CLIAMS:1. A process for preparation of a compound of Formula (I), comprising:

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

(b) cyclizing a compound of Formula (IV) to obtain a compound of Formula (V);

(c) hydrogenolysis of a compound of Formula (V) to obtain a compound of Formula (VI);

(d) sulfonating a compound of Formula (VI), followed by treatment with tetrabutylammonium hydrogen sulfate to obtain a compound of Formula (VII); and

(e) deprotecting a compound of Formula (VII) to obtain a compound of Formula (I).

2. A 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-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.

3. A process according to Claim 1, wherein a compound of Formula (V) is obtained by reacting compound of Formula (IV) with triphenylphosphine in presence of iodine and triethylamine.

4. A process according to Claim 1, wherein a compound of (VI) is obtained by hydrogenolysis of a compound of Formula (V) in presence of transition metal catalyst and a hydrogen source.

5. A process according to Claim 4, wherein the transition metal catalyst is palladium on carbon.

6. A process according to Claim 4, wherein hydrogen source is hydrogen gas.

7. A process according to Claim 1, wherein sulfonation of a compound of Formula (VI) is achieved by reacting with sulfur trioxide pyridine complex.

8. A process according to Claim 1, wherein deprotection of a compound of Formula (VII) is achieved by treating with trifluoroacetic acid.

9. A compound of Formula (I) having purity of at least about 90% as determined by HPLC.

10. A pharmaceutical composition comprising a compound of Formula (I) as claimed in Claim 9.
,TagSPECI:FIELD OF THE INVENTION

The invention relates to a process for preparation of trans-Sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[1,3,4]-oxadiazol-2-yl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl}ester trifluoroacetate.

BACKGROUND OF INVENTION

Several 1,6-diazabicyclo[3.2.1]octan-7-one derivatives have been described as antibacterial agents in PCT International Patent Application No. PCT/IB2012/054296. A compound of Formula (I), chemically known as trans-Sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[1,3,4]-oxadiazol-2-yl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl} ester trifluoroacetate has antibacterial properties and is disclosed in PCT International Patent Application No. PCT/US2013/034562.

SUMMARY OF THE INVENTION

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

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

(b) cyclizing a compound of Formula (IV) to obtain a compound of Formula (V);

(c) hydrogenolysis of a compound of Formula (V) to obtain a compound of Formula (VI);

(d) sulfonating a compound of Formula (VI), followed by treatment with tetrabutylammonium hydrogen sulfate to obtain a compound of Formula (VII); and

(e) deprotecting a compound of Formula (VII) to obtain 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 term “EDC” as used herein refers to 1-ethyl-3-(3-dimethylamino propyl)carbodiimide.
The term “HOBt” as used herein refers to 1-hydroxybenzotriazole.

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

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

(b) cyclizing a compound of Formula (IV) to obtain a compound of Formula (V);

(c) hydrogenolysis of a compound of Formula (V) to obtain a compound of Formula (VI);

(d) sulfonating a compound of Formula (VI), followed by the treatment with tetrabutylammonium hydrogen sulfate to obtain a compound of Formula (VII); and

(e) deprotecting a compound of Formula (VII) to obtain a compound of Formula (I).

In some embodiments, compound of Formula (I) is prepared by using a general procedure described in Scheme 1. Typically, compound of Formula (I) is prepared from sodium salt of 6-Benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (III). The sodium salt of 6-Benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (III) is reacted with 3-(tert-butoxycarbonyl-hydrazinocarbonylmethyl-amino)-azetidine-1-carbamic acid tert-butyl ester (II) in presence of coupling agent at a temperature ranging from -15 °C to 60 °C for about 1 hour to about 24 hours to provide intermediate compound of Formula (IV). Typical, non-limiting examples of coupling agent include EDC hydrochloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide (DIC), (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluroniumhexafluorophosphate (HBTU), O-(Benzotriazol-1-yl)- N,N,N’,N’-tetramethyluroniumtetrafluoroborate (TBTU), O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU), O-(3,4-Dihydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N’,N’-tetramethyl uronium tetrafluoroborate(TDBTU), 3-(Diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), Carbonyldiimidazole (CDI), pivalyl chloride, HOBt and the like. In some embodiments, compound of Formula (II) is reacted with compound of Formula (III) in presence of EDC hydrochloride and HOBt at temperature of about 25 ºC to about 35 ºC for about 15 hours to provide intermediate compound of Formula (IV). In some embodiments, compound of Formula (II) is reacted with compound of Formula (III) in presence of suitable solvents such as dimethylformamide, water or mixtures thereof.

The compound of Formula (IV) is cyclized to provide a compound of Formula (V). The cyclization of a compound of Formula (IV) is effected by treating with a reagent such as p-toluene sulfonyl chloride, p-nitrobenzene sulfonyl chloride, methane sulfonyl chloride or triphenylphosphine in a suitable solvent such as toluene, chloroform, dichloromethane, or N,N-dimethyl formamide at a temperature ranging from about -10 ° C to about 70 °C for about 15 minutes to about 4 hours to provide 1,3,4-oxadiazole intermediate compound of Formula (V). In some embodiments, compound of Formula (IV) is reacted with triphenylphosphine, in presence of iodine and triethylamine, at a temperature of about -10 °C to about 0 °C for about 30 minutes to provide a compound of Formula (V). In some embodiments, compound of Formula (IV) is cyclized to a compound of Formula (V) in presence of dichloromethane as solvent.

The compound of Formula (V) is subjected for hydrogenolysis by using hydrogen source in presence of transition metal catalyst in a suitable solvent such as methanol, ethanol, methanol dichloromethane mixture, or N,N dimethyl formamide dichloromethane mixture at a temperature ranging from 25° C to 60° C for about 1 hour to about 15 hours to provide compound of Formula (VI). 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. In some embodiments, compound of Formula (V) is treated with 10% palladium on carbon in presence of hydrogen gas at 50 psi pressure and at temperature of about 25 ºC to about 35 ºC for about 15 hours to provide compound of Formula (VI). In some embodiments, compound of Formula (V) is converted to a compound of Formula (VI) in presence of methanol as solvent.

The compound of Formula (VI) 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 25 °C to 80 °C for about 1 hour to 24 hours. Typical non-limiting examples of 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 (VI) is reacted with sulfur trioxide pyridine complex in presence of dichloromethane as solvent, at a temperature of about 25 ºC to about 35 ºC for about 2 hours to provide pyridine salt of sulfonic acid compound. The obtained pyridine salt of sulfonic acid compound is treated with tetrabutylammonium hydrogen sulfate to provide tetrabutylammonium salt of sulfonic acid compound of Formula (VII).

The compound according to the invention is finally isolated as trifluoroacetate salt, by removing the protecting groups of compound of Formula (VII). The compound of Formula (VII) is reacted with suitable deprotecting agent such as trifluoroacetic acid in presence of suitable solvent such as dichloromethane, chloroform or acetonitrile, at a temperature ranging from -15 °C to 40 °C for about 0.5 to about 14 hours. In some embodiments, compound of Formula (VII) is treated with trifluoroacetic acid in presence of dichloromethane at about 0 °C for about 3 hour to provide a compound of Formula (I).

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

In some embodiments, there is provided a compound of Formula (I) having a purity of at least about 90 % as determined by HPLC.

In some embodiments, there is provided a process for preparation of compound of Formula (I) having a purity of at least about 90 % 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 90 % as determined by HPLC. In some embodiments, the said pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients.

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

trans-Sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[1,3,4]-oxadiazol-2-yl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]ester trifluoroacetate (I)

Step 1: Preparation of trans-{3-[N-(6-Benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1] octane-2-carbonyl)-hydrazinocarbonyl]-2-oxo-ethyl}-tert-butoxycarbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (IV):

A solution of 3-(tert-butoxycarbonyl-hydrazinocarbonylmethyl-amino)-azetidine-1-carbamic acid tert-butyl ester (II) (2.8 g, 0.008 mol) in dimethylformamide (7 ml) was added to a stirred solution of sodium salt of 6-benzyloxy-7-bicyclo [3.2.1] octane-2-carboxylic acid (III) (2.43 g 0.008 mol) in water (41 ml). To this EDC.HCl (2.32 g, 0.012 mol) and HOBt (1.09 g, 0.008 mol) was added and stirred for 15 hours. Dichloromethane (50 ml) was added and layers were separated. Organic layer was dried over sodium sulfate and concentrated. The residue (6.1 gm) was purified by silica gel column chromatography using mixture of acetone and hexane as eluent to afford 3.4 g of trans-3-({2-[N-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazino]-2-oxo-ethyl}-tert-butoxy carbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (IV) in 70 % yield.

Analysis:
Mass: 603.3 (M+1); for Molecualr Weight: 602.6; Molecular Formula: C29H42N6O8; and
1H NMR (400 MHz, CDCl3): δ 8.45. (bs, 1H), 8.20 (bs, 1H) 7.38-7.45 (m, 5H), 5.04 (d, 1H), 4.91 (d, 1H), 4.13 (m, 2H), 3.97-4.04 (m, 5H), 3.30 (s, 1H), 3.07 (s, 2H), 2.91 (d, 1H), 2.31 (m, 1H), 2.20 (d, 1H), 1.93-2.00 (m, 2H), 1.45 (s, 18H).

Step 2: Preparation of trans-{2-[5-(6-Benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4]oxadiazol-2-yl]-2-oxo-ethyl}-tert-butoxycarbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (V):

Triethyl amine (3.6 ml, 0.026 mol) was added to a cooled (0 ºC) solution of iodine (1.62 gm, 0.0063 mol) and triphenylphosphine (1.67 g, 0.0063 mol) in dichloromethane (64 ml). After stirring for 15 minutes a solution of 3-({2-[N-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazino]-2-oxo-ethyl}-tert-butoxycarbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (IV) (3.2 g, 0.0053 mol) in dichloromethane (16 ml) was added. Reaction mixture was stirred at about -10 °C to about 0 °C for another 30 minutes. Dichloromethane was concentrated and ethyl acetate (35 ml) was added; stirred and filtered to remove triphenylphosphine oxide. Filtrate was concentrated and purified by silica gel column chromatography using mixture of methanol and chloroform as eluent to obtain 4.5 g of 3-{[5-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4] oxadiazol-2-yl-methyl]-tert-butoxycarbonyl-amino}-azetidine-1-carboxylic acid tert-butyl ester (V).

Analysis:
Mass: 585.4 (M+1); for Molecular Weight: 584.6 and Molecular Formula: C29H40N6O7; and
1H NMR (400 MHz, CDCl3): δ 7.64-7.68 (m, 6H), 7.52-7.56 (m, 3H) 7.42-7.48 (m, 7H), 7.36-7.38 (m, 2H), 5.07 (d, 1H), 4.92 (d, 2H), 4.72 (s, 1H), 4.68 (s, 2H), 4.15 (s, 2H), 4.01 (s, 2H), 3.36 (s, 1H), 2.91 (d, 1H), 2.79 (d, 1H), 2.27-2.30 (m, 2H), 2.11-2.14 (m, 1H), 1.97-1.99 (m, 1H), 1.42 (s, 18H).

Step 3: Preparation of trans-{2-[5-(6-Hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4]-oxadiazole-2-yl]-methyl}-tert-butoxycarbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (VI):

Palladium on carbon (10%) was added to a stirred solution of 3-{[5-(6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4]oxadiazol-2-yl-methyl]-tert-butoxy carbonyl-amino}-azetidine-1-carboxylic acid tert-butyl ester (V) (4.5 g) in methanol (45 ml). Resulting suspension was stirred under hydrogen gas pressure of about 50 psi for 15 hours. The reaction mixture was filtered through celite bed and washed using additional methanol (5 ml). The filtrate was concentrated to obtain 3.5 g of trans-{2-[5-(6-Hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4]-oxadiazole-2-yl]-methyl}-tert-butoxy carbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (VI) in 92 % yield.

Analysis:
Mass: 495.4 (M+1); for Molecualr Weight: 494.5 and Molecular Formula: C22H34N6O7; and
1H NMR (400 MHz, DMSO): δ 9.86 (s, 1H), 7.51-7.62 (m, 12H), 4.70 (s, 2H), 4.58 (d, 1H), 3.99 (d, 2H), 3.65 (s, 2H), 2.92 (d, 1H), 2.67 (d, 1H), 2.31 (s, 1H), 2.00-2.11 (m, 2H), 1.84 (m, 1H), 1.31 (s, 18H).

Step-4: Preparation of trans-Tetrabutyl ammonium salt-methyl-{2-[5-(7-oxo-6-sulphooxy-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4]oxadiazol-2-yl]-methyl}-tert-butoxycarbonyl-amino )-azetidine-1-carboxylic acid tert-butyl ester (VII):

Pyridine sulfur trioxide complex (3.17 g, 0.019 mol) and triethyl amine (4.5 ml, 0.033 mol) was added to a stirred solution of trans-{2-[5-(6-Hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4]-oxadiazole-2-yl]-methyl}-tert-butoxycarbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (VI) (2.62 g, 0.0066 mol) in dichloromethane (20 ml). The reaction mixture was stirred for 2 hours. Aqueous solution of 0.5 N potassium dihydrogen phosphate (50 ml) followed by ethyl acetate (40 ml) was added, stirred for 10 minutes and aqueous layer was separated. Aqueous layer was again extracted with the mixture of dichloromethane (10 ml) and ethyl acetate (20 ml). Combined organic layers were concentrated. The residue was dissolved in water (50 ml), washed with diethyl ether (2 × 25 ml) to remove triphenylphosphine oxide (a side product carried from the step-2) and extracted with dichloromethane (2 ×25 ml). Dichloromethane was dried over sodium sulfate and concentrated to give 2.7 g of residue (87 %). This residue was again dissolved in dichloromethane (50 ml) followed by addition of triethyl amine (5.70 ml, 0.042 mol). Tetrabutyl ammonium hydrogen sulphate (1.27 g, 0.0037 mol) was added and stirred for 2 hours. Water (30 ml) was added to the reaction mixture and layers were separated. Dichloromethane layer was dried on sodium sulfate and solvent was concentrated under vacuum. The residue (2.7 gm) was purified by silica gel column chromatography using methanol and chloroform as eluent to get 2.1 gm of trans-tetrabutyl ammonium salt-methyl-{2-[5-(7-oxo-6-sulphooxy-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4]oxadiazol-2-yl]-methyl}-tert-butoxycarbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (VII) in 48 % yield.

Analysis:
Mass: 575.4 (M+1) as free sulfonic acid; for Molecular Weight: 816.6 and Molecular Formula: C22H34N6O10S. C16H36N; and
1H NMR (400 MHz, CDCl3): δ 4.63-4.69 (m, 5H), 4.40 (s, 2H), 4.16 (s, 2H), 4.02 (s, 2H), 3.28-3.32 (m, 12H), 3.23 (s, 1H), 2.84 (d, 1H), 2.24-2.32 (m, 2H), 2.02-2.04 (m, 1H), 1.63-1.71 (m, 12H), 1.46-1.56 (m, 12H), 1.44 (s, 18H), 0.99-1.02 (m, 18H).

Step 5: Preparation of trans-Sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[1,3,4]-oxadiazol-2-yl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]ester trifluoroacetate (I)

trans-Tetrabutyl ammonium salt-methyl-{2-[5-(7-oxo-6-sulphooxy-1,6-diaza-bicyclo[3.2.1]oct-2-yl)-[1,3,4]oxadiazol-2-yl]-methyl}-tert-butoxycarbonyl-amino)-azetidine-1-carboxylic acid tert-butyl ester (VII) (2.1 gm, 0.003 mol) was cooled to 0 ºC and to this was added trifluoroacetic acid cooled at 0 ºC in 15 minutes and stirred for 3 hours. Trifluoroacetic acid was concentrated under high vacuum. Diethyl ether (20 ml) was added and solid precipitated was stirred and diethyl ether was decanted. This treatment was repeated twice. Solid separated was dried and dichloromethane (20 ml) was added and stirred; solid was allowed to settle and dichloromethane was decanted. Again this treatment was repeated twice and the solid was dried to get 1 g of trans-Sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[1,3,4]-oxadiazol-2-yl]-7-oxo-1,6-diazabicyclo [3.2.1]oct-6-yl]ester trifluoroacetate (I) in 76 % yield.

Analysis:
Mass: 375.2 (M+1) as free sulfonic acid; for Molecular Weight: 488.3 and Molecular Formula: C12H18N6O6S. CF3COOH; and
1H NMR (400 MHz, DMSO): δ 4.64 (d, 1H), 4.06 (s, 3H), 3.92 (s, 2H), 3.81-3.86 (m, 1H), 3.73 (s, 2H), 2.94-2.97 (d, 1H), 2.70 (d, 1H), 2.16 -2.19 (m, 1H), 1.88-2.14 (m, 2H), 1.86-1.88 (m, 1H).