Indian Patents. 277975:PROCESS FOR PREPARING ZALEPLONE REGIOISOMER

Title of Invention	PROCESS FOR PREPARING ZALEPLONE REGIOISOMER
Abstract	The present invention discloses a regiosiomer of zaleplon i.e. N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)pheny]-N-ethyl acetamide having formula.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENT RULES, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION PROCESS FOR PREPARING ZALEPLONE REGIOISOMER We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad - 380015, Gujarat, India. The following specification particularly describes the nature of the invention: 1 FIELD OF INVENTION: The present invention relates to an isolated impurity of Zaleplone, its preparation as well as the preparation of other impurities, and their use as reference standards Zaleplon is marketed as Sonata and chemically known by N- [3- (3-cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl] -N-ethyl acetamide of formula (I). Zaleplon is an anxiolytic, antiepileptic sedative, hypnotic agent and skeletal muscle relaxant. This compound is being effectively used in curative and prophylactic pharmaceutical compositions against manifestations of the aforesaid symptoms. BACKGROUND OF THE INVENTION: Zaleplon, whose systematic chemical name is N-[3-(3-cyanopyrazolo[l-5-a]pyrimidin-7-yl)phenyi]-N-ethylacetamide and represented by below mentioned formula (I). Zaleplon possesses anxiolytic, antiepileptic, sedative and hypnotic properties. It is approved by the U.S. Food and Drug Administration for short-term treatment of insomnia. Zaleplon and a process for preparing it are disclosed in U.S. Pat. No. 4,626,538, which is incorporated herein by reference. In the '538 patent process, shown in Scheme 1, N-(3-acetylphenyl)ethanamide is condensed with dimethylformamide dimethyl acetal to form N-[3-[3-(dimethylamino)-l-oxo-2-propenyl)]phenyl] acetamide. The primary amide of the acetamide is then alkylated with ethyl iodide, forming N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide 1. To prepare zaleplon in the last step, ethylacetamide 1 is condensed with 3-amino-4-cyanopyrazole 2 by refluxing the reactants in glacial acetic acid 2 for eight hours. The '538 patent does not indicate that byproducts were formed in any of the reactions or explain how byproducts could be separated from zaleplon if they did form. U.S. Pat. No. 5,714,607 discloses an improvement upon the '538 patent process. According to the '607 patent, zaleplon can be obtained in improved yield and purity if the final step of the '538 patent process is modified by adding water to the acetic acid solvent at about 10% to about 85% (v/v). It is also reported that the reaction is faster when water is added. As stated in the '607 patent, the improved conditions shorten the reaction time from about 3-3.5 to about 1-3.5 hours. According to Table 1 of the '607 patent, zaleplon was obtained in yields ranging from 81.7-90% and in HPLC purity ranging from 98.77 to 99.4%. WO2004/035585 discloses one-pot process for the preparation of N- [3- (3-cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl]-N-ethyl acetamide resulting in hitherto unreported yield and purity. US patent no. 6,825,858 discloses regioisomer of Zaleplone, which is identified as N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide from other components of crude product by chromatography on a silica gel column using a mixture of chloroform and acetone as eluent, wherein the amount of strong acid, on a mole basis, is at least 10 times the amount of either N-[3-[3(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide or 3-amino-4-cyanopyrazole, whichever is in excess, or of either of them if they are used in approximately equimolar amounts. 3 In order to obtain marketing approval for a new drug product, manufacturers have to submit to the regulatory authorities evidence to show that the product is acceptable for human administration. Such a submission must include, among other things, analytical data to show the impurity profile of the product to demonstrate that the impurities are absent, or are present only a negligible amount. For such a demonstration there is a need for analytical methods capable of detection of the impurities and reference markers for identification and assaying thereof. BRIEF DETAILS OF DRAWINGS: 1) Show as HPLC chromatogram of zaleplone Regio isomer Purity in FIG 1. 2) Show as HPLC chromatogram of zaleplone Regio isomer Purity in FIG 2. 3) Show as 'H NMR of zaleplone Regio isomer in FIG 3. 4) Show as IR of zaleplone Regio isomer in FIG 4. 5) Show as Mass spectrum of zaleplone Regio isomer in FIG 5. 