DESC:RELATED PATENT APPLICATION(S):

This application claims the benefit of Indian Patent Application No. 201741004641 filed on February 08, 2017; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION:

The present invention describes an improved process for the preparation of substantially pure 1-(1-(benzo[b]thiophen-2-yl) ethyl)-1-hydroxyurea, also known as Zileuton (I).

BACKGROUND OF THE INVENTION

Zileuton (I) was approved by the U.S. Food and Drug Administration for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.

The process for the preparation of Zileuton (I) has been described in various patents and patent applications. The process for the preparation of Zileuton (I) as disclosed in US4873259, US4992464, and WO2011036680 involves the conversion of 2-acetyl benzo thiophene to the corresponding oxime by reacting with hydroxyl amine hydrochloride. The processes disclosed in these references involve use of reagents like pyridine or borane pyridine complex but does not use any buffering agent.

US8933250 describes another process for the preparation of Zileuton (I) by reacting (1-benzo[b]thien-2-yl) ethanol with hydroxyurea in the presence of strong acidic cation exchanger or hydrogen sulphate as a catalyst.

US9670176 claims a process for the preparation of Zileuton (I) using the acetic acid-1-benzo[b]thiophen-2-yl-ethyl-ester as an intermediate. Zileuton was synthesized by reacting phenyl 1-(benzo[b]thiophen-2-yl) ethyl(hydroxyl) carbamate with ammonia in presence of dimethylformamide as solvent. The compound phenyl 1-(benzo[b]thiophen-2-yl) ethyl(hydroxyl) carbamate was synthesized by reacting acetic acid 1-benzo[b]thiophen-2-yl-ethyl ester and phenyl N-hydroxy carbamate in presence of boron trifluoride dietherate.

The Indian Patent Application No. 2307/CHE/2009 describes various processes for the preparation of Zileuton (I); however the overall yields in these processes are significantly low.

The present inventors have come up with an improved method for the preparation of substantially pure Zileuton, overcoming the limitations faced in the prior art processes.

SUMMARY OF THE INVENTION

One aspect of the invention is to provide a process for preparing pure Zileuton (I) having purity greater than 99%.

Accordingly, there is provided a process for the preparation of Zileuton (I),

the said process comprising the steps of:

a) reacting 1-(benzo[b]thiophen-2-yl) ethanone compound of formula (II) with hydroxyl amine hydrochloride in presence of protic solvent

to obtain (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III);

b) reacting (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime compound of formula (III) obtained in step a) with borane pyridine complex and isopropyl alcohol hydrochloride in presence of a protic solvent to obtain N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV);

c) treating N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine compound of formula (IV) with potassium cyanate to obtain Zileuton of formula (I); and

d) purifying Zileuton of formula (I) obtained in step c) using an aprotic solvent.

In some embodiment of the invention, the solvent used in step a) and step b) of the above described process for preparation of Zileuton of formula (I) is selected from the group comprising of methanol, ethanol, isopropyl alcohol or water.

In some other embodiment of the invention, the aprotic solvent used in step d) of the above described process for preparation of Zileuton of formula (I) is selected from toluene or hexane.

In another aspect of the invention, there is provided a process for purification of Zilueton of formula (I), comprising:
a) suspending Zileuton of formula (I) in a suitable aprotic solvent;
b) heating the suspension to 50-55°C and stirring for 60 to 90 minutes; and
c) filtering the solid under vacuum to isolate Zileuton of formula (I) having purity
greater than 99%.
In some embodiment of the invention, the aprotic solvent used in the above described process for purification of Zilueton of formula (I) is selected from the group consisting of toluene and hexane.

Another aspect of the invention is to provide a crystalline form of Zileuton of formula (I) which is designated as Form 1.

In some embodiment of the invention, Zileuton of formula (I) obtained after purification may produce an X-ray diffraction pattern represented as Form 1, comprising the 2 theta values tabulated in Table 1.

In another embodiment of the invention, there is provided a process for the preparation of Zileuton of formula (I) in crystalline Form I characterized by X-ray powder diffraction (XRPD) pattern having peaks at 4.39, 4.81, 8.45, 9.51, 14.30, 14.86, 15.43, 16.20, 16.90, 17.48, 19.52, 20.85, 22.06, 22.72, 24.04, 24.48, 25.98, 27.84, 28.88, 30.00, 30.56, 30.98, 31.80, 33.22, 36.76, 37.39 ±0.2 degrees 2 theta.

