CLIAMS:1. A amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyimino acetamide as hydrochloride salt, compound of formula-II

Formula-II
characterized by a powder X-ray diffraction pattern substantially in accordance with Figure 1.

2. The compound of claim 1, wherein (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyimino acetamide has purity more than 99%, when measured by HPLC.

3. A process for the preparation of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide or its salts thereof compound of formula-II

Formula-II
the process comprises the step of;
a. condensing (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-methoxyimin oethanethioate compound of formula III

Formula-III
with amino acetaldehyde dimethyl acetal in a halogenated solvent in presence of suitable base to obtain (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide, compound of formula IV,

Formula-IV
b. converting (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide to (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyimino acetamide or its salts thereof.

4. The process of claim 3, wherein halogenated solvent is selected from the group comprising one or more of dichloromethane, dichloroethane and chloroform.

5. The process of claim 3, wherein base is selected from the group comprising one or more of organic base and Inorganic base.

6. The process of claim 5, wherein organic base is selected from the group comprising one or more of dimethylamine, diethylamine, triethylamine, N,N-diisopropylethylamine and ammonia.

7. The process of claim 5, wherein inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

8. The process of claim 6, wherein base is triethylamine.

9. The process of claim 3, wherein (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide or its salts thereof has purity more than 99%, when measured by HPLC.
,TagSPECI:Field of Invention

The present invention provides a process for the preparation of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide or its salt thereof. In particular aspect of present invention provides amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide hydrochloride. In further aspect of present provides the use of a amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide hydrochloride as reference markers and/or reference standards during the synthesis of Cefepime.

Background of the invention

Cefepime hydrochloride is chemically known as 1-[[(6R,7R)7-[2-(2-amino-4-thiazolyl)-glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidiniumchloride,72-(Z)-(O-methyloxime), monohydrochloride, monohydrate and is structurally represented by Formula (I):

Formula I

Cefepime hydrochloride is approved for the treatment of infections that are proven or strongly suspected to be caused by bacteria and is available in the market under the trade name Maxipime®.

U.S. patent 4,406,899 describes Cefepime hydrochloride and process for the preparation thereof. The process for the preparation of Cefepime hydrochloride described in several patents, U.S. Patents 4,910,301; 4,680,389; 5,095,011; 5,594,130.

The object of present invention is to provide an improved process for the preparation of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide (referred herein after “Cefepime Impurity C”). The process of preparation Cefepime Impurity C is very simple cost effective and may be employed at commercial scale. The product obtained by using instant process provides better yield and purity.

Summary of the Invention

The present invention provides a amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide hydrochloride compound of formula-II

Formula-II

The present invention provides a use of amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide hydrochloride, as reference standards in a qualitative analysis of Cefepime hydrochloride.

The present invention provides a process for the preparation of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide or its salts thereof compound of formula-II

Formula-II

The present invention also provides a (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide or its salts, has purity more than 99 % when measured by HPLC.
Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of amorphous form of Cefepime Impurity C

Detailed description of the Invention

For purposes of the present invention, the following terms are defined below.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Ka radiation, having the wavelength 1.54 Å.

The salt or pharmaceutically acceptable salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic salt may include dimeglumine, acetate, mesylate, tosylate and the like.

As used herein, the term “reference standard” refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. A reference marker” is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

The present invention provides a amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide hydrochloride compound of formula-II

Formula-II

In another aspect, the present invention provides a amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide hydrochloride is characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1.

The amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide hydrochloride obtained as per Example 2 to the present invention was stored at 25°C for a period of 3 months and no conversion in the polymorphic form was observed.

Yet in one another aspect of the present invention provides the use of amorphous form of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide hydrochloride, as reference standards in a qualitative analysis of Cefepime hydrochloride.

Yet in one another aspect of the present invention provides (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide or its salt thereof, has purity more than 99% determined by HPLC.

The present invention provides a process for the preparation of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyiminoacetamide or its salts thereof compound of formula-II

Formula-II
which includes step of
a) condensing (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-methoxyimin oethanethioate compound of formula III

Formula-III
with amino acetaldehyde dimethyl acetal in a halogenated solvent in presence of base to obtain (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide, compound of formula IV,

Formula-IV
b) converting (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide to (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyimino acetamide or its salts thereof.

