WO2015150891A1 - A process for preparation of trans-sulfuric acid mono-[2-(5-azetidin-3-ylmethyl-[1,3,4]oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo [3.2.1]oct-6-yl]ester - Google Patents

Abstract

A process for preparation of a compound of Formula (I) is disclosed.

Description

A PROCESS FOR PREPARATION OF ΤΤΐΑΛΉ-SULFURIC ACID MONO-[2-(5-AZETIDIN-3-YLMETHYL-[l,3,4]OXADIAZOL-2-YL)- 7-OXO-l,6-DIAZABICYCLO [3.2.1]OCT-6-YL]ESTER

RELATED PATENT APPLICATIONS

This application claims priority to Indian Patent Application No. 1195/MUM/2014 filed on March 29, 2014, the disclosures of which are 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 irans-sulfuric acid mono-[2- (5-azetidin-3-ylmethyl-[l,3,4]oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo [3.2.1]oct-6-yl] ester.

BACKGROUND OF INVENTION

Several l,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-azetidin- 3-ylmethyl-[l,3,4]oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl]ester has antibacterial properties and is also disclosed in PCT International Patent Application No. PCT/US2013/034562.

Formula (I)

SUMMARY OF THE INVENTION

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

Formula (I)

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

cyclizing a compound of Formula (IV) to obtain a compound of Formula

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

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 ormula (VII)

(e) reacting a compound of Formula (VII) with trifluoro acetic acid 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 l-ethyl-3-(3-dimethylamino propyl)carbodiimide.

The term "HOBt" as used herein refers to 1 -hydro xybenzotriazole.

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

Formula (I)

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

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);

Formula (VI)

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

Formula (VII)

(e) reacting a compound of Formula (VII) with trifluoroacetic acid 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-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (III). The sodium salt of 6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (III) is reacted with (3-hydrazinocarbonyl-propyl)-carbamic acid tert-buty\ ester (II) in presence of coupling agent and suitable solvent such as NN-dimethylformamide, N,N - dimethylacetamide, or 1,4 dioxane; at a temperature ranging from -15°C to 60°C for about 1 hour to about 24 hour to provide an 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), 0-(benzotriazol-l- yl)-NN,N',N'-tetramethyluroniumhexafluorophosphate (HBTU), 0-(benzotriazol- 1-yl)- N,N,N',N'-tetramethyluroniumtetrafluoroborate (TBTU), 0-(7-bzabenzotriazol- 1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 0-(6-chlorobenzotriazol- l-yl)-N,NN',N'-tetramethyluronium hexafluorophosphate (HCTU), 0-(3,4-dihydro-4- oxo- 1 ,2,3-benzotriazine-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate(TDBTU), 3-(diethylphosphoryloxy)- 1 ,2,3-benzotriazin-4(3H)-one (DEPBT), carbonyldiimidazole (CDI), pivalyl chloride, HOBt and the like. In some embodiments, sodium salt of 6- benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (III) is reacted with (3-hydrazinocarbonyl-propyl)-carbamic acid tert-buty\ ester (II) in presence of EDC hydrochloride and HOBt; and in presence NN-dimethylformamide at a temperature ranging from 25 °C to 35°C for about 4 hour to provide an intermediate compound of Formula (IV).

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 j?-toluenesulfonyl chloride, j?-nitrobenzenesulfonyl chloride, or methanesulfonyl chloride; and in presence of a suitable solvent such as toluene, chloroform, dichloromethane, or NN-dimethylformamide; at a temperature ranging from 25°C to 110 °C for about 1 hour to about 14 hour to provide 1,3,4-oxadiazole intermediate compound of Formula (V). In some embodiments, compound of Formula (IV) is reacted with p- toluenesulfonyl chloride in presence of NN-dimethylformamide as solvent, at a temperature ranging from 55°C to 100°C for about 24 hour to provide a compound of Formula (V). The compound of Formula (V) is subjected for hydrogenolysis by using hydrogen source in presence of transition metal catalyst and in presence of suitable solvent such as methanol, ethanol, methanol dichloromethane mixture, or NN-dimethylformamide dichloromethane mixture; at a temperature ranging from 25 °C to 60 °C for about 1 hour to about 14 hour to provide a compound of Formula (VI). Typical, non- limiting examples of hydrogen source include hydrogen gas, ammonium formate, cyclohexene, lithium - liquid ammonia, ammonia - teri-butanol, sodium - liquid ammonia - teri-butanol, triethylsilyl 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 1 atmospheric pressure and methanol as solvent, at temperature ranging from 25°C to 35 °C for about 2 hour to provide a compound of Formula (VI).

