Solid state forms of lumateperone salts and processes for preparation of lumateperone and salts thereof
AssigneeTeva Czech Industries S.R.O.
InventorsNikolina Janton, Helena Ceric, Sanja Matecic Musanic, Natasa Mrsic, Lidija Lerman, Tina D. Momcilovic, Ivana Sagud, Alexandr Jegorov
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Abstract
The present disclosure relates to solid state forms of Lumateperone besylate and Lumateperone tosylate:R-(−)-mandelic acid, to various intermediates, to processes for their preparation and the preparation of Lumateperone or salt thereof, to pharmaceutical compositions and their use for the treatment of central nervous system disorders.
Claims102
A benzenesulfonate salt of Lumateperone having the formula:
- wherein x can be any number between 0.5 and 3.
A process for the preparation of crystalline Lumateperone Besylate, preferably crystalline form A of Lumataperone Besylate, comprising crystallisation of Lumateperone Besylate from a solvent comprising one or more polar solvents.
Crystalline Lumateperone tosylate:R-(−)-mandelic acid.
A compound of formula 2, 3, 4, 5, 8, 2a, 3a, 4a or 5a:
- wherein L is a leaving group and PG represents a protecting group.
A process for the preparation of a compound of formula 3:
- comprising N-alkylating a compound of formula 2:
- wherein L is a leaving group, preferably bromine, and PG is a protecting group, preferably carbobenzyloxy (cbz) or carboethoxy.
A process for the preparation of a compound of formula 4:
- comprising cyclizing a compound of formula 3:
- wherein L is a leaving group, preferably halo, and PG is a protecting group, preferably carbobenzyloxy (cbz) or carboethoxy.
A process for the preparation of a compound of formula 5:
- comprising reducing a compound of formula 4:
- wherein PG is a protecting group, preferably carbobenzyloxy (cbz) or carboethoxy.
A process for the preparation of a compound of formula 6:
- comprising reducing a compound of formula 5:
- wherein PG is a protecting group, preferably carbobenzyloxy (cbz) or carboethoxy.
A process for the preparation of a compound of formula 8:
- comprising:
- deprotecting a compound of formula 6:
- to obtain the compound rac-7:
- and
- reacting the compound rac-7 with (−)-di-p-toluoyl-L-tartaric acid (L-DTTA).
A process for the preparation of Lumateperone or salt thereof, comprising
- (i) basifying a compound of formula 8:
- to obtain compound 7:
- ii) alkylating compound 7, preferably with a 4-substituted-4′-fluorobutyrophenone wherein the substituent is a leaving group, to obtain Lumateperone;
- iii) optionally converting the Lumateperone to a salt thereof, preferably Lumateperone besylate;
- and
- iv) optionally converting the salt to a different salt of Lumateperone, preferably Lumateperone tosylate or a solid state form thereof, preferably Lumateperone tosylate:R-(−)-mandelic acid.
A process for preparation of Lumateperone or salt thereof wherein the process comprises:
- (i) reducing a compound of formula 5:
- wherein PG is a protecting group, preferably wherein PG is carbobenzyloxy (cbz) or carboethoxy, most preferably cbz, to obtain a compound of formula 6:
- (ii) removing the protecting group to obtain the compound rac-7:
- (iii) reacting the compound rac-7 with L-DTTA to obtain a compound of formula 8:
- (iv) basifying compound 8 to obtain a compound of formula 7:
- (v) Alkylating the compound (7) with 4-chloro-4′-fluorobutyrophenone to obtain Lumateperone;
- and
- (vi) optionally converting Lumateperone to a salt thereof or a solid state form thereof.
Dependencies are inferred from the claim text.