PROCESSES FOR PREPARING MARBOFLOXACIN

INTRODUCTION

The present invention relates to processes for the preparation of marbofloxacin and its intermediate compounds.

Marbofloxacin is 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,2,1]benzoxadiazine-6-carboxylic acid, and is structurally represented by Formula (I).

Marbofloxacin is a fluoroquinolone derivative with antibacterial activity useful as an effective antibacterial agent.

U.S. Patent No. 4,801,584 ("the '584 patent") discloses marbofloxacin, its pharmaceuticalty acceptable salts, and processes for its preparation, wherein one of the processes involves reacting 8-hydroxy-6,7*difluoro-1-(methylamino)-4-oxo-4H-qulnoline-3-carboxylic acid with para-formaldehyde in dioxane to obtain 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[3,2,1-ij][4,2,1]benzoxadiazine-6-carboxyllc acid, which is condensed with N-methylpiperazine in the presence of dry pyridine to give marbofloxacin.

The '584 patent also discloses another process for the preparation of marisofloxacin in which one of the process steps involves the aminatlon of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-quinoline-3-carboxylate using 0-(2,4-dinitrophenyl) hydroxylamine, which Is subsequently converted into 8-hydroxy-6,7-dlfluoro-1-(methylamino)-4-T)xo-4H'quinollne-3-carboxyllcacid.

Research Disclosure No. 1988, 291, 548-551 discloses an alternative route starting from commercially available 2,3,4,5-tetrafluorobenzoic acid. The process disclosed therein involves reacting ethyl 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-4H-quinoline-3-carboxylate with benzyl alcohol to obtain ethyl 8-benzyloxy-6-fluoro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate, which is deprotected to obtain ethyl 8-hydroxy-6-fluoro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate, which is hydrolyzed to obtain 8-hydroxy-6-fluoro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylic acid, which is cyclized to produce marbofloxacin.

U.S. Patent No. 5,892,040 ("the '040 patent") discloses a process for the preparation of marbofloxacin that involves:

a) reacting alkyl 6,8-difluoro-1 -(N-methylformamido)-7-(4-methyl-1 -
piperazinyl)-4-oxo*4H-quinoline-3-carboxylate with an alkali metal hydroxide in an
aqueous medium to form an alkali metal 8*hydroxy-6-fluoro-1-(methylamino)-7-(4-
methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate;

b) cyclizing the reaction product of Step a) with formic acid and formaldehyde
to obtain marbofloxacin dihydroformate salt; and

c) neutralizing the marbofloxacin dihydroformate salt with an aqueous base.

According to the process described in the '040 patent, Step a) involves the
use of potassium hydroxide in an aqueous medium at a temperature of about 80-120° C, preferably at reflux temperature, from about 20-100 hours. The reaction goes to practical completion by utilizing at least about 10 mole equivalents of alkali metal hydroxide and increasing the reaction time to 70-100 hours. The alkali metal hydroxide is preferably present in a concentration of about 10-20% by weight of the aqueous solution.

Italian Patent 1313683 discloses a process for the preparation of marbofloxacin. The process disclosed therein involves reacting ethyl 6,8-difluoro-1-{N-methylformamido)-7-{4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate with benzyl alcohol and sodium methoxide to obtain sodium 8-benzyloxy-6-fluoro-1-(methylamino)*7*(4-methyl-1-piperazinyl)-4-oxo-4H-quino!ine-3-carboxylate, which on deprotection gives 8-hydroxy-6-fluoro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylic acid, which is further cyclized with formaldehyde and formic acid to obtain marbofloxacin dihydroformate salt that may be hydrolyzed to produce marbofloxacin.

Despite existence of various process disclosures as discussed above, there is still an ongoing need for industrially amenable and cost effective processes for the preparation of marbofloxacin and its intemriediates.

