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BACTAM SERIES




MK 7655, RELEBACTAM
2 TAZOBACTAM
3 AVIBACTAM
4 ZIDEBACTAM, WCK 5107
5







MK 7655, RELEBACTAM

Votes

MK 7655, RELEBACTAM
(1R,2S,5R)-7-Oxo-N-(4-piperidinyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
MF C12H22N4O7S
MW366.39068 g/mol
CAS 1174020-13-3
β-Lactamase inhibitor
MK-7655 is a beta-lactamase inhibitor in phase III clinical studies at Merck & Co for the treatment of serious bacterial infections…….See clinicaltrials.gov, trial identifier numbers NCT01505634 and NCT01506271.
In 2014, Qualified Infectious Disease Product (QIDP) and Fast Track designations were assigned by the FDA for the treatment of complicated urinary tract infections, complicated intra-abdominal infections and hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia.
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PAPER

A concise synthesis of a beta-lactamase inhibitor
Org Lett 2011, 13(20): 5480

Abstract Image
MK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N–H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.1]urea at the core of the target.
H NMR (400 MHz, DMSO-d6): δ 8.30 (br s, 2H), 8.20 (d, J = 7.8 Hz, 1H), 4.01 (s, 1H), 3.97-3.85 (m, 1H), 3.75 (d, J = 6.5 Hz, 1H), 3.28 (dd, J = 12.9, 2.5 Hz, 2H), 3.05-2.93 (m, 4H), 2.08-1.97 (m, 1H), 1.95-1.79 (m, 3H), 1.73-1.59 (m, 4H);
13C NMR (DMSO-d6, 100 MHz) δ 169.7, 166.9, 59.8, 58.3, 46.9, 44.3, 42.9, 28.5, 28.3, 20.8, 18.9;
HRMS calculated for C12H20N4O6S (M+H): 349.1182, found: 349.1183.
[α]D 25 = -23.3 (c = 1.0, CHCl3)

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PATENT

WO 2009091856
EXAMPLE IA
(2S ,5 R)-7-Oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo [3.2.1 ]octane-2-carboxamide
Figure imgf000063_0001
Step 1 : tert-butyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yljcarbonyl } amino)piperidine- 1 -carboxylate : To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-l,6-diazabicyclot3.2.1]octane-
2-carboxylic acid (1.484 g, 5.37 mmol) in dry dichloromethane (60 ml) was added triethylamine (1.88 ml, 13.49 mmol), 2-chloro-l-methylpyridinium iodide (1.60 g, 6.26 mmol), and 4-amino-l- BOC-piperidine (1.30 g, 6.49 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 500C for 1 hour. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography on an Isco Combiflash (40 g silica gel, 40 mL/min, 254 nM, 15% to 100% EtOAc/hexane over 14 column volumes then 100% EtOAc for 4 column volumes; title compuond eluted at 65% ethyl acetate/hexane) to afford the title compound as a pale orange solid.
Step 2: tert-butyl 4-({[(2S,5R)-6-hydroxy-7-oxo-l ,6-diazabicyclo[3.2.1]oct-2- yl] carbonyl } amino)piρeridine- 1 -carboxylate:
Palladium on carbon (394 mg; 10% Pd/C) was added to a solution of the product of step 1 (1.81 g, 3.95 mmol) in methanol (50.6 mL) and the resulting mixture was stirred under hydrogen (balloon) overnight. LC/MS analysis indicated the reaction was not complete. Acetic acid (6 drops) and additional catalyst (159 mg of 10% Pd/C) were added to the reaction and the resulting mixture was stirred under hydrogen (balloon) for an additional 90 minutes. Additional catalyst (0.2085 g of 10% Pd/C) was added to the reaction and stirring under hydrogen was continued for an additional 2.5 hours at which time the reaction was judged complete by LC-MS analysis. The reaction was filtered through a celite pad and the collected solid was washed well wtih MeOH. The filtrate was concentrated under vacuum to afford the title compound as a colorless oil which was used without purification in the next step.
Step 3 : tert-butyl-4-({ [(2S,5R)-7-oxo-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]oct-2- yl] carbonyl } amino)ρiperidine- 1 -carboxylate:
To a solution of the product of step 2 (1.455 g, 3.95 mmol; theoretical yield of step 2) in dry pyridine (30 mL) was added sulfur trioxide pyridine complex (3.2 g, 20.11 mmol) at room temperature under nitrogen. The resulting thick mixture was stirred over the weekend.
The reaction was filtered and the white insoluble solids were washed well with dichloromethane. The filtrate was concentrated in vacuo. The residue was further azeotroped with toluene to remove excess pyridine to afford the title compound which was used without purification in the next step.
Step 4: (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2- carboxamide:
To a mixture of the product of step 3 (1.772 g, 3.95 mmol; theoretical yield of step 3) in dry dichloromethane (30 ml) at 00C under nitrogen was slowly added trifluoroacetic acid (6.1 ml, 79 mmol). Immediately the reaction became a solution. After 1 hour, additional trifluoroacetic acid (8 ml) was added to the reaction. The reaction was stirred at 00C until judged complete by LC-MS analysis then concentrated in vacuo. The residue was triturated with ether (3X) to remove excess TFA and organic impurities. The resulting white insoluble solid was collected via centrifugation, dried in vacuo, then purified by preparative HPLC (250X21.2 mm Phenomenex Synergi Polar-RP 80A column; 10 micron; 35 mL/min.; 210 nM; 0% to 30% methanol/water over 15 minutes; title compound eluted at 10% methanol/water). Fractions containing the title compound were combined and Iyophilized overnight to afford the title compound as a white solid. LC-MS (negative ionization mode) m/e 347 (M-H).

