FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS OF PREPARING (S, S)-2,8-DIAZABICYCLO [4.3.0] NONANE"
Enaltec Labs Pvt. Ltd, an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, PlotNo.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 (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 monohydrochloride salt of l-cyclopropyl-7-[(S, S)-2, 8-diazabicyclo [4.3.0] non-8-yl]-6-fluoro-8-methoxy-l, 4-dihydro-4-oxo-3-quinoline carboxylic acid having the 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

pneumonia (penicillin-susceptible strains) and streptococcus pyogenes, aerobic gram-negative microorganisms including haemophilus influenza, hemophilus parainfluenzae, klebisiella pneumonia. Moxifloxacin is commercially available under the brand name of AVELOX® marketed by Bayer Healthcare
(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 Nos. 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 Nos. 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 Nos. 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 alkyl 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;
European patent publication no. EP2423211A1 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; Ari 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 publication no. EP2423211A1 describes reduction of compound of structural formula XXVIII using reducing agent and activating agent to get compound of structural formula XXIX.
European patent publication no. EP2423211A1 describes generically the use of aluminum chloride (III), ferric chloride (III), zinc chloride, tin chloride (IV), gallium chloride (III), sulfuric acid, boron trifluoride, and iodine as an activating agent to reduce a compound of structural formula XXVIII. However the use of sulfuric acid as an activating agent to reduce a compound of structural formula XXVIII is exemplified.
European patent publication 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.

Japanese Patent publication no. 2001039979A describes reduction of compound of structural formula IV with reducing agent like metal borohydride in presence of activating agent as shown below in scheme no. VIII.


Japanese Patent publication no. 2001039979A describes generically the use of aluminum chloride (III), iron chloride (III), zinc chloride, tin chloride (IV), gallium chloride (III), as an activating agent to reduce a compound of structural formula IV. However the use of aluminium chloride (III) as an activating agent to reduce a compound of structural formula IV is exemplified.
The prior art process for reduction of compound of structural formula IV and compound of structural formula XXVIII using reducing agent in presence of activating agent involves direct addition of activating agent which is highly exothermic reaction and difficult to developed on plant scale. Another drawback of direct addition of activating agent is more than 20% reaction mixture get unreacted which leads to impure final product with low yield.
Accordingly there is provided an improved process for reduction using reducing agent in presence of an activating agent to obviate prior art problems.
SUMMARY OF THE INVENTION:
A first 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 second 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 the presence of activating agent, wherein the process is characterized by the addition of activating agent in more than one lots.

wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group
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 the presence of activating agent, wherein the process is characterized by increasing the temperature of reaction mixture periodically.
A fourth aspect of the present invention is to provide an improved process of preparing substantially pure compound of structural formula XXXII comprises reduction of compound of structural formula XXXI by reducing agent in the presence of activating agent and diglyme, wherein the process is characterized by the addition of activating agent in more than one lots.

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

A fifth aspect of the present invention is to provide an improved process of preparing substantially pure compound of structural formula XXXII comprises reduction of compound of structural formula XXXI by reducing agent in the presence of activating agent and diglyme, wherein the process is characterized by increasing the temperature of reaction mixture periodically.
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 the presence of activating agent, wherein the process is characterized by the addition of activating agent in more than one lots.

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 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 activating agent, wherein the process is characterized by increasing the temperature of reaction mixture periodically.
Another aspect of the present invention is to provide an improved process of preparing substantially pure compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in the presence of activating agent and diglyme, wherein the process is characterized by the addition of activating agent in more than one lots.


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 an improved process of preparing substantially pure compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in the presence of activating agent and diglyme, wherein the process is characterized by increasing the temperature of reaction mixture periodically.
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 the presence of activating agent.
The 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 or diisobutylaluminium hydride.
The activating agent is selected from the group consisting of ZnCl2, AlCl3, AlBr3, SbCls, BCl3, BF3, FeCl3, P0C13, PC15, CaCl2, BaCl2, CoCl2, MgCl2or SnCI4.
The reduction of compound of structural formula XXXI or compound of structural formula XXXIII was carried out in an ether solvent, 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 or mixture(s) thereof.
The reduction of compound of structural formula XXXI or compound of structural formula XXXIII was carried out in the presence of activating agent, wherein the addition of activating agent in more than one lots.
The details of addition of activating agent in lots and temperature are as shown below in table no.
1.

Sr. No. Activating agent Lot (in Gms) Temperature
[-C] Time (in Minutes)
1. 2.4 23 25
2. 2.3 24 20
3. 2.3 25 15
4. 7.0 23 30
5. 7.0 24 15
6. 7.0 24 15
7. 7.0 24 15
8. 7.0 23 30
9. 42.0 26 30
10. 42.0 25 30
11. 42.0 24 20
12. 42.0 27 20
13. 42.0 26 10
14. 42.0 25 10
15. 42.0 27 10
Table 1
The temperature of the reaction mixture was increases periodically after completion of addition of activating agent in lots which is summarized as below in table no. 2.

Sr. No. Temperature
[oc] Time (in Minutes)
1. 28 0
2. 75-80 60
3. 85-90 60
4. 100-105 55
5. 110-115 75
6. 120-125 315
Table 2

After completion reaction the resulting reaction mixture was cooled to 20-30'C.
The substantially pure compound of structural formula XXXII or compound of structural formula XXXIV was isolated by quenching the reaction mixture with water and then reaction mixture was acidified with concentrated hydrochloric acid. The resulting reaction mixture was heated up to 80-85°C for 30 minutes and then cooled to 20-30°C. The reaction mixture was then added organic solvent such as, toluene, xylene, ethyl acetate, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride and basified with inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. The resulting organic layer was separated, and aqueous layer was extracted with organic solvent such as, toluene, xylene, ethyl acetate, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride more than one time. The all organic layers were combined and washed with saturated aqueous sodium chloride solution 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 XXXll 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 less than 5% of compound of structural formula XXXI or compound of structural formula XXXIII respectively.

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 (200gm) in diglyme (600ml) was added sodium borohydride (93gm) and stirred for 15 minutes. The resulting reaction mixture was cooled to 20-25°C and then ZnCl2was added in lots at a temperature as shown below in table no. 1.

Sr. No. Activating agent Lot (in Gms) Temperature Time (in Minutes)
1. 2.4 23 25
2. 2.3 24 20
3. 2.3 25 15
4. 7.0 23 30
5. 7.0 24 15
6. 7.0 24 15
7. 7.0 24 15
8. 7.0 23 30
9. 42.0 26 30
10. 42.0 25 30
11. 42.0 24 20
12. 42.0 27 20
13. 42.0 26 10
14. 42.0 25 10
15. 42.0 27 10
Table 1

The temperature of the reaction mixture was increases periodically after completion of addition of activating agent in lots which is summarized as below in table no. 2.

Sr.No. Temperature
[oC] Time
(in Minutes)
1. 28 0
2. 75-80 60
3. 85-90 60
4. 100-105 55
5. 110-115 75
6. 120-125 315
Table 2
After completion reaction the resulting reaction mixture was cooled to 20-30°C. The resulting reaction mixture was quenched with water (1000ml) and acidified with concentrated hydrochloric acid (500ml). The resulting reaction mixture was heated up to 80-85°C for 30 minutes and then cooled to 20-30°C. The reaction mixture was then added toluene (400ml) and basified with aqueous sodium hydroxide solution (50%, 325 gm sodium hydroxide dissolved in 650ml of water). The resulting organic layer was separated, and aqueous layer was extracted with toluene (3x400ml). The all organic layers were combined and washed with saturated aqueous sodium chloride solution (2x400ml) and concentrated under reduced pressure at temperature below 60°C to get compound of structural formula VI as brownish oil. Yield: 145gm

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 activating agent, wherein the process is characterized by the addition of activating agent in more than one lots and increasing the temperature of reaction mixture periodically.

wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group
2. An improved process of preparing substantially pure compound of structural formula XXXII comprises reduction of compound of structural formula XXXI by reducing agent in the presence of activating agent and diglyme, wherein the process is characterized by the addition of activating agent in more than one lots and increasing the temperature of reaction mixture periodically.

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 activating agent, wherein the process is characterized by the addition of activating

agent in more than one lots and increasing the temperature of reaction mixture periodically.

wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group
4. An improved process of preparing substantially pure compound of structural formula XXXIV comprises reduction of compound of structural formula XXXIII by reducing agent in the presence of activating agent and diglyme, wherein the process is characterized by the addition of activating agent in more than one lots and increasing the temperature of reaction mixture periodically.

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 the 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 or diisobutylaluminium hydride; An

activating agent is selected from the group consisting of ZnCl2, AlCl3, AlBr3, SbCl5, BCl3, BF3, FeCl3, POCl3, PC15, CaCl2, BaCl2, CoCl2, MgCb or SnCl4.
6. The process according to claim nos. 1, 2, 3 or 4, wherein the reduction of compound of structural formula XXXI or compound of structural formula XXXIII was carried out in an ether solvent, 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 or mixture(s) thereof.
7. The process according to claim nos. 2 or 4, wherein the substantially pure compound of structural formula XXXII or compound of structural formula XXXIV was isolated by quenching the reaction mixture with water and then reaction mixture was acidified with concentrated hydrochloric acid. The resulting reaction mixture was heated up to 80-85°C
solvent such as, toluene, xylene, ethyl acetate, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride and basified with inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. The resulting organic layer was separated, and aqueous layer was extracted with organic solvent such as, toluene, xylene, ethyl acetate, chlorobenzene, dichloromethane, dichloroethane or carbon tetrachloride more than one time. The all organic layers were combined and washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure to get substantially pure compound of structural formula XXXII or compound of structural formula XXXIV.
8. Substantially pure compound of structural formula XXXII or compound of structural
formula XXXIV having less than 5% of compound of structural formula XXXI or
compound of structural formula XXXIII respectively.


wherein, P is benzyl, or substituted benzyl, alkyl sulfonyl, aryl sulfonyl or substituted aryl sulfonyl group
9. Use of substantially pure compound of structural formula XXXII or compound of structural formula XXXIV for the preparation of (S, S)-2, 8- diazabicyclo [4.3.0] nonane compound of structural formula II.
10. Use of substantially pure compound of structural formula XXXII or compound of structural formula XXXIV for the preparation of moxifloxacin hydrochloride compound of structural formula I.