WO2017046756A1

WO2017046756A1 - Proxetil and axetil esters of cefixime

Info

Publication number: WO2017046756A1
Application number: PCT/IB2016/055533
Authority: WO
Inventors: Avinash K. NANGIA; Girij Pal Singh; Anurag TRIVEDI; Sunil MURKUTE; Hitendra MAHETA
Original assignee: Lupin Limited
Priority date: 2015-09-18
Filing date: 2016-09-16
Publication date: 2017-03-23

Abstract

The present invention relates to compound of formula (II) wherein R = -OCH(CH₃)₂, -CH₃; or a pharmaceutically acceptable salt thereof. The present invention further relates to substantially pure cefixime proxetil; substantially pure cefixime axetil and their pharmaceutically acceptable salt thereof.

Description

PROXETIL AND AXETIL ESTERS OF CEFIXIME

FIELD OF THE INVENTION

The present invention relates to proxetil and axetil esters of cefixime and their treating bacterial infections.

BACKGROUND OF THE INVENTION

Cefixime is a broad spectrum third generation cephalosporin antibiotic. It is useful for the treatment of a number of bacterial infections and is chemically known as (6R,7R)-7-{ [2- (2-amino-l,3-thiazol-4-yl)-2-(carboxymethoxyimino)-acetyl]amino}-3-ethenyl-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid having chemical structure of formula I.

Formula I

It is sold under the brand name Suprax®.

SUMMARY OF THE INVENTION

The present invention relates to compound of formula II

Formula II wherein R = -OCH(CH₃)₂, -CH₃;

or a pharmaceutically acceptable salt thereof, and its use in treating bacterial infections.

The present invention further relates to substantially pure cefixime proxetil or a pharmaceutically acceptable salt thereof.

The present invention further relates to substantially pure cefixime axetil or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE FIGURE

Figure 1— X-ray diffraction spectrum of amorphous form of cefixime proxetil

Figure 2— X-ray diffraction spectrum of amorphous form of cefixime axetil

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides cefixime proxetil (cefixime 1-methyl ethoxycarbonyloxy ethyl ester), cefixime axetil (cefixime acetoxy ethyl ester) or a pharmaceutically acceptable salt thereof as a valuable prodrug ester of cefixime, particularly suitable for oral and parenteral administration in various animal species and in man for treatment of infections caused by gram-positive and gram-negative bacteria.

The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compound of the Formula II may be formed, for example, by reacting a compound of Formula II with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,

camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,

International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include alkali metal salts such as sodium or potassium salts; alkaline -earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts, and basic amino acid salts such as arginine salts or lysine salts.

The compound of Formula (II) contain asymmetric or chiral center, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compound of Formula (II) as well as mixtures thereof, including racemic mixtures, form part of the present invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.

Enantiomers can be separated by converting the enantiomeric mixture into a

diastereomeric mixture by reaction with an appropriate optically active compound, separating the diastereomers and converting the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of chiral HPLC column.

Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.

The present invention further relates to a process for the preparation of cefixime proxetil, wherein the process comprises,

a) Treating cefixime with 1-haloethyl isopropyl carbonate;

b) isolating cefixime proxetil; and

c) optionally purifying cefixime proxetil obtained in (b).

The present invention further relates to a process for the preparation of cefixime axetil, wherein the process comprises,

a) treating cefixime with 1-acetoxyethyl halide;

b) isolating cefixime axetil; and

c) optionally purifying cefixime axetil obtained in (b).

Halo/ halide means halogen such as iodo, chloro or bromo.

The reaction can be carried out in the presence of a solvent which is inert under the reaction conditions, for example dimethylacetamide, dimethylformamide,

dimethylsulphoxide, ethylacetate, acetonitrile, hexamethylphosphorictriamide, tetrahydrofuran, dichloromethane, and mixture thereof.

The reaction can be carried out in the presence of base.

The base may be organic or inorganic base or mixture thereof. Organic base may be for example pyridine, N- methylpiperidine, N-methyl pyrrolidine, triethylamine, tributylamine, N, N-dimethylaniline, dicyclohexylamine, N-methyl morpholine, collidine, lutidine, picoline, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

Inorganic base may be for example sodium carbonate, potassium carbonate and sodium bicarbonate.

The reaction can be carried out at a temperature in the range -50 ° to 100 °C, preferably at -10 °C to 50 °C, most preferably at about -10°C to about 0°C. The product may be purified by gravity column chromatography, flash chromatography, preparative HPLC.

The term 'substantially pure' means that the compound is at least 90% pure as determined by HPLC analysis.

In another embodiment, the present invention provides cefixime proxetil that is substantially pure.

In another embodiment, cefixime proxetil of present invention has a purity of more than 90 % by HPLC analysis.