6) Show as C13 spectrum of zaleplone Regio isomer in FIG 6. 7) Show as HPLC chromatogram of zaleplone Purity in FIG 7. DETAILED DESCRIPTION: The present invention is directed to an impurity of Zaleplone Regioisomer which was previously unidentified, its preparation as well as of other unknown impurities and to the use of these impurity as reference standards for the analytical quantification of Zaleplone purity, as required in the manufacture of high purity of Zaleplone. The present invention relates a method for preparation of a N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide, which is the regioisomer and main process impurity of zaleplon. This compound, which is characterized by NMR and MS investigations, can be used as a reference marker in analysis of zaleplon. In still a further aspect, the present invention relates to analytical methods for analyzing and determining the impurity profile of zaleplon. These methods are also suitable for analyzing and assaying zaleplon and its main impurity, which in the methods of the invention, serves as reference marker. 4 The present invention relates to an isolated impurity of Zaleplone and its process for preparation. In the first embodiment this invention is direct to preparation of Zaleplone Regioisomer as references standard. According to the embodiment of the present invention, there is provided a process for the preparation of Zaleplone Regioisomer by reacting N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide and 3-Amino-lH-pyrazole-4-carbonitrile in pretences of perchloric acid. In the other embodiment of the invention is preparation of Zaleplone Regioisomer by reacting N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide and 3-Amino-lH-pyrazole-4-carbonitrile in pretences of per choleric acid (35% w/v)[per chloride acid (70%) and water (330 mL)] under the process condition. In another embodiment, the present invention is directed to a method for the quantification of purity of zaleplone comprising the use of zaleplone regioisomer as reference standards, where the reference standards may be either external standards or internal standards. The present invention provide an isolated zaleplone regioisomer having the structure: 5 The present invention provide a process for the preparation of zaleplone regioisomer by reacting N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide and 3-Amino-lH-pyrazole-4-carbonitrile in pretences of per choleric acid (35% w/v)[per chloride acid (70%) and water (330 mL)] under the process condition this process comprises : a) combining N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide and 3-Amino-lH-pyrazole-4-carbonitrile at a temperature 25 to 35°C. b) Adding per choleric acid (35% w/v) at a temperature 25 to 35 °C. c) Maintain temperature 40-45°C for least 20 to 24 hours. d) Treating with water to provide regioisomer of Zaleplon. The Zaleplone regioisomer having NMR data: 6 TABLE 2 Chemical Shift (ppm) Assignment (b) (a) (c) C-CN (h) CN (g) (d) (f) (e) (i) Ar-Ci Ar-C2 (j) N-C= C=N c=o 13.15 22.93 44.00 83.32 107.61 112.75 127.08 127.39 130.54 131.58 136.48 137.35 144.03 148.21 149.84 158.38 169.63 IR Dates: 2227 cm-1 (CN),1731) cm-1 (C=0, ketone). Mass spectrum M/e value :306. Zaleplone Regioisomer purity by HPLC HPLC method disclosed: Quantitative analysis of Zaleplone Regioisomer may be performed using the following HPLC method: a) Column & Packing Prodigy ODS (2)(1504.6mm,5u) b) Mobile Phase Buffer : CAN (75 : 25). c) Flow Rate l.0mL/min. d) Detector 225 nm. e) Column temperature 25°C. f) Diluent Water : CAN (50: 50). g) Injection 10μv. Zaleplone purity b/HPLC HPLC method disclosed : Quantitative analysis of Zaleplone Regioisomer may be performed using the following HPLC method: h) Column & Packing Prodigy ODS (2)(1504.6mm,5u) i) Mobile Phase Buffer : CAN (75 : 25). J) Flow Rate 1.5 mL/min. k) Detector 225nm. 1) Column temperature 25°C. m) Diluent Water : CAN (50: 50). n) Injection lOuv. WORKING EXAMPLES: Example 1: Preparation of Zaleplone Regioisomer. N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide (0.0961 mole 25.0gm) and 3-Amino-lH-pyrazole-4-carbonitrile (0.0980 mole 10.60 gm) at temperature 25-35°C.Then add 330 mL in per choleric acid (35% w/v)[per chloride acid (70%) and water (330 mL)] at temperature 25-35°C, slowly heat and stir at 40-45°C for 20-24 hours. The reaction mixture adding in water (1250mL) at temperature 25-35°C,wash with water (3.25L).Dry the product at temperature 50-55°C, product obtain 17.00gm. Purity :98.71% Dated this the 7th day of May 2007 (SHALINA AHUJA) of SUBRAMANIAM, NATARAJ & ASSOCIATES ATTORNEY FOR THE APPLICANTS 8

