FORM 2
THE PATENT ACT, 1970
(39 of ,970)
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS OF PREPARING (S, S)-2, S-DIAZABICYCLO [4.3.0] NONANE"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS OF PREPARING (S, S)-2, 8-DIAZABICYCLO [4.3.0]
NONANE
FIELD OF THE INVENTION:
The present invention relates to an improved process of preparing substantially pure (S, S)-2, 8-diazabicyclo [4.3.0] nonane compound of structural formula II and its conversion to moxifloxacin hydrochloride compound of structural formula I.

BACKGROUND OF THE INVENTION:
Chemically moxifloxacin hydrochloride is monohydrochlorlde salt of 1 -cyclopropyl-7-[(S, S)-2, 8-diazabicyclo [4.3.0] non-8-yi]-6-fluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinoiine carboxylic acid, represented by compound of structural formula I and is known from U.S. Patent No. 5,607,942.

Moxifloxacin hydrochloride is a synthetic broad-spectrum antibacterial agent. The active moiety, moxifloxacin has been shown to be clinically active against most strains of microorganisms such as aerobic gram-positive microorganisms including staphylococcus aureus, streptococcus

pneumoniae (penicillin-susceptible strains) and streptococcus pyogenes, aerobic gram-negative microorganisms including Haemophilus influenza, haemophilus parainfluenzae, Klebsiella pneumoniae. Moxifloxacin is commercially available under the brand name of AVELOX® marketed by Bayer Healthcare.
The (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II is an important intermediate in the manufacture of many pharmaceutically active ingredients. Several processes are known in the literature for the preparation of this intermediate.
U.S. Patent No. 4,990,517 describes a process of preparing 2, 8- diazabicyclo [4.3.0] nonane as shown below in scheme no. I.

U.S. Patent No. 5,480,879 describes a process of preparing (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II as shown below in scheme no. II.

U.S. Patent No. 5,770,597 describes a process of preparing 2, 8- diazabicyclo [4.3.0] nonane as shown below in scheme no. III.


PCT Publication No. 2009/125425 describes a process of preparing (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II as shown below in scheme no. IV.

PCT Publication No. 2010/100215 describes a process of preparing (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II as shown below in scheme no. V.


wherein, Alk is a straight or branch C1-C5 alky1 group; and GP is protecting group preferably selected from benzylamine or benzylamine substituted with alkyl, p-nitro, fluoro, trifluoromethyl in the ortho or para positions.
PCT Publication No. 2010/122774 describes a process of preparing (S. S)-2, 8- diazabicyclo [4.3,0] nonane compound of structural formula II as shown below in scheme no. VI.

wherein * indicates an asymmetric carbon; Ar1 is an optionally substituted C6-20 aryl group or an optionally substituted C3-20 heteroaryl group; R1 is an optionally substituted C1-20 alkyl group.
European Patent Application No. EP0550903A1 describes a process of preparing (S, S)-2, 8-diazabicyclo [4.3.0] nonane compound of structural formula II as shown below in scheme no. VII.

PCT Publication No. 2012/131629 describes a process for the preparation of racemic or chiral octahydro-6-(phenylmethyl)- lH-pyrrolo[3,4-b]pyridine, comprising reacting racemic or chiral tetrahydro-6-(phenylmethyl)-lH- pyrrolo[3.4-b]pyridine-5,7(6H)-dione with a reducing agent in the presence of a polar solvent at a temperature ranging from 15°C to 45°C to obtain racemic or chirai octahydro-6-(phenylmethyl)- lH-pyrrolo[3,4-b]pyridine, wherein said reducing agent is a mixture of two reducing agents used in a molar ratio ranging from I : 1 to 1 : 4. The reducing agent used is a mixture of dimethyl sulphate and sodium borohydride or mixture of aluminum chloride and sodium borohydride.
The aforementioned prior art processes of preparing (S, S)-2. 8- diazabicyclo [4.3.0] nonane compound of structural formula II involves reduction reaction using reducing agent. The present applicant of the patent found that the reduction reaction was incomplete and yields impure (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II.
The present applicant of the patent surprisingly found that reduction reaction using reducing agent in presence of dimethyl sulfate at a temperature in the range of 50°C to 120°C leads to complete reaction and yields substantially pure (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II.

