DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
Besifloxacin Hydrochloride and intermediates thereof,which is represented by the following
structural formula-I.
5
Formula-I
Background of the Invention:
10 Besifloxacin Hydrochloride, is a new generation of fluoroquinolones, having chemical name
as 7- [(3R) -3- aminoazepan-1-yl] -8- chloro -1- cyclopropyl -6- fluoro -4- oxoquinoline -3-
carboxylic acid hydrochloride.
Besifloxacin hydrochloride is marketed as Besivance® (Besifloxacin ophthalmic
suspension) 0.6% sterile ophthalmic drops for the treatment of bacterial conjunctivitis
15 developed by Bausch & Lomb Inc and approved by the US FDA in May 2009.
Besifloxacin hydrochloride has shown very good bactericidal effects in clinical trials
and has a broad-spectrum antibacterial activity against ocular pathogens that cause bacterial
conjunctivitis. It is the first drug specifically developed for ophthalmic use of non-systemic
fluoroquinolones. Besifloxacin hydrochloride is an 8-chlorofluoroquinolone drug with N20
cyclopropyl group, which acts against gram-positive and negative bacteria by inhibiting
bacterial DNA gyrase and topoisomerase IV. DNA gyrase is a key enzyme required for
bacterial DNA replication, transcription, and repair; topoisomerase IV is a key enzyme
required for chromosomal DNA separation during bacterial division.
Besifloxacin hydrochloride is first disclosed in US Patent No. 5447926 (herein after
25 designated as US’926). The synthetic process described in this patent is carried out by
reacting 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid of
Formula-5 with (R)-azepan-3-amine in acetonitrile followed by chlorination in presence of
3
sulfuryl chloride to give besifloxacin a compound of Formula-1a, which is purified through
column chromatography. The reaction sequence is shown in scheme-I.
Scheme-I
5
The major drawback of the above said process is poor yield and low purity of besifloxacin.
The reaction method disclosed in US’926, requires large time for completion, hence not
10 suitable for plant scale production. Also use of column chromatography for purification
purpose is neither economical nor environmental friendly, especially when performed at large
scale.
PCT application No. WO2008/045673, describes a process for preparation of
Besifloxacin , which encompasses use of intermediate, 8-chloro-l-cyclopropyl- 6-fluoro-7-
15 (3-((3- nitro benzylidene) amino) azepan-l-yl )-4- oxo -l,4- dihydroquinoline -3-carboxylic
acid as shown in Scheme-II.
Scheme-II
20 There are various processes reported for the preparation of quinonilinic acid
derivatives such as 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
4
compound of formula-5, compound of formula-A, which are key intermediate in the preparation of Besifloxacin hydrochloride the compound of formula-I. The US4588726 (herein after US’726) disclosed a process for preparation of 1-cyclo propyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid compound of formula-5. The US’726 generically disclosed a process for preparation of compound of formula-5 5, which involves isolation of each intermediate, and involves various purification's. The disclosed synthetic process is represented in a schematic way in Scheme-III. Scheme-III:
10 There are various processes reported for 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid compound of formula-5, which are having more number of steps, impurities, purifications and are time consuming. Based on drawbacks of the prior art processes, there is a need for providing an improved process for the preparation of 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro 15 quinoline-3-carboxylic acid of formula-5 and formula-I which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords high pure Besifloxacin hydrochloride and intermediates thereof. The present invention provides an improved process for preparation of 1-cyclopropyl-20 6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid compound of formula-5, also
5
process for preparation of Besifloxacin hydrochloride and intermediates thereof, which is efficient, industrially viable and cost effective.
Brief Description:
The first aspect of the present invention is to provide a one pot process for the preparation of compound of formula-5. 5
The second aspect of the present invention is to provide an improved process for the preparation of compound of formula-I.
Brief description of the drawings: Figure 1: Illustrates the PXRD pattern of Besifloxacin hydrochloride obtained by the example-4 10 Figure 2: Illustrates the IR absorption spectrum of Besifloxacin hydrochloride obtained by the example-4
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, 15 cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl 20 acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as 25 acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoro ethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol,
6
diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the
like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or
organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
5 potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as
sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like;
10 alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the
like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl
ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine
(DMAP), N-methyl morpholine (NMM), or mixtures thereof.