The compound of Formula (VI) is sulfonated by reacting with suitable sulfonating reagent in a suitable solvent such as pyridine or NN-dimethylformamide, at a temperature ranging from 25°C to 80°C for about 1 hour to 24 hour. Typical, non- limiting examples of sulfonating reagent include sulfur trioxide pyridine complex, sulfur trioxide trimethylamine complex, sulfur trioxide triethylamine complex, sulfur trioxide NN-dimethylaniline complex, sulfur trioxide 2-methylpyridine complex, sulfur trioxide dioxane complex, sulfur trioxide thioxane complex, sulfur trioxide dimethyl sulfide complex, sulfur trioxide dimethylsulfoxide complex, or sulfur trioxide N,N- dimethylformamide complex. In some embodiments, compound of Formula (VI) is reacted with sulfur trioxide pyridine complex in presence of pyridine as solvent, at a temperature ranging from 25 °C to 35°C for about 6 hour 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).

Scheme 1

The compound according to the invention is finally isolated as zwitterions, by treating intermediate compound of Formula (VII) with trifluoroacetic acid in a 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 hour. In some embodiments, compound of Formula (VII) is treated with trifluoroacetic acid in presence of dichloromethane at a temperature ranging from -15°C to -5°C for about 1 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 process for preparation of a compound of Formula (I), comprising:

Formula (I)

(a) reacting a compound of Formula (II) with a compound of Formula (III) in presence of 1-hydroxybenzotriazole and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride to obtain a compound of Formula (IV);

(b) cyclizing a compound of Formula (IV) in presence of j?-toluenesulfonyl chloride to obtain a compound of Formula (V);

(c) hydrogenolysis of a compound of Formula (V) in presence of palladium on carbon and hydrogen gas to obtain a compound of Formula (VI);

Formula (VI)

(d) sulfonating a compound of Formula (VI) in presence of sulfur trioxide pyridine complex, followed by the treatment with tetrabutylammonium hydrogen sulfate to obtain a compound of Formula (VII); and

Formula (VII)

(e) reacting a compound of Formula (VII) with trifluoroacetic acid to obtain a compound of Formula (I).

In some embodiments, there is provided a compound of Formula (I) having a purity of at least about 88% 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 88% 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

Synthesis of traras-sulfuric acid mono-[2-(5-azetidin-3-ylmethyl-[l,3,4]oxadiazol-2- yl)-7-oxo-l,6-diazabicyclo [3.2.1]oct-6-yl]ester (I)

Step-1: Synthesis of tr «s-3-{2-[N'-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane-2-carbonyl)-hydrazino]-2-oxo-ethyl}-azetidine-l-carboxylic acid tert-butyl ester (IV):

To a clear solution of sodium salt of ira7?s-6-benzyloxy-7-oxo-l, 6-diaza-bicyclo [3.2.1] octane-2-carboxylic acid (III) (8.45 g, 0.028 mol) in water (100 ml) was added EDC hydrochloride (7.47 g, 0.039 mol), followed by HOBt (3.48 g, 0.025 mol) at about 25 °C under stirring. The reaction mixture was stirred for 15 minute and a solution of 3- hydrazinocarbonylmethyl-azetidine-l-carboxylic acid tert-butyl ester (II) (5.9 g, 0.026 mol) was added. The reaction mixture was stirred at about 25 °C for 18 hour. The precipitated solid was filtered, washed with water (100 ml) and dried under reduced pressure. The residue was suspended in water (100 ml) and stirred at about 45°C for 3 hour. The reaction mixture was filtered and the solid was washed with water (100 ml). The solid was dried under reduced pressure and dissolved in dichloromethane (250 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give 10.0 g of the titled compound (IV) in 80% yield.

