Title of Invention

A PROCESS FOR THE PREPARATION OF NOVEL INTERMEDIATE OF MOXIFLOXACIN THEREFOR AND PRODUCTION METHOD OF THE INTERMEDIATE

Abstract The present invention relates to a process for the preparation of novel intermediate (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo [4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxylic acid-O3,O4)bis (acyloxy-O)borate by the reaction of ethyl l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3- quinoline carboxylate with boric acid and acetic anhydride without using any catalyst gives (1-Cyclopropyl-6,7-difluoro-8-methoxy-4- oxo-l,4-dihydro-3-quinoline carboxylic acid-O3,O4)bis (acyloxy- O)borate which upon condensation in presence of a base(s) with (S,S)-2,8-diazabicyclo[4.3.0]nonane in organic polar solvent results the novel intermediate (4aS-Cis)-1-cyclopropyl-7-(2,8- diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro- 3-quinoline carboxylic acid-O3,O4)bis (acyloxy-O) borate.
Full Text


Field of the Invention: -
The present invention relates to a novel intermediate, (4aS-Cis)-(1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-O)borate and the process for its preparation
Background of the Invention: -
(4aS-CisH1-cyGlopropyl-7-(2,8-dia2abicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-0X0-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-O)borate is an useful intermediate for the preparation of Moxifloxacin Hydrochloride namely (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-0X0-1,4-dihydro-3-quinoline carboxylic acid hydrochloride has the structure

Moxifloxacin is a fluoroquinolone broad spectrum antibacterial particularly against gram-positive bacteria significantly better than those of Sparfloxacin and Ciprofloxacin that was disclosed in European patent no's EP 350,733 and EP 550,903. Moxifloxacin has activity against gram-negative and Gram-positive organisms, including Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, particularly against the respiratory disease-causing pathogens like Mycoplasma pneumonia, Mycobacterium tuberculosis. Chlamydia pneumoniae and the activity shown to be unaffected by B-lactamases.
US Patent No 5,157,117 discloses (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0 ,0 )bis (acyloxy-O)borate and a process for its preparation by reacting the ethyl 1-cyclopropyl-6 ,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate with Boric acid and acetic

anhydride in presence of zinc chloride and conversion to Gatifioxacin hydrochloride.
European Patent No's EP 350,733, EP 550,903 & EP 657,448 discloses preparation of Moxifloxacin by the condensation of 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline carboxylic acid or its esters with (S,S) 2,8-Diaza bicyclo[4,3.0]nonane in presence of a base, followed by conversion to hydrochloride.
It is a long felt of the industry to provide high yielding and cost effective process for the preparation of Moxifloxacin hydrochloride
Summary of the invention: -
The main object of the invention is to provide a process for the preparation of the novel intermediate (4aS-Cis)-1-cyclopropyl-7- (2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-clihydro-3-quinoline carboxylic acid-O^.C^jbis (acyloxy"0)borate.
Another object of the invention is to provide a novel intermediate (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-0) borate for its use in the preparation for moxifloxacin hydrochloride .
Another object of the invention is to provide fingerprinting of the novel intermediate (4aS-Cis)-1-cyclopropyl"7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O^,^^) bis (acyloxy-0) borate using NMR, IR and x-ray diffraction.
Yet, another object of the invention is to provide a process for the preparation of (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-O)borate without using the catalyst and its use for the preparation of (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O^.O'^jbis (acyloxy-O)borate.
Accordingly, the present invention relates to a method for the preparation of novel intermediate (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo [4,3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O^.O'^jbis (acyloxy-O)borate from the ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate. The reaction of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate with boric acid and acetic anhydride without using any catalyst gives (1-Cyclopropyi-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-0)borate which upon condensation in presence of a base(s) with (S,S)-2,8-diazabicyclo[4.3.0]nonane in organic polar solvent results the novel intermediate



Brief description of the drawings: -
Fig.1: X-ray diffraction pattern of the (4aS-Cis)-1"Cyclopropyl-7-(2,8"
diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'*)bis (acyloxy-0) borate.
Fig.2: FTIR spectrum of the (4aS-Cis)-1-cyclopropyl-7- (2,8-diazabicyclo [4.3.0] non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0 ,0'^)bis (acyloxy-O)borate.
Fig.3: NMR spectrum of the (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo [4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'*)bis (acyloxy-O)borate.
Detailed descripion of the Invention: -
The process of the present invention comprises steps as:
- Reaction of Ethyl 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate with a mixture of boric acid and acetic anhydride at temperature above 50*^C without the use of catalyst
- Separation of (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxO"1,4-dihydro-3-quinoline carboxylic acid-0 ,0'^)bis (acyloxy-O)borate by cooling to low temperature followed by dilution with water

