WO2016157057A1 - A process for preparation of sodium salt of (2s, 5r) sulfuric acid mono-(2-[1,3,4]oxadiazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1 ]oct-6-yl)ester - Google Patents
A process for preparation of sodium salt of (2s, 5r) sulfuric acid mono-(2-[1,3,4]oxadiazol-2-yl-7-oxo-1,6-diazabicyclo[3.2.1 ]oct-6-yl)ester Download PDFInfo
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- 0 *S(ON([C@]1CC[C@](c2nnc[o]2)N2C1)C2=O)(=O)=O Chemical compound *S(ON([C@]1CC[C@](c2nnc[o]2)N2C1)C2=O)(=O)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the invention relates to a process for preparation of sodium salt of 2S, 5R) mono-(2- [ 1 ,3 ,4]oxadiazol-2-yl-7-oxo- 1 ,6-diazabicyclo[3.2.1 ]oct-6-yl)ester
- a compound of Formula (I), chemically known as sodium salt of 2S, 5R) mono-(2- [l,3,4]oxadiazol-2-yl-7-oxo-l,6-diazabicyclo[3.2.1 ]oct-6-yl)ester has antibacterial properties and is disclosed in PCT International Patent Application No. PCT/US2013/034562.
- the compound of Formula (I) is also generically disclosed in PCT International Patent Application No. PCT/IB2012/054296.
- the present invention discloses a process for preparation of a compound of Formula (I).
- Figure 1 is an X-ray powder diffraction pattern of a compound of Formula (I) in crystalline form.
- EDC l-ethyl-3-(3-dimethylamino propyl)carbodiimide.
- HOBt 1 -hydroxybenzotriazole.
- Suitable coupling agent include EDC.HC1, HOBt, N,N'-dicyclohexyldiimde, (1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU) or a mixture thereof.
- Typical non-limiting examples of a suitable base include triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, morpholine, N-methylmorpholine or a mixture thereof.
- Suitable solvent include water, N,N- dimethylformamide, N,N-dimethylacetamide or a mixture thereof.
- compound of Formula (II) is treated with formyl hydrazide in presence of EDC.HC1, HOBt and diisopropylethylamine at a temperature of about 20°C to 35°C to provide a coupled intermediate compound of Formula (III).
- the coupled intermediate (III) was subjected to ring formation by treating it with a suitable cyclizing agent in presence of a suitable base and a solvent at a temperature ranging from 0°C to 80°C to provide 1,3,4-oxadiazole ring intermediate compound of Formula (IV).
- cyclizing agent include methanesulfonic acid chloride, p-nitrophenylsulphonic acid chloride, p-tolylsulfonylchloride, iodine/triphenylphosphine/triethylamine combination and the like.
- suitable base include triethylamine, diisopropylethylamine, pyridine, ⁇ , ⁇ -diemthylaminopyridine, morpholine, N-methyl morpholine and the like.
- suitable solvent include dichloromethane, chloroform, ethylenedichloride and the like.
- compound of Formula (III) is cyclized by the action of p- tolylsulfonylchloride in the presence of diisopropylethylamine and chloroform at a temperature of about 50°C to 70°C to provide a compound of Formula (IV).
- Suitable solvent include methanol, ethanol, ethylacetate, tetrahydrofuran or a mixture thereof.
- a compound of Formula (IV) is treated with 10% palladium on carbon and hydrogen gas in presence of methanol a temperature of about 25°C to 30°C to obtain a compound of Formula (V).
- the compound of Formula (V) is reacted with a suitable sulphonating reagent in presence of a suitable base and a solvent at a temperature of about 0°C to 60°C to provide a sulphonated compound.
- a suitable sulphonating reagent include sulfur trioxide pyridine complex, sulfur trioxide dimethylformamide complex, sulfur trioxide triethylamine complex and the like.
- suitable base include triethylamine, pyridine, disiopropylethylamine, morpholine, N-methylmorpholine ant the like.