In yet another embodiment, cefixime proxetil of present invention has a purity of more than 95 % by HPLC analysis. In another embodiment, cefixime proxetil of present invention has a purity of more than 97 % by HPLC analysis.

In another embodiment, cefixime proxetil of present invention has a purity of more than 99 % by HPLC analysis.

In yet another embodiment, the present invention provides cefixime proxetil that is substantially free from the compound of formula III as an impurity.

Formula III

'Substantially free' means less than 1% of the compound of formula III is present as an impurity.

In another embodiment, the present invention provides cefixime proxetil containing less than 0.5 % of the compound of formula III as an impurity. In another embodiment, the present invention provides cefixime proxetil containing less than 0.2 % of the compound of formula III as an impurity.

In another embodiment, the present invention provides cefixime proxetil containing less than 0.1 % of the compound of formula III as an impurity.

In another embodiment, the present invention provides cefixime axetil that is substantially pure.

In another embodiment, cefixime axetil of present invention has a purity of more than 90 % by HPLC analysis.

In yet another embodiment, cefixime axetil of present invention has a purity of more than 95 % by HPLC analysis. In yet another embodiment, the present invention provides cefixime axetil that is

la IV as an impurity.

Formula IV

'Substantially free' means less than 1% of the compound of formula IV is present as an impurity.

In another embodiment, the present invention provides cefixime axetil containing less than 0.5 % of the compound of formula IV as an impurity.

In another embodiment, the present invention provides cefixime axetil containing less than 0.2 % of the compound of formula IV as an impurity. In another embodiment, the present invention provides cefixime axetil containing less than 0.1 % of the compound of formula IV as an impurity.

The present invention further relates to a process for the preparation of amorphous form of compound of formula II, wherein the process comprises,

a) forming a solution of compound of formula II in a solvent;

b) isolating compound of formula II from the solution by using a suitable separation technique; and

c) collecting amorphous form compound of formula II. The solvent may comprise at least one of water, alcohol (such as methanol, ethanol, propanol, isopropanol), nitrile (such as acetonitrile), N, N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, ketone (such as acetone), ester (such as ethyl acetate), and chlorinated hydrocarbons (such as dichloromethane).

The suitable separation technique may comprise at least one of lyophilization (freeze drying), spray drying, thin film drying (rotary evaporation)and agitated thin film drying.

In another embodiment, the present invention provides an amorphous cefixime proxetil.

In yet another embodiment, the present invention provides an amorphous cefixime proxetil which is characterized by X-ray diffraction spectrum substantially as shown in figure 1. In another embodiment, the present invention provides an amorphous cefixime axetil.

In yet another embodiment, the present invention provides an amorphous cefixime axetil which is characterized by X-ray diffraction spectrum substantially as shown in figure 2. The compound of formula II or pharmaceutically acceptable salt thereof may be formulated as compositions for oral or parenteral administration in conventional manner, with the aid of any necessary pharmaceutical carriers or diluents. The compositions are conveniently prepared as tablets, capsules or sachets, advantageously in unit dose form, and may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants and wetting agents. Tablets may be coated in conventional manner. The active compounds may further be formulated in rectal compositions such as suppositories or retention enemas.

The compositions may contain from 0.1-99% of compound of formula II or

pharmaceutically acceptable salt thereof, depending on the method of administration. Compositions in dosage unit form conveniently contain 50-500 mg of the active ingredient (calculated as cefixime). Doses employed for adult human treatment will typically be in the range 100-1000 mg per day, e.g. 400 mg per day, (calculated as cefixime), although the precise dose will depend on the frequency of administration.

The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.

Experimental

HPLC Method for purity determination:

Inertsil ODS 3 V, 5 micron, 250x4.6 mm column.

Mobile phase A: 0.05 M ammonium acetate in water. 50 ml buffer replaced with methanol and adjusted to pH 4.2 with orthophosphoric acid.

Mobile phase B : 0.05 M ammonium acetate in water. 500 ml buffer replaced with methanol and adjusted to pH 4.2 with orthophosphoric acid. Injection volume: 20 μΐ..

Sample preparation: 5 mg in 5 ml diluent.

Diluent is prepared by mixing a and b in ratio of 39:61.

a. 0.908 g potassium dihydrogen phosphate in 100 ml water

b. 2.38 g disodium hydrogen phosphate in 100 ml water

Flow rate: 1.5 ml/minute. HPLC column was used at ambient temperature. FTIR spectrum was recorded using a Perkin Elmer Precisely Spectrum 400 instrument using KBr method.

^JHNMR spectrum was recorded using a 400 MHz Bruker AVANCE-II. Mass spectrum was recorded using a Waters Xevo G2 DT of mass spectrometer.