SUMMARY OF THE INVENTION

The present invention includes processes for the preparation of marbofloxacin, which processes comprise one or more of the following steps, individuaily or in the sequence recited:

a) reacting the compound of Formula (II),

wherein R Is a straight or branched chain Ci^ alkyl and PG is an amino protecting group, with N-methylpiperazine to obtain a compound of Formula (III);

b) optionally reacting the compound of Formula (111) with an acid to obtain an acid addition salt thereof;

c) reacting the compound of Formula (III) or an acid addition salt thereof with an alkali metal hydroxide in the presence of a non-aqueous medium for about 4-15 hours to produce a compound of Formula (IV),

wherein M is an alkali metal; and

d) converting the compound of Formula (IV) into marbofloxacin.

The present invention includes intermediate compounds of Formulae (IHb) and (iVb) or their salts,


DETAILED DESCRIPTION OF THE INVENTION

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25ºC and about normal pressure unless otherwise designated. All temperatures are In degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. The terms "about," "generally," "substantially," and the like, are to be construed as modifying another term or value such that it is not an absolute, but does not read on the prior art, as defined by the circumstances and context as understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value. Whether so indicated or not, all values recited herein are approximate.

The present invention includes processes for the preparation of marbofloxacin, which processes comprise one or more of the following steps, individually or in the sequence recited:


wherein R is a straight or branched chain C1-4alkyl and PG is an amino protecting group, with N-methylpiperazine to obtain a compound of Formula (III);

b) optionaily reacting the compound of Formula (III) with an acid to obtain an acid addition salt thereof;

c) reacting the compound of Formula (III) or an acid addition salt thereof with an alkali metal hydroxide in the presence of a non-aqueous medium for about 4-16 hours to produce a compound of Fomiula (IV),

wherein M is an alkali metal; and

d) converting the compound of Formula (IV) into marbofloxacin.

Step a) involves reacting the compound of Formula (II), wherein R is a straight or branched chain C1-4 alkyl and PG is an amino protecting group, with N-methyl piperazine to obtain a compound of Formula (III).

Suitable amino protecting groups include and are not limited to tert-butyloxycarbonyl (Boc), phenoxycarbonyl, benzyloxycarbonyl. p-nitrobenzyloxycarbonyl and the like.

Suitable solvents that may be used in the above reaction include and are not limited to acetonitrile, toluene, and the like.

For example, the reaction may be carried out by combining a compound of Formula (II) in acetonitrile with N-methylpiperazine at room temperature and heating the reaction mass to a temperature in the range of about 70-100° C, or about 80-90° C, distilling the reaction mass at a temperature in the range of 60-90° C, or 60-65°C. and recovering the condensation product.

After the completion of the reaction, the condensation product may be recovered or isolated by adding a suitable solvent to the reaction mass.

Suitable solvents used for recovering the condensation product after the completion of the reaction include and are not limited to dichloromethane, ethyl acetate, hexane, diisopropyl ether, methyl tert butyl ether, water, and mixtures thereof-

The amount of solvent used in the above isolation may range between 2 to 10 volumes with respect to the compound of Formula (II). For example, the amount of solvent used may be about 2.5 volumes with respect to the compound of Formula (II).

Step b) involves optionally reacting the compound of Formula (III) with an acid to obtain an acid addition salt thereof.

Suitable acids that may be used in the above reaction include and are not limited to mineral acids, such as, for example, HCI, H2SO4, HNO3, and HBr. For example, the acid may be HCI.

The acid used in the reaction may have a concentration of about 5-20% or about 8-14%. The amount of acid used may be about 2-10 equivalents or about 3-8 equivalents with respect to the compound of Formula (II). For example, the amount of acid used may be about 2-10 equivalents of a 5-20% acid or about 3-8 equivalents of an 8-14% acid.

The temperature for the reaction of Step b) may range from about 0° to about 11 OX.

For example, the temperature of the reaction may be ranged from 80-100° C for a time sufficient to complete the reaction.

The obtained acid salt may be isolated or used in situ for the next step.

Step c) involves reacting the compound of Formula (III) or an acid addition salt thereof with an alkali metal hydroxide in the presence of a non-aqueous medium for about 4-15 hours to produce a compound of Formula (IV).

Suitable alkali metal hydroxides include and are not limited to lithium hydroxide, potassium hydroxide, sodium hydroxide, and cesium hydroxide.

The alkali metal hydroxide used in the above reaction may be used in an amount between 2-20 equivalents, 5-15 equivalents, 11-13 equivalents, or 10 equivalents with respect to the compound of Formula (III).

The reaction may be carried out In a non-aqueous medium. The non-aqueous medium may be selected from any glycol medium, such as, for example, ethylene glycol or a mixture of glycols with other solvents like alcohols, ketones, nitriles and the like.. The present inventors have surprisingly found that, by carrying out the reaction of Step c) in a non-aqueous medium, the time period for completion of the reaction is less than about 15 hrs.

The temperature of the reaction of Step c) may be in the range of 90-160°C, 120"135'C, or 115-125X. The time period to achieve the desired product yield and purity may range from about 4 to 16 hours.

For example, a compound of Formula (V) may be reacted with potassium hydroxide in ethylene glycol to produce potassium 8-hydroxy-6-difluoro-1-(N-methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate, which may be isolated or used in situ for the next step.

Step d) involves converting the compound of Formula (IV) to marbofloxacin.

For example, the compound of Formula (IV) may be converted to marbofloxacin through cyclization by treatment with aqueous formaldehyde in the presence of an acid to obtain marbofloxacin. Since, the compound of Formula (IV) maintains an acid-labile N-protecting group (e.g., tert-butyloxycarbonyl (BOC)), a suitable acid may be employed to remove it prior to cyclization.

Suitable acids for cyclization include and are not limited to organic acids, such as, for example para-toluenesulphonic acid; Inorganic acids, such as, for example, hydrochloric acid, sulfuric acid, and the like; and mixtures thereof.

In an embodiment, the acid used in the cyclization reaction may have a concentratioh of about 36-38% or about 35%. The amount of acid used may be about 1-5 volumes or about 2-3 volumes with respect to the compound of Formula (V). For example, the amount of acid used may be about 1-5 volumes of a 36-38% acid or about 2-3 volumes of a 35% acid.

The formaldehyde used in the cyclization reaction may have a concentration of about 37-41% or about 37%. The amount of formaldehyde used may be about 0.5--5 volumes or about 0.5-1.5 volumes with respect to the compound of formula

(V). For example, the amount of acid used may be about 0.5-5 volumes of 37-41% formaldehyde or about 0.5-1.5 volumes of 37% formaldehyde.

The temperature for cycllzation reaction may range from about O^C to about 110X, orOXto75X.

The product of Step d) may be an acid salt, which may be neutralized to the corresponding acid by means of an aqueous base, such as ammonia, an alkali metal hydroxide, or an alkyl amine, in combination with solvents, such as methanol, Isopropyi alcohol, ethanol, and acetone. Suitable alkali metal hydroxides include and are not limited to potassium hydroxide and sodium hydroxide. Suitable alkyl amines Include and are not limited to C1-4 alkyl amines, such as, for example, triethylamine and tributylamine.

The temperature for neutralization reaction may be range from about O^'C to about 120''C. The time period to achieve the desired product yield and purity ranges from about 1 to about 110 hours.

For example, hydrochloric acid may be added to the reaction mass containing a compound of Formula (V) followed by the addition of aqueous formaldehyde. After being stirred and heated to about 70°C, the reaction mass may be cooled, dried, and neutralized with ammonia to obtain marbofloxacin of Formula (I).

In an embodiment, the present invention includes processes for the preparation of marbofloxacin, which processes comprise one or more of the following steps, individually or in the sequence recited: a) reacting the compound of Formula (lla),

wherein R is a straight or branched chain C1-4 alkyl and Boc is tert-butyloxycarbonyl, with N-methylpiperazine to obtain a compound of Formula (Ilia)


b) reacting alkyl 6,8-difluorO'1-(tert-butyloxycarbonyl(methyl)amino)-7-(4-
methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate of Formula (Ilia) with an
alkali metal hydroxide to obtain an alkali metal 8-hydroxy-6-fluoro-1-(tert-
butyloxycarbonyl(methyl)amino)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-qulnoline-3-
carboxylate of Formula (IVa);

c) converting the compound of Formula (IVa) to produce marbofloxacin.
The present invention includes intermediate compounds of Formula (lllb) and (IVb) or their salts,

Ethyl 6,8-difluoro-1-(tert-butyloxyGarbonyl(methyl)amino)-7-(4-methyl-1-
piperazinyl)-4-oxo-4H-quinollne-3-carboxylate of Formula (111b) may be prepared according to^h^rocess described in Example 2 herein below.

Potassium 6.8-difluoro-1-(tert-butyloxycarbonyl{methyl)amino)-7-(4-methy!-1-pipera2inyl)-4-oxo-4H-quinoline-3-carboxylate of Formula (IVb) may be prepared according to the process described in Example 3 herein below.

Certain specific aspects and embodiments will further be described by the following examples, being provided only for the purposes of illustration and not to be construed as limiting in any manner,

EXAMPLES

Example 1; Preparation of ethyl 1-(tert-butyloxycarbonyl (methyl)amino)-6,7,8-trifluoro-4-oxo-4H-quinoline-3-carboxylate of Fonnula (Mb)

a) Preparation of the BOC side chain (Tert-butyi 1-methylhydrazlne carboxylate)

Water (750 mi) and methyi hydrazine sulphate (50 g) are mixed and the reaction mass is cooled to 5-10°C. The pH is adjusted to 8-10 by adding sodium hydrogen carbonate (250 g) at 5-1 O^C. Boc anhydride (83.2 g) in tetrahydrofuran (125 ml) Is added at 5-10°C over 1 hr. The temperature is raised to 25-30X and maintained for 10-12 hrs. The layers are separated and the aqueous layer is extracted with ethyl acetate (2x100 ml) at room temperature. The organic layer is dried over sodium sulphate and distilled completely under vacuum at 50-60*'C. The oily product obtained is cooled.

Yield: 43.10 g (85%).

b) Preparation of (Z)-tert-butyl 2-(3-ethoxy-3-oxo-2-(2.3.4,5-tetrafluorobenzoyl)prop- 1-enyl)-1-methylhydrazinecarboxylate.

Methanol (180 ml) and ethyl 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (60 g) are charged in to a round-bottom flask at room temperature. The mass is cooled to 0-10*C. Tert-butyl 1-methylhydrazine carboxylate (30.12 g) in'methanol (120 ml) is slowly added at 0-10'C over a period of 30-60 minutes. The reaction mixture is stirred for 1 hour at 0-10'C and the product Is filtered. The wet cake is washed with chilled methanol (60 ml) and the product obtained is dried in an oven at 60-65"C for 2-3 hrs.

Yield: 67.0 g (85%)

c) Preparation of ethyl 1-(tert-butyloxycarbonyl(methyl)amino)-6,7,8-trifluoro-4-oxo-4H-quinoline-3-carboxylate of Formula (lib)

Dimethyl formamide (150 ml) and (Z)-tert-butyl 2-(3-ethoxy-3-oxO"2-(2,3,4,5-tetrafluorobenzoyl)prop-1*enyl)-1-methylhydrazinecarboxylate (60 g) are charged into a round-bottom flask. Potassium carbonate (21.7 g) is added. The reaction mass is heated to 75-80X and maintained for 1-2 hrs. Then the reaction mass is poured into ice cold water (600 ml), stirred for 1 hour at 5-10"C, filtered at 5-1 O^C, and washed with chilled water. The obtained solid is suction dried and then dissolved in DCM (240 ml). The solution is dried with sodium sulphate (24 g). The DCM is evaporated completely at 40-45°C. The residue obtained is cooled to room temperature. TBME (120 ml) is added and stin-ed for 30 minutes at room temperature. The solid is filtered and washed with TBME (60 ml). The material is suction dried and dried at SO-eOX for 2-3 hours.

Yield: 48.5 g (85%).

Example 2: Preparation of ethyl 1-(tert-butyloxycarbonyl(methyl)amino)-6,8-difluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H-quinoline-3-carboxylate of Formula (Itib)

Acetonitrile (112.5 ml) is charged into a round-bottom flask at room temperature and the compound of Formula (lib) (45 g) is added. N-methyl piperazine (54 g) is added. The reaction mass is heated to reflux at 80-90''C and maintained at reflux for 1 fTr. The solvent Is distilled completely under vacuum at 60-65X and the residue is dissolved in DCM (225 ml). Demlnerallzed water (-394 ml) is added and the layers are separated. The DCM layer is washed with demineralized water (2x394 ml) at room temperature, collected, washed with water again, and dried over sodium sulphate (18 g). The DCM layer is distilled off completely at 40-45°C. TBME (135 ml) Is added and stirred for 30 minutes at 25-30°C, cooled to 0-5°C, the solid mass is filtered and the wet cake is washed with TBME (45 ml). The material is dried at 50-60°C to obtain the title compound.

Yield: 43.2 g (80%).

A compound of Formula (IIIb) (15 g) and potassium hydroxide (7.5 g) are charged into a round-bottom flask at room temperature. Demlneralized water (75ml) is added at room temperature, The reaction mass is heated to 100^0 and distilled azeotropically to remove ethanol and water to a constant boiling point. Potassium hydroxide (17 g) in water (19.5 ml) is added at 40-45ºC. The reaction mass is heated to 104X and maintained for 72 hrs to form the compound of Formula (IVb). Demlneralized water (19.5 ml) is added at g0-95X. Concentrated hydrochloric acid (45 ml) is charged into at 40-45*C and stirred for 30 minutes at 40-45'*C. Formaldehyde (6 ml) is charged into the round-bottom flask at 40-45*C and stirred for 30 minutes. The reaction mass is heated to 70-75*'C, stirred for 30 minutes, cooled to 0-5'C, and stirred for another 30 minutes. The solid is filtered and washed with demlneralized water (7.5 ml) and dried. The solid is taken into a round-bottom flask at room temperature. Ethanol (52.5 ml) and demlneralized water (19.5 ml) are added. 25% aqueous ammonia solution (7.5 ml) is slowly added over 30 minutes. The turbid solution is filtered through a glass fiber filter at room temperature. The filtrate is collected and distilled under vacuum at 50-55^C to 30 ml. The suspension is cooled to O-S'^C and maintained for 30 minutes. The solid is filtered and wash with ethanol (33 mi). The material is dried at 50°C under vacuum for 18 hrs to yield the title compound.

Yield: 2.3 g.

We Claim:

1. A process for the preparation of marbofloxacin comprising the steps of:

a) reacting the compound of Formula (II),

wherein R is a straight or branched chain Ci^ alkyl and PG is an amino protecting group, with N-methylpiperazine to obtain a compound of Formula (III);

b) optionally reacting the compound of Formula (III) with an acid to obtain an acid addition salt thereof;

c) reacting the compound of Formula (III) or an acid addition salt thereof with an alkali metal hydroxide in the presence of a non-aqueous medium for about 4-15 hours to produce a compound of Formula (IV),

wherein M is an alkali metal; and

d) converting the compound of Formula (IV) into marbofloxacin,

2. The process of claim 1, wherein the amino protecting group used in the step a) are selected from tert butyloxycarbonyl (Boc), phenoxycarbonyl, benzyloxycarbonyl and p-nitro benzyloxycarbonyl.

3. The process of claim 1, wherein the acid used in the step b) are selected from HCI. H2SO4. HNO3. and HBr.

4. The process of claim 1, wherein the alkali metal hydroxide used in the step b) are selected from lithium hydroxide, potassium hydroxide, sodium hydroxide and cesium hydroxide and the non-aqueous medium is selected from ethylene glycol or mixtures of glycols with other solvents.

5. The process of claim 1, wherein in the step d), the compound of Formula (IV) is converted into marbofloxacin by treatment with aqueous formaldehyde solution in the presence of an acid.

6. A process for the preparation of marbofloxacin comprising the steps of:

a) reacting the compound of Formula (lla),

wherein R is a straight or branched chain C^^ all