- the intermediate tetrabutylammonium salt compound of Formula (VI) is converted to compound of Formula (I) by exchanging tetrabutylammonium group by sodium.
- compound of Formula (VI) is treated with sodium-2-ethylhexanoate in a suitable solvent selected from dimethylfomamide, ethanol, acetone or a mixture thereof to obtain a compound of Formula (I).
- compound of Formula (VI) is contacted with sodium exchange resin and eluted with a suitable solvent to obtain a compound of Formula (I).
- Typical, non-limiting examples of sodium exchange resin include Amberlite IR 120, DOWEX and then like.
- suitable solvent include mixture of tetrahydrofuran and water.
- a compound of Formula (I) is prepared using a process described in Scheme 1.
- the suspension was filtered under suction and the wet cake was washed with additional cyclohexane (50 ml).
- the soild was dried under vacuum to provide 4.5 g of the titled compound as a whitish solid in 92% yield, which was used for the next reaction immediately.
- Step IV Synthesis of tetrabutylammonium salt of (25, 5R)-sulfuric acid mono-(2- [l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (VI):
- Step V Sodium salt of (25, 5R)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza- bicyclo[3.2.1]oct-6-yl) ester (I):
- the compound sodium salt of (2S, 5i?)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6- diaza-bicyclo[3.2.1]oct-6-yl) ester of Formula (I) was prepared by loading tetrabutylammonium salt of sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (VI, 7 g) on a column packed with Amberlite IR 120 Na form of resin, and by eluting the column with methanol water mixture (9: 1). Fractions containing compound were collected and solvent was evaporated under vacuum below 40°C, to provide formula- 1 compound in 4 gm (62%) quantity as a white solid.
- Typical X-ray analysis was performed as follows. Pass the test substance through sieve #100 BSS or gently grind it with a mortar and pestle. Place the test substance uniformly on a sample holder having cavity surface on one side, press the sample and cut into thin uniform film using a glass slide in such a way that the surface of the sample should be smooth and even. Record the X-ray diffractogram using the following instrument parameters.
- Antiscattering slit (Incident beam) : 1°
- Anti-scattering slit (Diffracted beam) : 5.5 mm
Abstract
A process for preparation of sodium salt of (2S, 5R)-sulfuric acid mono-(2-[1,3,4] oxadiazol-2- yl-7-oxo-1,6-diaza-bicyclo[3.2.1]oct-6-yl) ester is disclosed.
Description
A PROCESS FOR PREPARATION OF SODIUM SALT OF (2S, 5R) SULFURIC ACID MONO-(2-[1 ,3,4]OXADIAZOL-2-YL-7-OXO-1 ,6-DIAZABICYCLO[3.2.1 ]OCT-6-YL)ESTER
PRIORITY APPLICATION
This application claims priority to Indian Patent Application No. 1077/MUM/2015 filed on March 27, 2015, 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 sodium salt of 2S, 5R) mono-(2- [ 1 ,3 ,4]oxadiazol-2-yl-7-oxo- 1 ,6-diazabicyclo[3.2.1 ]oct-6-yl)ester
BACKGROUND OF THE INVENTION
A compound of Formula (I), chemically known as sodium salt of 2S, 5R) mono-(2- [l,3,4]oxadiazol-2-yl-7-oxo-l,6-diazabicyclo[3.2.1 ]oct-6-yl)ester has antibacterial properties and is disclosed in PCT International Patent Application No. PCT/US2013/034562. The compound of Formula (I) is also generically disclosed in PCT International Patent Application No. PCT/IB2012/054296. The present invention discloses a process for preparation of a compound of Formula (I).
In one general aspect, there is provided a process for preparation of a compound of Formula (I), comprising:
cyclizing a compound of Formula (III) to obtain a compound of Formula (IV);
(c) hydrogenolysis of a compound of Formula (IV) to obtain a compound of Formula (V);
Formula (V)
(e) converting a compound of Formula (VI) to a compound of Formula (I).
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.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is an X-ray powder diffraction pattern of a compound of Formula (I) in crystalline form.