- Isolation and drying of the (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4"dihydro-3-quinoline carboxylic acid-0 ,0'^)bis (acyloxy-O)borate
- Condensation of (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-O)borate with (S,S)-2,8-Diazabicyclo[4.3.0]nonane in presence of base(s) in organic polar solvent(s)
- Crystallization of (4aS-Cis)-1 -Cyclopropyl"7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^0'^)bis (acyloxy-O)borate
- Isolation and drying of (4aS-Cis)-1-Cyclopropyl-7-(2,8-diazabicyclo [4.3.0] non-8-Yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0 ,0'^)bis (acyloxy-O)borate
The prepared 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-O)borate is a hydrate. The novel

intermediate (4aS-Cis)-1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0lnon-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0 ,0'*)bis (acyloxy-0)borate is aniiydrous. Tiiese compounds are ciiaracterized by chemical analysis, NMR, FTIR and XRD analysis data.
The starting materials Ethyl 1-cyclopropyl-6,7"difluoro-8-methoxy-4-oxO"1,4-dihydro-3-quinoline carboxylate and [S,S]-2,8-Diaza bicyclo[4.3.0]nonane are prepared by literature reported methods.
Acetic anhydride is heated to about 70^C, and boric acid is added in lots. The reaction mass is stirred for about 1hr to about 2 hrs at temperatures of about 70^C - about 125^C, preferably at about 110^C to - about 120^C, cooled to temperature of about 60*^C - about 100*^C, preferably to about 70*^0. To this mixture, ethyl(1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate is added, the temperature raised to about 90^C - about 120^C, preferably to about 100^C - about 110^C and mixed for about 1hr to about 5 hrs preferably for about 1 hr. The reaction mass is cooled to temperature below 35*^C, preferably to about O^C - about 20^C, preferably to about O^C followed by addition of cold water and then mixed for about 1 to about 4 hrs. The product formed is separated by conventional means, washed with water and dried to obtain 1-Cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-O)borate.
(1-Cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O^.C^jbis (acyloxy-O)borate is suspended in organic polar solvents preferably DMSO, DMF, acetonitrile, ethanol and mixed with [S,S]-2,8-diaza bicyclo[4.3.0]nonane in presence of organic, inorganic base(s) preferably triethyl amine, DBU, diisopropvl ethyl amine, potassium carbonate at temperatures about 20^C - about 120X, preferably at about 60*^C - about 80^C for about 1 hr to 6 hrs. After the completion of reaction the reaction mass is cooled and the novel intermediate (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O^.O'^jbis (acyloxy-O)borate is separated by removal of solvent under vacuum below 60 C preferably at about 40^C - 45*^C followed by addition of the hydrocarbons preferably hexane, heptane, cyclohexane, methyl cyclohexane and mixed for about 2 hrs the product is filtered and dried.

The invention is now illustrated with a few non-limiting examples.
EXAMPLE-I
Stage-1
Acetic anhydride (175 gms) is heated to 70oC and boric acid (30 gms) is slowly added lot wise in a temperature range of about 70oC to about 90oC. The temperature is then raised, maintained under reflux for 1 hr followed by cooling to about 70oC. Ethyl 1 -cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate (100 gms ) is added under stirring. The temperature is then raised and maintained for 1 hr in the range of about l00oC to 105oC. The reaction mass is cooled to 0*oC, chilled water (400 ml) is added slowly followed by cold water (600 ml) at temperature 0*oC to 5*oC and maintained for 2 hrs at about OoC to about 5oC. The product which is a boron acetate complex is filtered, washed with water (500 ml) and dried at about 55°C to about 60°C under vacuum to constant weight.
The dry wt is 130.0 gms corresponding to yield of 95.2%
Stage - 2 :
The boron acetate complex (130 gms) prepared in stage-1 is suspended in acetonitrile (650 ml), and [S,S]-2,8-Diazabicyclo[4.3.0]nonane (47 gms) and triethyl amine (72.9 gms) are added. The temperature is raised to reflux and maintained for 1 hr. at reflux, followed by cooling to about 40oC. The solvent is removed under vacuum at temperature below 40*oC, and n-hexane (200 ml) is added. After maintaining the reaction mass for 1 hr at room temperature the product is isolated by filtration followed by washing of the wet cake with n-hexane. The product is dried at about 45oC to about 50*oC to constant weight. Dry wt of the novel intermediate is 117.0 gms corresponding to yield of 71.5%.
Elemental analysis: C: 56.42%, H: 5.62%, N: 7.76% and calculated values for the intermediate formula is C25H29BFN3O8 C: 56.6%, H: 5.47%, N: 7.92%
IR Spectrum (KBr,cm-^): 3415,3332,2936, 1718, 1630, 1573, 1526, 1445, 1273, 1042, 935, 860, 798, 682
^HNMR(200MHz. CDCI3, ppm): 9.00 (1H), 7.82 (1H), 4.12 (4H), 3,57 (3H), 3.43 (4H), 3.07 (2H), 2.75 (2H), 2.4 (1H), 2.1 (6H), 1.84 (2H), 1.6 (1H), 1.31 (2H)
Mass Spectrum (M^): 530.3 [M^H], 470.2 [M^ - CH3COOH], 428.2 [M^-(CH3CO)20, 100%], 402.2, 388.2