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide substantially pure (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II.

A second aspect of the present invention is to provide an improved process of preparing substantially pure (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II.
A third aspect of the present invention is to provide an improved process of preparing compound of structural formula XXXII comprises reduction of compound of structural formula XXXI by reducing agent in presence of dimethyl sulfate at a temperature in the range of 50°C to 120°C.

wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group.
Another aspect of the present invention is to provide a process of preparing substantially pure compound of structural formula XXXII comprises reduction of compound of structural formula XXXI by reducing agent in presence of dimethyl sulfate at a temperature in the range of 50°C to 120°C.

Another aspect of the present invention is to provide an improved process of preparing compound of structural formula XXXII comprises reduction of compound of structural formula XXXI by reducing agent in presence of dimethyl sulfate and diglyme at a temperature in the range of 50°C to l20°C.

wherein. P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group.
Another aspect of the present invention is to provide a process of preparing substantially pure compound of structural formula XXXII comprises reduction of compound of structural formula XXXI by reducing agent in presence of dimethyl sulfate and diglyme at a temperature in the range of 50°C to l20°C.
Another aspect of the present invention is to provide an improved process of preparing compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in presence of dimethyl sulfate at a temperature in the range of 50°C to 120°C.

wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl. aryl sulfonyl or substituted aryl sulfonyl group.

Another aspect of the present invention is to provide a process of preparing substantially pure compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in presence of dimethyl sulfate at a temperature in the range of 50°C
to 120°C.
Another aspect of the present invention is to provide an improved process of preparing compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in presence of dimethyl sulfate and diglyme at a temperature in the range of 50°C to 120°C.

wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group.
Another aspect of the present invention is to provide a process of preparing substantially pure compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in presence of dimethyl sulfate and diglyme at a temperature in the range of 50°C to 120°C.
Another aspect of the present invention is to provide an improved process of preparing substantially pure moxifloxacin hydrochloride compound of structural formula I.
Another aspect of the present invention is to use of substantially pure compound of structural formula XXXII for the preparation of (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II.

Another aspect of the present invention is to use of substantially pure compound of structural formula XXXIV for the preparation of (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II.
Another aspect of the present invention is to use of substantially pure compound of structural formula XXXII for the preparation of moxifloxacin hydrochloride compound of structural formula I.
Another aspect of the present invention is to use of substantially pure compound of structural formula XXXIV for the preparation of moxifloxacin hydrochloride compound of structural formula I.
DETAIL DESCRIPTION OF THE INVENTION:
The compound of structural formula XXXI and compound of structural formula XXXIII used in the present invention may be prepared by method known in art such as those described in background of the invention, which are incorporated herein by reference only.
The substantially pure compound of structural formula XXXII or compound of structural formula XXXIV was prepared by reducing compound of structural formula XXXI or compound of structural formula XXXIII respectively with reducing agent in presence of dimethyl sulphate in an organic solvent.
The reduction of compound of structural formula XXXI or compound of structural formula XXXIII with reducing agent in presence of dimethyl sulphate was carried out at a temperature in the range of 50°C to 120°C.
The addition of reducing agent and dimethyl sulphate was carried out in one or more than one
lots.

