DESC:PRIORITY APPLICATION(S)

This application claims priority to Indian Patent Application No. 3788/MUM/2015 filed on October 06, 2015, the disclosures of which is incorporated herein by reference in its entirety as if fully rewritten herein.

FIELD OF THE INVENTION

The invention relates to a process for preparation of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile.

BACKGROUND OF THE INVENTION

A compound of Formula (I), chemically known as sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (also known as (2S, 5R)-1,6-diaza-bicyclo [3.2.1]octane-2-carbonitrile-7-oxo-6-(sulfooxy)-mono sodium salt) has antibacterial properties and is disclosed in PCT International Patent Application No. PCT/IB2012/054706. The present invention discloses an improved process for preparation of a compound of Formula (I).

SUMMARY OF THE INVENTION

Accordingly, there is provided an improved process for preparation of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (compound of Formula (I)) with higher yield and greater purity.

In one general aspect, there is provided a process for preparation of a compound of Formula (I), comprising

(a) amidation of a compound of Formula (II) to obtain a compound of Formula (III);

(b) dehydration of a compound of Formula (III) to obtain a compound of Formula (IV);

(c) debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V);

(d) sulfonation of a compound of Formula (V); followed by tetrabutylammonium salt formation to obtain a compound of Formula (VI); and

(e) converting a compound of Formula (VI) to a compound of Formula (I).

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the following description including claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. All references including patents, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.

The inventors have surprisingly discovered an improved process for preparation of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile with higher yield and greater purity. The process disclosed also provides large scale preparation of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (compound of Formula (I)) with higher yield and greater purity.

The term “Bn” as used in herein refers to benzyl group.

In one general aspect, there is provided a process for preparation of a compound of Formula (I), comprising:

(a) amidation of a compound of Formula (II) to obtain a compound of Formula (III);

(b) dehydration of a compound of Formula (III) to obtain a compound of Formula (IV);

(c) debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V);

(d) sulfonation of a compound of Formula (V); followed by tetrabutylammonium salt formation to obtain a compound of Formula (VI); and

(e) converting a compound of Formula (VI) to a compound of Formula (I).

In some embodiments, a compound of Formula (I) is prepared by using a general procedure described in Scheme 1. Typically, a compound of Formula (I) is prepared from a compound of Formula (II) (prepared as per the procedure disclosed in International Patent Application No. WO2014135929)). A compound of Formula (II) is first reacted with a suitable acylating agent in presence of suitable solvent and suitable base, followed by the reaction with aqueous ammonia, to obtain a compound of Formula (III). Typical, non-limiting examples of acylating agent include pivaloyl chloride, ethylchloroformate and the like. Typical, non-limiting examples of solvent include dichloromethane, dimethylformamide, tetrahydrofuran, dimethylacetamide, dioxane or a mixture thereof. Typical, non-limiting examples of bases include triethylamine, triethylamine hydrochloride, 1-methyl-2-pyrrolidinone, 1-methylpyrrolidine, N-methylmorpholine, N-ethyldiisopropylamine or a mixture thereof. In some embodiments, a compound of Formula (II) is reacted with pivaloyl chloride in presence of dichloromethane as solvent and triethylamine as base, followed by the reaction with aqueous ammonia, to obtain a compound of Formula (III). In some embodiments, compound of Formula (II) is converted to a compound of Formula (III) at a temperature of about 0°C to about 5°C. In some embodiments, compound of Formula (III) is having a purity of at least about 99% as determined by HPLC.

