An improved process for the preparation of 4-Amino-2-fluoro-N-methylbenzamide and its pharmaceutically acceptable salts thereof.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 4-amino-2-fiuoro-N-methylbenzamide of formula I, a key intermediate for the synthesis of cyclic N,N'-diarylthioureas or N,N'-diarylureas which can be used as an anti-androgen and anticancer drugs. The present invention in particular relates to an efficient and economical process for the preparation of 4-amino-2-fluoro-N-methylbenzamide in field of process chemistry of pharmaceutical drug substances.

BACKGROUND OF THE INVENTION

4-amino-2-fluoro-N-methylbenzamide of Formula (I) is a key intermediate for the preparation of diarylthiohydantoins which can be used as androgen receptor antagonist for the treatment of hormone refractory prostate cancer.

US7709517 discloses the process for the preparation of diarylthiohydantoins including the process for the preparation of compound of formula I by oxidizing 2-fluoro-4-nitro toluene (IV) with chromium trioxide in acetonitrile to obtain 2-fluoro-4-nitro benzoic acid of formula (III) which on reaction with thionyl chloride in dimethyl formamide followed by reacting with methylamine provides N-methyl-2-fluoro-4-nitro-benzamide of formula (II) which on reduction with iron powder in acetic acid yields the corresponding amino compound of formula (I).

The process of preparation of compound of formula (I) as disclosed by the above US'517 patent can be depicted by the following synthetic Scheme-1.

US8461343 discloses a process of preparation of compound of formula (I) from 2,4-difluorobenzoyl chloride which can be depicted by the following synthetic Scheme-2.

CA2859224 discloses a process of preparation of compound of formula (I) from 2 fluoro-4-nitro-benzoic acid (III) which can be depicted by the following synthetic Scheme-3.

The prior art process for the preparation of compound of formula (I) which is the key intermediate compound for the preparation of pharmaceutical compounds such as diarylthioureas or N,N'-diarylureas involves long hour reaction time and poses disadvantage of non-satisfactory results of the desired compound (I). Mainly, the compound (I) obtained by the prior art methods comprises significant amount of impurities which are difficult to remove at this stage and can carry along with further reactions steps for the preparation of final compound.

Mainly, it has been observed that during the process of reduction of nitro group of compound of formula (11) in above prior art schemes, formation of the corresponding desfluoro impurity of formula (la) as a by-product thus effecting overall purity and yield of the desired compound of formula (I).

There is a need to develop an efficient process for the preparation of compound of formula (I) which should be cost effective, suitable for large scale production and should provide higher yield with less impurity levels.

Summary of the Invention

The main object of the present invention to provide an improved process for the preparation of compound of formula (I) or its pharmaceutically acceptable salts thereof or derivatives to overcome the deficiencies of the prior art processes.

Another object of the invention is to provide an improved process for the preparation of highly pure compound of formula (I) which is substantially free from impurities mainly substantially free from impurity namely desfluoroimpurity.

One another object of the present invention is to provide a process for the preparation of highly pure compound of formula (I), wherein the formation of impurity of formula la is minimized by using suitable reducing agent and performing suitable reducing methods.

Another object of the invention is to provide an improved process for the preparation of highly pure compound of formula (I) with good yield and quality.

Another objective of the present invention is to prepare substantially pure crystalline compound of formula (I) or its pharmaceutically acceptable salts thereof.

One more object of the present invention is to provide an improved process for the preparation of highly pure compound of formula (I) and its conversion for the preparation of pharmaceutical compounds such as diarylthioureas or N,N'-diarylureas by subsequent processes.

Detailed description

The present invention discloses a process for preparing compound of formula (I) comprising up to 0.5 to 1.0 % of total impurities with the desfluoro impurity (la) below 0.1%.

The present invention also relates to isolation & characterization of desfluoro impurity (la) which was formed during the preparation of compound of formula (I).

The present invention provides an improved process for the preparation of compound of formula (I) which in turn can be used in the process of making pharmaceutical compounds specially compounds such as diarylthioureas or N,N'-diarylureas etc.

According to the present invention, the process for the preparation of compound of formula (I) or pharmaceutically acceptable salt thereof comprising, (A) reacting the starting material of the compound of formula (III) with a chlorinating agent in an organic solvents or mixture of organic solvents at a suitable conditions and subsequently reacting with a solution of methylamine followed by isolating the compound of formula (II) by conventional methods, and (B) reducing the compound of formula (II) with a reducing agent by controlled hydrogenation method in a suitable solvents at a suitable method to obtain the compound of formula (I) with high purity with a negligible or minimum impurities.

The process of compound of formula (I) of the present invention is outlined by the following synthetic scheme-4.

The process for the preparation of compound of formula (I) or pharmaceutical^ acceptable salt thereof comprising the steps (A) and (B) is explained below in detail.
A. conversion of compound of formula (III) to compound of Formula (II) which comprises,
a. addition of 2-fluoro-4-nitro-benzoic acid of formula (III) to an organic solvent;
b. addition of a second organic solvent to the reaction solution of step a, under stirring;
c. addition of a chlorinating agent to the reaction solution of step b, under stirring for about
30 minutes to 2 hours;
d. stirring the reaction contents of step c, at about 40-85 °C for about 30 minutes to 6 hours;
e. addition of reaction solution of step d, to a solution of methylamine at -10 to 20 °C for
about 20 minutes to 60 minutes;

f. stirring the reaction contents of step e, for about 0-40 °C for about 30 minutes to 2 hours;
g. addition of water to the reaction solution of step f and stirring the contents for about 60 minutes for the separation of solid;
h. filtering the separated solid of step g and washing with water followed by suck drying for about 30-60 minutes and
i. drying the solid of step h, at about 45 to 75 °C for about 4-8 hours to get compound of formula (II).

The organic solvent of step a, is selected from the group of alcohol, hydrocarbon, aromatic hydrocarbon, ether, halogenated hydrocarbon solvents, a solvent mixture thereof. Preferably organic solvent is selected from hydrocarbon solvent or aromatic hydrocarbon solvent. Most preferably organic solvent is aromatic hydrocarbon solvent.

The second organic solvent of step b, is selected from the group of polar solvent, polar aprotic solvent and a solvent mixture thereof. Preferably the second organic solvent is selected from polar aprotic solvent a mixture thereof. Most preferably the second organic solvent is dimethylformamide.

The chlorinating agent of step c, is selected from phosphorous pentachloride, phophorous trichloride, thionyl chloride, Oxalyl chloride, Sulfuryl chloride, triphenylphosphine dichloride. Preferably the chlorinating agent is thionyl chloride.

The methylamine solution of step e, may be a solution in methanol, tetrahydrofuran and water. Preferably the methylamine solution is in water. Most preferably the methylamine solution is 40% in water.
Optionally methylamine gas can also be used in the place of methylamine solution.

B. Conversion of compound of formula (II) to compound of Formula (I) which comprises,

i. addition of a reducing catalyst to an organic solvent in a reaction vessel or hydrogenating
vessel;
ii. addition of compound of formula (II) to the reaction solution of step (i) at about 15 to 40
°C;
iii. passing hydrogen gas to the reaction solution of step (ii);
iv. maintaining the reaction mass of step (iii) under hydrogen gas pressure at about 5-25 °C
for about 2-15 hours;
v. removing the hydrogen gas from the reaction vessel of step (iv);
vi. filtering the reaction mass of step (v) through hyflo bed and washing with the organic
solvent of step (i) under nitrogen atmosphere;
vii. concentrating the filtrate of step (vi) under reduced pressure;
viii. isolating the solid from the residue of step (vii) from second organic solvent and i
x. drying the solid of step (viii) at 40-60 °C for about 3-9 hours to get compound of Formula
I.

The reducing catalyst of step (i) is selected from platinum, palladium, rhodium, ruthenium, nickel preferably nickel.

The organic solvent of step (i), is selected from the group of alcohol, hydrocarbon, aromatic hydrocarbon, ether, halogenated hydrocarbon solvents, a solvent mixture thereof. Preferably organic solvent is selected from C1-C5 alcohol solvent. Most preferably organic solvent is methanol.

The reaction mass of step (iv) is maintained under controlled hydrogen gas pressure. Preferably, the reaction mass maintained at different hydrogen gas pressure for the specific periods.

The second organic solvent of step (viii), is selected from the group of alcohol, hydrocarbon, aromatic hydrocarbon, ether, halogenated hydrocarbon solvents, a solvent mixture thereof.
Preferably organic solvent is selected from hydrocarbon solvent or aromatic hydrocarbon solvent. Most preferably organic solvent is aromatic hydrocarbon solvent.

Optionally, the obtained solid of step (viii) is purified by known methods. Wherein, purification is performed by dissolving the wet solid of step (viii) in an organic solvent at an ambient temperature and isolating the solid by adding an anti-solvent.

Preferably, the organic solvent used for the purification is selected from an alcohol solvent comprises methanol, ethanol, propoanol, isopropanol, n-butanol, isobutanol or mixture thereof. Most preferably, the solvent is methanol.

The anti-solvent used in purification of compound of formula (I) is selected from diethyl ether, isopropyl ether, hexane, water or mixture thereof.

The compound of formula (I) obtained according the present invention used as a key intermediate in the process of making of pharmaceutical compounds specially compounds such as diarylthioureas or N,N'-diarylureas etc.

It was established that the compound of formula (I) obtained according the present invention has purity more than 99.98% and impurities not more than 0.02% or undetectable range whereas compound of formula (I) obtained according the prior art processes has purity only 98.52 to 99.22% and having impurities in the range of 1.0-1.4%, these impurities will carry to the further

steps in conversion of the compound (I) to the corresponding pharmaceutical compounds specially compounds such as diarylthioureas or N,N'-diarylureas etc.

Another aspect of the invention is to provide an improved process for the preparation of highly pure compound of formula (I) which is substantially free from impurities mainly substantially free from impurity namely desfluoroimpurity of compound of formula (la).

Another aspect of the present invention is the isolated compound of formula (la) characterized by data selected from NMR, Mass

One more aspect of the present invention is to provide a process for the preparation of highly pure compound of formula (I) containing less than about 1.0% by area HPLC of impurity la.

According to another aspect of the present invention the compound of formula (I) obtained according the present invention further comprises preparation of pure 4((2-cyanopropan-2-yl) amino)-2-fluoro-N-methyl benzamide of a compound of formula (A), or a pharmaceutically acceptable salt thereof which further comprises preparation of pharmaceutical compounds specially compounds such as diarylthioureas or N,N'-diarylureas etc.

According to another aspect of the present invention there is provided a process for the preparation of pure 4((2-cyanopropan-2-yl) amino)-2-fluoro-N-methyl benzamide of a compound of formula (A), or a pharmaceutically acceptable salt thereof from the highly pure compound of formula (I) obtained according to the present invention as outlined by the below Schme-5

The process as outlined in above Scheme-5 comprises,
(a) addition of compound of formula (I) to the solution of mixture of acetone cyanohydrin and anhydrous magnesium sulphate under stirring;

(b) heating the reaction contents of step (a) to about 55 to 100 °C;
(c) maintaining the reaction mass of step (b) at reflux temperature for about 10-25 hours;
(d) addition of organic solvent to the reaction mass of step (c) at 40-65 °C for about 15 to 60 minutes;
(e) addition of water to the reaction solution of step (d) at 15 to 40 °C for about 30 to 90 minutes;
(f) stirring the reaction solution at 20-35 °C under nitrogen bubbling for about 1-3 hours;
(g) filtering the separated solid from step (f) and washing the solid with water;
(h) dissolving the wet solid of step (g) in the organic solvent of step (d) under stirring;
(i) addition of water to the r eaction solution of step (h) at 15 to 40 °C and stirring the
contents for about 30 to 90 minutes;
(j) filtering the s eparated solid from step (i) and washing the solid with water, and
(k) drying the solid of step (j) under reduced pressure at about 30 to 70 °C for about 3-15
hours to the compound of formula (A).

The organic solvent of step (d) is selected from acetone, acetonitrile, ethyl acetate, dimethylformamide, dimethylsulfoxide or tetrahydrofuran. Preferably the organic solvent is acetone.

Another aspect of the invention is to provide an improved process for the preparation of highly pure compound of formula (A) which is substantially free from impurities mainly substantially free from impurity namely desfluoroimpurity of compound of formula (Al).

One more aspect of the present invention which provides the isolated compound of formula (Al) characterized by data selected from NMR, Mass

One another aspect of the present invention is to provide a process for the preparation of highly pure compound of formula (A) containing less than about 1.0% by area HPLC of impurity Al.

One another aspect of the present invention is to provide a process for the preparation of highly pure compound of formula (A) containing less than about 0.5% by area HPLC of impurity Al.

The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be construed in any way to limit the scope of the present invention.

Examples
Example-1

2-Fluoro-N-methyl-4-nitrobenzamide

To a solution of Toluene (600 mL) and 2-Fluoro-4-nitro-benzoic acid (150 g), was added 6.0 ml of dimethylformamide at 25-35 °C. To the resulting solution, 88.17 mL of thionyl chloride was added slowly and maintained the reaction mass at 55-75 °C. The reaction mass was cooled and slowly added the solution of methylamine (628.8 mL, 40% solution in water) at 0-20 °C. Water (450 ml) was added to precipitate out the solid. The resulting solid was filtered and dried to afford the title compound. (Yield 150 gm, Purity >99%)
Example-2

4-Amino-2-fluoro-A'-methylbenzamide

To a mixture of Raney Nickel (1.5g) and methanol (500 ml), was added compound of example-1 (50 g) into Autoclave at 20-35 °C, Filled the Autoclave with Hydrogen and maintained at 5-25 °C until the starting material was not more than 0.5% by TLC. Hydrogen gas was removed from the autoclave, reaction mass was filtered through hyflobed and washed with methanol (250 ml). The resulting filtrate was concentrated under reduced pressure at 50-60 °C. Toluene (50 ml), was added to the residue and distilled off completely under reduced pressure at 60 °C. Toluene (150 ml), was added to the residue, filtered the resulting solid and washed with toluene (50 ml). The solid was dried under reduced pressure to afford the title compound. (Yield 39.5 gm, Purity >99.7%)

Example-3

Purification of 4-Amino-2-fluoro-iV-methylbenzamide

Dissolved wet solid of compound of example 2 in methanol (79 ml) at 60-70 °C under stirring. 197.5 ml of water was added to the reaction solution at 60-70 °C and stirred for 30-60 minutes.

Stirred the reaction solution at 5-10 "C for 1-2 hours. Filtered the resulting solid and washed with water (10 ml). The solid was dried to afford the title compound. (Yield 35.5 gm, Purity >99.9%)

Example-4

4-((2-Cyanopropan-2-yl) amino)-2-fluoro-N-methylbenzamide

A mixture of acetone cyanohydrin (108.4 ml), a compound of Example 2 (50 g) and anhydrous magnesium sulphate (71.64 g) was heated to 90-97 °C and stirred for till the starting material was . not more than 4.0% by TLC. Acetone (100 ml), was added to the reaction mass at 50-55 °C and cooled to 25-35 °C. To the reaction mass, was added water (600 ml) and stirred at 25-35 °C for 2 hours. Filtered the resulting solid and washed with water (150 ml). The solid was dried under reduced pressure to afford the title compound. (Yield 63.5 gm, Purity 99.8%).

Claims
1. A process for the preparation of compound of formula (I) or pharmaceutical^ acceptable salt thereof,
comprising the steps (A) and (B), A. conversion of compound of formula (III) to compound of Formula (II)
comprising,
(a) addition of 2-fluoro-4-nitro-benzoic acid of formula (III) to an organic solvent;
(b) addition of a second organic solvent to the reaction solution of step (a), under stirring;
(c) addition of a chlorinating agent to the reaction solution of step (b), under stirring for about 30 minutes to 2 hours;
(d) stirring the reaction contents of step (c), at about 40-85 °C for about 30 minutes to 6 hours;
(e) addition of reaction solution of step (d), to a solution of methylamine at -10 to 20 °C for about 20 minutes to 60 minutes;

(f) stirring the reaction contents of step (e), for about 0-40 °C for about 30 minutes to 2 hours;
(g) addition of water to the reaction solution of step (f) and stirring the contents for about 60 minutes for the separation of solid;
(h) filtering the separated solid of step (g) and washing with water followed by suck
drying for about 30-60 minutes and
(i) dr ying the solid of step (h), at about 45 to 75 °C for about 4-8 hours to get
compound of formula (II).
and,

B. Conversion of compound of formula (II) to compound of Formula (I) which comprises,
i. addition of a reducing catalyst to an organic solvent in a reaction vessel or
hydrogenating vessel;
ii. addition of compound of formula (II) to the reaction solution of step (i) at about
15 to 40 °C;
iii. passing hydrogen gas to the reaction solution of step (ii);
iv. maintaining the reaction mass of step (iii) under hydrogen gas pressure at about
5-25 °C for about 2-15 hours;
v. removing the hydrogen gas from the reaction vessel of step (iv);
vi. filtering the reaction mass of step (v) through hyflo bed and washing with the organic solvent of step (i) under nitrogen atmosphere;
vii. concentrating the filtrate of step (vi) under reduced pressure;
viii. isolating the solid from the residue of step (vii) from second organic solvent and
ix. drying the solid of step (viii) at 40-60 °C for about 3-9 hours to get compound of
Formula I.

2. A process according to claim 1, wherein the organic solvent of step A (a) is an aromatic
hydrocarbon solvent.

3. A process according to claim 2, wherein the organic solvent is toluene.

4. A process according to claiml, wherein the second organic solvent of step A (b) is selected from polar aprotic solvent.

5. A process according to claim 4, wherein the second organic solvent of step A (b) is dimethylformamide.

6. A process according to claiml, wherein the chlorinating agent of step A (c) is selected from phosphorous pentachloride, phophorous trichloride, thionyl chloride, Oxalyl chloride, sulfuryl chloride and triphenylphosphine dichloride.

7. A process according to claim 6, wherein the chlorinating agent is thionyl chloride.

8. A process according to claiml, wherein the reducing catalyst of step B (i) is Raney nickel.

9. A process according to claim 1, wherein the organic solvent of step B (i) and (vi) is methanol.

10. A process according to claim 1, wherein the reaction mass of step B (iv) is maintained
under controlled hydrogen gas pressure.

11. A process according to claim 1, wherein the second organic solvent of step B (viii) is toluene.

12. A process according to claim 1, wherein the obtained compound of formula (I) has purity more than 99.8%.

13. A compound of formula (I) obtained according to claim 1, used as a key intermediate in the synthesis of pharmaceutical compounds.

14. The isolated compound of formula (la) characterized by data selected from NMR, Mass

15. The process of claim 1-12, wherein the obtained compound of formula (I) contains less than about 1% by area HPLC of Impurity (la).

16. A method of purification of compound of formula (I) comprising dissolving the crude solid of compound (I) in an organic solvent at an ambient temperature and isolating the solid by adding an anti-solvent.

17.- A method of purification according to claim 16 wherein the organic solvent is selected from an alcohol solvent comprises methanol, ethanol, propoanol, isopropanol, n-butanol, isobutanol or mixture thereof and the anti-solvent is selected from diethyl ether, isopropyl ether, hexane, water or mixture thereof.

18. The process according to claim 1-17 for the preparation of compound of formula (I) further comprises preparation of pure 4((2-cyanopropan-2-yl) amino)-2-fluoro-N-methyl benzamide of a compound of formula (A) or a pharmaceutical^ acceptable salt thereof.

19. The isolated compound of formula (Al) characterized by data selected from NMR, Mass

20. The process of claim 18, wherein the obtained compound of formula (A) contains less than about 0.5% by area HPLC of Impurity (Al).