DESC:PRIORITY APPLICATION(S)

This application claims priority to Indian Patent Application No. 3787/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 trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl]ester.

BACKGROUND OF THE INVENTION

A compound of Formula (I), chemically known as trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl]ester (also known as (2S, 5R)-sulphuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazino carbonyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl] ester) has antibacterial properties and is disclosed in PCT International Patent Application No. PCT/IB2012/054290. The present invention provides 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 trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-1,6-diaza-bicyclo [3.2.1]oct-6-yl]ester (Formula I) with higher yield and greater purity.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention 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 trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-1,6-diaza-bicyclo [3.2.1]oct-6-yl]ester with higher yield and greater purity. The process disclosed also provides large scale preparation of trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazino carbonyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl]ester (compound of Formula (I)) with higher yield and greater purity.

The term “EDC.HCl” as used herein refers to 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.

The term “HOBt” as used herein refers to 1-hydroxybenzotriazole.

The term “TBAHS” as used herein refers to tetrabutylammonium hydrogen sulfate.
In one general aspect, there is provided a process for preparation of a compound of Formula (I), said process comprising:

(a) reacting a compound of Formula (II) with a compound of Formula (III) to obtain a compound of Formula (IV);

(b) debenzylating a compound of Formula (IV) at a temperature between about -10°C to about 10°C to obtain a compound of Formula (V);

(c) sulfonating a compound of Formula (V), followed by tetrabutyl ammonium salt formation to obtain a compound of Formula (VI); and

(d) deprotecting a compound of Formula (VI) to obtain a compound of Formula (I).

In general, the compound of Formula (I) can be prepared according to the general procedure given in Scheme 1. A person of skills in the art would appreciate that the described method can be varied or optimized further to provide the desired and related compounds.
The compound of Formula (II) is coupled with a compound of Formula (III) (sodium salt of trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid, prepared as per the procedure disclosed in International Patent Application No. WO2014135929) in presence of suitable coupling agent, a suitable solvent at a temperature ranging from about -15°C to about 50°C for about 1 hour to about 48 hours to obtain a compound of Formula (IV). Typical, non-limiting examples of suitable coupling agents include 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOsu), 1-hydroxy-7-azabenzotriazolo (HOAt), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (HATU), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrop), O-(7-azabenzotriazol-1-yl)-1,3-dimethyl-1,3-trimethylene uranium hexafluorophosphate (HAMTU), 2-(5-norborene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), 2-(2-Pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), and the like, or a mixture thereof. Typical, non-limiting examples of suitable solvents include N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, water, and the like, or a mixture thereof. In some embodiments, compound of Formula (II) is reacted with a compound of Formula (III) in presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole (HOBt) and water at a temperature ranging from about 25°C to about 35°C for about 24 hours to obtain a compound of Formula (IV).

The compound of Formula (IV) is debenzylated by carrying out hydrogenolysis in presence of hydrogen, transition metal catalyst and a suitable solvent at a temperature ranging from about -15°C to about 60°C for about 1 hour to about 14 hour to provide a compound of Formula (V). Typical, non-limiting examples of hydrogen source include hydrogen gas, ammonium formate, cyclohexene, lithium –liquid ammonia, ammonia – tert-butanol, sodium – liquid ammonia – tert-butanol, triethyl silyl hydride and the like. Typical, non-limiting examples of transition metal catalyst include 5% palladium on carbon, 10% palladium on carbon, 20% palladium hydroxide on carbon, Raney-Nickel and the like. Typical, non-limiting examples of suitable solvent include methanol, ethanol, dichloromethane, N,N dimethylformamide, ethyl acetate, tetrahydrofuran, and the like, or a mixture thereof. In some embodiments, compound of Formula (IV) is hydrogenated by action of 5% palladium on carbon and hydrogen gas in presence of methanol at a temperature ranging from about -10°C to about 10°C for about 2 hours to provide a compound of Formula (V). The debenzylation reactions carried at temperatures of about -10°C to about 10°C provide the hydroxy compound of Formula (V) in higher yield and greater purity stability and assay.

