WO2017154024A4

WO2017154024A4 - A process for synthesis of paracetamol

Info

Publication number: WO2017154024A4
Application number: PCT/IN2017/050084
Authority: WO
Inventors: G. Pratap REDDY; Nithun REDDY
Original assignee: Reddy G Pratap
Priority date: 2016-03-08
Filing date: 2017-03-08
Publication date: 2017-11-30
Also published as: WO2017154024A1

Abstract

Provided herein are processes for manufacture of acetylated amines including paracetamol.

Claims

AMENDED CLAIMS received by the International Bureau on 17 October 2017(17.10.2017)

1. (Amended) A process for manufacture of acetylated amines comprising

i) placing acetic acid in a reaction vessel;

ii) adding a compound of Formula I and a metal catalyst to the reaction vessel and heating the reaction mixture;

R-NO2 I

wherein R is an optionally substituted aromatic ring or an alkyl group, to obtain a reaction mixture comprising a compound of Formula II:

R-NH-C(=0)CH₃ II;

iii) (a) cooling the reaction mixture of step (ii) and filtering the cooled reaction mixture to obtain a filtrate;

OR

{£ (b)cooling the reaction mixture of step (ii) and diluting the reaction mixture of step (ii) with a solvent;

( ) (c) heating the mixture of step (iii)(b) at a temperature of about the boiling point of said solvent;

(d) cooling the mixture of step (iii)(c) and filtering the cooled mixture to obtain a filtrate and a residue;

(e) optionally, suspending the residue of step (iii)(d) in said solvent and repeating steps (iii)(c) - (iii)(d) 1-2 times, and combining the filtrates;

iv) removing the solvent from the filtrate of step (iii)(a) or from the combined filtrates of step (iii)(e) to obtain a crude product cake comprising a compound of Formula II wherein R is phenyl substituted with a hydroxy group.

2. The process of claim 1, wherein the reaction vessel is a pressure reactor, a bus loop reactor, a flow reactor, a continuous column, a gas induction pressure reactor, or a round bottom flask.

3. The process of claim 1, wherein the metal catalyst of step (ii) is palladium, palladium on charcoal (Pd-C), silica gel, platinum (IV) oxide (Pt0₂), chromium (II) chloride (CrCl₂), Tin (II) chloride, Titanium (III) chloride, aluminum, nickel, iron, zinc, stannous chloride (SnCl₂), samarium or rhodium, or a combination thereof.

4. The process of claim 1, wherein the metal catalyst of step (ii) is palladium on charcoal (Pd-C), or iron.

5. The process of claim 1, wherein the metal catalyst of step (ii) is palladium on charcoal (Pd-C) and the process further comprises passage of hydrogen in the reaction vessel.

6. The process of claim 1, wherein the metal catalyst of step (ii) is iron, and the metal catalyst and the compound of Formula I are added to the reaction vessel in portions such that the reaction temperature in step (ii) is at least 110 °C.

7. The process of claim 1, wherein the solvent of step (iii) is acetic acid, acetic anhydride, a Ci-C₆ aliphatic primary alcohol, a C3-C6 aliphatic secondary alcohol, a C₄-C₆ aliphatic tertiary alcohol, a Cs-Cg aliphatic cyclic alcohol, tetrahydrofuran, 1,4-dioxane, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, morpholine, toluene, xylenes, ethyl acetate, propyl acetate, butyl acetate, pyridine, or water, or a combination thereof.

8. The process of claim 1, wherein the solvent of step (iii) is methanol, ethanol, or ethyl acetate, or a combination thereof.

9. The process of claim 1, wherein the solvent of step (iii) is ethyl acetate.

10. (Amended) The process of claim 1, wherein R is phenyl substituted with a para- hydroxy group.

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11. The process of claim 1, further comprising purification of the crude product cake of step (iv) comprising the steps of:

v) dissolving the crude product in water, optionally by heating, and adding activated charcoal to the mixture;

vi) filtering the mixture of step (v) and cooling the filtrate;

vii) filtering the cooled filtrate of step (vi) to obtain a solid comprising the compound of Formula II; and

viii) optionally repeating steps (v) to (vii) 1 -2 times with the solid of step (vii) to obtain a purified compound of Formula II.

12. The process of claim 11, wherein R is phenyl substituted with a para hydroxy group and the yield of the purified compound of Formula II is at least 90%.

13. The process of claim 1, wherein the compound of Formula I is added to the reaction vessel as a solid or as a solution in acetic acid.

14. (Amended) A process for manufacture of paracetamol comprising

i) placing acetic acid in a reaction vessel;

ii) adding para-nitrophenol aminophonol, a solvent, and a metal catalyst to the reaction vessel;

iii) heating the reaction mixture under pressure to obtain a reaction mixture comprising paracetamol;

iv) cooling the reaction mixture of step (iii) and filtering the cooled reaction mixture to obtain a filtrate;

v) removing the solvent and acetic acid from the filtrate of step (iv) to obtain a crude product comprising paracetamol.

15. The process of claim 14, further comprising purification of the crude product comprising paracetamol of step (v) by recrystallization or precipitation from water.

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16. The process of claim 14, wherein the solvent of step (ii) is acetic acid, acetic anhydride, a Ci-C₆ aliphatic primary alcohol, a C3-C6 aliphatic secondary alcohol, a C₄-C₆ aliphatic tertiary alcohol, a Cs-Cg aliphatic cyclic alcohol, tetrahydrofuran, 1,4-dioxane, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, morpholine, toluene, xylenes, ethyl acetate, propyl acetate, butyl acetate, pyridine, or water, or a combination thereof.

17. The process of claim 14, wherein the solvent is 1,4-dioxane.

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