The step (a) of the present invention involves the addition of amino acetaldehyde dimethyl acetal to the solution of (Z)-S-benzo [d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-methoxyiminoethanethioate in halogenated solvent at temperature in between range of 5?C to 15?C, followed by addition of base. The reaction mixture stirred for the period of 1 to 2 hours at temperature in between range of 0?C to 5?C. After completion of reaction, filter the product, washed with halogenated solvent to obtain (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide as white solid crystalline. Wherein base is selected from the group comprising one or more of organic base and inorganic base; organic base is selected from the group comprising one or more of dimethylamine, diethylamine, triethylamine, N,N-diisopropylethylamine and ammonia. Inorganic base is selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The halogenated solvent is selected from the group comprising one or more of dichloromethane, dichloroethane and chloroform.

The step (b) of the present invention involves addition of (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide to the solution of water and hydrochloric acid at temperature in between range of 20?C to 25?C under maintained temperature. Wherein the ratio of water and solvent to (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide is in the range of about 8-12 : 3-6 : 1, wherein solvent is selected from the group comprising one or more of ketone solvent, water and mixtures thereof, ketone solvents is selected from the group comprising one or more of acetone, methyl ethyl ketone, methyl isobutyl ketone and methyl tert-butyl ketone and the hydrochloric acid has concentration of about 30-35% w/v.

The reaction mixture further heated at temperature in between range of 40?C to 60?C for the period of 20 to 35 hours. After completion of reaction, reaction mass is quenched with addition of diethyl ether, wherein the ratio of diethyl ether to (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide is in the range of about 8-12 : 1. After the layer separation, aqueous layer is collected at temperature in between range of 25?C to 35?C and concentrated under vacuum to obtain (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxyimino acetamide as light yellow solid.

The process of the present invention is depicted in the following scheme 1:

Scheme 1

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES

Example-1: Preparation of (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide.

To the solution of (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-methoxyimino ethanethioate (25.0gm) and dichloromethane (380mL) was added into aminoacetaldehyde dimethyl acetal (9.0gm) at temperature 10-150C, followed by addition of triethylamine (20.6gm). The reaction mixture was stirred the period of 90 minute at temperature 0-50C. After completion of reaction, filter the reaction mass, washed with dichloromethane (100ml) and dried to get titled compound as white solid crystalline.
Yield: 18 gm
1H NMR (400 MHz, DMSO-d6): 3.22 t,3H; 3.28 s, 3H; 3.31 s,3H; 3.93 s,3H; 4.43 t,1H; 7.05 bs,1H; 7.41 s, 1H; 8.42 t, 1H
13C NMR (400 MHz, DMSO-d6): 168.38; 162.53; 149.76; 142.97; 109.36; 101.75; 61.85; 53.30; 40.25.
Mass (M+1): 289.32

Example-2: Preparation of (Z)-2-(2-aminothiazol-4-yl)-N-(formylmethyl)-2-methoxy imino acetamide

To the solution of (Z)-2-(2-aminothiazol-4-yl)-N-(2,2-dimethoxyethyl)-2-methoxyimino acetamide (10.0g), water (100ml) and acetone (40ml) was added slowly solution of 35% of concentrated hydrochloric acid (5.0 mL) at temperature 20-250C. After addition, heat the reaction mass to temperature 45-500C and maintain for the period of 30 hours. After completion of reaction, quench the reaction mass with diethyl ether (100mL).Separate the layer & collect aqueous layer and concentrated the aqueous layer below temperature 30°C to to get titled compound as light yellow solid (9.0gm).
Yield: 9 gm
HPLC purity: 86.44%
Mass (M+1): 243.1
1H NMR (400 MHz, DMSO-d6): 3.95, s, 3H; 4.14, d, 2H; 7.02, bs, 3H; 7.18, s,1H; 9.20 t, 1H; 9.53, s, 1H.
13C NMR (400MHz, DMSO-d6): 198.96; 170.80; 160.30; 144.30; 130.89; 111.57; 63.67; 49.66.