FORM-2
THE PATENTS ACT, 1970
COMPLETE
SPECIFICATION
SECTION 10
TITLE : NOVEL PROCESS FOR PREPARATION OF MOXIFLOXACIN.
APPLICANT (S): CIPLA LIMITED, 289, BELLASIS ROAD, MUMBAl CENTRAL,
MUMBAl 400 008, MAHARASHTRA, INDIA. AN INDIAN COMPANY
The following Specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed:-

Novel Process for Preparation of Moxifloxacin
Technical field
[001] The present invention relates to an improved method for preparation of
moxifloxacin; more particularly a method wherein the active group is protected before reaction and deprotected thereafter to obtain a high yield of high quality of moxifloxacin.
Background and Prior Art
[002] The broad antibacterial spectrum of the fluoroquinolones, their marked
effectiveness, particularly against gram-negative bacteria, as well as their favorable pharmacokinetics have resulted in this class of anti-infective compound, such as Ciprofloxacin, to be widely used as antimicrobial agents. Various derivatives of fluoro quinolones later emerged such as Pefloxacin, Oflaxacin, Sparfloxacin ,Gatifloxacin etc to combat the growing number of drug resistant bacteria. These derivatives were found to be poorly active against Gram positive bacteria. One new compound belonging to the fluoro-quinolones, i.e Moxifloxacin (I) was introduced by Bayer, which showed very high antibacterial activity against most aerobic and anaerobic bacteria including Gram-positive cocci.


(I)

[003] Synthetic processes for preparation of Moxifloxacin are reported in EP
0424851 and Drugs of the Future 1997,22 (2) 109-113. The process generally describes the preparation of the key intermediate (4aS,7aS)-octahydro-6H-pyrrolo-{3,4-b]-pyridine and its condensation with l-cyclopropyl-6,7-difluor-8-methoxy-4-oxo-quinoline-3-carboxylic acid as shown in scheme 1.
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Scheme 1:

[004] The process to make the key intermediate (4aS,7aS)-octahydro-6H-
pyrrolo-{3,4-b]-pyridine is disclosed in patents EP 0350733, EP 550903 and US Patent 6235908.
[005] The process of prior art suffers from disadvantage with respect to the
impurities formed during the condensation of the nonane derivative with the quinolone. Several byproducts are formed which include the dimeric and isomeric derivatives, which are difficult to separate by normal purification procedures.
Summary of Invention
[006] The present invention relates to an improved method for preparation of
moxifloxacin; more particularly a method wherein the nonane group is protected prior to reaction and deprotected thereafter to obtain a high quality moxifloxacin with higher yields.
Detailed Description
[007] We have surprisingly found that if the condensation is performed with the
R= Carbamate ester or alkyl or aryl amide
protected nonane (IV) where the protection can be carbamate ester or alkyl or aryl amide group, followed by a deprotection step, the product obtained is of a very high quality and surprisingly the yield is also increased.

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[008] The present invention discloses a process for making Moxifloxacin by
reacting 1-protected (4aS,7aS)-octahydro-6H-pyrrolo-{3,4-b]-pyridine (formula IV) with l-cyclopropyl-6,7-difluor-8-methoxy-4-oxo-quinoline-3-carboxylic acid ( formula III) to yield novel intermediates of the formula V (Scheme II)