15 The term “reducing” agent used in the present invention refers suitable reducing reagents are
selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C,
Ray-nickel;
The term “protecting” agent / group (PG) used in the present invention refers to a suitable
protecting reagents that are selected selected from di-tert-butyl dicarbonate, chlorobenzyl
20 formate, benzoylchloride, benzylbromide, benzylchloride, acetylchloride, fluorenyl
methyloxy carbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present
invention refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammonium
bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl
ammonium chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium chloride;
25 The first aspect of the present invention provides a one pot process for the preparation of
compound of formula-5
Formula-5
7
comprising of:
a) Reacting a compound of formula-1
Formula-1
Where 5 R is alkyl, such as methyl, ethyl, propyl, butyl
with 1,1-dimethoxy-N,N-dimethylmethanamine in suitable solvent to provide compound of
formula-2, in-situ reacting with cyclopropylamine to provide compound of formula-3,
10
Formula-2 Formula-3
further cyclising the compound of formula-3 in presence of a base, optionally phase transfer
catalyst to get compound of formula-4, hydrolyzing the compound of formula-4 in-situ with
15 a suitable reagent to get compound of formula-5,
Formula-4 Formula-5
b) optionally purifying in a suitable solvent to get pure compound of formula-5.
wherein in step-a), b) the suitable solvent is selected from hydrocarbon solvents” such as n20
hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl
cyclohexane, m-, o-, or p-xylene and the like; “polar-aprotic solvents such as dimethyl
acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl
pyrrolidone (NMP) and thereof; polar solvents” such as water or mixtures thereof. suitable
8
acid reagents refer as hydrochloric acid, hydrobromic acid or inorganic bases thereof;
suitable base reagents refer as sodium hydroxide, potassium hydroxide, lithium hydroxide
and the like; suitable “phase transfer catalyst (PTC)” refer as triethylbenzyl ammonium
chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl
5 ammonium acetate, methyl tributyl ammonium chloride, tetrabutyl ammonium hydroxide, tri
butylbenzylammonium chloride thereof; suitable temperature is 0-100°C.
The preferred embodiment of the present invention provides one pot process for the
preparation of compound of formula-5.
10
Formula-5
comprising of,
a) reacting the compound of formula-1a
15 Formula-1a
with 1,1-dimethoxy-N,N-dimethylmethanamine in toluene to provide compound of formula-
2a,
20 Formula-2a Formula-3a
In-situ condensation with cyclopropyl amine to provide compound of formula-3a, further
cyclization with sodium hydroxide, tetrabutyl ammonium bromide in water to provide
9
compound of formula-4a, in-situ hydrolyzed with hydrochloric acid get compound of
formula-5,
Formula-4a Formula-5
5
The second aspect of the present invention provides an improved process for the
preparation of compound of formula-I.
Formula-I
10 comprising of:
a) Reacting the compound of formula-1
Formula-1
with 1,1-dimethoxy-N,N-dimethylmethanamine in suitable solvent to provide compound of
15 formula-2, in-situ reacting with cyclopropylamine to provide compound of formula-3,
Formula-2 Formula-3
further cyclised in presence of a base, phase transfer catalyst to get compound of formula-4,
in-situ hydrolyzed with suitable reagent to get compound of formula-5.
10
Formula-4 Formula-5
b) reacting (R)-azepan-3-amine dihydrochloride with 3-nitrobenzaldehyde in presence of
suitable base, solvent to produce compound of formula-6, in-situ reacting with the
5 compound of formula-5,
Formula-6
in presence of suitable base, solvent to provide compound of formula-7, further deprotecting
with suitable reagent, solvents to get compound of formula-8,
10
Formula-7 Formula-8
c) chlorinating the compound of formula-8 with suitable regent, solvent to provide compound
of formula-9,
15 Formula-9
d) purifying the compound of formula-9, in suitable solvent to provide compound of formula-
I.
11
Formula-I
wherein in step-a) suitable acid refer as hydrochloric acid, hydrobromic acid or
inorganic bases thereof; suitable base reagents refer as sodium hydroxide, potassium
hydroxide, lithium hydroxide and the like; suitable “phase 5 transfer catalyst (PTC)” refer as
triethylbenzyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium
chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium chloride, tetrabutyl
ammonium hydroxide, tributylbenzylammonium chloride and mixture thereof; suitable
temperature is 0-100°C.
