Process for the preparation of 2-amino-1,3-propane diol compounds and salts thereof

Patent metadata

Field	Value
Publication number	US-9815772-B2
Application number	US-201414772739-A
Country	US
Kind code	B2
Filing date	Mar 4, 2014
Priority date	Mar 5, 2013
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

The present disclosure relates to processes for the preparation of 2-amino-1,3-propane diol compounds and their hydrochloride salts. Particularly, the present disclosure relates to processes for synthesizing 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol and its hydrochloride salt 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol hydrochloride respectively. The said process is safe, commercially feasible for large-scale synthesis and has improved efficacy along with many other advantages. The present disclosure also relates to the novel polymorphs of 2-amino-1,3-propane diol compound and its hydrochloride salt, where in 2-amino-1,3-propane diol compound is 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol, and its hydrochloride salt is 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol hydrochloride.

First claim

We claim:

1. A process for preparing 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6), said process comprising acts of:
a. reacting a compound of Formula 3 with diethylacetamido malonate (Formula 2) to obtain 2-(Acetylamino)-2-(2-(4-octylphenyl)ethyl)propanedioic acid diethyl ester (Formula 4);

and
b. converting the 2-(Acetylamino)-2-(2-(4-octylphenyl)ethyl)propanedioic acid diethyl ester obtained in step (a) to obtain 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6);

or
c. converting the 2-(Acetylamino)-2-(2-(4-octylphenyl)ethyl)propanedioic acid diethyl ester obtained in step (a) to N-(1,1-bis hydroxymethyl-3-(4-octyl phenyl)-propyl)-acetamide (Formula 5), followed by hydrolysis of the N-(1,1-bis hydroxymethyl-3-(4-octyl phenyl)-propyl)-acetamide to obtain 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6);

or
d. converting the 2-(Acetylamino)-2-(2-(4-octylphenyl)ethyl)propanedioic acid diethyl ester obtained in step (a) to N-(1,1-bis hydroxymethyl-3-(4-octyl phenyl)-propyl)-acetamide (Formula 5), followed by converting the N-(1,1-bis hydroxymethyl-3-(4-octyl phenyl)-propyl)-acetamide (Formula 5) to 2-Acetamido-2-(4-octylphenethyl) propane-1,3-diyl diacetate (Formula 5a), followed by hydrolysis of the Acetamido-2-(4-octylphenethyl) propane-1,3-diyl diacetate (Formula 5a) to obtain 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6)

wherein the reaction of step (a) comprises a phase transfer catalyst, and
wherein the process further comprises
e. adding hydrochloric acid in isopropanol to 2-amino-2-(26-(4-octylphenyl)ethyl)-1,3-propanediol (Formula 6) in a solvent to yield 2-amino-2-(2-(4-octylphenyflethyl)-1,3-propanediol hydrochloride (Formula 1).

2. The process as claimed in claim 1 , wherein the reaction of step (a) is carried out in presence of solvent selected from a group comprising toluene, xylene, heptanes, hexanes, diethyl ether, methyl tertiary butyl ether and tetrahydrofuran or any combination thereof; and further comprises adding reagent selected from a group comprising alkaline metal carbonate and alkaline earth metal carbonate or a combination thereof.

3. The process as claimed in claim 2 , wherein volume of the solvent ranges from about 1 to about 30 volumes; and wherein the alkaline metal carbonate and alkaline earth metal carbonate is selected from a group comprising lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate and barium carbonate.

4. The process as claimed in claim 1 , wherein the step (a) is carried out at temperature ranging from about 10° C. to about 160° C. and for a time period ranging from about 3 hours to about 24 hours.

5. The process as claimed in claim 1 , wherein the conversion of step (b) or step (c) or step (d) is carried out in presence of a reagent in a solvent, wherein the solvent is a C1 to C4 lower chain alcohol and wherein the reagent is selected from a group comprising alkaline earth metal borohydride and alkaline earth metal alkoxy borohydride or a combination thereof.

6. The process as claimed in claim 5 , wherein the C1-C4 lower chain alcohol is selected from a group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tertiary butanol, tetrahydrofuran, toluene, water, diethyl ether, methyl tertiary butyl ether or any combination thereof, having volume ranging from about 2 to about 30 volumes; wherein the alkaline earth metal borohydride is selected from a group comprising magnesium borohydride, calcium borohydride, sodium borohydride and barium borohydride; and wherein the alkaline earth metal alkoxy borohydride is selected from a group comprising magnesium triacetoxy borohydride, calcium triacetoxy borohydride and barium triacetoxy borohydride.

7. The process as claimed in claim 5 , wherein the reagent is a combination of alkaline metal borohydride and a salt selected from a group comprising barium sulphate, barium chloride, magnesium sulphate, calcium acetate, calcium chloride, magnesium chloride and magnesium acetate or any mixture of salt thereof.

8. The process as claimed in claim 1 , wherein the conversion of step (b) or step (c) or step (d) is carried out at temperature ranging from about −5° C. to about 110° C.; pH ranging from about 1 to about 14; and wherein said pH range is achieved using solution selected from acid solution, base solution or a combination thereof.

9. The process as claimed in claim 8 , wherein the acid solution is selected from a group comprising hydrochloric acid and acetic acid or a combination thereof; and wherein the base solution is selected from a group comprising lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and barium hydroxide or any combination thereof.

10. The process as claimed in claim 1 , wherein the phase transfer catalyst is tetra alkyl ammonium halide; and wherein said tetra alkyl ammonium halide is selected from a group comprising tetramethyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium bromide and tetrabutyl ammonium iodide or any combination thereof.

11. The process as claimed in claim 1 , wherein the hydrolysis is carried out either in presence of:
a. an inorganic base solution; or
b. hydrochloric acid followed by pH adjustment with base selected from a group comprising sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide.

12. The process as claimed in claim 11 , wherein the inorganic base is selected from a group comprising lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and barium hydroxide or any combination thereof.

13. The process as claimed in claim 11 , wherein addition of the inorganic base solution or the hydrochloric acid is followed by refluxing for a time period ranging from about 0.5 hours to about 24 hours.

14. The process as claimed in claim 1 , wherein the conversion of 2-(Acetylamino)-2-(2-(4-octylphenyl)ethyl)propanedioic acid diethyl ester to 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol and the hydrolysis of N-(1,1-bis hydroxymethyl-3-(4-octyl phenyl)-propyl)-acetamide to 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol further comprises the steps of adding solvent, stirring, filtration and drying.

15. The process as claimed in claim 1 , wherein the 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol obtained is crystalline in nature and is designated as polymorph A.

16. The process as claimed in claim 1 , wherein the solvent in step (e) is selected from a group comprising toluene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, methyl isobutyl ketone and methyl ethyl ketone or a combination thereof; and wherein volume of the solvent ranges from about 2 volumes to about 25 volumes.

17. The processes as claimed in claim 1 , wherein the 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol or the 2-amino-2-(2-(4-octylphenyl)ethyl)-1,3-propanediol hydrochloride is optionally purified and dried; and wherein the purification is carried out by recrystallization in presence of solvent selected from group comprisin

Assignees

• Biocon Ltd

Inventors

• Kumar Kothakonda Kiran
• Aswathanarayanappa Chandrashekar
• Chandregowda Dharshan Jakkali
• Duvva Chandrasekhar
• Pullela Venkata Srinivas

Classifications

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C213/08 Primary

  by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C233/18

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title

• C07C215/28 Primary

  and containing six-membered aromatic rings · CPC title

• C07C233/47

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title