Analysis:

Mass: 486.4 (M-l); for Molecular Weight: 487.6 and Molecular Formula:

Step-2: Synthesis of tr «s-3-[5-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)- [l,3,4]oxadiazol-2-ylmethyl]-azetidine-l-carboxylic acid tert-butyl ester (V):

To a single neck round bottom flask equipped with magnetic stirrer was charged a solution of ir ns-3-{2-[N'-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2- carbonyl)-hydrazino]-2-oxo-ethyl}-azetidine-l-carboxylic acid tert-buty\ ester (IV) (4.0 g, 0.008 mmol) in chloroform (70 ml), followed by diisopropyl ethylamine (4.4 ml, 0.025 mmol) and j?-toluenesulfonyl chloride (2.34 g, 0.012 mmol) under stirring at about 25°C. The reaction mixture was stirred at temperature of about 60°C for 12 hour. The solvent was evaporated under vacuum to provide a residue. The residue was purified on 100-200 mesh silica gel column chromatography to provide 3.3 g of titled compound (V) in 86% yield.

Analysis:

Mass: 470.4 (M+l); for Molecular Weight: 469.6 and Molecular Formula:

1H NMR (DMSO-d₆): δ 7.36-7.45 (m, 5 H), 5.07-5.10 (d, 1 H), 4.92-4.95 (d, 1 H), 4.69-4.71 (m, 1 H), 4.10-4.15 (m, 2 H), 3.68-3.72 (m, 2 H), 3.37 (s, 1 H), 3.13-3.15 (m, 2 H), 2.91-3.01 (m, 2 H), 2.76-2.79 (s, 1 H), 2.27-2.30 (m, 2 H), 2.16 (m, 1 H), 1.97 (m, 1 H), 1.43 (s, 9 H).

Step-3: Synthesis of tr «s-3-[5-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)- [l,3,4]oxadiazol-2-ylmethyl]-azetidine-l-carboxylic acid tert-butyl ester (VI):

To a clear solution of tra«s-3-[5-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct- 2-yl)-[l,3,4]oxadiazol-2-ylmethyl]-azetidine-l-carboxylic acid tert-butyl ester (V) (3.3 g, 0.007 mol) in methanol (30 ml), 10% palladium on carbon (0.4 g) was added at about 25 °C. The reaction mixture was stirred under hydrogen balloon pressure at about 25 °C for 2 hour. The catalyst was filtered under suction over a celite bed. The bed was washed with methanol (15 ml). The combined filtrate was evaporated under vacuum at temperature of below 35°C to provide 2.65 g of titled compound (VI) in 99% yield. It was used as such for further reaction.

Analysis:

Mass: 378.2 (M-l); for Molecular Weight: 379.4 and Molecular Formula: C₁₇H₂₅N₅05.

Step-4: Synthesis of tetrabutyl ammonium salt of tr «s-3-[5-(7-Oxo-6-sulfooxy-l,6- diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-ylmethyl]-azetidine-l-carboxylic acid fert-butyl ester (VII):

To a 1 L single neck round bottom flask equipped with magnetic stirrer was charged a solution of ir ns-3-[5-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)- [l,3,4]oxadiazol-2-ylmethyl]-azetidine-l-carboxylic acid tert-buty\ ester (VI) (2.65 g, 0.007 mol) in dichloromethane (50 ml), followed by triethylamine (5.0 ml, 0.036 mol) and sulfur trioxide pyridine complex (2.2 g, 0.009 mol) under stirring. The reaction mixture was stirred for 2 hour at 25 °C. The solvent was evaporated under vacuum at temperature of below 40°C to provide a residue which was stirred in 0.5 N aqueous potassium dihydrogen phosphate solution (50 ml) for 1 hour. The resulting solution was extracted successively with ethyl acetate (25 ml) and a mixture of ethyl acetate (25 ml) and dichloromethane (12.5 ml). To the aqueous layer was added tetrabutylammonium hydrogen sulfate (2.18 g, 0.006 mol) and the mixture was stirred for 2 hour at about 25°C. The product was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography to provide 2.1 g of the titled compound (VII) in 42% yield. Analysis:

Mass: 458.3 (M-l) as free sulfonic acid; for Molecular Weight: 702.5 and Molecular Formula: Ci₇H₂₄N₅0₈S. N(C₄H₉)₄.

Step-5: Synthesis of trans -sulfuric acid mono-[2-(5-azetidin-3-ylmethyl- [l,3,4]oxadiazol-2-yl)-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl] ester (I):

To a 50 ml round bottom flask equipped with magnetic stirrer was charged a solution of tetrabutyl ammonium salt of irans-3-[5-(7-oxo-6-sulfooxy-l,6-diaza- bicyclo [3.2.1] oct-2-yl)- [1,3,4] oxadiazol-2-ylmethyl] -azetidine- 1 -carboxylic acid tert- butyl ester (VII) (2.1 g, 0.005 mol) in dichloromethane (10.0 ml). The solution was cooled to -10°C under stirring and to it was added trifluoro acetic acid (10.0 ml) drop wise. The reaction mixture was stirred at temperature of about -10°C for 2 hour. Solvents were evaporated under vacuum and the residue was taken in diethyl ether (30.0 ml) and stirred for 1 hour. The mixture was filtered; the solid was washed with diethyl ether (15.0 ml) and dried under reduced pressure to yield 0.3 g of the compound of invention (I) in 30% yield.

Analysis:

Mass: 358.2 (M-l) as a free sulfonic acid; for Molecular Weight: 359.2 and Molecular Formula: Ci₂Hi₇N₅06S;

1H NMR (DMSO-d6): δ 8.35-8.41 (m, 2 H), 4.59-4.61 (d, 1 H), 4.06 (s, 3 H), 3.82-93 (m, 2 H), 3.21-3.27 (m, 3 H), 2.93-2.96 (m, 1 H), 2.75 (d, 1 H), 2.12-2.17 (m, 1 H), 1.98-2.05 (m, 2 H), 1.82-1.88 (m, 1 H); and

Purity as determined by HPLC: 88.29%.

Claims

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

Formula (I)

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

cyclizing a compound of Formula (IV) to obtain a compound of Formula

(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

Formula (VII)

(e) reacting a compound of Formula (VII) with trifluoroacetic acid 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 l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.

3. A process according to Claim 1, wherein cyclization of a compound of Formula (IV) is carried in presence of j?-toluenesulfonyl chloride.

4. A process according to Claim 1, wherein the hydrogenolysis of a compound of Formula (V) is carried out 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 the hydrogen source is hydrogen gas.

7. A process according to Claim 1, wherein sulfonation of a compound of Formula (VI) is carried in presence of sulfur trioxide pyridine complex.

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

Formula (I)

(a) reacting a compound of Formula (II) with a compound of Formula (III) in presence of 1-hydroxybenzotriazole and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride to obtain a compound of Formula (IV);

(Formula

(b) cyclizing a compound of Formula (IV) in presence of j?-toluenesulfonyl chloride to obtain a compound of Formula (V);

(c) hydrogenolysis of a compound of Formula (V) in presence of palladium on carbon and hydrogen gas to obtain a compound of Formula (VI);

(d) sulfonating a compound of Formula (VI) in presence of sulfur trioxide pyridine complex, followed by the treatment with tetrabutylammonium hydrogen sulfate to obtain a compound of Formula (VII); and

(e) reacting a compound of Formula (VII) with trifluoroacetic acid to obtain a compound of Formula (I).

9. A compound of Formula (I) having purity of at least about 88% as determined by HPLC.

10. A pharmaceutical composition comprising a compound of Formula (I) according to Claim 9.