Novel salts and polymorphic form of bempedoic acid
AssigneeLupin Limited
InventorsNavnath Ambadas Kadam, Rohidas Shivaji Sulake, Rajinder Singh Siyan, Nandu Baban Bhise, Girij Pal Singh, Rajesh Harishankar Vyas
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Abstract
The present invention relates to novel pharmaceutically acceptable salts of Bempedoic acid, novel intermediates of Bempedoic acid, novel crystalline form of Bempedoic acid and novel processes for the preparation of Bempedoic acid or its intermediates thereof.
Claims14
A compound of structure:
- or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
2-16. (canceled)
A process for the preparation of Bempedoic acid comprising the steps of:
- i. treating diethyl-3-oxopentanedioate with ethyl 6-halo-2,2-dimethylhexanoate to give compound of Formula 4a;
- ii. treating compound of Formula 4a with a base to give compound of Formula 5 or compound of Formula 6;
- and
- iii. converting isolated compounds of step ii (Formula 5 or Formula 6) to Bempedoic acid.
A process for the preparation of Bempedoic acid (Formula I) comprising the steps of:
- a) treating ethyl isobutyrate with 1,5-dibromopentane in presence of base, potassium iodide to give compound of Formula 2a;
- b) treating compound of Formula 2a with compound of Formula 2b in presence of a base to give compound of Formula 6;
- c) converting compound of formula 6 to compound of Formula 7;
- and
- d) converting compound of formula 7 to Bempedoic acid (Formula I).
A process for the preparation of Bempedoic acid (Formula I) comprising the steps of:
- a) treating caprolactone with ethyl acetate in presence of base to give ethyl 8-hydroxy-3-oxooctanoate;
- b) treating ethyl-8-hydroxy-3-oxooctanoate with ethyl 6-bromo-2,2-dimethylhexanoate to give diethyl 7-(6-hydroxyhexanoyl)-2,2-dimethyloctanedioate (Formula 2);
- c) reacting diethyl 7-(6-hydroxyhexanoyl)-2,2-dimethyloctanedioate (Formula 2) with alkali metal halide or tetrabutylammonium halide to give diethyl 7-(6-hydroxyhexanoyl)-2,2-dimethyloctanedioate (Formula 3);
- d) treating diethyl 7-(6-hydroxyhexanoyl)-2,2-dimethyloctanedioate (Formula 3) with ethyl isobutyrate in presence of a base to give triethyl 2,14-dimethyl-8-oxopentadecane-2,7,14-tricarboxylate (Formula 4);
- e) treating triethyl 2,14-dimethyl-8-oxopentadecane-2,7,14-tricarboxylate (Formula 4) with a base to give 2,14-dimethyl-8-oxopentadecanedioic acid (Formula 5);
- f) optionally treating, triethyl 2,14-dimethyl-8-oxopentadecane-2,7,14-tricarboxylate (Formula 4) with a base to give diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Formula 6);
- g) treating diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate (Formula 6) with a reducing reagent to give diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (Formula 7);
- h) optionally treating, 2,14-dimethhyl-8-oxopentadecanedioic acid (Formula 5) with a reducing reagent to give Bempedoic acid (Formula I);
- and
- i) treating diethyl 8-hydroxy-2,2,14,14-tetramethylpentadecanedioate (Formula 7) with a base to give Bempedoic acid (Formula I).
A process for the preparation of diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate comprising the steps of:
- a) treating diethyl malonate with ethyl 6-bromo-2,2-dimethylhexanoatein presence of base to give compound of Formula XA;
- b) treating compound of Formula XA with a base to give compound of compound of Formula XB;
- c) reacting compound of Formula XB with potassium 3-ethoxy-3-oxopropanoate to give compound of Formula XC;
- d) treating compound of Formula XC with ethyl 6-bromo-2,2-dimethylhexanote in presence of a base to give compound of Formula 4;
- e) treating compound of formula 4 with a base to give diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate;
- and
- f) optionally, using diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate intermediate to prepare Bempedoic acid.
A process for the preparation of crystalline Bempedoic acid comprising the steps of:
- a) treating ethyl isobutyrate with 1,5-dibromopentane in presence of base, potassium iodide to give compound of formula 2a;
- b) treating compound of formula 2a with compound of formula 2b in presence of a base to give compound of formula 6;
- c) converting compound of formula 6 to compound of formula 7;
- and
- d) converting compound of formula 7 to crystalline Bempedoic acid.
A process for the preparation of crystalline form of Bempedoic acid having PXRD characteristic peaks at 10.2°±0.2°, 17.4°+0.2°, 17.8°±0.2°, 18.6°±0.2°, 20.2°±0.2°, 21.7°±0.2°, 22.4°+0.2° and 23.4°±0.2° degrees 2θ, comprising the steps of:
- a) dissolving Bempedoic acid in a solvent;
- b) optionally adding second solvent, heating the reaction mass;
- c) cooling the reaction mass;
- and
- d) isolating crystalline form of Bempedoic acid.
Dependencies are inferred from the claim text.