH, OMs, OTs, OT.sub.f and the like, or organometallic groups. The invention also include the detailed procedure to convert the precursor compounds of cyclopentanone group to cyclopentanone, followed by the transformation of the precursor compounds of loxoprofen to loxoprofen.

The invention belongs to the pharmaceutical manufacturing field, which relates to a novel process for the preparation of substituted phenylacetic acids derivatives, especially relates to the preparation of 2-(4-(2-oxocyclopentyl)phenyl)propanoic acid. The process for the preparation of the precursor form of loxoprofen which use 1,4-di-halobenzyl compounds or disubstituted benzyl compounds as starting material, is through the substitution reaction of cyclopentanone groups or its precursor compounds.

##STR00001##

Wherein X is halogen, L.sub.1 is a suitable leaving group selected from halogen, OH, OMs, OTs, OTf and the like; L.sub.2 is a suitable leaving group selected from halogen, CN, OH, CH.sub.2OH, CHO, CH.sub.3NO.sub.2, ester group, NR.sub.4R.sub.5, OTf, OTs, OMs, CCR.sub.6, CCR.sub.7 and the like, wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7 are short chain alkyl groups; Z is cyclopentanone group and its precursor form selected from

##STR00002##

and the like; R.sub.3 is short chain alkyl groups. L.sub.3 is a suitable leaving group selected from halogen, OH, OMs, OTs, OT.sub.f and the like, or organometallic groups. The invention also include the detailed procedure to convert the precursor compounds of cyclopentanone group to cyclopentanone, followed by the transformation of the precursor compounds of loxoprofen to loxoprofen.

The present invention relates to a process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides by reacting (a) cyclopropylcarbonitrile to a cyclopropylcarbaldehyde, (b) further reacting to a cyclobutanone, or (d) further reacting to an enamide, 5 (c) further reacting to enantiomerically and diastereomerically enriched cyclobutane amines, or (d) further reacting to an enamide and (e) to an enantiomerically and diastereomerically enriched cyclobutylamide to obtain (f) an enantiomerically and diastereomerically enriched cyclobutane amine, and (g) further reacting to an enantiomerically and diastereomerically enriched cyclobutane amide.

The present invention relates to a process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides by reacting (a) cyclopropylcarbonitrile to a cyclopropylcarbaldehyde, (b) further reacting to a cyclobutanone, or (d) further reacting to an enamide, 5 (c) further reacting to enantiomerically and diastereomerically enriched cyclobutane amines, or (d) further reacting to an enamide and (e) to an enantiomerically and diastereomerically enriched cyclobutylamide to obtain (f) an enantiomerically and diastereomerically enriched cyclobutane amine, and (g) further reacting to an enantiomerically and diastereomerically enriched cyclobutane amide.