The examples of reducing agent is selected from the group consisting of boron hydride metal compound such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride or sodium borohydride cyanide; an aluminium hydride metal compound such as lithium aluminium hydride, sodium aluminium hydride and diisobutylaluminium hydride.
The examples of an organic solvent is selected from the group comprising of ether solvents such as bis(2-methoxyethyI) ether (diglyme). tetrahydrofuran, dioxane. diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether; aromatic hydrocarbon solvents such as toluene, xylene, cresol or mixture(s) thereof.
The substantially pure compound of structural formula XXXII or compound of structural formula XXXIV was isolated by quenching the reaction mixture with chilled water followed by adding dilute hydrochloric acid solution (50%) up to pH 1.5 to 2.0 and then organic layer and aqueous layer was separated. The pH of aqueous layer was adjusted to 10.5 to 11.5 with aqueous sodium hydroxide solution (30%) and extracted with toluene one or more than one times. The all organic layers were combined and concentrated under reduced pressure to get substantially pure compound of structural formula XXXII or compound of structural formula XXXIV.
The substantially pure compound of structural formula XXXII or compound of structural formula XXXIV can be converted in to (S. S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II by method known in art such as those described in background of the invention, which are incorporated herein by reference only.
The substantially pure compound of structural formula XXXII or compound of structural formula XXXIV can be converted in to moxifloxacin hydrochloride compound of structural formula I by method known in art such as those described in background of the invention, which are incorporated herein by reference only.

The term "substantially pure compound of structural formula XXXII or compound of structural formula XXXIV" described herein referred to compound of structural formula XXXII or compound of structural formula XXXIV having purity more than 99% as detected by HPLC.
The example of compound of structural formula XXXI may include compound of structural formula XXX.

The example of compound of structural formula XXXIII may include compound of structural formula IV.

The example of compound of structural formula XXXII may include compound of structural formula VI.



The example of compound of structural formula XXXIV may include compound of structural formula V.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of compound of structural formula VI.
A solution of compound of structural formula XXX (15gm) in diglyme (60ml) was added sodium borohydride (9.3gm) and dimethyl sulphate (7.7gm) and stirred for 5-10 minutes. The resulting reaction mixture was heated to 70-75°C and stirred for 3 hours at the same temperature. Then the reaction mixture was cooled to 20-25°C and sodium borohydride (4.6gm) and dimethyl sulphate (23.2gm) was added to the reaction mixture. The resulting reaction mixture was heated to 70-75 °C and stirred for 3 hours at the same temperature. Then the reaction mixture was cooled to 20-25°C and dimethyl sulphate (23.2gm) was added to the reaction mixture and reaction mixture was again heated to 70-75°C and stirred for 6 hours at the same temperature. The resulting reaction mixture was cooled to 20-25°C and quenched with chilled water (30ml). Then the reaction mixture was added water (130ml) followed by dilute hydrochloric acid solution (50%, 20ml) up to pH 1.5 to 2.0 and organic layer was separated. The resulting aqueous layer was added sodium hydroxide solution (30%) up to pH 10.5 to 11.5 and then extracted with toluene (2x15ml). Then the resulting aqueous layer was again added sodium hydroxide solution (30%) up to pH 10.5 to 11.5 and then extracted with toluene (3x30ml). The all organic layer were combined and concentrated under reduced pressure at temperature below 60°C to get compound of structural formula VI as oil. Yield: 12.0gm

Purity: 99.9% (By HPLC)
Example 2: Preparation of compound of structural formula VI.
A solution of compound of structural formula XXX (I5gm) in diglyme (30ml) and toluene (90ml) was added sodium borohydride (9.3gm) and dimethyl sulphate (7.7gm) and stirred for 5-10 minutes. The resulting reaction mixture was heated to 70-75°C and stirred for 3 hours at the same temperature. Then the reaction mixture was cooled to 20-25°C and sodium borohydride (4.6gm) and dimethyl sulphate (23.2gm) was added to the reaction mixture. The resulting reaction mixture was heated to 70-75°C and stirred for 3 hours at the same temperature. Then the reaction mixture was cooled to 20-25°C and dimethyl sulphate (23.2gm) was added to the reaction mixture and reaction mixture was again heated to 70-75°C and stirred for 9 hours at the same temperature. The resulting reaction mixture was cooled to 20-25°C and quenched with chilled water (30ml). Then the reaction mixture was added water (130ml) followed by dilute hydrochloric acid solution (50%, 20ml) up to p'H 1.5 to 2.0 and organic layer was separated. The resulting aqueous layer was added sodium hydroxide solution (30%) up to pH 10.5 to 11.5 and then extracted with toluene (2x15ml). Then the resulting aqueous layer was again added sodium hydroxide solution (30%) up to pH 10.5 to 11.5 and then extracted with toluene (3x30ml). The all organic layer were combined and concentrated under reduced pressure at temperature below 60°C to get compound of structural formula VI as oil. Yield: 10.8gm Purity: 99.8% (By HPLC)
Example 3: Preparation of compound of structural formula V.
A solution of compound of structural formula IV (15gm) in diglyme (60ml) was added sodium borohydride (9.3gm) and dimethyl sulphate (7.7gm) and stirred for 5-10 minutes. The resulting reaction mixture was heated to 70-75°C and stirred for 3 hours at the same temperature. Then the reaction mixture was cooled to 20-25°C and sodium borohydride (4.6gm) and dimethyl sulphate (23.2gm) was added to the reaction mixture. The resulting reaction mixture was heated to 70-75°C and stirred for 3 hours at the same temperature. Then the reaction mixture was cooled to 20-25°C and dimethyl sulphate (23.2gm) was added to the reaction mixture and reaction mixture

was again heated to 70-75°C and stirred for 6 hours at the same temperature. The resulting reaction mixture was cooled to 20-25°C and quenched with chilled water (30ml). Then the reaction mixture was added water (130ml) followed by dilute hydrochloric acid solution (50%, 20ml) up to pH 1.5 to 2.0 and organic layer was separated. The resulting aqueous layer was added sodium hydroxide solution (30%) up to pH 10.5 to 11.5 and then extracted with toluene (2x15ml). Then the resulting aqueous layer was again added sodium hydroxide solution (30%) up to pH 10.5 to 11.5 and then extracted with toluene (3x30ml), The all organic layer were combined and concentrated under reduced pressure at temperature below 60°C to get compound of structural formula V as oil. Yield: 11.8gm Purity: 99.9% (By HPLC)

WE CLAIM:
1. An improved process of preparing compound of structural formula XXXII comprises reduction of compound of structural formula XXXI by reducing agent in the presence of dimethyl sulfate at a temperature in the range of 50°C to 120°C.

Formula XXX] Formula XXXII
wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group.
2. An improved process of preparing compound of structural formula XXXII comprises reduction of compound of structural formula XXX] by reducing agent in the presence of dimethyl sulfate and diglyme at a temperature in the range of 50°C to 120°C.

Formula XXXI Formula XXXII
wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl. aryl sulfonyl or substituted aryl sulfonyl group.
3. An improved process of preparing compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in the presence of dimethyl sulfate at a temperature in the range of 50°C to 120°C.


Formula XXXIII Formula XXXIV
wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group.
4. An improved process of preparing compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in the presence of dimethyl sulfate and diglyme at a temperature in the range of 50°C to 120°C.

Formula XXXIII Formula XXXIV
wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group.
5. The process according to claim nos. 1, 2, 3 or 4 wherein reduction of compound of structural formula XXXI or compound of structural formula XXXIII is carried out in an organic solvent.
6. The process according to claim nos. 1, 2, 3 or 4 wherein reducing agent is selected from the group consisting of boron hydride metal compound such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride or

sodium borohydride cyanide; an aluminium hydride metal compound such as lithium aluminium hydride, sodium aluminium hydride and diisobutylaluminium hydride.
7. The process according to claim no. 5 wherein organic solvent is selected from the group comprising of ether solvents such as bis(2-methoxyethyl) ether (diglyme), tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether; aromatic hydrocarbon solvents such as toluene, xylene, cresol or mixture(s) thereof.
8. Use of substantially pure compound of structural formula XXXII or compound of structural formula XXXIV prepared according to one of claim nos. 1, 2, 3 or 4 for the preparation of (S, S)-2. 8- diazabicyclo [4.3.0] nonane compound of structural formula II.
9. The process according to claim no. 1 or 2, wherein compound of structural formula XXXII includes compound of structural formula VI.


10. The process according to claim no. 3 or 4, wherein compound of structural formula XXXIV includes compound of structural formula V.