In some aspect of the invention, there is provided a process for the preparation of crystalline form of Zileuton of formula (I) characterized by X-ray powder diffraction (XRPD) pattern having peaks at 4.39, 4.81, 8.45, 9.51, 14.30, 14.86, 15.43, 16.20, 16.90, 17.48, 19.52, 20.85, 22.06, 22.72, 24.04, 24.48, 25.98, 27.84, 28.88, 30.00, 30.56, 30.98, 31.80, 33.22, 36.76, 37.39 ±0.2 degrees 2 theta,

said process comprising steps of:
a) reacting 1-(benzo[b]thiophen-2-yl) ethanone compound of formula (II) with hydroxyl amine hydrochloride in presence of protic solvent

to obtain (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III);

b) reacting (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime compound of formula (III) obtained in step a) with borane pyridine complex and isopropyl alcohol hydrochloride in presence of a protic solvent to obtain N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV);

c) treating N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine compound of formula (IV) with potassium cyanate to obtain Zileuton of formula (I);
d) suspending the crude Zileuton of formula (I) obtained in step c) in a suitable
aprotic solvent;
e) heating the suspension obtained in step d) to 50-55°C and stirring for 60 to 90 minutes; and
f) isolating the crystalline form of Zileuton of formula (I).

In another object of the invention, Zileuton of formula (I) produced after purification is having total impurities level less than 1.0 %, impurity A less than 0.2%, impurity B less than 0.1%, and impurity C less than 0.1%.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 is characteristic X-ray powder diffraction of Zileuton of formula (I)
Figure 2 is characteristic Differential scanning calorimetry (DSC), ofZileuton of formula (I)
Figure 3 is characteristic Fourier-transform infrared (FT-IR) spectrumof Zileuton of formula (I)

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of Zileuton of formula (I) with purity greater than 99.0%

In one aspect of the invention, there is provided a process for the preparation of Zileuton (I),

the said process comprising the steps of:

a) reacting 1-(benzo[b]thiophen-2-yl) ethanone compound of formula (II) with hydroxyl amine hydrochloride in presence of protic solvent

to obtain (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III);

b) reacting (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime compound of formula (III) obtained in step a) with borane pyridine complex and isopropyl alcohol hydrochloride in presence of a protic solvent to obtain N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV);

c) treating N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine compound of formula (IV) with potassium cyanate to obtain Zileuton of formula (I); and

d) purifying Zileuton of formula (I) obtained in step c) using an aprotic solvent.

The present invention for the preparation of Zileuton of formula (I) is schematically represented in Scheme-I.

In one embodiment of the invention, in step a) (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III) is prepared from 1-(benzo[b]thiophen-2-yl) ethanone of formula (II) by reacting with hydroxylamine hydrochloride in the presence of sodium acetate and suitable protic solvent. After completion of reaction, the pure compound of formula (III) can be obtained by adding water to the reaction mass and precipitating from water at 0-5°C. The purity of compound of formula (III) obtained in step a) is more than 95%.

In some embodiment of the invention, the solvent used in step a) and step b) of the above described process for preparation of Zileuton of formula (I) is selected from the group comprising of methanol, ethanol, isopropyl alcohol or water.

Scheme-I

The suitable protic solvent used in step a) is selected from the group comprising of methanol, ethanol, isopropyl alcohol, water or the like; preferably water is used. Further, sodium acetate is added in step a) to maintain the pH of the reaction mass between 2 to 2.5. The molar ratio of compound of formula (II) and sodium acetate is about 1: 3.

The Step b) of the invented process involves conversion of (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III) obtained in the above step a) to N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV) in the presence of borane pyridine complex and isopropyl alcohol hydrochloride in a protic solvent. After completion of reaction, the reaction mass is added to the water and pH is adjusted to 9.0 to 10.0 to precipitate the product from the reaction mass. The precipitated compound of formula (IV) is extracted with ethyl acetate and distilled off to isolate the product. Optionally, the compound of formula (IV) is purified by dissolving in water and adjusting pH of the solution to 2.0 using hydrochloric acid to remove the unreacted compound of formula (III). The reaction mixture is extracted with suitable aprotic solvent and adjusted pH to 8.0 to 9.0 using aqueous sodium carbonate solution to precipitate the compound of formula (IV) with purity more than 99.5%.