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 -hydroxybenzotriazole.
In one general aspect, there is provided a process for preparation of a compound of Formula (I), comprising:
Formula (I)
(a) converting a compound of Formula (II) to a compound of Formula (III);
(c) hydrogenolysis of a compound of Formula (IV) to obtain a compound of Formula (V);
Formula (V)
(e) converting a compound of Formula (VI) to a compound of Formula (I)
In some embodiments, compound of Formula (I) is prepared by using a general procedure described in Scheme 1. Typically, a compound of Formula (I) is prepared from sodium salt of 6- benzyloxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (II). The sodium salt of 6- benzyloxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (II) was coupled with formyl hydrazide in the presence of coupling agent, suitable base and suitable solvent at a temperature ranging from -5°C to 60°C to obtain a compound of Formula (III). Typical, non-limiting examples of suitable coupling agent include EDC.HC1, HOBt, N,N'-dicyclohexyldiimde, (1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU) or a mixture thereof. Typical non-limiting examples of a suitable base include triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, morpholine, N-methylmorpholine or a mixture thereof. Typical non-limiting examples of suitable solvent include water, N,N- dimethylformamide, N,N-dimethylacetamide or a mixture thereof. In some embodiments, compound of Formula (II) is treated with formyl hydrazide in presence of EDC.HC1, HOBt and diisopropylethylamine at a temperature of about 20°C to 35°C to provide a coupled intermediate compound of Formula (III).
The coupled intermediate (III) was subjected to ring formation by treating it with a suitable cyclizing agent in presence of a suitable base and a solvent at a temperature ranging from 0°C to 80°C to provide 1,3,4-oxadiazole ring intermediate compound of Formula (IV). Typical, non-limiting examples of cyclizing agent include methanesulfonic acid chloride, p-nitrophenylsulphonic acid chloride, p-tolylsulfonylchloride, iodine/triphenylphosphine/triethylamine combination and the like. Typical, non-limiting examples of suitable base include triethylamine, diisopropylethylamine, pyridine, Ν,Ν-diemthylaminopyridine, morpholine, N-methyl morpholine and the like. Typical, non- limiting examples of suitable solvent include dichloromethane, chloroform, ethylenedichloride and the like. In some embodiments, compound of Formula (III) is cyclized by the action of p- tolylsulfonylchloride in the presence of diisopropylethylamine and chloroform at a temperature of about 50°C to 70°C to provide a compound of Formula (IV).
The compound of Formula (IV) is debenzylated by catalytic hydrogenolysis to obtain a compound of Formula (V). The compound of Formula (IV) is subjected to catalytic hydrogenolysis in presence of a suitable catalyst, a suitable hydrogen source and a suitable solvent at a temperature ranging from about 0°C to 40°C to obtain the hydroxy 1 compound of Formula (V). Typical, non- limiting examples of suitable catalyst include 5% palladium on carbon, 10% palladium on carbon, 20% palladium hydroxide and the like. Typical, non-limiting examples of suitable hydrogen source include hydrogen gas, cyclohexene, ammonium formate, hydrazinehydrate and the like. Typical, non-limiting examples of suitable solvent include methanol, ethanol, ethylacetate, tetrahydrofuran or a mixture thereof. In some embodiments, a compound of Formula (IV) is treated with 10% palladium on carbon and hydrogen gas in presence of methanol a temperature of about 25°C to 30°C to obtain a compound of Formula (V).
The compound of Formula (V) is reacted with a suitable sulphonating reagent in presence of a suitable base and a solvent at a temperature of about 0°C to 60°C to provide a sulphonated compound. Typical, non-limiting examples of sulphonating reagent include sulfur trioxide pyridine complex, sulfur trioxide dimethylformamide complex, sulfur trioxide triethylamine complex and the like. Typical, non-limiting examples of suitable base include triethylamine, pyridine, disiopropylethylamine, morpholine, N-methylmorpholine ant the like. Typical, non-limiting examples of suitable solvent include dichloromethane, chloroform, ethylene dichloride, pyridine or a mixture thereof. In some embodiments, a compound of Formula (V) is treated with sulfur trioxide pyridine
complex in presence of triethylamine and dichloromethane at a temperature of about 25°C to 35°C to obtain the sulphonated compound. The so obtained sulfonated compound is further converted to its corresponding tetrabutylammonium salt. In some embodiments, the sulfonated compound is treated with tetrabutylammonium hydrogen sulfate or tetrabutylammnoium acetate to provide tetrabutylammonium salt compound of Formula (VI).