Claims:
We claim
1. A process for the preparation of a novel intermediate (4aS-Cis)-1-
Cyclopropyl-7-(2,8 diazabicyclo[4.3.0lnon-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-
dihydro-3-quinoline carboxylic acid-0 ,0'^)bis (acyloxy-O)borate comprising:
- Reaction of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate with a mixture of boric acid and acetic anhydride at temperature above 50oC without the use of catalyst
- Separation of (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O3O4jbis (acyloxy-O)borate by cooling to low temperature followed by dilution with water

- Isolation and drying of the (1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'*)bis (acyloxy-O)borate
- Condensation of (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'*)bis (acyloxy-O)borate with (S,S)-2,8-Diazabicyclo[4.3.0]nonane in presence of base(s) in organic polar solvent(s)
- Crystallizat of (4aS-Cis)-1 -cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'*)bis (acyloxy-O)borate
- Isolation and drying of (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo [4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-O)borate
2. A process as claimed in claim 1, wherein the temperature for the reaction
of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate with the mixture of boric acid and acetic anhydride is in the range of about 90^C to about 120^C.
3. A process as claimed in claim 1, wherein the organic polar solvents are
acetonitrile, DMSO, DMF.^
4. A process as claimed in claims 1-3, wherein the base(s) used is organic or inorganic bases
5. A process as claimed in claims 1 & 4 wherein the organic base(s) is triethyl amine, di isopropyl ethylamine, DBU

6. A process as claimed in claims 1 & 5 wherein the inorganic base is potassium
carbonate
7. A process as claimed in claim 1, wherein the temperature for the condesation reaction is in the range of about 30oC to about 100oC, preferably from about 60oC to about 80°C
8. A process as claimed in claim 1, wherein the crystallization of (4aS-Cis)-1-Cyclopropyl-7-(2,8-diazabicyclo [4.3.0]non-8-yl)-6-fluoro-8-methoxy -4-oxo-1,4-dihydro-3-quinoline carboxylic acid-O^.C^jbis (acyloxy-O)borate is carried out by removal of solvent and addition of a second solvent
9. A process as claimed in claims 1& 8 wherein the second solvent is selected
from hydrocarbons of C-5 to C-7
10. A process as claimed in claims 1,8 & 9 wherein the hydrocarbon is alkyl,
cycloalkyi or mixtures thereof
11. A process as claimed in claims 1,8,9 & 10 wherein the hydrocarbon is n-
hexane, n-heptane, cyclohexane, methyl cyclohexane or mixtures thereof
12. A process as claimed in claim 1, wherein the intermediate (4aS-Cis)-1-
Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-
1,4-dihydro-3-quinoline carboxylic acid-0 ,0'^)bis (acyloxy-O)borate is
isolated or without isolation processed for the preparation of moxifloxacin or
its salts or hydrates
13. The compound (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-
8-yl)-6-fluorO"8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis(acyloxy-0)-borate


The present invention relates to a method for the preparation of novel intermediate (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0Jnon-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0 ,0'*)bis (acyloxy-0)borate by the reaction of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylate with boric acid and acetic anhydride without using any catalyst gives (1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0^)bis (acyloxy-O)borate which upon condensation in presence of a base(s) with (S,S)-2,8-diazabicyclo[4.3.0]nonane in organic polar solvent results the novel intermediate (4aS-Cis)-1-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-0^,0'^)bis (acyloxy-O)borate.

Documents:

638-che-2003-abstract.pdf

638-che-2003-claims duplicate.pdf

638-che-2003-claims original.pdf

638-che-2003-correspondnece-others.pdf

638-che-2003-correspondnece-po.pdf

638-che-2003-description(complete) duplicate.pdf

638-che-2003-description(complete) original.pdf

638-che-2003-drawings.pdf

638-che-2003-form 1.pdf

638-che-2003-form 19.pdf

638-che-2003-form 3.pdf


Patent Number 202962
Indian Patent Application Number 638/CHE/2003
PG Journal Number 05/2007
Publication Date 02-Feb-2007
Grant Date 06-Nov-2006
Date of Filing 05-Aug-2003
Name of Patentee M/S. MATRIX LABORATORIES LTD
Applicant Address 1-1-151/1, IV FLOOR, SAIRAM TOWERS, ALEXANDER ROAD, SECUNDRABAD 500 003.
Inventors:
# Inventor's Name Inventor's Address
1 DR. CHAVA SATYANARAYANA PLOT NO 40, PARKVIEW ENCLAVE MANOVIKAS NAGAR, HASAMATHPET ROAD, SECUNDERABAD-500 009.
2 DR. GORANTLA SEETA RAMANJANEYULU PLOT NO-10, SAI ANSH ARCADE DURGAVIHAR COLONY, TIRUMALGHERRY, SECUNDERABAD-500 015, INDIA.
3 MR. DAMMALAPATI VENKATA LAKSHMI NARASIMHARAO 201, SHOBHANA TOWERS, ROAD NO-3 VIVEKANANDA NAGAR COLONY, KUKATPALLY HYDERABAD-500 072.
4 DR. VASIREDDI UMAMAHESWARA RAO 101, RUKMINI APARTMENTS, YUSUFGUDA CHECKPOST HYDERABAD-500 045, INDIA.
PCT International Classification Number A61K 31/69
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA