The present invention relates to the salts of a compound and the crystalline forms thereof. More specifically, the present invention belongs to the pharmaceutical field, and provides the pharmaceutically acceptable salts of the compound 4-chloro-3-(2-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)amino)pyrimidin-5-yl)ethyl)-5-methoxy-N- methylbenzamide and the crystalline forms thereof, the pharmaceutical compositions comprising the same as well as the methods for preparing the same and the use 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 disclosure discloses a method for safely preparing pimavanserin and tartrate thereof by using triphosgene. The synthesis route includes: ##STR00001##
Raw materials used in the method of the present disclosure are safe and inexpensive, thereby effectively reducing the production costs. The method of the present disclosure has mild reaction conditions, and avoids using phosgene, which is highly toxic and difficult to handle is avoided. Thus, the method is readily implemented industrially.

The present disclosure discloses a method for safely preparing pimavanserin and tartrate thereof by using triphosgene. The synthesis route includes: ##STR00001##
Raw materials used in the method of the present disclosure are safe and inexpensive, thereby effectively reducing the production costs. The method of the present disclosure has mild reaction conditions, and avoids using phosgene, which is highly toxic and difficult to handle is avoided. Thus, the method is readily implemented industrially.

The present disclosure discloses a method for safely preparing pimavanserin and tartrate thereof by using triphosgene. The synthesis route includes:

##STR00001##

Raw materials used in the method of the present disclosure are safe and inexpensive, thereby effectively reducing the production costs. The method of the present disclosure has mild reaction conditions, and avoids using phosgene, which is highly toxic and difficult to handle is avoided. Thus, the method is readily implemented industrially.

The present disclosure discloses a method for safely preparing pimavanserin and tartrate thereof by using triphosgene. The synthesis route includes:

##STR00001##

Raw materials used in the method of the present disclosure are safe and inexpensive, thereby effectively reducing the production costs. The method of the present disclosure has mild reaction conditions, and avoids using phosgene, which is highly toxic and difficult to handle is avoided. Thus, the method is readily implemented industrially.

The present invention discloses a crystalline form of the (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethanol (formula (I)) hemi-(2R,3R)-tartrate salt characterised by a melting point of 211 C. and the XRPD pattern of FIG. 1. The present invention also relates to said hemi-tartrate salt for use in the treatment of hyperglycaemia and type 2 diabetes through activation of the beta2-adrenergic receptor. Importantly, such salts are thought to have a beneficial side-effect profile as they do not exert their effect through significant cAMP release.

The present invention discloses a crystalline form of the (R)-2-(tert-butylamino)-1-(5-fluoropyridin-3-yl)ethanol (formula (I)) hemi-(2R,3R)-tartrate salt characterised by a melting point of 211 C. and the XRPD pattern of FIG. 1. The present invention also relates to said hemi-tartrate salt for use in the treatment of hyperglycaemia and type 2 diabetes through activation of the beta2-adrenergic receptor. Importantly, such salts are thought to have a beneficial side-effect profile as they do not exert their effect through significant cAMP release.

The present disclosure relates to co-crystal of Aficamten and tartaric acid, and preparation methods thereof, pharmaceutical compositions containing the crystalline forms, and uses of the co-crystal for preparing cardiac myosin inhibitor and drugs for treating hypertrophic cardiomyopathy.