The intermediate tetrabutylammonium salt compound of Formula (VI) is converted to compound of Formula (I) by exchanging tetrabutylammonium group by sodium. In some embodiments, compound of Formula (VI) is treated with sodium-2-ethylhexanoate in a suitable solvent selected from dimethylfomamide, ethanol, acetone or a mixture thereof to obtain a compound of Formula (I). In some embodiments, compound of Formula (VI) is contacted with sodium exchange resin and eluted with a suitable solvent to obtain a compound of Formula (I). Typical, non-limiting examples of sodium exchange resin include Amberlite IR 120, DOWEX and then like. Typical, non-limiting examples of suitable solvent include mixture of tetrahydrofuran and water.
In some embodiments, a compound of Formula (I) is prepared using a process described in Scheme 1.
(VI) Compound of Formula (I)
SCHEME-1
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 formyl hydrazine in presence of 1- hydroxybenzotriazole and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to obtain a compound of Formula (III);
(b) cyclizing a compound of Formula (III) in presence of p-tolylsulfonylchloride to obtain a compound of Formula (IV);
(c) hydrogeno lysis of a compound of Formula (IV) in presence of 10% palladium over carbon and hydrogen gas to obtain a compound of Formula (V);
Formula (V)
(d) reacting a compound of Formula (V) with a suphonating reagent, followed by the treatment with tetrabutylammonium hydrogen sulphate to obtain a compound of Formula (VI); and
Formula (VI)
O O " ON(Bu)4
(e) contacting a compound of Formula (VI) with a sodium exchange resin to obtain a compound of Formula (I).
In some embodiments, there is provided a compound of Formula (I) in crystalline form.
In some embodiments, there is provided a compound of Formula (I) in a crystalline form and having an X-ray powder diffraction pattern comprising a peak selected from the group consisting of 11.30 (± 0.2), 13.01 (± 0.2), 13.67 (± 0.2), 14.19 (± 0.2), 15.16 (± 0.2), 16.85 (± 0.2), 17.77 (± 0.2), 18.13 (± 0.2), 18.93 (± 0.2), 19.18 (± 0.2), 20.37 (± 0.2), 21.35 (± 0.2), 22.12 (± 0.2), 22.65 (± 0.2), 23.97 (± 0.2), 25.09 (± 0.2), 25.33 (± 0.2), 26.03 (± 0.2), 26.38 (± 0.2), 26.84 (± 0.2), 28.37 (± 0.2), 28.63 (± 0.2), 29.15 (± 0.2), 29.65 (± 0.2), 30.61 (± 0.2), 31.95 (± 0.2), 33.41 (± 0.2) and 33.96 (± 0.2) degrees 2 theta
In some embodiments, there is provided a compound of Formula (I) in a crystalline form and having an X-ray powder diffraction pattern comprising a peak selected from the group consisting of 11.30 (± 0.2), 13.01 (± 0.2), 13.67 (± 0.2), 14.19 (± 0.2), 15.16 (± 0.2), 16.85 (± 0.2), 17.77 (± 0.2), 20.37 (± 0.2), 21.35 (± 0.2), 22.12 (± 0.2), 23.97 (± 0.2), 26.03 (± 0.2), 26.84 (± 0.2), 28.63 (± 0.2), 30.61 (± 0.2), 31.95 (± 0.2) and 33.96 (± 0.2) degrees 2 theta.