[009] The present invention discloses 1-carbamate esters of the compounds of
formula IV. These esters can be formed by reacting suitably compounds of the formula II or its 6-protected derivative with a suitable chloroformate ester. The chloroformate ester may be selected from alkyl chloroformate or aryl or aryl alkyl chloroformates or halo derivatives thereof.
[010] Another aspect of this invention is the disclosure of 6-substitued amides of
the formula IV. These amides can be prepared conveniently by reacting suitably compounds of the formula II or its 6-protected derivative with a suitable acid chlorides or anhydrides. The corresponding acids can be selected from alkanoic acids or benzoic acid or derivatives thereof.
[011] A further aspect of the invention discloses de-protection of the compounds
of formula V using suitable techniques to obtain compound of the of the formula I.
[012] The following examples are illustrative of the invention but in no way
limit the scope of the invention.
Example 1:
(4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(l-benzyloxy-octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-1,4-dihyro-3-quinoline
25 gms of l-benzyloxy-(4aS,7aS)-octahydro-6H-pyrrolo-{3,4-b]-pyridine and 30 gms l-cyclopropyl-6,7-difluor-8-methoxy-4-oxo-quinoline-3-carboxylic acid is added to 25 ml sulfolane. The reaction mixture is heated to 150°C for 14 hours. The reaction mass is cooled and quenched in ice-cooled water. The precipitated product is filtered and washed with water to give the title product. (4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(l-benzyloxy-octahydro-6h-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-l,4-dihyro-3-quinoline.
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Example 2:
(4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-1,4-dihyro-3 -quinoline.
15 gms (4aS,7aS)-1 -cyclopropyl-6-fluoro-8-methoxy-7-( 1 -benzyloxy-octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-l,4-dihyro-3-quinoline is mixed with 3 gms sodium hydroxide in 30 ml n-butanol. The reaction mixture is heated to 110°C for 10 hours. The n-butanol is distilled under vacuum. To the residue, water is added and the pH adjusted with dilute Hydrochloric acid to between pH 6-7. The precipitated product is filtered and washed to neutral with water to give the title product.
Example 3:
(4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(l-acetoxy-octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-1,4-dihyro-3 -quinoline
50 gms of l-benzyloxy-(4aS,7aS)-octahydro-6H-pyrrolo-{3,4-b]-pyridine and 85gms 1-cyclopropyl-6,7-difluor-8-methoxy-4-oxo-quinoline-3-carboxylic acid is added to 200 ml dimethyl acetamide. The reaction mixture is heated to 120°C for 8 hours. The reaction mass is cooled to room temperature and quenched in ice-cooled water. The precipitated product is filtered and washed with water to give the title product. (4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-( 1-acetoxy-octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-1,4-dihyro-3-quinoline.
Example 4:
(4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-l,4-dihyro-3-quinoline.
50 gms (4aS,7aS)-1 -cyclopropyl-6-fluoro-8-methoxy-7-( 1 -acetoxy-octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-l,4-dihyro-3-quinoline is mixed with 15gms sodium hydroxide in 100 ml alcohol The reaction mixture is heated to 110°C for 10 hours. The alcohol is distilled under vacuum. To the residue, water is added and the pH adjusted with dilute acetic acid pH,6,4. The, precipitated product is filtered and washed to neutral with water to give the title product.
(4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(l-ethoxy carbonyl-octahydro-6H-pyrrol-
[3,4-b]-pyridine-6-yl)-4-oxo-l,4-dihyro-3-quinoline
25 gms of (4aS,7aS)-l-ethoxy carbonyl-octahydro-6H-pyrrolo-{3,4-b]-pyridine and 36 gms
l-cyclopropyl-6,7-difluor-8-methoxy-4-oxo-quino1ine-3-carboxylic acid is added to 100 ml
diglyme. The reaction mixture is heated to 120°C for 24 hours. Diglyme is distilled under
vacuum.the reaction mass cooled and quenched in ice-cooled water. The precipitated product
is filtered and washed with water to give the title product. (4aS,7aS)-l-cyclopropyl-6-fluoro-
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8-methoxy-7-(l-ethoxy carbonyl-octahydro-6h-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-l,4-
dihyro-3-quinoline.
Example 6:
(4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-l,4-dihyro-3-quinoline.
20 gms (4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(l-ethoxy carbonyl-octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-l,4-dihyro-3-quinoline is mixed with 5 gms potassium hydroxide in 25 ml methanol The reaction mixture is heated to 60°C for 10 hours. The reaction is cooled to 40°C, water is added and the pH adjusted with dilute hydrochloric acid to pH 6.8. The precipitated product is filtered and washed to neutral with water to give the title product.
Example7:
t;4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(l-phenoxy carbonyl-octahydro-6H-pyrrol-f^,4-b]-pyridine-6-yl)-4-oxo-1,4-dihyro-3-quinoline
75 gms of (4aS,7aS)-l-phenoxy carbonyl-octahydro-6H-pyrrolo-{3,4-b]-pyridine and 89 gms l-cyclopropyl-6,7-difluor-8-methoxy-4-oxo-quinoline-3-carboxylic acid is added to 150 ml Toluene. The reaction mixture is heated to 120°C for 24 hours. Toluene is distilled under vacuum, the reaction mass cooled and quenched in ice-cooled water. The precipitated product is filtered and washed with water to give the title product. (4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(l-phenoxy carbonyl-octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-1,4-dihyro-3 -quinoline.
Example 8:
(4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-1,4-dihyro-3 -quinoline.
100 gms (4aS,7aS)-l-cyclopropyl-6-fluoro-8-methoxy-7-(l-phenoxy carbonyl-octahydro-6H-pyrrol-[3,4-b]-pyridine-6-yl)-4-oxo-l,4-dihyro-3-quinoline is mixed with 25 gms potassium hydroxide in 100 ml methanol The reaction mixture is heated to 45°C for 20 hours. The reaction is cooled to 40°C, water is added and the pH adjusted with dilute Hydrochloric acid to pH 6.5. The precipitated product is filtered and washed to neutral with water to give the title product.
[013] While the present invention is described above in connection with
preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.
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We Claim
1. A process for the preparation of Moxifloxacin or analogs thereof of formula I characterized in that,
the said process comprises of
a) preparation of compound of formula IV by reacting compound of formula II with specific reagents

b) reacting a compound of formula IV with a compound of formula III to obtain a compound of formula V

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c) de-protecting the compound of the formula V to obtain moxifloxacin of formula I

2. A process as claimed in claim 1(a) wherein the protected group R of compound of formula (IV) selected from carbamate ester, alkyl or aryl amide
3. A process as claimed in claim 1(a) wherein the specific reagents used are alkyl chloroformate, aryl chloroformate, aryl alkyl chloroformate, acid chlorides, anhydrides, benzoic acids or halogen derivatives thereof
4. A process as claimed in claim 1 (b) wherein the condensation of compound of formula III with compound of formula IV is done in presence of a solvent having boiling point between 100°C - 250°C
5. The process as claimed in claim 1 (b) wherein the condensation is done in absence of base
6. The process as claimed in claim 1(c) wherein the de-protection is carried out in presence of alkali metal hydroxides or alkoxides
7. A process as claimed in claim 1(c) wherein the de-protection is carried out in presence of solvent selected from C-l to C-4 alcohols.

To,
The Controller of Patents
The Patent Office
At Mumbai
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Abstract
The present invention describes a novel process for preparation of moxifloxacin involving protection of a group prior to reaction and deprotection thereafter to obtain high quality moxifloxacin in higher yields.