The suitable protic solvent used in step b) is selected from the group comprising of ethanol, methanol, isopropyl alcohol, water or the like; preferably isopropyl alcohol and water is used in the present invention.

The step c) involves reaction of N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV) with potassium cyanate in the presence of water and aprotic solvent. To the reaction mass concentrated hydrochloric acid and water is added and stirred for 1-2 hours at 25-30°C. After the completion of the reaction, the reaction mass is stirred at 0-5°C and the precipitated solid is filtered.

Aprotic solvents used in step c) and step d) is selected from the group comprising of ethyl acetate, dimethyl formamide, tetrahydrofuran, acetonitrile, benzene, toluene, hexane or the like, preferably ethyl acetate and toluene is used in the present invention.

In some other embodiment of the invention, the aprotic solvent used in step d) of the above described process for preparation of Zileuton of formula (I) is selected from toluene or hexane.

Finally, the compound Zileuton of formula (I) was purified from aprotic solvent. Step d) involves purification of Zileuton of formula (I) by using an aprotic solvent.

In another aspect of the invention, there is provided a process for purification of Zilueton of formula (I), comprising:
a) suspending Zileuton of formula (I) in a suitable aprotic solvent;
b) heating the suspension to 50-55°C and stirring for 60 to 90 minutes; and
c) filtering the solid under vacuum to isolate Zileuton of formula (I) having purity
greater than 99%.

In some embodiment of the invention, the aprotic solvent used in the above described process for purification of Zilueton of formula (I) is selected from the group consisting of toluene and hexane.

Another aspect of the invention is to provide a crystalline form of Zileuton of formula (I) which is designated as Form I.

In some embodiment of the invention, Zileuton of formula (I) obtained after purification may produce an X-ray diffraction pattern represented as Form I, comprising the 2 theta values tabulated in Table 1.

In another embodiment of the invention, there is provided a process for the preparation of Zileuton of formula (I) in crystalline Form I characterized by X-ray powder diffraction (XRPD) pattern having peaks at 4.39, 4.81, 8.45, 9.51, 14.30, 14.86, 15.43, 16.20, 16.90, 17.48, 19.52, 20.85, 22.06, 22.72, 24.04, 24.48, 25.98, 27.84, 28.88, 30.00, 30.56, 30.98, 31.80, 33.22, 36.76, 37.39 ±0.2 degrees 2 theta.

In some aspect of the invention, there is provided a process for the preparation of crystalline form of Zileuton of formula (I) characterized by X-ray powder diffraction (XRPD) pattern having peaks at 4.39, 4.81, 8.45, 9.51, 14.30, 14.86, 15.43, 16.20, 16.90, 17.48, 19.52, 20.85, 22.06, 22.72, 24.04, 24.48, 25.98, 27.84, 28.88, 30.00, 30.56, 30.98, 31.80, 33.22, 36.76, 37.39 ±0.2 degrees 2 theta,

said process comprising steps of:
a) reacting 1-(benzo[b]thiophen-2-yl) ethanone compound of formula (II) with hydroxyl amine hydrochloride in presence of protic solvent

to obtain (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III);

b) reacting (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime compound of formula (III) obtained in step a) with borane pyridine complex and isopropyl alcohol hydrochloride in presence of a protic solvent to obtain N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV);

c) treating N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine compound of formula (IV) with potassium cyanate to obtain Zileuton of formula (I);
d) suspending the crude Zileuton of formula (I) obtained in step c) in a suitable
aprotic solvent;
e) heating the suspension obtained in step d) to 50-55°C and stirring for 60 to 90 minutes; and
f) isolating the crystalline form of Zileuton of formula (I).

The Zileuton of formula (I) prepared by the process of present invention provides compound of formula (I) is having a HPLC purity greater than 99 % or more preferably greater than 99.5 %.

In another aspect, the present invention provides a purification process to produce Zileuton of formula (I) devoid of impurity A, impurity B, impurity C identified by HPLC analysis and the total impurities should be less than 1.0 %.

The Zileuton of formula (I) obtained after purification may produce an X-ray diffraction pattern represented as Form I, comprising one or more of the 2 theta values as tabulated in Table 1 and as illustrated in Figure 1.

Table 1: X-ray diffraction pattern of Form I of Zileuton of formula (I)
2 Theta ° d value Angstrom Relative intensity (I/I0) %
4.39 20.09 19
4.81 18.32 56
8.45 10.45 14
9.51 9.28 45
14.30 6.18 20
14.86 5.95 31
15.43 5.73 100
16.20 5.46 3
16.90 5.24 7
17.48 5.06 10
19.52 4.54 21
20.85 4.25 17
22.06 4.02 17
22.72 3.91 18
24.04 3.69 25
24.48 3.63 23
25.98 3.42 29
27.84 3.20 6
28.88 3.08 10
30.00 2.97 6
30.56 2.92 9
30.98 2.88 12
31.80 2.81 6
33.22 2.69 4
36.76 2.44 5
37.39 2.40 3

Another object of the invention is to provide Form I of Zileuton of formula (I) having a Differential scanning calorimetry (DSC) endothermic peak at 160°C as illustrated in Figure 2.

In another object of the invention, Form I of Zileuton of formula (I) has a characteristic Fourier-transform infrared (FT-IR) spectrum with absorption band at ranges 3463, 3327, 3267, 3180, 2935, 2872, 1680, 1572, 1469, 1457, 1445, 1357, 1249, 1192, 1153, 1127, 773, 728 ±2 cm-1; the FT-IR spectrum is as shown in Figure 3.

The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.

EXAMPLES

EXAMPLE 1

Preparation of (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III):
100 g of 1-(benzo[b]thiophen-2-yl) ethanone or 2-acetyl benzothiopheneof formula (II) was dissolved in methanol and stirred for 10-20 minutes. To this 79 g of hydroxyl amine hydrochloride, 600 mL of water and 140 g of sodium acetate were added and stirred for further 10-20 minutes at 25-30°C. The reaction mass temperature was raised to 65-70°C and stirred for 3-4 hours. After completion of reaction, the reaction mixture was cooled to 25-30°C, 600 mL of water was added and further cooled to 0-5°C. The solid so precipitated was filtered, washed with water and dried under vacuum at below 60°C to obtain (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III).
Yield: 77-85 %
Purity by HPLC: 99.6 %

EXAMPLE 2

Preparation of N-(1-( benzo[b]thiophen-2-yl) ethyl) hydroxylamineof formula (IV):
100 g of (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III) was dissolved in 800 mL of isopropyl alcohol under nitrogen atmosphere and stirred for 10-20 minutes at 25-30°C. The reaction mass was cooled to 0-5°C and 185 g of borane pyridine complex was added and stirred for 30-40 minutes. To the reaction mass 347 g of isopropyl alcohol hydrochloride was added over a period of 3-4 hours at 0-5°C. After completion of reaction, the reaction mass was added to the 500 mL of water at 0-5°C. The pH of the reaction mass was adjusted to 9.0 to 10.0 using 50% aqueous sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was distilled off under vacuum. To the crude solid, 500 mL of water was added and adjusted pH of the reaction mass to 2.0 using concentrated hydrochloric acid at 25-30°C. The reaction mass extracted with dichloromethane and the aqueous layer was filtered. The pH of the aqueous phase was adjusted to 8.0 to 9.0 using 50% aqueous sodium carbonate solution and stirred for 40-60 minutes at 10-15°C. The solid so precipitated was filtered and washed with water. The product so formed was dried under vacuum at below 45°C to obtain N-(1-( benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV).
Yield: 65-75 %
Purity by HPLC: 98 %

EXAMPLE 3

Preparation of 1-(1-(benzo[b]thiophen-2-yl) ethyl)-1-hydroxyurea or Zileuton of formula (I):
100 g of N-(1-( benzo[b]thiophen-2-yl)ethyl) hydroxylamineof formula (IV) was dissolved in 1200 mL of ethyl acetate and stirred for 10-20 minutes at 25-30°C.To this 100 ml of water and 83.3 g of potassium cyanate were added and stirred for 10-20 minutes. The above reaction mixture was passed through micron filter and the filtrate was stirred for another 1-2 hours. To the filtrate 70 mL of concentrated hydrochloric acid and 700 mL of water were added and filtered under vacuum. The filtrate was stirred for 60-90 minutes at 25-30°C. On completion of reaction, the reaction mass was cooled to 0-5°C and stirred for 30-45 minutes. The solid so formed was filtered under vacuum and washed with chilled toluene to obtain 1-(1-(benzo [b]thiophen-2-yl) ethyl)-1-hydroxyurea or Zileuton of formula (I).

EXAMPLE 4

Purification of 1-(1-(benzo[b]thiophen-2-yl) ethyl)-1-hydroxyurea or Zileuton of formula (I):
500 mL toluene was added to 100 g of 1-(1-(benzo [b]thiophen-2-yl) ethyl)-1-hydroxyurea of formula (I) at 25-30°C. The reaction mixture was heated to 50-55°C and stirred for 60-90 minutes. The solid was filtered under vacuum and washed with 100 mL of toluene at 25-30°C, dried under vacuum at below 40-45°C to obtain pure 1-(1-(benzo [b]thiophen-2-yl) ethyl)-1-hydroxyurea or Zileuton of formula (I).

Yield: 75-80 %
Purity by HPLC: 99.99 %
XRD: Figure-1
Moisture content: 0.7 % (w/w)
,CLAIMS:

1. A process for the preparation of Zileuton of formula (I),

the said process comprising the steps of:

a) reacting 1-(benzo[b]thiophen-2-yl) ethanone compound of formula (II) with hydroxyl amine hydrochloride in presence of protic solvent

to obtain (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III);

b) reacting (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime compound of formula (III) obtained in step a) with borane pyridine complex and isopropyl alcohol hydrochloride in presence of a protic solvent to obtain N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV);

c) treating N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine compound of formula (IV) with potassium cyanate to obtain Zileuton of formula (I); and

d) purifying Zileuton of formula (I) obtained in step c) using an aprotic solvent.

2. The process as claimed in claim 1, wherein the solvent used in step a) and step b) is selected from the group comprising of methanol, ethanol, isopropyl alcohol or water.

3. The process as claimed in claim 1, wherein the aprotic solvent used in step d) is selected from toluene or hexane.

4. A process for purification of Zileuton of formula (I), comprising:
a) suspending Zileuton of formula (I) in a suitable aprotic solvent;
b) heating the suspension to 50-55°C and stirring for 60 to 90 minutes; and
c) filtering the solid under vacuum to isolate Zileuton of formula (I) having purity greater than 99%.

5. The process as claimed in Claim 4, wherein the aprotic solvent is selected from the group consisting of toluene and hexane

6. The process as claimed in any of the claim 1 or 4, wherein Zileuton of formula (I) obtained is crystalline Form I characterized by X-ray powder diffraction (XRPD) pattern having peaks at 4.39, 4.81, 8.45, 9.51, 14.30, 14.86, 15.43, 16.20, 16.90, 17.48, 19.52, 20.85, 22.06, 22.72, 24.04, 24.48, 25.98, 27.84, 28.88, 30.00, 30.56, 30.98, 31.80, 33.22, 36.76, 37.39 ±0.2 degrees 2 theta.

7. A process for the preparation of crystalline form of Zileuton of formula (I) characterized by X-ray powder diffraction (XRPD) pattern having peaks at 4.39, 4.81, 8.45, 9.51, 14.30, 14.86, 15.43, 16.20, 16.90, 17.48, 19.52, 20.85, 22.06, 22.72, 24.04, 24.48, 25.98, 27.84, 28.88, 30.00, 30.56, 30.98, 31.80, 33.22, 36.76, 37.39 ±0.2 degrees 2 theta


said process comprising steps of:

a) reacting 1-(benzo[b]thiophen-2-yl) ethanone compound of formula (II) with hydroxyl amine hydrochloride in presence of protic solvent

to obtain (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime of formula (III);

b) reacting (E)-1-(benzo[b]thiophen-2-yl) ethanone oxime compound of formula (III) obtained in step a) with borane pyridine complex and isopropyl alcohol hydrochloride in presence of a protic solvent to obtain N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine of formula (IV);

c) treating N-(1-(benzo[b]thiophen-2-yl) ethyl) hydroxylamine compound of formula (IV) with potassium cyanate to obtain Zileuton of formula (I);

d) suspending the crude Zileuton of formula (I) obtained in step c) in a suitable
aprotic solvent;
e) heating the suspension obtained in step d) to 50-55°C and stirring for 60 to 90 minutes; and

f) isolating the crystalline form of Zileuton of formula (I).