In some embodiments, there is provided a compound of Formula (I) in a crystalline form and having an X-ray powder diffraction pattern comprising a peak selected from the group consisting of 13.01 (± 0.2), 13.67 (± 0.2), 14.19 (± 0.2), 16.85 (± 0.2), 20.37 (± 0.2), 21.35 (± 0.2), 22.12 (± 0.2), 26.03 (± 0.2), 26.84 (± 0.2) and 31.95 (± 0.2) degrees 2 theta.
In some embodiments, there is provided a compound of Formula (I) in a crystalline form and having an X-ray powder diffraction pattern substantially the same as shown in Figure 1.
In some embodiments, there is provided a compound of Formula (I) having a purity of at least about 89% as determined by HPLC.
In some embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) in a crystalline form and having an X-ray powder diffraction pattern substantially the same as shown in Figure 1. In some embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) having a purity of at least about 89% as determined by HPLC. In some embodiments, the said pharmaceutical compositions 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
Sodium salt of (25, 5R) sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza- bicyclo[3.2.1]oct-6-yl) ester
Step I: Synthesis of (25,5R)-2-(iV'-formyl-hydrazinocarbonyl)-6-benzyloxy-7-oxo-l,6-diaza- bicyclo[3.2.1] octane (III):
To a turbid solution of sodium salt of (2<S',5i?)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1 ] octane-2-carboxylic acid (II, 20 g, 0.067 mol) (prepared according to process disclosed in PCT/IB2013/059264) in dimethylformamide (200 ml) was added EDC hydrochloride (19.44 g, 0.10 mol) followed by formyl hydrazide (4.02 g, 0.067 mol) and N-hydroxybenzotriazole (9 g, 0.67 mol) at about 25°C under stirring. Diisopropylethylamine (35.62 ml, 0.20 mol) was added to the reaction mixture and stirred at 25°C temperature for 18 hours. The reaction mixture was evaporated under vacuum to provide a residue. The residue was dissolved in ethyl acetate (500 ml) and washed with water (500 ml χ 2), followed by saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum to provide a crude intermediate, which was purified by silica gel column chromatography to provide 11 g of the titled compound as solid in 52% yield.
Analysis:
Mass: 319.1 (M+l); for Molecular Formula of C15H18N4O4 and Molecular Weight of 318.34;
H1 NMR (DMSO-d6): δ 9.93 (s, 1H), 9.87 (s, 1H), 8.01 (s, 1H), 7.36-7.46 (m, 5H), 4.91-4.97 (dd, 2H), 3.83-3.84 (br s, 1H), 3.70 (s, 1H), 3.15-3.18 (br s, 1H), 2.90-2.95 (m, 1H), 1.99-2.03(m, 1H), 1.86(br s, 1H), 1.73-1.75 (m, 1H), 1.66 (m, 1H).
Step II: Synthesis of (25,5R)-2-([l,3,4]-oxadiazol-2-yl)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (IV):
To a clear solution of (2<S',5i?)-2-(N'-formyl-hydrazinocarbonyl)-6-benzyloxy-7-oxo-l ,6-diaza- bicyclo[3.2.1 ] octane (III, 11 g, 0.0345 mol) in chloroform (120 ml) was added diisopropylethylamine (18.31 ml, 0.1035 mol) and p-tolylsulfonylchloride (9.83 g, 0.0517 mol). The solution was stirred at 60°C for 15 hours. Reaction mixture was cooled to room temperature and water (100 ml) was added. Organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum to provide a crude residue, which was purified by silica gel column chromatography to provide 7 g of the titled compound as a solid in 68% yield.
Analysis:
Mass: 301.3 (M+l); for Molecular Formula of Ci5Hi6N403 and Molecular Weight of 300.32;
H1 NMR (CDC13): δ 8.45 (s, 1H), 7.25-7.44 (m, 5H), 5.07-5.10 (dd, 1H), 4.92-4.95 (dd, 1H), 4.76-4.78 (br s, 1H), 3.37 (br s, 1H), 2.93-.95 (br s, 1H), 2.75-2.77 (m, 1H), 2.32-2.33 (m, 2H), 2.13- 2.16 (m, 1H), 1.93-2.01 (m, 1H).
Step III: Synthesis of (25,5R)-2-([l,3,4]-oxadiazol-2-yl)-6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane (V):
To a clear solution of (2<S',5i?)-2-([l,3,4]-oxadiazol-2-yl)-6-benzyloxy-7-oxo-l,6-diaza- bicyclo[3.2.1 ] octane (IV, 7.0 g, 0.0233 mmol) in methanol (70 ml) was added 10% palladium on carbon (2.5 g). The suspension was stirred under atmospheric hydrogen pressure at a temperature 25° C for 2 hrs. The catalyst was filtered over a celite bed and the bed was washed with methanol (30 ml). The filtrate was concentrated under vacuum to provide an oily residue. The residue was triturated with cyclohexane (100 ml) to effect solid formation. The suspension was filtered under suction and the wet cake was washed with additional cyclohexane (50 ml). The soild was dried under vacuum to provide 4.5 g of the titled compound as a whitish solid in 92% yield, which was used for the next reaction immediately.
Analysis:
Mass: 211.2 (M+l); for Molecular Formula of C8Hi0N4O3 and Molecular Weight of 210.19; 1H NMR (DMSO-d6): δ 9.88 (br s, 1H), 9.29 (s, 1H), 4.65 (d, 1H ), 4.64 (br s, 1H), 2.94-2.97 (br d, 1H), 2.63-2.66 (d, 1H), 1.89-2.09 (m,3H), 1.82-1.86 (m, 1H).
Step IV: Synthesis of tetrabutylammonium salt of (25, 5R)-sulfuric acid mono-(2- [l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (VI):
To a clear solution of (2<S',5i?)-2-([l,3,4]-oxadiazol-2-yl)-6-hydroxy-7-oxo-l ,6-diaza- bicyclo[3.2.1 ] octane (V, 4.5 g, 0.0214 mol) in dichloromethane (50 ml) was added triethylamine (9 ml, 0.642 mol), followed by the addition of sulfur trioxide pyridine complex (6.83 g, 0.428 mol). The resulting reaction mixture was stirred for 2 hours. Tetrabutylammonium hydrogen sulfate (7.26 g,
0.0214 mol) was added to the reaction mixture and it was stirred for 1.5 hours. A solution of aqueous 0.5 N KH2PO4 (100 ml) was added to the reaction mixture. Layers were separated and the aqueous layer was washed with dichloromethane (125 ml). Combined organic layer was dried over Na2S04, and was evaporated under vacuum to yield crude foam, which was purified on silica gel column chromatography to give 7 g of the titled compound as white foam in 98% yield.
Analysis:
1H NMR (DMSO-d6): δ 9.30 (s, 1H), 4.69 (d, 1H), 4.06 (br s, 1H ), 3.14-3.18 (m, 8H), 2.94-2.97 (br d, 1H), 2.67-2.70 (d, 1H), 1.98-2.05 (m,lH), 2.85-2.92 (m, 1H), 1.53-1.60 (m, 8H), 1.27-1.36 (m, 8H), 0.91-0.95 (m, 12H).
Step V: Sodium salt of (25, 5R)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza- bicyclo[3.2.1]oct-6-yl) ester (I):
The compound sodium salt of (2S, 5i?)-sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6- diaza-bicyclo[3.2.1]oct-6-yl) ester of Formula (I) was prepared by loading tetrabutylammonium salt of sulfuric acid mono-(2-[l,3,4]oxadiazol-2-yl-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl) ester (VI, 7 g) on a column packed with Amberlite IR 120 Na form of resin, and by eluting the column with methanol water mixture (9: 1). Fractions containing compound were collected and solvent was evaporated under vacuum below 40°C, to provide formula- 1 compound in 4 gm (62%) quantity as a white solid.
Analysis:
H1 NMR (DMSO-d6): δ 9.29 (s, 1H), 4.70(d, 1H), 4.061 (d, 1H), 2.95 (d, 1H), 2.69 (d, 1H), 2.19 (m, 1H), 2.07 (m, 2H), 1.90 (m, 1H);
Purity as determined by HPLC: 89 86%;
X-ray powder diffraction pattern (2 Theta Values): 11.30 (± 0.2), 13.01 (± 0.2), 13.67 (± 0.2), 14.19 (± 0.2), 15.16 (± 0.2), 16.85 (± 0.2), 17.77 (± 0.2), 18.13 (± 0.2), 18.93 (± 0.2), 19.18 (± 0.2),
20.37 (± 0.2), 21.35 (± 0.2), 22.12 (± 0.2), 22.65 (± 0.2), 23.97 (± 0.2), 25.09 (± 0.2), 25.33 (± 0.2), 26.03 (± 0.2), 26.38 (± 0.2), 26.84 (± 0.2), 28.37 (± 0.2), 28.63 (± 0.2), 29.15 (± 0.2), 29.65 (± 0.2), 30.61 (± 0.2), 31.95 (± 0.2), 33.41 (± 0.2) and 33.96 (± 0.2).
Typical X-ray analysis was performed as follows. Pass the test substance through sieve #100 BSS or gently grind it with a mortar and pestle. Place the test substance uniformly on a sample holder having cavity surface on one side, press the sample and cut into thin uniform film using a glass slide in such a way that the surface of the sample should be smooth and even. Record the X-ray diffractogram using the following instrument parameters.
Instrument : X-Ray Diffractometer
(PANalytical, Model X'Pert Pro MPD)
Target source : CuK(a)
Antiscattering slit (Incident beam) : 1°
Programmable Divergent slit : 10 mm (fixed)
Anti-scattering slit (Diffracted beam) : 5.5 mm
Step width : 0.02°
Voltage : 40 kV
Current : 40 mA
Time per step : 30 seconds
Scan range : 3 to 40°
Claims
1. A process for preparation of a compound of Formula (I), comprising:
(b) cyclizing a compound of Formula (III) to obtain a compound of Formula (IV);
(c) hydrogenolysis of a compound of Formula (IV) to obtain a compound of Formula (V);
Formula (V)
(e) converting a compound of Formula (VI) to a compound of Formula (I).
2. The process according to Claim 1, wherein the compound of Formula (III) is obtained by reacting the compound of Formula (II) with formyl hydrazine in presence of the coupling agent.
3. The process according to Claim 2, wherein the coupling agent is 1 -hydroxybenzotriazole, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexyldiimde, (1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) or a mixture thereof.
4. The process according to Claim 1, wherein the compound of Formula (IV) is obtained by cyclizing a compound of Formula (III) in presence of a cyclizing agent selected from methanesulfonic acid chloride, p-nitrophenylsulphonic acid chloride, p-tolylsulfonylchloride, or iodine/triphenylphosphine/triethylamine combination.
5. The process according to Claim 1, wherein the compound of Formula (V) is obtained by carrying out hydrogenolysis of the compound of Formula (IV) in presence of the transition metal catalyst and a hydrogen source.
6. The process according to Claim 5, wherein the transition metal catalyst is palladium on carbon and hydrogen source is hydrogen gas.
7. The process according to Claim 1, wherein the compound of Formula (VI) is obtained by sulphonating the compound of Formula (V), followed by the formation of tetrabutylammonium salt.
8. The process according to Claim 7, wherein sulphonation is carried out in the presence of the sulfonating reagent selected from sulphur trioxide pyridine complex, sulfur trioxide dimethylformamide complex, sulfur trioxide triethylamine complex or a mixture thereof.
9. The process according to Claim 1, wherein the compound of Formula (VI) is converted to the compound of Formula (I) by contacting with a sodium exchange resin.