The compound of Formula (III) is dehydrated with a suitable reagent to obtain a compound of Formula (IV). Typical, non-limiting examples of dehydrating agent include trifluoroacetic anhydride, thionyl chloride, phosphorous oxychloride, acetic anhydride, phosphorous pentoxide, N,N’-carbonyldiimidazole, dicyclohexylcabodimide, diphenylhydrogen phosphonate, bis(triphenyl)oxodiphosphoniumtrifluoromethane sulfonate, 1-trifluoroacetyl imidazole, 2,4,6-trichlorotriazine, 1,1’-carbonyldibenzotriazole, 1,1’-sulfonyldibenzotriazole, diethylchlorophosphate, hexamethylphosphorous triamide, titanium tetrachloride or a mixture thereof. In some embodiments, the dehydrating agent used for conversion of a compound of Formula (III) to a compound of Formula (IV) is trifluoroacetic anhydride. In some embodiments, the compound of Formula (III) is dehydrated to obtain a compound of Formula (IV) is presence of trifluoroacetic anhydride and triethylamine at a temperature of about 0°C to about 5°C under inert atmosphere.
The compound of Formula (V) is obtained by debenzylation of a compound of Formula (IV). In some embodiments, debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V) is carried out in presence of a transition metal catalyst and a hydrogen source. Typical, non-limiting examples of transition metal include platinum, palladium, rhodium, ruthenium, nickel and the like. Typical, non-limiting examples of hydrogen source include hydrogen gas, ammonium formate, cyclohexene and the like. In some other embodiments, the transition metal catalyst is palladium on carbon and hydrogen source is hydrogen gas. In some other embodiments, the debenzylation reaction is carried out in presence of a suitable solvent selected from dichloromethane, dimethylformamide, alcohol, acetone, tetrahydrofuran, ethyl acetate, dioxane or a mixture thereof. In some embodiments, the debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V) is carried out using 5% palladium on carbon catalyst, and in presence of a mixture of tetrahydrofuran and acetone as solvent. In some embodiments, debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V) is carried out at a temperature between about -20°C to about 30°C.

The compound of Formula (V) is reacted with a suitable sulfonating reagent in presence of suitable solvent, followed by tetrabutylammonium salt formation to obtain a compound of Formula (VI). Typical non-limiting examples of sulphonating reagent include sulfur trioxide pyridine complex, sulfur trioxide dimethylformamide complex or sulfur trioxide triethylamine complex and the like. In some embodiments, compound of Formula (V) is reacted with sulfur trioxide pyridine complex in presence of suitable solvent such as dichloromethane to obtain the sulfonated compound. The obtained sulfonated compound is further converted to tetrabutylammonium salt of Formula (VI). In some embodiments, tetrabutylammonium salt formation is carried out in presence of tetrabutylammonium hydrogen sulfate. In some other embodiments, the obtained sulfonated compound is directly converted to a compound of Formula (I). In some embodiments, the sufonated compound is treated with sodium-2-ethylhexanoate to obtain a compound of Formula (I).

The tetrabutylammonium salt of compound of Formula (VI) is converted to sodium salt of compound of Formula (I). The sodium salt formation is carried out either by treating with sodium exchange resins such as Amberlite sodium, Indion sodium and the like; or by reacting with sodium-2-ethylhexanoate or inorganic bases such as sodium carbonate sodium bicarbonate and the like. In some embodiments, a compound of Formula (VI) is reacted with sodium-2-ethylhexanoate in presence of a suitable solvent such as water, isopropanol or a mixture thereof to obtain a compound of Formula (I). In some embodiments, compound of Formula (I) has a purity of at least about of 98.5% as determined by HPLC.

In some embodiments, a compound of Formula (VI) is first deprotected and then sodium salt formation is carried to obtain a compound of Formula (I). In some embodiments, compound of Formula (VI) is treated with trifluoroacetic acid in presence of dichloromethane at a temperature ranging from about -5°C to about 0°C for about 1 hour to provide the deprotected compound, which is further treated with sodium-2-ethylhexanoate to obtain a compound of Formula (I). In some embodiments, compound of Formula (I) has a purity of at least about of 99% as determined by HPLC.

In some embodiments, there is provided a process for preparation of a compound of Formula (I) having a purity of at least about 98.5% as determined by HPLC.

In some embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) having a purity of at least about 98.5% as determined by HPLC. In some other embodiments, pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients.

In some embodiments, compound of Formula (I) is prepared using a process described in Scheme I.

In some embodiments, there is provided a process for preparation of a compound of Formula (I), comprising:

(a) acylating a compound of Formula (II) in presence of pivaloyl chloride, triethylamine and dichloromethane; followed by amidation with aqueous ammonia to obtain a compound of Formula (III);

(b) dehydrating a compound of Formula (III) in presence of trifluoroacetic anhydride, triethylamine and ethyl acetate to obtain a compound of Formula (IV);

(c) debenzylating a compound of Formula (IV) in presence of 5% palladium on carbon and hydrogen gas to obtain a compound of Formula (V);

(d) sulfonating a compound of Formula (V) in presence of sulfur trioxide_pyridine complex; followed by treatment with tetrabutylammonium hydrogen sulfate to obtain a compound of Formula (VI); and

(e) converting a compound of Formula (VI) to a compound of Formula (I).

In some embodiments, there is provided a process for preparation of a compound of Formula (I), comprising

(a) amidation of a compound of Formula (II) to obtain a compound of Formula (III);

(b) dehydration of a compound of Formula (III) to obtain a compound of Formula (IV);

(c) debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V); and

(d) sulfonation of a compound of Formula (V); followed by sodium salt formation to obtain a compound of Formula (I).

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will recognize that the invention may be practiced using a variety of different compounds within the described generic descriptions.

EXAMPLES

The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

Example 1
Synthesis of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile

Step 1: Preparation of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (III):

To a suspension of sodium (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (II) (100 g, 0.335 mol) in dichloromethane (1000 ml) was added triethylamine (93.60 ml, 0.670 mol ), pivaloylchloride (82.48 ml, 0.670 mol ) sequentially at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred at 0-10°C for 60 minutes; and then aqueous ammonia (80 ml) was slowly added at 0-5°C. The resulting mixture was stirred for 60 minutes at 0-5°C. The completion of the reaction was confirmed by thin layer chromatography. The reaction mass was quenched with water (1000 ml) and organic and aqueous layers were separated. The organic phase was concentrated under reduced pressure at temperature not more than 35°C and the resulting residue was triturated with ethyl acetate to afford 79.6 g of the titled compound (III) in 85% yield.
Analysis:
Purity as determined by HPLC: 99%.

Step 2: Preparation of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonitrile (IV):

To a suspension of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (III) (100 g, 0.363 mol) in ethyl acetate (1000 ml) was added triethylamine (228 ml, 1.633 mol) and trifluoroacetic anhydride (103 ml, 0.731 mol) sequentially at 0-5°C under nitrogen atmosphere. The resulting mixture was stirred at 0-5°C for 1 hour. The completion of the reaction was monitored by thin layer chromatography. The reaction mass was quenched with water (500 ml) organic and aqueous layers were separated. The organic phase was concentrated under reduced pressure at temperature not more than 35°C and the resulting residue triturated with water (1000 ml) to obtain 91.7 g of the titled compound (IV) as yellow solid in 98% yield.

Step 3: Preparation of (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonitrile (V):

To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carbonitrile (IV) (20 g, 0.077 mol) in the mixture of tetrahydrofuran (200 ml) and acetone (200ml) was added 5% palladium on carbon (6 g) and the resulting mixture was stirred under hydrogen gas bubbling at 25-30°C for 60 minutes. The completion of the reaction was monitored by thin layer chromatography. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford 13 g of the titled compound as a thick semi solid.
Analysis:
Purity as determined by HPLC: 97.92%.

Step 4: Preparation of tetrabutylammonium salt of (2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbonitrile (VI):
The product obtained in step 3 (13 g, 0.077 mol) was dissolved in dichloromethane (130 ml) and to the clear solution was added triethyl amine (11.7 g, 0.115 mol) and sulfur trioxide-pyridine complex (14.7 g, 0.092 mol). The suspension was stirred at 25-35°C for 2 hours. The resulting reaction mixture was quenched by 6% aqueous potassium dihydrogen phosphate solution and organic and aqueous layers were separated. To the aqueous phase was added tetrabutylammonium hydrogen sulfate (31.4 g, 0.092 mol) and stirred for 60 minutes at 25-35°C. The mixture so obtained was further extracted with dichloromethane (2 × 130 ml). The combined organic phase was dried on sodium sulfate and evaporated under vacuum to obtain 36 g of the titled compound in 95% yield.
Analysis:
Purity as determined by HPLC: 97.2%.

Step 5: Synthesis of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile:

To a solution of the product obtained in step 4 (18 g, 0.037 mol) in isopropanol (150 ml) was added sodium-2-ethyl hexanoate(13 gm, 0.078 mole) in isopopanol (150ml) and water (2 ml) at 25-30°C. The resulting mixture was stirred at 25-30°C for 60 minutes. The suspension was cooled to 0-10°C for 4 hours. The separated crystals were filtered and washed with pre cooled 5% aqueous isopropanol (2 × 20 ml). The crystals were dried under vacuum at 30-35°C to obtain 5.8 g of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (I) as white solid in 53.8 % yield.
Analysis:
Purity as determined by HPLC: 98.86%

Example 2:

Synthesis of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (I)

Step 1: Preparation of (2S,5R)-6-(hydroxy)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (V):

To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (IV) (100 g, 0.3886 mol) in tetrahydrofuran/dimethylformamide (1000 ml) was added palladium on carbon (20 g, 5% Pd/C) and the resulting mixture was stirred under hydrogen gas bubbling for 2 to 4 hours. The reaction mixture was filtered through celite bed and washed with tetrahydrofuran (100 ml) and the filtrate was concentrated under vacuum at a temperature of 35°C to afford the title compound (V) as a syrupy liquid as quantitative yield and was immediately used for the next reaction without further purification.

Step 2: Preparation of tetrabutylammonium salt of (2S,5R)-7-oxo-6-(sulphoxy)-1, 6-diazabicyclo [3.2.1]-octane-2-carbonitrile (VI):

To a solution of product obtained in Step 1 in dichloromethane (1000 ml) was added triethylamine (135 ml, 0.9715 mol) and sulfur trioxide pyridine complex (90 g, 0.5674 mol). The mixture was stirred at a temperature of 25-35°C for 60 minutes. After completion of the reaction as indicated by HPLC analysis, 10% aqueous potassium dihydrogen phosphate solution (2000 ml) was added. The resulting mixture was separated and aqueous layer was washed with dichloromethane. To the aqueous layer was added tetrabutylammonium hydrogen sulfate (132 g, 0.3886 mol) at room temperature and stirred for 90 minutes. The so obtained mixture was extracted with dichloromethane (1×1000 ml). The organic layer was distilled off under vacuum at 40°C to afford 138 g of the titled compound (VI) as a syrupy liquid in 70% yield.
Analysis:
Purity as determined by HPLC: 95%.

Step 3: Preparation of sodium salt of (2S,5R)-7-oxo-6-(sulphoxy)-1, 6-diazabicyclo [3.2.1]-octane-2-carbonitrile (I):

To the solution of the product obtained in Step 2 (13 g, 0.0267 mol) in anhydrous dichloromethane (50 ml) was added trifluoroacetic acid (6 ml) dropwise at -5 to 0°C under nitrogen. The reaction mixture was stirred for 1 hour then concentrated under vacuum at temperature below 30°C. The resulting residue was taken in dichloromethane and sodium-2-ethyl hexanoate (13.5 g, 0.0812 mol) was added under stirring. The reaction mixture was stirred to obtain cream colored precipitate. Methyl-tert-butyl ether was added to the precipitate and the resulting creamy precipitate was collected by filtration to obtain the titled compound (I). The obtained solid was suspended in isopropanol and the pH was adjusted in the range of 5.0 - 7.0 using 10% aqueous sodium-2-ethyl hexanoate solution. After adjusting the required pH, reaction mass was stirred for 2 hours and filtered to obtain 7 g of the titled compound (I) as white solid in 97% yield.
Analysis:
Purity as determined by HPLC: 99.25%.

Example 3

Synthesis of sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile

Step 1: Preparation of (2S,5R)-6-(hydroxy)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (V):

To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (IV) (10 g, 0.0388 mol) in tetrahydrofuran/dimethylformamide (100 ml) was added palladium on carbon (1 g, 5% Pd/C). The resulting reaction mixture was stirred under hydrogen gas bubbling for 2-4 hours. The reaction mixture was filtered through celite bed and washed with tetrahydrofuran (20 ml) and the filtrate was concentrated under vacuum at a temperature of 35°C to afford the titled compound (V) as a syrupy liquid in quantitative yield and was immediately used for the next reaction.

Step 2: Preparation of sodium salt of (2S,5R)-7-oxo-6-(sulphoxy)-1, 6-diazabicyclo [3.2.1]-octane-2-carbonitrile (I):
To a solution of Step 1 product in dichloromethane (100 ml), was added dimethylformamide sulfur trioxide complex (7.2 g, 0.047 mol) at 0-5°C and stirred to completion of the reaction as monitored by thin layer chromatography. After completion of the reaction, sodium-2-ethyl-hexanoate (97 g, 0.0583 mol) was added to the reaction mixture under stirring. After complete conversion, dichloromethane was distilled off under vacuum at 30°C. The residue was triturated with isopropyl alcohol to obtain the solid. The filtered solid was dissolved in water (20 ml) and acetone (100 ml). The obtained solution was filtered and the filtrate was concentrated under vacuum at 35°C. The obtained residue was triturated with isopropyl alcohol (100 ml) until the solid separates out. The obtained solid was filtered to provide 3 g of titled compound (I) in 29% yield.
Analysis:
Purity as determined by HPLC: 98.96%.
,CLAIMS:1. A process for preparation of a compound of Formula (I), comprising

(a) amidation of a compound of Formula (II) to obtain a compound of Formula (III);

(b) dehydration of a compound of Formula (III) to obtain a compound of Formula (IV);

(c) debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V);

(d) sulfonation of a compound of Formula (V); followed by tetrabutylammonium salt formation to obtain a compound of Formula (VI); and

(e) converting a compound of Formula (VI) to a compound of Formula (I).

2. The process according to Claim 1, wherein amidation of a compound of Formula (II) to obtain a compound of Formula (III) is carried out at temperature of about 0°C to about 5°C.

3. The process according to Claim 2, wherein a compound of Formula (III) is obtained by amidation of a compound of Formula (II) in presence of an acylating agent, base and solvent; followed by a reaction with an aqueous ammonia.

4. The process according to Claim 3, wherein acylating agent is pivaloyl chloride, base is triethylamine and solvent is dichloromethane.

5. The process according to Claim 1, wherein dehydration of a compound of Formula (III) to obtain a compound of Formula (IV) is carried out in presence of trifluoroacetic anhydride at temperature of about 0°C to about 5°C.

6. The process according to Claim 1, wherein debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V) is carried out in presence of a transition metal catalyst, a hydrogen source and a solvent at a temperature between about -20°C to about 30°C.

7. The process according to Claim 6, wherein transition metal catalyst is palladium on carbon, hydrogen source is hydrogen gas and solvent is a mixture of tetrahydrofuran and acetone.

8. The process according to Claim 1, wherein sulfonation of a compound of Formula (V) is carried out in presence of a reagent selected from sulfur trioxide-dimethylformamide complex or sulfur trioxide-pyridine complex.

9. The process according to Claim 1, wherein a compound of Formula (VI) is treated with trifluoroacetic acid, followed by reaction with sodium-2-ethylhexanoate to obtain a compound of Formula (I).

10. A process for preparation of a compound of Formula (I), comprising

(a) amidation of a compound of Formula (II) to obtain a compound of Formula (III);

(b) dehydration of a compound of Formula (III) to obtain a compound of Formula (IV);

(c) debenzylation of a compound of Formula (IV) to obtain a compound of Formula (V); and

(d) sulfonation of a compound of Formula (V); followed by sodium salt formation to obtain a compound of Formula (I).