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
PROCESS FOR PREPARING ZALEPLONE REGIOISOMER
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad - 380015, Gujarat, India.
The following specification particularly describes the nature of the invention:
1
FIELD OF INVENTION:
The present invention relates to an isolated impurity of Zaleplone, its preparation as well as the preparation of other impurities, and their use as reference standards
Zaleplon is marketed as Sonata and chemically known by N- [3- (3-cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl] -N-ethyl acetamide of formula (I). Zaleplon is an anxiolytic, antiepileptic sedative, hypnotic agent and skeletal muscle relaxant. This compound is being effectively used in curative and prophylactic pharmaceutical compositions against manifestations of the aforesaid symptoms.
BACKGROUND OF THE INVENTION:
Zaleplon, whose systematic chemical name is N-[3-(3-cyanopyrazolo[l-5-a]pyrimidin-7-yl)phenyi]-N-ethylacetamide and represented by below mentioned formula (I). Zaleplon possesses anxiolytic, antiepileptic, sedative and hypnotic properties. It is approved by the U.S. Food and Drug Administration for short-term treatment of insomnia.

Zaleplon and a process for preparing it are disclosed in U.S. Pat. No. 4,626,538, which is incorporated herein by reference. In the '538 patent process, shown in Scheme 1, N-(3-acetylphenyl)ethanamide is condensed with dimethylformamide dimethyl acetal to form N-[3-[3-(dimethylamino)-l-oxo-2-propenyl)]phenyl] acetamide. The primary amide of the acetamide is then alkylated with ethyl iodide, forming N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide 1. To prepare zaleplon in the last step, ethylacetamide 1 is condensed with 3-amino-4-cyanopyrazole 2 by refluxing the reactants in glacial acetic acid
2

for eight hours. The '538 patent does not indicate that byproducts were formed in any of the reactions or explain how byproducts could be separated from zaleplon if they did form.

U.S. Pat. No. 5,714,607 discloses an improvement upon the '538 patent process. According to the '607 patent, zaleplon can be obtained in improved yield and purity if the final step of the '538 patent process is modified by adding water to the acetic acid solvent at about 10% to about 85% (v/v). It is also reported that the reaction is faster when water is added. As stated in the '607 patent, the improved conditions shorten the reaction time from about 3-3.5 to about 1-3.5 hours. According to Table 1 of the '607 patent, zaleplon was obtained in yields ranging from 81.7-90% and in HPLC purity ranging from 98.77 to 99.4%.
WO2004/035585 discloses one-pot process for the preparation of N- [3- (3-cyanopyrazolo [1,5-a] pyrimindin-7-yl) phenyl]-N-ethyl acetamide resulting in hitherto unreported yield and purity.
US patent no. 6,825,858 discloses regioisomer of Zaleplone, which is identified as N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide from other components of crude product by chromatography on a silica gel column using a mixture of chloroform and acetone as eluent, wherein the amount of strong acid, on a mole basis, is at least 10 times the amount of either N-[3-[3(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-ethylacetamide or 3-amino-4-cyanopyrazole, whichever is in excess, or of either of them if they are used in approximately equimolar amounts.
3

In order to obtain marketing approval for a new drug product, manufacturers have to submit to the regulatory authorities evidence to show that the product is acceptable for human administration. Such a submission must include, among other things, analytical data to show the impurity profile of the product to demonstrate that the impurities are absent, or are present only a negligible amount. For such a demonstration there is a need for analytical methods capable of detection of the impurities and reference markers for identification and assaying thereof.
BRIEF DETAILS OF DRAWINGS:
1) Show as HPLC chromatogram of zaleplone Regio isomer Purity in FIG 1.
2) Show as HPLC chromatogram of zaleplone Regio isomer Purity in FIG 2.
3) Show as 'H NMR of zaleplone Regio isomer in FIG 3.
4) Show as IR of zaleplone Regio isomer in FIG 4.
5) Show as Mass spectrum of zaleplone Regio isomer in FIG 5.
6) Show as C13 spectrum of zaleplone Regio isomer in FIG 6.
7) Show as HPLC chromatogram of zaleplone Purity in FIG 7.
DETAILED DESCRIPTION:
The present invention is directed to an impurity of Zaleplone Regioisomer which was previously unidentified, its preparation as well as of other unknown impurities and to the use of these impurity as reference standards for the analytical quantification of Zaleplone purity, as required in the manufacture of high purity of Zaleplone.
The present invention relates a method for preparation of a N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide, which is the regioisomer and main process impurity of zaleplon. This compound, which is characterized by NMR and MS investigations, can be used as a reference marker in analysis of zaleplon.
In still a further aspect, the present invention relates to analytical methods for analyzing and determining the impurity profile of zaleplon. These methods are also suitable for analyzing and assaying zaleplon and its main impurity, which in the methods of the invention, serves as reference marker.
4

The present invention relates to an isolated impurity of Zaleplone and its process for preparation.
In the first embodiment this invention is direct to preparation of Zaleplone Regioisomer as references standard.
According to the embodiment of the present invention, there is provided a process for the preparation of Zaleplone Regioisomer by reacting N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide and 3-Amino-lH-pyrazole-4-carbonitrile in pretences of perchloric acid.