The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X'Pert PRO diffractogram with Cu Ka radiation (λ = 1.54060 A), running at 45 kV and 40 mA.

Example 1

Preparation of cefixime proxetil Cefixime (25 g) was dissolved in N, N- dimethylacetamide (160 ml) and the mixture was cooled to -5 °C. Sodium carbonate (3 g) was added. A solution of racemic 1-iodoethyl isopropylcarbonate (14.2 g) in N, N- dimethylacetamide (15 ml) was added at -5 to 0 °C in 35 minutes. The reaction mixture was stirred for about 2 hours at the same temperature. This reaction mixture was then added to a solution of sodium thiosulfate (2.5 g) in water (500 ml). The solid was filtered, washed with water (100 ml) and dried in a vacuum oven. Dry weight = 12.3 g.

HPLC purity: 72.6 % Example 2

Preparation of cefixime proxetil

Cefixime (50 g) was dissolved in N, N- dimethylacetamide (300 ml) and the mixture was cooled to -5 °C. Sodium carbonate (5.8 g) was added. A solution of racemic 1-iodoethyl isopropylcarbonate (28 g) in N, N- dimethylacetamide (50 ml) was added at -5 to 0 °C in 60 minutes. The reaction mixture was stirred for about 2 hours at the same temperature. This reaction mixture was then added to a solution of sodium thiosulfate (5 g) in water (1000 ml). The solid was filtered, washed with water (250 ml) followed by

diisopropylether (100 ml) and dried in a vacuum oven. Dry weight = 22 g.

HPLC purity: 69.0 %

Example 3

Purification of cefixime proxetil by preparative HPLC:

Cefixime proxetil obtained in example 1 and 2 was purified by preparative HPLC.

Mobile phase preparation:

Mobile phase A - 0.05 M ammonium acetate in water.

Mobile phase B - Acetonitrile

Conditions: Column - YMC Pack ODS-A HG (20X 250 mm) 10 μ .

Flow rate: 25 ml/minute

Wavelength- 254 nm

Sample preparation: 175 mg dissolved in methanol (2 ml). Fractions containing cefixime proxetil were collected using 30% -40 % Mobile phase B in Mobile phase A as eluent. Collected fractions were concentrated on rotary evaporator and concentrated solution was passed through gradient column using 40% - 60 % acetonitrile in water as eluent. Fractions containing cefixime proxetil were collected, concentrated and lyophilized. Cefixime proxetil (3g) having HPLC purity of 99.35 % was isolated.

IR (in KBr)cm^_1:3430, 3202, 2986, 2937, 1760, 1672, 1617, 1584, 1537, 1425, 1376, 1315, 1277, 1220, 1159, 1099, 1075, 1039, 995, 905, 813, 788, 741.

*H NMR (DMSO d₆ + D₂0) δ: 1.24-1.20 (6H, d), 1.48-1.46 (3H, d), 3.57-3.52 (1H, m), 3.92-3.84 (1H, m), 4.31 (2H, s), 4.82-4.74 (1H, m), 5.20-5.16 (1H, d), 5.71-5.32 (2H, m), 5.81-5.77 (1H, m), 6.84-6.76 (3H, m).

Mass (m/z): 584.30 (M+H)⁺, 1167.62 (2M+H)⁺ Example 4

Preparation of cefixime axetil

Cefixime (25 g) was dissolved in N, N- dimethylacetamide (125 ml) and sodium carbonate (3.2 g) was added. The mixture was cooled to -5 °C. A solution of racemic 1- acetoxyethyl bromide (9.2 g) in N, N- dimethylacetamide (25 ml) was added at -5 to 0 °C in 30 minutes. The reaction mixture was stirred for about 4 hours at the same temperature. Water (500 ml) was added and stirred for 60 minutes. The solid was filtered, washed with water (250 ml) and dried in a vacuum oven. Dry weight = 13.3 g.

Example 5

Preparation of cefixime axetil

Cefixime (25 g) was dissolved in N, N- dimethylacetamide (125 ml) and sodium carbonate (3.2 g) was added. The mixture was cooled to -5 °C. A solution of racemic 1- acetoxyethyl bromide (9.2 g) in N, N- dimethylacetamide (25 ml) was added at -5 to 0 °C in 30 minutes. The reaction mixture was stirred for about 4 hours at the same temperature. Water (500 ml) was added and stirred for 60 minutes. The solid was filtered, washed with water (250 ml) and dried in a vacuum oven. Dry weight = 18.5 g. Example 6

Purification of cefixime axetil

Cefixime axetil (31 g) obtained in example 1 and 2 was stirred in acetonitrile (465 ml) for one hour. The undissolved solid was filtered off and washed with acetonitrile (62 ml). The filtrate was treated with activated carbon (1.5 g) and stirred for 30 min at room temperature. The mixture was filtered and the filtrate was concentrated on rotary evaporator to obtain a solid.