10 wherein in step-b) suitable organic bases such as like dimethylamine, diethylamine,
diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine,
piperidine, 4-dimethyl amino pyridine (DMAP) or mixtures thereof; suitable acid reagents
refer as hydrochloric acid, hydrobromic acid or inorganic base; suitable temperature is 0-
100°C.
15 wherein in step-c) suitable chlorinating reagent such as sulfuryl chloride; suitable
polar protic solvents such as acetic acid, formic acid and mixture thereof; polar-aprotic
solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide
(DMSO), N-methylpyrrolidone (NMP) and thereof; suitable temperature is 0-70°C.
wherein in step-a) to d) suitable solvent refer as “nitrile solvents” such as acetonitrile,
20 propionitrile, isobutyronitrile and the like; alcoholic solvents” such as methanol, ethanol, npropanol,
isopropanol, n-butanol, isobutanol and mixture thereof; “polar-aprotic solvents
such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO),
N-methylpyrrolidone (NMP); polar solvents” such as water or mixture thereof; ester solvents
such as ethyl acetate, methyl acetate; ether solvents such as diethyl ether, dimethyl ether,
25 dioxane, tetrahydrofuran and mixture thereof; suitable temperature is 0-100°C.
The preferred embodiment of the present invention provides an improved process for the
preparation of compound of formula-I.
12
Formula-I
a) reacting the compound of formula-1a
5 Formula-1a
with 1,1-dimethoxy-N,N-dimethylmethanamine in toluene to provide compound of formula-
2a,
Formula-2a Formula-3a
10 in-situ condensation with cyclopropyl amine to provide compound of formula-3a, further
cyclization with sodium hydroxide, tetrabutyl ammonium bromide in water to provide
compound of formula-4a, in-situ hydrolyzed with hydrochloric acid get compound of
formula-5,
15 Formula-4a Formula-5
b) reacting (R)-azepan-3-amine dihydrochloride react with 3-nitro benzaldehyde in presence
of triethylamine in DMF to produce compound of formula-6, in-situ reacting with the
compound of formula-5,
13
Formula-6
in presence of triethylamine in methanol to provide compound of formula-7, followed by
hydrolysis with hydrochloric acid in acetonitrile, methanol to get compound of formula-8,
5
Formula-7 Formula-8
c) chlorinating the compound of formula-8 with sulfuryl chloride in presence of DMF, acetic
acid to get compound of formula-9,
10 Formula-9
d) purifying the compound of formula-9, in a mixture of acetone, water to provide
compound of formula-I.
Formula-I
15
14
Besifloxacin hydrochloride produced by the present invention can be further
micronized or milled to get the desired particle size to achieve desired solubility profile based
on different forms of pharmaceutical composition requirements. Techniques that may be
used for particle size reduction include, but not limited to ball, roller and hammer mills, and
5 jet mills. Milling or micronization may be performed before drying, or after the completion
of drying of the product.
PXRD analysis of Besifloxacin hydrochloride was carried out using BRUKER D8
ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A°
and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FT-IR
10 spectrometer.
The process for the preparation of compound of formula-I developed by the present
inventors produces highly pure compound of formula-I with good yield. All the related
substances and residual solvents are controlled well within the limits as suggested by ICH
guidelines and most of the related substances are controlled in non-detectable levels.
15
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC
20 Process for preparation of Compound of formula-6:
15
The present invention described as follows in a schematic representation:
5
16
The process described in the present application was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of compound of formula-5. 5 A round bottom flask was charged with compound of formula-1a (100 g), N,N-dimethyl formamide dimethyl acetal (72.6 g) and toluene (500 mL) at 25-35°C and heated to 85-95°C and stirred for 2 hr. The reaction mixture was cooled to 25-35°C, added cyclopropyl amine (34.7 g) and stirred for 4 hr. The reaction mass was washed with a citric acid solution (25 g in 250 mL of water) at 25-35°C and the toluene layer was charged with tetrabutyl ammonium 10 bromide (6 g) and sodium hydroxide solution (24.5 g in 100 mL of water) stirred for 3 hr at 35-45°C. The reaction mixture was cooled to 25-35°C, charged with hydrochloric acid (500 mL), heated to 90-100°C and stirred for 10 hr. The reaction mixture was cooled to 25°C and stirred for 2 hr. Filtered the obtained compound, washed with toluene (100 mL) and the wet compound was charged with water (500 mL), heated to 60-70°C and stirred for 60 min. 15 Filtered the obtained compound and washed with water (100 mL), dried to get the title compound.