In the other embodiment of the invention is preparation of Zaleplone Regioisomer by reacting N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide and 3-Amino-lH-pyrazole-4-carbonitrile in pretences of per choleric acid (35% w/v)[per chloride acid (70%) and water (330 mL)] under the process condition.
In another embodiment, the present invention is directed to a method for the quantification of purity of zaleplone comprising the use of zaleplone regioisomer as reference standards, where the reference standards may be either external standards or internal standards.
The present invention provide an isolated zaleplone regioisomer having the structure:

5

The present invention provide a process for the preparation of zaleplone regioisomer by reacting N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide and 3-Amino-lH-pyrazole-4-carbonitrile in pretences of per choleric acid (35% w/v)[per chloride acid (70%) and water (330 mL)] under the process condition this process comprises :
a) combining N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide and 3-Amino-lH-pyrazole-4-carbonitrile at a temperature 25 to 35°C.
b) Adding per choleric acid (35% w/v) at a temperature 25 to 35 °C.
c) Maintain temperature 40-45°C for least 20 to 24 hours.
d) Treating with water to provide regioisomer of Zaleplon.
The Zaleplone regioisomer having NMR data:

6

TABLE 2

Chemical Shift (ppm)

Assignment

(b) (a)
(c)
C-CN
(h)
CN
(g) (d) (f) (e)
(i) Ar-Ci
Ar-C2
(j) N-C=
C=N
c=o
13.15
22.93
44.00
83.32
107.61
112.75
127.08
127.39
130.54
131.58
136.48
137.35
144.03
148.21
149.84
158.38
169.63

IR Dates: 2227 cm-1 (CN),1731) cm-1 (C=0, ketone). Mass spectrum M/e value :306.

Zaleplone Regioisomer purity by HPLC
HPLC method disclosed: Quantitative analysis of Zaleplone Regioisomer may be performed using the following HPLC method:

a) Column & Packing Prodigy ODS (2)(150*4.6mm,5u)
b) Mobile Phase Buffer : CAN (75 : 25).
c) Flow Rate l.0mL/min.
d) Detector 225 nm.
e) Column temperature 25°C.
f) Diluent Water : CAN (50: 50).
g) Injection 10μv.

Zaleplone purity b/HPLC
HPLC method disclosed : Quantitative analysis of Zaleplone Regioisomer may be performed using the following HPLC method:

h) Column & Packing Prodigy ODS (2)(150*4.6mm,5u)
i) Mobile Phase Buffer : CAN (75 : 25).
J) Flow Rate 1.5 mL/min.
k) Detector 225nm.
1) Column temperature 25°C.
m) Diluent Water : CAN (50: 50).
n) Injection lOuv.
WORKING EXAMPLES:
Example 1: Preparation of Zaleplone Regioisomer.
N-[3-(3-Dimethylamino-acryloyl)-phenyl]-N-ethyl-acetamide (0.0961 mole 25.0gm) and 3-Amino-lH-pyrazole-4-carbonitrile (0.0980 mole 10.60 gm) at temperature 25-35°C.Then add 330 mL in per choleric acid (35% w/v)[per chloride acid (70%) and water (330 mL)] at temperature 25-35°C, slowly heat and stir at 40-45°C for 20-24 hours. The reaction mixture adding in water (1250mL) at temperature 25-35°C,wash with water (3.25L).Dry the product at temperature 50-55°C, product obtain 17.00gm. Purity :98.71%
Dated this the 7th day of May 2007

(SHALINA AHUJA)
of SUBRAMANIAM, NATARAJ & ASSOCIATES ATTORNEY FOR THE APPLICANTS
8

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Patent Number

277975

Indian Patent Application Number

891/MUM/2007

PG Journal Number

51/2016

Publication Date

09-Dec-2016

Grant Date

07-Dec-2016

Date of Filing

10-May-2007

Name of Patentee

CADILA HEALTHCARE LIMITED

Applicant Address

ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD.

Inventors:

#	Inventor's Name	Inventor's Address
1	KETAN AMBALAL DOSHI	ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD 380015.
2	DWIVEDI SHRIPRAKSH DHAR	ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD 380015.

PCT International Classification Number

C07D487/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA