Zidebactam, WCK 5107
Wockhardt Limited
Useful for treating bacterial infections
CAS 1436861-97-0, UNII: YPM97423DB, Wockhardt Biopharm
Molecular Formula, C13-H21-N5-O7-S
Molecular Weight, 391.4029
Disclosed in PCT International Patent Application No. PCT/IB2012/054290D
- 01 Aug 2015 Phase-I clinical trials in Bacterial infections (In volunteers, Combination therapy) in USA (IV) (NCT02532140)
(2S, 5R)-sulphuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl] ester
(1R,2S,5R)-l,6-Diazabicyclo [3.2.1] octane-2-carboxylic acid, 7-oxo-6-(sulfooxy)-, 2-[2-[(3R)-3-piperidinylcarbonyl]hydrazide]
trans- sulphuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl] ester
(2S, 5R)-sulphuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl] ester
(lR,2S,5R)-l,6-Diazabicyclo [3.2.1] octane-2-carboxylic acid, 7-oxo-6-(sulfooxy)-, 2-[2-[(3R)-3 -piperidinylcarbonyl] hydrazide]
1,6-Diazabicyclo(3.2.1)octane-2-carboxylic acid, 7-oxo-6-(sulfooxy)-, 2-(2-((3R)-3-piperidinylcarbonyl)hydrazide), (1R,2S,5R)-
Zidebactam potassium
cas is 1706777-49-2
Zidebactam sodium ………..below
Cas 1706777-46-9
Sodium;[(2S,5R)-7-oxo-2-[[[(3R)-piperidine-3-carbonyl]amino]carbamoyl]-1,6-diazabicyclo[3.2.1]octan-6-yl] sulfate
UNII-NHY7N0Y9DG; NHY7N0Y9DG; Zidebactam sodium; Zidebactam sodium, (-)-; 1,6-Diazabicyclo(3.2.1)octane-2-carboxylic acid, 7-oxo-6-(sulfooxy)-, 2-(2-((3R)-3-piperidinylcarbonyl)hydrazide), sodium salt (1:1), (1R,2S,5R)-; 1706777-46-9;
| Molecular Formula: | C13H20N5NaO7S |
|---|---|
| Molecular Weight: | 413.381969 g/mol |
In September 2015, the drug was reported to be in phase I clinical trial.One of the family members US09132133, claims a combination of sulbactam and WCK-5107.
Bacterial infections continue to remain one of the major causes contributing towards human diseases. One of the key challenges in treatment of bacterial infections is the ability of bacteria to develop resistance to one or more antibacterial agents over time. Examples of such bacteria that have developed resistance to typical antibacterial agents include: Penicillin-resistant Streptococcus pneumoniae, Vancomycin-resistant Enterococci, and Methicillin-resistant Staphylococcus aureus. The problem of emerging drug-resistance in bacteria is often tackled by switching to newer antibacterial agents, which can be more expensive and sometimes more toxic. Additionally, this may not be a permanent solution as the bacteria often develop resistance to the newer antibacterial agents as well in due course. In general, bacteria are particularly efficient in developing resistance, because of their ability to multiply very rapidly and pass on the resistance genes as they replicate.
Treatment of infections caused by resistant bacteria remains a key challenge for the clinician community. One example of such challenging pathogen is Acinetobacter baumannii (A. baumannii), which continues to be an increasingly important and demanding species in healthcare settings. The multidrug resistant nature of this pathogen and its unpredictable susceptibility patterns make empirical and therapeutic decisions more difficult. A. baumannii is associated with infections such as pneumonia, bacteremia, wound infections, urinary tract infections and meningitis.
Therefore, there is a need for development of newer ways to treat infections that are becoming resistant to known therapies and methods. Surprisingly, it has been found that a compositions comprising cefepime and certain nitrogen containing bicyclic compounds (disclosed in PCT/IB2012/054290) exhibit unexpectedly synergistic antibacterial activity, even against highly resistant bacterial strains.
PATENT
http://www.google.com/patents/WO2013030733A1?cl=en
o ormua –
Scheme-2
Example-2 trans-sulfuric acid mono-r2-(N,-r(R)-piperidin-3-carbonyll-hvdrazinocarbonyl)-7-oxo-l,6- diaza-bicyclo Γ3.2.11 oct-6-νΠ ester
By using the procedure described in Step-1 of Example- 1 above, and by using trans-6- benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (25 gm, 0.084 mol), N,N- dimethyl formamide (625 ml), EDC hydrochloride (24 gm, 0.126 mol), HOBt (16.96 gm, 0.126 mol), (R)-N-tert-butoxycarbonyl-piperidin-3-carboxylic acid hydrazide (21.40 gm , 0.088 mol) to provide the title compound in 17.0 gm quantity, 41% yield as a white solid.
Analysis: MS (ES+) CzsHasNsOe = 502.1 (M+l);
I^NMR (CDCI3) = 8.40 (br s, IH), 7.34-7.44 (m, 5H), 5.05 (d, IH), 4.90 (d, IH), 4.00 (br d, IH), 3.82 (br s, IH), 3.30 (br s, IH), 3.16-3.21 (m, IH), 3.06 (br d, IH), 2.42 (br s, IH), 2.29-2.34 (m, IH), 1.18-2.02 (m, 4H), 1.60-1.75 (m, 4H), 1.45-1.55 (m, 2H),1.44 (s, 9H).
Step-2: Preparation of trans-3-[N’-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2- carbonyl)-hydrazinocarbonyl]-(R)-piperidin-l-carboxylic acid tert-butyl ester:
By using the procedure described in Step-2 of Example- 1 above, and by using trans-3- [N ‘ -(6-benzyloxy-7-oxo- 1 ,6-diaza-bicyclo [3.2.1 ]octane-2-carbonyl)-hydrazinocarbonyl] -(R)- piperidin-l-carboxylic acid tert-butyl ester (16.5 gm , 0.033 mol), methanol (170 ml) and 10% palladium on carbon (3.5 gm) to provide the title compound in 13.5 gm quantity as a pale pink solid and it was used for the next reaction immediately.
Analysis: MS (ES+) CiglfeNsOe = 411.1 (M+l);
Step-3: Preparation of tetrabutylammonium salt of trans-3-[N’-(6-sulfooxy-7-oxo-l,6-diaza- bicyclo [3.2.1] octane-2-carbonyl)-hydrazinocarbonyl] -(R)-piperidin- 1 -carboxylic acid tert- butyl ester:
By using the procedure described in Step-3 of Example- 1 above, and by using trans-3- [N’-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)- piperidin-1 -carboxylic acid tert-butyl ester (13.5 gm , 0.033 mol), pyridine (70 ml) and pyridine sulfur trioxide complex (26.11 gm, 0.164 mol), 0.5 N aqueous potassium dihydrogen phosphate solution (400 ml) and tetrabutylammonium sulphate (9.74 gm, 0.033 mol) to provide the title compound in 25 gm quantity as a yellowish solid, in quantitative yield.
Analysis: MS (ES-)
Step-4: trans-sulfuric acid mono-[2-(N’-[(R)-piperidin-3-carbonyl]-hydrazinocarbonyl)-7- oxo-l,6-diaza-bicyclo[3.2.1]oct-6-yl]ester:
By using the procedure described in Step-4 of Example- 1 above, and by using tetrabutylammonium salt of trans-3-[N’-(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2- carbonyl)-hydrazinocarbonyl]-(R)-piperidin-l-carboxylic acid tert-butyl ester (24 gm , 0.032 mmol), dichloromethane (60 ml) and trifluoroacetic acid (60 ml) to provide the title compound in 10 gm quantity as a white solid, in 79% yield.
Analysis: MS (ES-)= C13H21N5O7S = 390.2 (M-l) as a free sulfonic acid;
HXNMR (DMSO-d6) = 9.97 (d, 2H), 8.32 (br s, 2H), 4.00 (br s, IH), 3.81 (d, IH), 3.10-3.22 (m, 3H), 2.97-3.02 (m, 2H), 2.86-2.91 (m, IH), 2.65-2.66 (m, IH), 1.97-2.03 (m, IH), 1.57-1.88 (m, 7H).
-32.6°, (c 0.5, water).
PATENT
http://www.google.com/patents/WO2015059643A1?cl=en
Both, cefepime and a compound of Formula (I) may be present in the composition in their free forms or in the form of their pharmaceutically acceptable derivatives (such as salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, or adducts).
Individual amounts of a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof, and cefepime or pharmaceutically acceptable derivative thereof in the composition may vary depending on clinical requirements. In some embodiments, a compound of Formula (I) or a stereoisomer or a pharmaceutically acceptable derivative thereof in the composition is present in an amount from about 0.01 gram to about 10 gram. In some other embodiments, cefepime or a pharmaceutically acceptable derivative thereof in the composition is present in an amount from about 0.01 gram to about 10 gram.
PATENT
http://www.google.com/patents/WO2015063653A1?cl=en
PATENT
WO 2015110885
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015110885
Formula (I)
(a) hydrogenolysis of a compound of Formula (II) to obtain a compound of Formula (III);
convertin a compound of Formula (III) to a compound of Formula (IV);
Example 1
Synthesis of (25, 5R)-7-oxo-6-sulphooxy-2-[((3R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I):
Step-1: Preparation of (25, 5R)-6-hydroxy-7-oxo-2-[((3R)-iV-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (III):
(25, 5i?)-6-benzyloxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazino-carbonyl] -l,6-diazabicyclo[3.2.1]octane (II) (130 g, 0.259 mol) was dissolved in methanol (1040 ml) to obtain a clear solution. To this solution, was added 10% palladium on carbon (13 g, 0.26 mol). The suspension was stirred under 230-250 psi hydrogen atmosphere at temperature of about 30 °C for about 2 hour. The catalyst was filtered over celite bed and catalyst containing bed was washed with additional methanol (400 ml). The methanolic solution was re-filtered through fresh celite bed and washed with methanol (100 ml). The filtrate was concentrated under vacuum at temperature of about 30°C to obtain the off white solid as product. The so obtained solid was stirred with cyclohexane (750 ml). The solid was then filtered and washed with cyclohexane (320 ml) and dried under suction to obtain 107 g of (25, 5i?)-6-hydroxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo [3.2.1]octane (III).
Analysis:
Mass: 412.4 (M+l); for Molecular Formula of C18H29N5O6 and Molecular Weight of 411.5; and
Purity as determined by HPLC: 98.02%.
Step-2: Preparation of tetrabutylammonium salt of (25, 5R)-6-sulfooxy-7-oxo-2-[((3R)-iV-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l, 6-diaza-bicyclo[3.2.1] octane (IV):
A solution of (25, 5i?)-6-hydroxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (III) (106 g, 0.26 mol) in dichloromethane was charged with triethyl amine (110 ml, 0.78 mol) under stirring. To this clear solution was added pyridine sulfur trioxide complex (82.5 g, 0.53 mol) under nitrogen atmosphere and stirred at temperature of about 30°C for about 2 hour. The reaction mixture was diluted with 0.5 N aqueous potassium dihydrogen phosphate solution (2100 ml) followed by ethyl acetate (2100 ml). The turbid solution was stirred for 15 minute and then the layers were separated. The aqueous layer was washed with dichloromethane (530 ml) and then with ethyl acetate (1060 ml). Tetrabutyl ammonium sulfate (79 g, 0.23 mol) was added to the separated aqueous layer and stirred for 12 hour. The extraction of the product was done using dichloromethane as solvent (1150 ml x 2). The organic layer was dried over sodium sulfate and then evaporated under vacuum at temperature below 40°C to furnish 108 g of tetrabutylammonium salt of (25, 5i?)-6-sulfooxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l, 6-diaza-bicyclo
[3.2.1] octane (IV).
Analysis:
Mass: 490.3 (M-l) as free sulfonic acid; for Molecular Formula of Ci8H28N509S.N(C4H9)4 and Molecular weight of 733.0; and
Purity as determined by HPLC: 86.50 %.
Step-3: Preparation of (25, 5R)-7-oxo-6-sulphooxy-2-[((3R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I):
Tetrabutylammonium salt of (25, 5i?)-6-sulfooxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l, 6-diaza-bicyclo[3.2.1]octane (IV) (88 g, 0.12 mol) was dissolved in dichloromethane (225 ml). The reaction mass was cooled to about -10°C and to this trifluoroacetic acid (225 ml) was added slowly. The reaction mixture was stirred for 1 hour at temperature of about -10°C. The solvent was removed under high vacuum at about 30°C. The residue (280 g) was stirred with diethyl ether (1320 ml) for 1 hour. The precipitated solid was filtered and the cake was washed with fresh diethyl ether (440 ml). This process was repeated with fresh diethyl ether (1320 ml + 440 ml). The obtained white solid was dried at temperature of about 30°C and suspended in acetone (1320 ml). The pH of the suspension was adjusted to 6.5-7.0 using 10% solution of sodium 2-ethyl hexanoate in acetone. The resulting suspension was filtered under suction and the wet cake was washed with acetone (440 ml) to provide the crude solid. The solid was further dried under vacuum at 40°C to yield 40 g of (25, 5i?)-7-oxo-6-sulphooxy-2-[((3i?)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I).
Analysis:
Mass: 392.2 (M+l); for Molecular formula of C13H21N5O7S and Molecular Weight of 391.4;
Purity as determined by HPLC: 92.87%; and
Melting point as determined by DSC: 274°C.
Example 2
Synthesis of Pure (25, 5R)-7-oxo-6-sulphooxy-2-[((3R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I):
Step-1: Preparation of (25, 5R)-6-hydroxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (III):
The procedure for the synthesis of (25, 5i?)-6-hydroxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (III) is same as given in Step- 1 of Example 1.
Step-2: Preparation of tetrabutylammonium salt of (25, 5R)-6-sulfooxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l, 6-diaza-bicyclo[3.2.1] octane (IV):
A solution of (25, 5i?)-6-hydroxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (III) (106 g, 0.26 mol) in dichloromethane was charged with triethylamine (110 ml, 0.78 mol) under stirring to provide a clear solution. To this clear solution was added pyridine sulfur trioxide complex (82.5 g, 0.53 mol) under nitrogen atmosphere and stirred at temperature of about 30 °C for 2 hours. The reaction mixture was diluted with 0.5 N aqueous potassium dihydrogen phosphate solution (2100 ml) followed by ethyl acetate (2100 ml). The turbid solution was stirred for 15 minutes and then the layers were separated. The aqueous layer was washed with dichloromethane (530 ml) and then with ethyl acetate (1060 ml) respectively. Tetrabutyl ammonium sulfate (79 g, 0.23 mol) was added to the separated aqueous layer and stirred for 12 hours. The extraction of the product was done using dichloromethane as solvent (1150 ml x 2). Aliquot of the organic layer was dried over sodium sulfate for purity check. Considering the purity of the product as obtained above, silica gel (530 g) was added to the dichloromethane layer and stirred for 1 hour. This was filtered and again silica was taken in dichloromethane (3200 ml) and stirred for 45 minutes and filtered. Combined dichloromethane layer was filtered through the celite bed again and washed with additional 200 ml dichloromethane. The solvent was removed to obtain 88 g of tetrabutylammonium salt of (25, 5i?)-6-sulfooxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-!, 6-diaza-bicyclo[3.2.1]octane (IV) as white foam.
Analysis:
Mass: 490.3 (M-l) as a free sulfonic acid; for Molecular Formula of Ci8H28N509S.N(C4H9)4 and Molecular Weight of 733.0; and
Purity as determined by HPLC: 98.34%.
Step-3: Preparation of (25, 5R)-7-oxo-6-sulphooxy-2-[((3R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I):
The above obtained tetrabutylammonium salt of (25, 5i?)-6-sulfooxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l, 6-diaza-bicyclo[3.2.1]octane (IV) having purity of more than 98% (88 g, 0.12 mol) was dissolved in dichloromethane (225 ml). The reaction mass was cooled to temperature of about -10°C and to this trifluoroacetic acid (225 ml) was added slowly. The reaction mixture was stirred for 1 hour at about -10°C. The solvent was removed under high vacuum at temperature of about 30°C. The residue (280 g) was stirred with diethyl ether (1320 ml) for 1 hour. The precipitated solid was filtered and the cake was washed with fresh diethyl ether (440 ml). This process was repeated with fresh diethyl ether (1320 ml + 440 ml). The obtained white solid was dried at about 30°C and suspended in acetone (1320 ml). The pH of the suspension was adjusted to 6.5-7.0 using 10% solution of sodium 2-ethyl hexanoate in acetone. The resulting suspension was filtered under suction and the wet cake was washed with acetone (440 ml) to provide the crude solid. The solid was further dried under vacuum at 40°C to yield 40 g of (25, 5i?)-7-oxo-6-sulphooxy-2-[((3i?)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I).
Analysis:
Mass: 392.2 (M+l); for Molecular Formula of C13H21N5O7S and Molecular Weight of 391.4; and
Purity as determined by HPLC: 98.7%.
Recovery of tetrabutylammonium salt of (25, 5R)-6-sulfooxy-7-oxo-2-[((3R)-iV-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1] octane (IV):
The silica recovered from the Step-2 was stirred with dichloromethane containing 2%
methanol (2000 ml) for one hour. Silica was filtered, washed with additional same composition of solvents (500 ml). Combined dichloromethane was filtered through the celite bed and washed with same composition of solvents (200 ml), evaporated to afford 1 1 g of tetrabutylammonium salt of (25, 5i?)-6-sulfooxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l , 6-diaza-bicyclo[3.2.1] octane (IV) as off white solid.
Repeating Step-3 with the above obtained tetrabutylammonium salt of (25, 5R)-6-sulfooxy-7-oxo-2- [((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl] – 1 , 6-diaza-bicyclo [3.2.1] octane (IV) produced additional 7 g of compound of Formula (I).
Analysis:
Mass: 392.2 (M+l); for Molecular Formula of CnH^NsOvS and Molecular Weight of 391.4;
Purity as determined by HPLC: 98.7%; and
Assay as determined by HPLC: 104% against reference standard of compound of Formula (I).
Example 3
Preparation of amorphous form of (25, 5R)-7-oxo-6-sulphooxy-2-[((3R)-piperidine-3-carbonyl)-hydrazinocarbonyl] – 1, 6-diaza-bicyclo[3.2. l]octane (I) :
Tetrabutylammonium salt of (25, 5i?)-6-sulfooxy-7-oxo-2-[((3i?)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l, 6-diaza-bicyclo[3.2.1]octane (IV) (60 g, 0.081 mol), obtained in Step-2 of Example-2 was dissolved in dichloromethane (150 ml, 2.5 volume) to obtain a clear solution. Reaction mass was cooled to about -10°C and to it trifluoroacetic acid (150 ml) was slowly added. The reaction mixture was stirred for 1 hour at about – 10°C. The solvent was removed under high vacuum at about 30°C. Diethyl ether (600 ml x 3) was added to the residue ( 184 g) and stirred for 15 minute every time. The solvent was decanted off and the residue was washed with acetonitrile (600 ml x 3). This process was also repeated with dichloromethane (600 ml x 3). The off white solid was
isolated and dried under high vacuum at about 35 °C for 3 hour to obtain 33 g of amorphous form of (25, 5i?)-7-oxo-6-sulphooxy-2-[((3i?)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I). The XRD is shown in Figure 1.
Analysis:
Mass: 392.2 (M+l); for Molecular Formula of C13H21N5O7S and Molecular Weight of 391.4;
HPLC purity: 92.26%; and
Melting point as determined by DSC: 210°C (loss of moisture below 100°C).
Example 4
Preparation of crystalline form of (25, 5R)-7-oxo-6-sulpho-oxy-2-[((3R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I):
The (25, 5i?)-7-oxo-6-sulphooxy-2-[((3i?)-piperidine-3-carbonyl)-hydrazino carbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I) obtained as white solid (40 g) in Step-3 of Example 2 was dissolved in demineralised water (40 ml) to obtain a clear solution. To this isopropyl alcohol (280 ml) was added under stirring at room temperature. The obtained turbid solution became sticky initially then slowly started to convert into white solid, stirring continued for about 17 hours at temperature of about 30°C. The precipitated solid was filtered and washed with water: isopropyl alcohol mixture (20 ml: 140 ml). White solid was dried under high vacuum at temperature of about 45 °C for 5 hours to get 34 g of crystalline form of (25, 5i?)-7-oxo-6-sulphooxy-2-[((3i?)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1] octane (I).
Analysis:
Mass: 392.2 (M+l) for Molecular Formula of C13H21N5O7S and Molecular Weight of 391.4;
Purity as determined by HPLC: 98.7%;
Assay as determined by HPLC: 104% against reference standard of compound of Formula (I); and
Melting point as determined by DSC: 278°C (9% loss of moisture at 143-152°C).
X-ray powder diffraction pattern comprising a peak selected from the group consisting of 10.31 (± 0.2), 10.59 (± 0.2), 12.56 (± 0.2), 13.84 (± 0.2), 15.65 (± 0.2), 18.19 (± 0.2), 18.51(± 0.2), 20.38 (± 0.2), 20.65 (± 0.2), 24.30 (± 0.2), 24.85 (± 0.2) and 25.47 (± 0.2) degrees 2 theta.
PATENT
WO 2014135931
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014135931
Scheme 1.
Formula (I)
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);
Formula (II) Formula (III)
Formula (IV)
(b) hydrogenolysis of a compound of Formula (IV) to obtain a compound of Formula
X. Formula (V)
(c) sulfonating a compound of Formula (V) to obtain a compound of Formula (VI); and
Formula (VI)
(d) converting a compound of Formula (VI) into a compound of Formula (I).
Example -1
Preparation of (R)-N-Boc-piperidine-3-carboxylic acid hydrazide (II):
Step-1: Preparation of (R)-Ethyl-N-Boc-piperidine-3-carboxylate (VIII)
To a solution of (R)-N-Boc-piperidine-3-carboxylic acid (1 kg. 4.36 mol) in N,N-dimethylacetamide (3 L) was charged potassium carbonate (0.664 kg, 4.80 mol) under mechanical stirring and the resulting suspension was stirred for 30 minutes at room temperature. To the reaction mass, ethyl iodide (0.75 kg, 4.80 mol) was charged via addition funnel and the reaction mass was stirred for 15 minutes at room temperature followed by at 50°C for 1 hour. The reaction was monitored using TLC (ethyl acetate: hexane 1:1). After the reaction was complete, the reaction mass was allowed to cool to room temperature and diluted with ethyl acetate (5 L). The suspension was filtered under suction and the wet cake was washed with ethyl acetate (5 L). The filtrate was stirred with 5% w/v sodium thio sulfate (15 L) and layers were separated. The aqueous layer was re-extracted with additional ethyl acetate (5 L). The combined organic layer was washed with water (5 L) and dried over sodium sulfate. The organic layer was evaporated under vacuum to provide semi-solid which solidifies upon standing as (R)-ethyl-N-Boc-piperidine-3-carboxylate in 1.1 kg quantity in 99.5% yield.
Analysis:
NMR: (CDC13): 4.63 (q, 2H), 3.90 (d, 1H), 2.87-2.95 (m, 2H), 2.73 (td, 1H), 2.32-2.39 (m, 1H), 1.66-2.01 (m, 2H), 1.52-1.68 (m, 2H), 1.39 (s, 9H), 1.19 (t, 3H).
Mass: (M+l): 258.1 for C13H23N04;
Step-2: Preparation of (R)-N-Boc-piperidine-3-carboxylic acid hydrazide (II):
(R)-N-Boc-ethyl-piperidine-3-carboxylate (1.1 kg, 4.28 mol) was liquefied by warming and transferred to a round bottom flask (10 L), to this was charged hydrazine hydrate (0.470 kg, 9.41 mol) and stirring was started. The reaction mixture was stirred at about 120°C to 125°C for 5 hours. As the TLC showed (Chloroform: methanol 9:1) completion of reaction, the reaction mixture was cooled to room temperature and diluted with water (5.5 L) followed by dichloromethane (11 L) and was stirred for 20 minutes. The layers were separated and aqueous layer was extracted with additional dichloro methane (5.5 L). Combined organic layer was washed with water (2.75 L). The organic layer was dried over sodium sulfate and evaporated under vacuum to provide a thick gel which upon stirring and seeding in the presence of cyclohexane (5.5 L) provided white solid. The suspension was filtered and wet cake was washed with fresh cyclohexane (0.5 L). The cake was dried at 35°C under vacuum to provide (R)-N-Boc-piperidine-3-carboxylic acid hydrazide as a white solid in 0.90 kg quantity in 87% yield.
Analysis
NMR: (CDC13): 7.42 (br s, 1H), 3.92 (d, 1H), 3.88 (s, 2H), 3.54-3.65 (br s, 1H), 3.17 (br t, 1H), 2.98 (br s, 1H), 2.22-2.32 (br s, 1H), 1.82-1.90 (br m, 2H), 1.76 (s, 1H), 1.60-1.70 (m, 1H), 1.45 (s, 9H).
Mass (M+l): 244.1 for C11H21N303.
Specific rotation: [ ]25D = -53.5° (c 0.5, Methanol).
HPLC purity: 99%
Example 2
Preparation of (2S, 5R)-7-oxo-6-sulphooxy-2-[((3R)-piperidine-3-carbonyl)- hydrazinocarbonyl] -l,6-diaza-bicyclo[3.2.1]octane (I):
Step-1: Preparation of (2S, 5R)- 6-benzyloxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl] – 1 ,6-diaza-bicyclo [3.2.1 ] octane(IV) :
Sodium (2S, 5R)-7-oxo-6-benzyloxy-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylate (III, 200 gm, 0.67 mol; prepared using a method disclosed in Indian Patent Application No 699/MUM/2013) was dissolved in water (2.8 L) to obtain a clear solution under stirring at room temperature. To the clear solution was added successively, (R)-N-Boc-piperidine-3-carboxylic acid hydrazide (171 gm, 0.70 mol), EDC hydrochloride (193 gm, 1.01 mol), and HOBt (90.6 gm, 0.67 mol) followed by water (0.56 L) under stirring at 35°C. The reaction mixture was stirred at 35°C for 20 hours. As maximum precipitation was reached, TLC (acetone: hexane 35:65) showed completion of reaction. The suspension was filtered under
suction and the wet cake was washed with additional water (2 L). The wet cake was suspended in warm water (10 L) and stirred for 5 hours. It was filtered under suction and dried under vacuum at 45°C to furnish (2S, 5R)-6-benzyloxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (IV) as a white powder in 270 gm quantity in 87% yield.
Analysis
NMR: (CDC13): 8.40 (br s, 1H), 7.34-7.44 (m, 5H), 5.05 (d, 1H), 4.90 (d, 1H), 4.00 (br d, 1H), 3.82 (br s, 1H), 3.30 (br s, 1H), 3.16-3.21 (m, 1H), 3.06 (br d, 1H), 2.42 (br s, 1H), 2.29-2.34 (m, 1H), 1.18-2.02 (m, 4H), 1.60-1.75 (m, 4H), 1.45-1.55 (m, 2H),1.44 (s, 9H).