10. A compound of Formula (I) in a crystalline form.
11. The compound of Formula (I) according to Claim 10, having an X-ray powder diffraction pattern comprising a peak selected from the group consisting of 11.30 (± 0.2), 13.01 (± 0.2), 13.67 (± 0.2), 14.19 (± 0.2), 15.16 (± 0.2), 16.85 (± 0.2), 17.77 (± 0.2), 20.37 (± 0.2), 21.35 (± 0.2), 22.12 (± 0.2), 23.97 (± 0.2), 26.03 (± 0.2), 26.84 (± 0.2), 28.63 (± 0.2), 30.61 (± 0.2), 31.95 (± 0.2) and 33.96 (± 0.2) degrees 2 theta.
12. The compound of Formula (I) according to Claim 10, having an X-ray powder diffraction pattern comprising a peak selected from the group consisting 11.30 (± 0.2), 13.01 (± 0.2), 13.67 (± 0.2), 14.19 (± 0.2), 15.16 (± 0.2), 16.85 (± 0.2), 17.77 (± 0.2), 18.13 (± 0.2), 18.93 (± 0.2), 19.18 (± 0.2), 20.37 (± 0.2), 21.35 (± 0.2), 22.12 (± 0.2), 22.65 (± 0.2), 23.97 (± 0.2), 25.09 (± 0.2), 25.33 (± 0.2), 26.03 (± 0.2), 26.38 (± 0.2), 26.84 (± 0.2), 28.37 (± 0.2), 28.63 (± 0.2), 29.15 (± 0.2), 29.65 (± 0.2), 30.61 (± 0.2), 31.95 (± 0.2), 33.41 (± 0.2) and 33.96 (± 0.2) degrees 2 theta.
13. A compound of Formula (I) having purity of at least 89% as determined by HPLC.
14. A pharmaceutical composition comprising a compound of Formula (I) according to any one of the Claims 10 to 13.
(a) reacting a compound of Formula (II) with formyl hydrazine in presence of 1- hydroxybenzotriazole and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride to obtain a compound of Formula (III);
(b) cyclizing a compound of Formula (III) in presence of p-tolylsulfonylchloride to obtain a compound of Formula (IV);
(c) hydrogeno lysis of a compound of Formula (IV) in presence of 10% palladium over carbon and hydrogen gas to obtain a compound of Formula (V);
Formula (V)
(d) reacting a compound of Formula (V) with a suphonating reagent, followed by the treatment with tetrabutylammonium hydrogen sulphate to obtain a compound of Formula (VI); and
(e) contacting a compound of Formula (VI) with a sodium exchange resin to obtain a compound of Formula (I).
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013030735A1 (en) * | 2011-08-30 | 2013-03-07 | Wockhardt Limited | 1,6- diazabicyclo [3,2,1] octan- 7 - one derivatives and their use in the treatment of bacterial infections |
WO2013149121A1 (en) * | 2012-03-30 | 2013-10-03 | Cubist Pharmaceuticals, Inc. | 1,3,4-oxadiazole and 1,3,4-thiadiazole beta-lactamase inhibitors |
WO2014135929A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | Sodium salt of (2s, 5r)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1 ] octane-2-carboxylic acid and its preparation |
WO2014135930A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | A process for sodium salt of (2s, 5r)-2-carboxamido-7-oxo-6-sulfooxy -1,6-diaza-bicyclo[3.2.1]octane |
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2016
- 2016-03-25 WO PCT/IB2016/051719 patent/WO2016157057A1/en active Application Filing
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WO2013030735A1 (en) * | 2011-08-30 | 2013-03-07 | Wockhardt Limited | 1,6- diazabicyclo [3,2,1] octan- 7 - one derivatives and their use in the treatment of bacterial infections |
WO2013149121A1 (en) * | 2012-03-30 | 2013-10-03 | Cubist Pharmaceuticals, Inc. | 1,3,4-oxadiazole and 1,3,4-thiadiazole beta-lactamase inhibitors |
WO2014135929A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | Sodium salt of (2s, 5r)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo [3.2.1 ] octane-2-carboxylic acid and its preparation |
WO2014135930A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | A process for sodium salt of (2s, 5r)-2-carboxamido-7-oxo-6-sulfooxy -1,6-diaza-bicyclo[3.2.1]octane |
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