The compound of Formula (V) is sulfonated by reacting with suitable sulfonating reagent in a suitable solvent such as pyridine, dichloromethane or N,N-dimethylformamide, at a temperature ranging from about 0°C to about 80°C for about 1 hour to about 24 hour. Typical, non-limiting examples of suitable sulfonating reagent include sulfur trioxide - pyridine complex, sulfur trioxide - trimethylamine complex, sulfur trioxide - triethylamine complex, sulfur trioxide - N,N-dimethylaniline complex, sulfur trioxide - 2-methylpyridine complex, sulfur trioxide - dioxane complex, sulfur trioxide - thioxane complex, sulfur trioxide - dimethyl sulfide complex, sulfur trioxide - dimethylsulfoxide complex, sulfur trioxide - N,N-dimethylformamide complex and the like. In some embodiments, compound of Formula (V) is reacted with sulfur trioxide - pyridine complex in presence of triethylamine and dichloromethane at a temperature ranging from about 25°C to about 35°C for about 2 hours to provide the sulfonated compound. The obtained sulfonated compound is converted to its corresponding tetrabutylammonium salt of Formula (VI). In some embodiments, the obtained sulfonated compound is treated with tetrabutylammonium hydrogen sulfate at a temperature ranging from about 25°C to about 35°C for about 2 hours to obtain a compound of Formula (VI).

The compound of Formula (VI) is treated with a suitable deprotecting agent in presence of a suitable solvent such as dichloromethane, chloroform or acetonitrile, at a temperature ranging from about -15°C to about 40°C for about 0.5 hours to about 14 hours 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 a compound of Formula (I) in crude form.

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

(a) reacting a compound of Formula (II) with a compound of Formula (III) in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole and water at a temperature of about 25°C to about 35°C to obtain a compound of Formula (IV);

(b) debenzylating a compound of Formula (IV) in presence of 5% palladium over carbon, hydrogen, methanol at a temperature of about 0°C to about 10°C to obtain a compound of Formula (V);

(c) sulfonating a compound of Formula (V) by treating with sulfur trioxide - pyridine complex in presence of triethyamine and dichloromethane at a temperature of about 25°C to about 35°C; followed by treatment with tetrabutylammonium hydrogen sulfate to obtain a compound of Formula (VI);

(d) deprotecting a compound of Formula (VI) by treating with trifluoroacetic acid in presence of dichloromethane at a temperature of about 0°C to about 5°C to obtain a compound of Formula (I); and

(e) isolation and purification of a compound of Formula (I) obtained in step (d).

In some embodiments, there is provided a process for isolating a compound of Formula (I) in crude form, said process comprising:
(a) triturating the residue obtained after deprotection step (d) with methyl-tert-butyl ether to obtain solid;
(b) adding acetone to the solid obtained in step (a);
(c) adjusting the pH of step (b) between about 5 to about 7 to isolate a compound of Formula (I) in crude form.

In some other embodiments, in the process of isolation of compound of Formula (I) in crude form, pH is adjusted between about 5.5 to about 6.2. In some other embodiments, the pH adjustment is carried out by addition of aqueous sodium-2-ethylhexanoate solution. In some embodiments, sodium-2-ethylhexanoate used for pH adjustment is 10% aqueous solution. In some other embodiments, the isolation of a compound of Formula (I) in crude form is carried out at temperature of about 0°C to about 10°C.

The compound of Formula (I) obtained in crude form is further purified in presence of suitable solvent at suitable pH to obtain a compound of Formula (I) having a purity of at least about 98%.

In some embodiments, there is provided a process for purification of a compound of Formula (I), said process comprising:
(a) dissolving crude compound of Formula (I) in water to obtain a clear solution;
(b) adjusting pH of the solution obtained in step (a) between about 5.5 to about 6.2;
(c) adding isopropyl alcohol to the solution obtained in step (b) and maintaining at room temperature to obtain compound of Formula (I); and
(d) isolating the compound of Formula (I) obtained in step (c).