Weight = 24.6 g.

HPLC purity: 42.65 %

Example 7

Purification of cefixime axetil by preparative HPLC:

Cefixime proxetil obtained in example 6 was purified by preparative HPLC.

Mobile phase preparation:

Mobile phase A - 0.05 M ammonium acetate in water.

Mobile phase B - Acetonitrile

Conditions: Column - YMC Pack ODS-A HG (20X 250 mm) 10 μ.

Flow rate: 25 ml/minute

Wavelength- 254 nm

Sample preparation: 4 g + 40 ml methanol + 20 ml mobile phase A. 1.5 ml injected.

Fractions containing cefixime axetil were collected using 40 % Mobile phase B in Mobile phase A as eluent. Collected fractions were concentrated on rotary evaporator and concentrated solution was passed through gradient column using 70% - 95 % acetonitrile in water as eluent. Fractions containing cefixime proxetil were collected, concentrated and lyophilized. Cefixime axetil (2g) having HPLC purity of 96.95 % was isolated.

IR (in KBr)cm ¹: 3430,1775, 1666, 1584, 1536, 1425, 1376, 1315, 1237, 1212, 1158, 1074, 1039, 995, 944, 864, 813, 726.

^XH NMR (DMSO d₆ + D₂0) δ: 1.46-1.41 (3H, m), 2.04-2.02 (3H, s), 3.56-3.52 (IH, m), 3.91-3.84 (IH, m), 4.32 (2H, s), 5.21-5.16 (IH, m), 5.40-5.35 (IH, m), 5.69-5.64 (IH, m), 5.81-5.77 (IH, m), 6.98-6.71 (3H, m).

Mass (m z): 540.24 (M+H)⁺, 1079.50 (2M+H)⁺

Claims

Formula II

wherein R = -OCH(CH₃)₂, -CH₃;

or a pharmaceutically acceptable salt thereof.

Claim 2. Substantially pure cefixime proxetil or a pharmaceutically acceptable salt thereof.

Claim 3. Cefixime proxetil or a pharmaceutically acceptable salt thereof, that is

la III as an impurity.

Formula III

Claim 4. An amorphous cefixime proxetil or a pharmaceutically acceptable salt thereof.

Claim 5. The amorphous cefixime proxetil or pharmaceutically acceptable salt thereof of claim 4 characterized by X-ray diffraction spectrum substantially as shown in figure 1.

Claim 6. Substantially pure cefixime axetil or a pharmaceutically acceptable salt thereof.

Claim 7. Cefixime axetil or a pharmaceutically acceptable salt thereof, that is

la IV as an impurity.

Formula IV

Claim 8. An amorphous cefixime axetil or a pharmaceutically acceptable salt thereof.

Claim 9. The amorphous cefixime axetil or pharmaceutically acceptable salt thereof of claim 8 characterized by X-ray diffraction spectrum substantially as shown in figure 2.

Claim 10. A pharmaceutical composition comprising a therapeutically effective amount of compound of formula II or a pharmaceutically acceptable salt thereof of claim 1, together with a pharmaceutically acceptable carrier or diluent.

Claim 11. The pharmaceutical composition of claim 10, which is adapted for oral or parenteral administration.

Claim 12. A method of treating a bacterial infection in subject, comprising administering to said subject a therapeutically effective amount of compound of formula II or a pharmaceutically acceptable salt thereof of claim 1.

Claim 13. The method of claim 12, wherein the infection is caused by gram-positive bacteria.

Claim 14. The method of claim 12, wherein the infection is caused by gram- negative bacteria.

Claim 15. A process for the preparation of cefixime proxetil, wherein the process comprises,

a) treating cefixime with 1-haloethyl isopropylcarbonate;

b) isolating cefixime proxetil; and

c) optionally purifying cefixime proxetil obtained in (b).

Claim 16. A process for the preparation of cefixime axetil, wherein the process comprises,

a) treating cefixime with 1-acetoxyethyl halide;

b) isolating cefixime axetil; and

c) optionally purifying cefixime axetil obtained in (b).

Claim 17. A process for the preparation of amorphous form of compound of formula II, wherein the process comprises,

a) forming a solution of compound of formula II in a solvent;

c) collecting amorphous form compound of formula II.

Claim 18. The process according to claim 17, wherein the solvent comprises at least one of water, alcohol, nitrile, N, N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, ketone, ester, and chlorinated hydrocarbon.

Claim 19. The process according to claim 17, wherein the suitable separation technique comprises at least one of lyophilization, spray drying, thin film drying and agitated thin film drying.