Yield : 93.50 g :
Purity by HPLC: >99 %.
Example-2: Preparation of compound of formula-8. 20
A round bottom flask was charged with compound of formula-12 (91.75 g), 3-nitro benzaldehyde (80 g), triethylamine (134 g) and DMF (400 mL) at 25-35°C and stirred for 3 hr, added compound of formula-5 (100 g) and triethylamine (98 g) to reaction mixture at same temperature, heated to 85-95°C and stirred for 10 hr. The reaction mass was cooled to 25-35°C, added methanol (1350 mL) and stirred for 2 hr. Filtered the precipitated compound 25 and washed with methanol (100 mL) to get compound of formula-7. Acetonitrile (720 mL) and hydrochloric acid (90 mL) were charged to the above wet compound at 25-35°C and stirred for 45 min, heated to 55-65°C and stirred for 4 hr. The reaction mass was cooled to 25-35°C, filtered the precipitated compound and washed with acetonitrile (90 mL) and dried to get the title compound. 30
17
Yield : 121.0 g
Example-3: Preparation of compound of formula-9.
A round bottom flask was charged with compound of formula-8 (125 g), sulfuryl chloride (64 g) and acetic acid (400 mL) at 25-35°C stirred for 3 hr. The reaction mixture was diluted with N,N-dimethylformamide (125 mL) and stirred for 4 hr. Filtered the precipitated compound 5 and washed with acetonitrile (120 mL) and dried to get the title compound.
Yield : 97.0 g Purity by HPLC: 98.42%; HIUI: 0.79%.
Example-4: Preparation of compound of formula-I.
A round bottom flask was charged with a compound of formula-9 (200 g), acetonitrile (1800 mL) and water (1200 mL) at and heated to 40-50°C and stirred for 3 hr. Filtered the 10 undissolved solid and washed with acetonitrile (200 mL) at 40-50°C. The filtrate was concentrated to half of the volume at same temperature, the resulting solution was cooled to 25-35°C and stirred for 45 min. Filtered the obtained solid and washed with acetonitrile (100 mL) and dried to get the title compound.
The obtained PXRD was depicted in Figure-1 15
Yield: 170.0 g.
Example-5: Preparation of compound of formula-10.
A round bottom flask was charged with (R)-2,6-diaminohexanoicacid hydrochloride (50 g), methanol (250 mL) stirred for 10 min. Thionyl chloride (36 g) was added slowly in 45 min to the above reaction mixture at 25-35°C, and heated to 60-70°C stirred for 3 hr. The reaction 20 mixture was cooled to 25-35°C stirred for 30 min, further cooled to 5°C and stirred for 2 hr. Filtered the precipitated compound and washed with methanol (50 mL), dried to get the title compound.
Yield: 58.3 g
Example-6: Preparation of compound of formula-11. 25
A round bottom flask was charged with compound of formula-10 (100 g), methanol (500 mL) and sodium methoxide solution (25%, 185 mL) are heated to 40-50°, stirred for 5 hr. The reaction mixture was cooled to 25-35°C, filtered the unwanted solid and washed with methanol (50 mL). Distilled off solvent completely from the filtrate, co-distilled with ethanol (50 mL). The crude compound was cooled to 25-35°C, charged ethanol (250 mL) and filtered 30
18
to remove the unwanted solid particles. The filtrate solution was cooled to 10-20°C, adjusted the pH to 2.5 with ethanolic HCl (150 mL) and stirred for 2 hr. Filtered the precipitated compound and washed with ethanol (50 mL) and dried to get the title compound.
Yield: 70.6 g
Example-7: Preparation of compound of formula-12. 5
A round bottom flask was charged with vitride ( 294.5 g, 70% solution), tetrahydrofuran (600 mL) under nitrogen atmosphere. The reaction mixture was cooled to 0-10°C, added compound of formula-11 (60 g) in portions over a period of 1 hr, heated to 40-50°C stirred for 4 hr. The reaction mixture was cooled to 0-10°C, slowly added potassium carbonate (47 g) in 1 hr, the temperature is gradually raised to 25-35°C. Filtered the reaction mass washed 10 with tetrahydrofuran (200 mL). The filtrate solution pH was adjusted to 1.5 with isopropanol.HCl (210 mL) at 10-20°C and stirred for 3 hr. Filtered the precipitated solid, washed with isopropanol (60 mL) and dried to get the title compound.
Yield: 51.0 g
Example-8: Preparation of compound of formula-8. 15
A round bottom flask was charged with 3-nitro benzaldehyde (24 g), compound of formula-12 (25.4 g), triethylamine (40 g) and DMF (120 mL) at 25-35°C and stirred for 0.5 hr and heated to 40-45°C and stirred for 4 hr. Cooled the reaction mixture to 25-35°C, added compound of formula-5 (30 g) and triethylamine (32 g) at same temperature and gradually heated to 85-95°C and stirred for 10 hr. The reaction mass was cooled to 25-35°C, added 20 methanol (600 mL) and stirred for 2 hr. Filtered the precipitated compound and washed with methanol (60 mL) to get compound of formula-7. The obtained wet compound was charged with acetonitrile (225 mL) and hydrochloric acid (27 mL) were heated to 60-70°C and stirred for 3 hr. The reaction mass was cooled to 25-35°C, charged with methanol (15 mL) and stirred for 2 hr, filtered the precipitated compound and washed with acetonitrile (30 mL). The 25 obtained compound was stirred in methanol (150 mL), filtered the solid and dried to get the title compound.
Yield : 33 g
Example-9: Preparation of compound of formula-9.
A round bottom flask was charged with acetic acid (160 mL), compound of formula-8 (50 g), 30
19
and sulfuryl chloride (64 g) was added slowly about 2 hr and stirred for 3 hr at 25-35°C. The reaction mixture was diluted with N,N-dimethylformamide (500 mL) and stirred for 5 hr at 25-35°C. Filtered the precipitated compound and washed with N,N-dimethylformamide (50 mL), the obtained wet compound was stirred in N,N-dimethylformamide (250 mL) and stirred for 2 hr. Filtered the obtained compound and washed with N,N-dimethylformamide 5 (50 mL) and dried to get the title compound.
Yield : 34 g;
Purity by HPLC: >99 % , HIUI:< 0.5%;
Example-10: Preparation of compound of formula-I.
A round bottom flask was charged with a compound of formula-9 (70 g), acetone (700 mL) 10 and water (630 mL) and heated to 55-65°C, stirred for 1 hr. Charged carbon (7 g) to the reaction mixture at same temperature, filtered through hyflow bed and washed with a mixture of acetone (35 mL) and water (35 mL). The filtrate solution was concentrated to half of the volume at same temperature, the resulting solution was cooled to 25-35°C and stirred for 6 hr. Filtered the obtained solid and washed with acetone (70 mL), again the wet compound 15 was slurried in acetone (350 mL) for 2 hr, filtered the solid and dried to get the title compound.
The obtained PXRD was similar to the Figure-1.
Purity by HPLC: >99.5 %;
Yield: 53 g. ,CLAIMS:We claim:
1. A one pot process for the preparation of compound of formula-5
5 Formula-5
comprising of:
a) Reacting a compound of formula-1
Formula-1
10 Where R is alkyl, such as methyl, ethyl, propyl, butyl
with 1,1-dimethoxy-N,N-dimethylmethanamine in suitable solvent to provide compound of
formula-2, in-situ reacting with cyclopropylamine to provide compound of formula-3,
15 Formula-2 Formula-3
further cyclising in presence of base, phase transfer catalyst to get compound of formula-4,
in-situ hydrolysing with suitable reagent to get compound of formula-5.
Formula-4 Formula-5
21
b) optionally purifying in a suitable solvent to get pure compound of formula-5.
2. A one pot process for the preparation of compound of formula-5.
5 Formula-5
comprising of,
a) reacting the compound of formula-1a
Formula-1a
10 with 1,1-dimethoxy-N,N-dimethylmethanamine in toluene to provide compound of formula-
2a,
Formula-2a Formula-3a
In-situ condensation with cyclopropyl amine to provide compound of formula-3a, further
15 cyclization with sodium hydroxide, tetrabutyl ammonium bromide in water to provide
compound of formula-4a, in-situ hydrolyzed with hydrochloric acid get compound of
formula-5,
20 Formula-4a Formula-5
22
3. An improved process for the preparation of compound of formula-I.
5 Formula-I
comprising of:
a) Reacting the compound of formula-1
Formula-1
10 with 1,1-dimethoxy-N,N-dimethylmethanamine in suitable solvent to provide compound of
formula-2, in-situ reacting with cyclopropylamine to provide compound of formula-3,
Formula-2 Formula-3
15 further cyclised in presence of base, phase transfer catalyst to get compound of formula-4,
in-situ further hydrolyzed with suitable reagent to get compound of formula-5.
Formula-4 Formula-5
23
b) reacting (R)-azepan-3-amine dihydrochloride with 3-nitrobenzaldehyde in presence of
suitable base, solvent to produce compound of formula-6, in-situ reacting with the
5 compound of formula-5,
Formula-6
in presence of suitable base, solvent to provide compound of formula-7, further deprotecting
with suitable reagent, solvents to get compound of formula-8,
10
Formula-7 Formula-8
c) chlorinating the compound of formula-8 with suitable regent, solvent to provide compound
of formula-9,
15
Formula-9
d) purifying the compound of formula-9, in suitable solvent to provide compound of formula-
I.
24
Formula-I
4.The process according to claim 1 and 3 wherein in step-a) suitable acid reagents refer as
hydrochloric acid, hydrobromic acid or inorganic bases thereof; suitable base reagents refer
as sodium hydroxide, potassium hydroxide, lithium hydroxide 5 and the like; suitable “phase
transfer catalyst (PTC)” refer as triethylbenzyl ammonium chloride, tetrabutyl ammonium
bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl
ammonium chloride, tetrabutyl ammonium hydroxide, tri butylbenzylammonium chloride
and mixture thereof; suitable temperature is 0-100°C.
10 wherein in step-b) suitable organic bases such as like dimethylamine, diethylamine,
diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine,
piperidine, 4-dimethyl amino pyridine (DMAP) or mixtures thereof; suitable acid reagents
refer as hydrochloric acid, hydrobromic acid or inorganic base; suitable temperature is 0-
100°C.
15 wherein in step-c) suitable chlorinating reagent such as sulfuryl chloride; suitable
polar protic solvents such as acetic acid, formic acid and mixture thereof; polar-aprotic
solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide
(DMSO), N-methylpyrrolidone (NMP) and thereof; suitable temperature is 0-70°C.
5.The process according to claim 1 and 3 wherein in step a to d) suitable solvent refer as
20 “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; alcoholic
solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and
mixture thereof; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethyl
formamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP); polar
solvents” such as water or mixture thereof; ester solvents such as ethyl acetate, methyl
25 acetate; ether solvents such as diethyl ether, dimethyl ether, dioxane, tetrahydrofuran and
mixture thereof; suitable temperature is 0-100°C.
6. An improved process for the preparation of compound of formula-I.
25
Comprising of:
a) reacting the compound of formula-1a
Formula-1a
with 1,1-dimethoxy-N,N-dimethylmethanamine 5 in toluene to provide compound of formula-
2a,
Formula-2a Formula-3a
in-situ condensation with cyclopropyl amine to provide compound of formula-3a, further
10 cyclization with sodium hydroxide, tetrabutyl ammonium bromide in water to provide
compound of formula-4a, in-situ hydrolyzed with hydrochloric acid get compound of
formula-5,
Formula-4a Formula-5
15
b) reacting (R)-azepan-3-amine dihydrochloride react with 3-nitro benzaldehyde in presence
of triethylamine in DMF to produce compound of formula-6, in-situ reacting with the
compound of formula-5,
20 Formula-6
26
in presence of triethylamine in methanol to provide compound of formula-7, followed by
hydrolysis with hydrochloric acid in acetonitrile, methanol to get compound of formula-8,
5 Formula-7 Formula-8
c) chlorinating the compound of formula-8 with sulfuryl chloride in presence of DMF, acetic
acid to get compound of formula-9,
Formula-9
10 d) purifying the compound of formula-9, in acetone, water to provide compound of formula-
I.
Formula-I
7. The compound of formula-I produced by any of the proceeding claims having purity of
15 greater than 99.5%, preferably greater than 99.7%, more preferably greater than 99.9% by
HPLC.
27
8. Crystalline form of besifloxacin hydrochloride compound of formula-I obtained according to any preceding claims having particle size of D(0.9) < 200 µm, preferably D(0.9) < 100 µm and most preferably <20 µm.
9. Crystalline forms of Besifloxacin hydrochloride compound of formula-I obtained according to any preceding claims.