In some embodiments, compound of Formula (I) is dissolved in water and the pH is adjusted to between about 5.5 to about 6.2 with 10% aqueous sodium-2-ethylhexanoate solution, followed by further addition of isopropyl alcohol; and so obtained solution is allowed to stand for about 10 to 12 hours at temperature ranging from about 25°C to about 35°C to obtain a compound of Formula (I) having purity of at least about 98%. In some embodiments, the amount of isopropyl alcohol used for purification of a compound of Formula (I) is about 1 to 5 times the amount of water. In some other embodiments, the amount of isopropyl alcohol used is 4 times the amount of water.
In some embodiments, there is provided a process for preparation of a compound of Formula (I) having purity of at least about 98% purity as determined by HPLC.

In some embodiments, there is provided a compound of Formula (I) having purity of at least about 98% as determined by HPLC.

In some embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) having purity of at least about 98% as determined by HPLC. The pharmaceutical composition comprising a compound of Formula (I) according to invention may include one or more pharmaceutically acceptable inactive ingredients.

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 trans-sulfuric acid mono-[2-(N’[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl]ester

Step 1: Preparation of trans-3-[N’-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-piperidin-1-carboxylic acid tert-butyl ester (IV):

To a clear solution of sodium salt of trans-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (100 g, 0.335 mol) in water (1500 ml), was added (R)-N-tert-butoxycarbonyl-piperdin-3-carboxylic acid hydrazide (82 g, 0.337 mol) followed by EDC hydrochloride (96 g, 0.501 moles) at about 25 - 35°C under stirring. The reaction mixture was stirred for 10 minutes and HOBt (45 g, 0.333 moles) was added; the resulting reaction mixture was stirred at room temperature between 25 - 35°C for 24 hours. The reaction mixture was filtered and washed with water (1000 ml). The resulting wet cake was suspended in water at 50 - 55°C and then stirred for 6 hours. The mixture was then filtered and the wet cake was washed with hot water to provide purified 140 g of trans-3-[N’-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-piperidin-1-carboxylic acid tert-butyl ester (IV) in 83% yield.
Analysis:
Purity as determined by HPLC: 98.4%

Step 2: Preparation of trans-3-[N’-(6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-piperidin-1-carboxylic acid tert-butyl ester (V):

To a clear solution of trans-3-[N’-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-piperidin-1-carboxylic acid tert-butyl ester (IV, 100 g, 0.249 mol) in methanol (400 ml) was added 5% palladium on carbon (10 g). The suspension was stirred under hydrogen gas bubbling below 10°C for 2 hours. The catalyst was filtered over a celite bed and same was washed with ethyl acetate (200 ml). The filtrate was concentrated under reduced pressure at 40°C to provide 82 g of hydroxy compound (V) as thick pasty mass in 100% yield. The obtained product was directly taken to next step.
Analysis:
Purity as determined by HPLC: 94.3%
Step 3: Preparation of tetrabutylammonium salt of trans-3-[N’-(6-sulfoxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-piperidin-1-carboxylic acid tert-butyl ester (VI):

To the clear solution of the hydroxy compound (V) in dichloromethane (800 ml) was added triethylamine (50 g, 0.4941 mol) and sulfur trioxide – pyridine complex (57 g, 0.3581 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 (1.6 L) and followed by ethyl acetate (400 ml). This biphasic reaction mixture was stirred for 15 minutes and then allowed to settle for 30 minutes. The aqueous phase was separated and then extracted with the mixture of dichloromethane and ethyl acetate (280 ml/120 ml) for 15 minutes. The mixture was allowed to settle for 30 minutes and the aqueous layer was separated. To the aqueous layer so obtained tetrabutylammonium hydrogen sulfate (60 g, 0.1767 mol) was added and stirred for two hours at 25-35°C. The mixture was extracted with dichloromethane (2 × 500 ml). The combined organic phase was evaporated under vacuum to provide 90 g of tetrabutylammonium salt (VI) as semisolid mass in 61.64% yield. The obtained product was taken directly to next step.
Analysis:
Purity as determined by HPLC: 95.53%.

Step 4: Preparation of trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-1,6-diaza-bicyclo [3.2.1]oct-6-yl]ester (I):

To the clear solution of the compound of Formula (VI) in dichloromethane (400 ml) was added trifluoroacetic acid (200 ml) slowly at -5-0°C over a period of 45 minutes. The reaction mixture was stirred for an hour and then the solvent was distilled off under reduced pressure at temperature of not more than 25°C. The residue obtained was triturated with methyl-tert-butyl ether (2500 ml) at 0-10°C and the resulting solid was filtered. The obtained white solid was further triturated with methyl-tert-butyl ether (1500 ml) at 0-10°C. The resultant solid was filtered and vacuum dried under nitrogen. To the so obtained solid was added acetone (1500 ml) at 0-10°C under stirring. The pH of the resulting mixture was adjusted in between 5.0 - 7.0 by using 10% aqueous solution of sodium-2-ethylhexanoate and stirred for 30 minutes. The mixture so obtained was filtered and the residue was further washed with chilled acetone. The wet cake was dried under vacuum to provide 59 g of compound of Formula (I) as white solid in 75.64% yield.
Analysis:
Purity as determined by HPLC: 90.82%.

Step 5: Purification of trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-1,6-diaza-bicyclo [3.2.1]oct-6-yl]ester (I):

The compound of Formula (I) obtained in crude form (20 g) was dissolved in water (50 ml) under stirring to obtain a clear solution. The pH of the solution was then adjusted in between 5.5 to 6.2 with 10% aqueous solution of sodium ethylhexanoate. To the so obtained solution, isopropyl alcohol (200 ml) was added at room temperature and the mixture was stirred for 10 to 12 hours. The separated solid was filtered under suction and dried to obtain 12 g of trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-1,6-diaza-bicyclo [3.2.1]oct-6-yl]ester in 60% yield.
Analysis:
Purity as determined by HPLC: 98.7%.
,CLAIMS:1. A process for preparation of a compound of Formula (I), said process comprising:

(a) reacting a compound of Formula (II) with a compound of Formula (III) to obtain a compound of Formula (IV);

(b) debenzylating a compound of Formula (IV) at a temperature between about -10°C to about 10°C to obtain a compound of Formula (V);

(c) sulfonating a compound of Formula (V), followed by tetrabutyl ammonium salt formation to obtain a compound of Formula (VI); and

(d) deprotecting a compound of Formula (VI) to obtain a compound of Formula (I).

2. The process according to Claim 1, wherein a compound of Formula (IV) is obtained by reacting a compound of Formula (II) with a compound of Formula (III) in presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole at a temperature of about 25°C to about 35°C.

3. The process according to any one of Claims 1 or 2, wherein a compound of Formula (IV) is obtained by reacting a compound of Formula (II) with a compound of Formula (III) in presence of water as a solvent.

4. 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 and a hydrogen source.

5. The process according to Claim 4, wherein the transition metal catalyst is palladium on carbon and hydrogen source is hydrogen gas.

6. The process according to Claim 1, wherein a compound of Formula (VI) is obtained by sulfonating a compound of Formula (V) in presence of sulfur trioxide - pyridine complex; followed by treatment with tetrabutylammonium hydrogen sulfate.

7. The process according to Claim 1, wherein a compound of Formula (I) is obtained by deprotecting a compound of Formula (VI) in presence of triflouroacetic acid temperature of about 0°C to about 5°C.

8. A process for purification of a compound of Formula (I), said process comprising:
(a) dissolving crude compound of Formula (I) in water to obtain a clear solution;
(b) adjusting pH of the solution obtained in step (a) between about 5.5 to about 6.2;
(c) adding isopropyl alcohol to the solution obtained in step (b) and maintaining at room temperature to obtain compound of Formula (I); and
(d) isolating the compound of Formula (I) obtained in step (c).

9. The process according to Claim 8, wherein the pH is adjusted in step (b) by adding sodium ethyl hexanoate solution.

10. The process according to Claim 8, wherein the amount of isopropyl alcohol used is about 1 to 5 times the amount of water.