Mass: (M+l) = 502.1 for C25H35N506
HPLC purity: 98.4%
Step-2: Preparation of (2S, 5R)-6-hydroxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2. l]octane (V):
(2S,5R)-6-benzyloxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazino-carbonyl]-l,6-diaza-bicyclo[3.2.1]octane (153 gm, 0.305 mol) was dissolved in methanol (1.23 L) to obtain a clear solution. To this solution, was added 10% Pd-C (15.3 gm, 50% wet) catalyst. The suspension was stirred for 3 hours under 100 psi hydrogen atmosphere at 35°C. As reaction showed completion on TLC (TLC system methanol: chloroform 10:90), the catalyst was filtered through celite under suction. The catalyst was washed with additional methanol (600 ml). The filtrate was evaporated under vacuum below 40°C to provide a crude residue. The residue was stirred with cyclohexane (1.23 L) for 1 hour. The solid was filtered at suction and the wet cake was washed with additional cyclohexane (0.25 L) to furnish (2S, 5R)-6-hydroxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2.1]octane (V) in 125 gm quantity as a solid in quantitative yield. The product being unstable was used immediately for the next reaction.
Analysis:
NMR: (CDC13): 9.0 (br s, 2H), 4.01 (br d, 2H), 3.80 (br s, 1H), 3.74 (br s, 1H), 3.48 (s, 1H), 3.13-3.26 (m, 3H), 2.96 (br s, 1H), 2.47 (br s, 1H), 2.28-2.32 ( br dd, 1H), 2.08 (br s, 1H), 1.90-2.0 (m, 3H),1.65-1.80 (m, 3H) 1.44 (s, 9H).
Mass: (M-l): 410.3 for C18H29N506
HPLC purity: 96.34%
Step-3: Preparation of Tetrabutyl ammonium salt of (2S, 5R)-6-sulfooxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazinocarbonyl]- 1 ,6-diaza-bicyclo[3.2.1 ] octane (VI) :
A solution of (2S, 5R)-6-hydroxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazino carbonyl]-l,6-diaza-bicyclo[3.2.1]octane (113 gm, 0.274 mol), in dichloromethane (1.13 L) was charged with triethylamine (77 ml, 0.548 mol) under stirring to provide a clear solution. To the clear solution, was added pyridine sulfur trioxide complex (57 gm, 0.356 mol) under stirring at 35°C. The reaction mixture was stirred for 3 hours. The reaction mixture was worked up by adding 0.5 M aqueous potassium dihydrogen phosphate (1.13 L) followed by ethyl acetate (2.26 L) and the biphasic mixture was stirred for 15 minutes at 35°C. Layers were separated. Aqueous layer was re-extracted with dichloromethane ethyl acetate mixture (1:2 v/v, 2.26 L twice). Layers were separated. To the aqueous layer, was added solid tetrabutyl ammonium hydrogen sulfate (84 gm, 0.247 mol) and stirring was continued for 3 hours at room temperature. Dichloromethane (1.13 L) was added to the reaction mixture. Layers were separated. The aqueous layer was re-extracted with additional dichloromethane (0.565 L). Layers were separated. To the combined organic layer was added silica gel (226 gm) and the suspension was stirred for 1 hour. Suspension was filtered and silica gel was washed with dichloromethane (1 L). The combined filtrate was evaporated under vacuum to provide solid mass. To the solid mass was added cyclohexane (0.9 L) and stirred till complete solidification occurred (about 1 to 2 hours). The suspension was filtered under suction and the wet cake was dried under vacuum below 40°C to furnish tetrabutyl ammonium salt of (2S, 5R)-6-sulfooxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazino carbonyl]-l,6-diaza-bicyclo[3.2.1]octane (VI) as a white solid in 122 gm quantity in 60% yield.
Analysis
NMR: (CDC13): 8.50 (br s, 2H), 4.32 (br s, 1H), 3.97 (d, 2H), 3.15-3.37 (m, 12H), 2.43 (br s, 1H), 2.33 (d, 1H), 2.10-2.2 (br m, 1H), 1.84-1.95 (m, 3H), 1.60-1.73 (m, 13H), 1.39-1.48 (m, 19H), 0.98 (t, 12H).
Mass: (M-l): 490.4 as a free sulfonic acid for C18H28N509S.N(C4H9)4;
HPLC purity: 96.3%
Step-4: Synthesis of (2S, 5R)-6-sulfooxy-7-oxo-2-[((3R)-piperidine-3-carbonyl)-hydrazinocarbonyl]-l,6-diaza-bicyclo[3.2. l]octane (I):
Tetra-butyl ammonium salt of (2S, 5R)-6-sulfooxy-7-oxo-2-[((3R)-N-Boc-piperidine-3-carbonyl)-hydrazino carbonyl]-l,6-diaza-bicyclo[3.2.1]octane (113 gm, 0.154 mol) was dissolved in dichloromethane (280 ml) and to the clear solution was slowly added trifluoroacetic acid (280 ml) between 0 to 5°C. The reaction mixture was stirred between 0 to 5°C for 1 hour. The solvent and excess trifluoroacetic acid was evaporated under vacuum below 40°C to approximately 1/3 of it’s original volume to provide pale yellow oily residue. The oily residue was stirred with diethyl ether (2.25 L) for 1 hour to provide a suspension. The precipitate was filtered under suction and transferred to a round bottom flask, to it was added diethyl ether (1.1 L) under stirring. The suspension was stirred for 30 minutes and filtered under suction to provide a solid. The solid was charged in a round bottom flask and to it was added acetone (1.130 L). The pH of suspension was adjusted to 4.5 to 5.5 by adding 10% solution of sodium-2-ethyl hexanoate in acetone carefully. The resulting suspension was filtered under suction and the wet cake was washed with acetone (550 ml) to provide a crude solid. The obtained solid was dried under vacuum below 40°C to furnish 65 gm of a crude mass. The crude mass was dissolved in water (65 ml) under stirring and to the clear solution was added isopropyl alcohol (455 ml). The suspension was stirred for 24 hours and filtered under suction. The wet cake was washed with isopropyl alcohol (225 ml) and dried under vacuum below 40°C to provide a crystalline (2S, 5R)-6-sulfooxy-7-oxo-2-[((3R)-piperidine-3-carbonyl)-hydrazino carbonyl]-l,6-diaza-bicyclo[3.2.1]octane (I) free from impurities in 48 gm quantity in 80% yield.
Analysis:
NMR: (DMSO-d6) = 9.97 (d, 2H), 8.32 (br s, 2H), 4.00 (br s, IH), 3.81 (d, IH), 3.10-3.22 (m, 3H), 2.97-3.02 (m, 2H), 2.86-2.91 (m, IH), 2.65-2.66 (m, IH), 1.97-2.03 (m, IH), 1.57-1.88 (m, 7H).
Mass: (M-l): 390.3 for C13H21N507S
HPLC purity: 95.78%
Specific rotation: [(X]25D: – 32.6° (c 0.5, water)
X-ray powder diffraction pattern comprising peak at (2 Theta Values): 10.28 (+ 0.2), 10.57 (± 0.2), 12.53 (± 0.2), 13.82 (± 0.2), 15.62 (± 0.2), 18.16 (± 0.2), 18.49 (± 0.2), 20.35 (+ 0.2), 20.64 (± 0.2), 21.33 (+ 0.2), 22.99 (+ 0.2), 23.18 (+ 0.2), 24.27 (± 0.2), 24.81 (+ 0.2), 25.45 (± 0.2), 29.85 (+ 0.2), 30.45 (± 0.2), 32.39 (+ 0.2), 36.84 (± 0.2).
REFERENCES
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of WCK-5107 Alone and in Combination With Cefepime (NCT02532140) https://clinicaltrials.gov/show/NCT02532140
ClinicalTrials.gov Web Site 2015, September 01, To evaluate the safety,tolerability and pharmacokinetics of single intravenous doses of WCK 5107 alone and in combination with cefepime in healthy adult human subjects.
| WO2013030733A1 * | Aug 24, 2012 | Mar 7, 2013 | Wockhardt Limited | 1,6- diazabicyclo [3,2,1] octan-7-one derivatives and their use in the treatment of bacterial infections |
| WO2014135931A1 * | Oct 12, 2013 | Sep 12, 2014 | Wockhardt Limited | A process for preparation of (2s, 5r)-7-oxo-6-sulphooxy-2-[((3r)-piperidine-3-carbonyl)-hydrazino carbonyl]-1,6-diaza-bicyclo [3.2.1]- octane |
| IB2012054290W | Title not available |
Mr Habil Khorakiwala, Chairman, Wockhardt Ltd.
C1C[C@H](CNC1)C(=O)NNC(=O)[C@@H]2CC[C@@H]3C[N@]2C(=O)N3OS(=O)(=O)O
or
O=C(NNC(=O)[C@@H]2CC[C@@H]1CN2C(=O)N1OS(=O)(=O)O)[C@@H]3CCCNC3
C1CC(CNC1)C(=O)NNC(=O)C2CCC3CN2C(=O)N3OS(=O)(=O)[O-].[Na+]
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see..........http://newdrugapprovals.org/2015/11/23/wck-5107-in-phase-1-from-wockhardt/