PAPER

Discovery of MK-7655, a beta-lactamase inhibitor for combination with Primaxin
Bioorg Med Chem Lett 2014, 24(3): 780
Image for unlabelled figure
PATENT
WO 2014200786



Exemplary Scheme
– 50% isolated yield overall from 1 to 5
O via crystallization
XAMPLE 1
(2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide 
Preparation of (15′,45)-5-((2-nitrophenyl)sulfonyl)-2-oxa-5-azabicyclo[2.2.2]octan-3 one (2)
To a reactor (R-1) equipped with an additional funnel, nitrogen inlet and agitator was charged (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (77.3 wt%) (50.0 g, 344 mmol), and water (150 mL). Agitation was begun, the pH adjusted to 10-11 by addition of 10 N NaOH (~ 46.5 mL) and the reactor charged with acetone (50.0 mL).
In a separate reactor (R-2) equipped with an agitator and nitrogen inlet was charged 2-nitrobenzene-l-sulfonyl chloride (97%) (106.0 g, 478 mmol) and acetone (80 mL). The contents of R-2 were transferred to R-1 at 23-30 °C while the pH of the solution was maintained at 10-11 by simultaneously addition of 10 N NaOH. After 15 to 30 min, the pH was adjusted to about 6 by addition of 12 N HC1. The solution was charged with EtOAc (500 mL) and the pH adjusted to 3.0 by addition of 12 N HC1. The layers were separated and the aqueous back-extracted with EtOAc (150 mL x 2).
To a separate reactor (R-3) was charged product la in the combined organic layers, 2-nitrobenzene-l-sulfonyl chloride (73.0 g, 329 mmol), and triethylamine (130 mL). The batch in R-3 was agitated at 20-28°C for 30 min. The solution was charged with water (100 mL), the layers separated, and the aqueous back extracted with EtOAc (150 mL x 2). The combined EtOAc layer was washed with 10% NaHC03 (100 mL) and brine (100 mL). The organic phase was concentrated to 150 mL upon which a crystalline slurry was formed. The concentrated solution was agitated at 13-18°C for 2-3 hours followed by filtration of crystalline solids. The resulting wet cake was washed with EtOAc (60 mL) and then dried under vacuum oven at 25-30°C to afford 2 (65.6 g, 79% yield), m.p. 126.0-126.7 °C. 1H NMR (CDC13, 400 MHz) δ: 8.02 (m, 1 H), 7.80-7.71 (m, 2 H), 7.66 (m, 1 H), 4.88 (m, 1 H), 4.55 (dd, J= 3.8, 2.7 Hz, 1 H), 3.78 (dt, J= 11.2, 3.0 Hz, 1 H), 3.66 (dd, J = 11.2, 1.1 Hz, 1 H), 2.44 (m, 1 H), 2.11 (m, 2 H), 1.91 (m, 1 H); 13C NMR (CDC13, 100 MHz) δ: 168.4, 148.3, 134.4, 132.1, 131.0, 130.7, 124.2, 73.5, 51.4, 48.0, 25.1, 23.2
Preparation oftert-butyl 4-((25*,55)-l-((2-nitrophenyl)sulfonyl)-5-(((2- nitrophenyl)sulfony l)oxy)piperidine-2-carboxamido)piperidine- 1 -carboxylate (3)
To a reactor (R-l) was charged lactone 2 (65.5 g, 210 mmol), THF (131 mL) and tert-butyl 4-aminopiperidine-l -carboxylate (44.5 g, 222 mmol). The stirred solution was heated to reflux (typical temperature 72 °C) for ~18 hr. The reaction was cooled to 25-35 °C and then charged with THF (325 mL) and 4-dimethylaminopyridine (40.1 g, 328 mmol) followed by agitation for 30 minutes.
To a separate reactor (R-2) was charged 2-nitrobenzene-l-sulfonyl chloride (60.9 g,
275 mmol) and THF (200 mL). The contents of R-2 were added to R-l over the course of 45 to 75 minutes maintaining batch temperature of 20 to 30°C. The batch in R-l was agitated for 2 to 4 hours at a temperature of 20 to 30°C.
To a separate reactor (R-3) was charged water (600 mL) and methanol (600 mL). The contents of R-3 were charged to the main batch over the course of 45 to 75 minutes with agitation while maintaining temperature of 20 to 30°C. The batch was cooled to 5 to -5°C and then agitated at 5 to -5°C for at least 4 hours. The solids were filtered and then washed twice with methanol (130 mL x 2). The wet cake was dried in a vacuum oven at 40 to 50°C to afford 3 (144.0 g, 98% yield), m.p. 131.8-133.1 °C. 1H NMR (CDC13, 400 MHz) δ: 8.14 (m, 2 H), 7.83-7.74 (m, 6 H), 6.50 (d, J= 7.9 Hz, 1 H), 4.69 (m, 1 H), 4.43 (s, 1H), 4.11 (dd, , J= 13.7, 4.9 Hz, 1H), 3.95 (m, 2H), 3.83 (m, 1H), 3.47 (s, 1H), 3.10 (dd, J= 13.7, 11.0 Hz, 1H), 2.81 (m, 2H), 2.51 (m, 1H), 2.12 (m, 1H), 1.85-1.72 (m, 4H), 1.45 (s, 9H), 1.26 (m, 1H); 13C NMR (CDC13, 100 MHz) δ: 166.9, 154.6, 148.2, 147.6, 135.2, 134.8, 132.6, 132.5, 131.9, 131.6, 131.4, 129.7, 124.9, 124.7, 79.8, 76.5, 55.0, 47.1, 46.0, 31.8, 31.5, 28.4, 27.3, 24.4.
Preparation of N-4-nitrobenzene sulfonyl-O-benzylhydroxylamine
To a reactor (R-l) was charged O-benzylhydroxylamine hydrochloride (61.0g, 382 mmol) and pyridine (400 mL). The solution cooled to 5 to -5°C.
To a separate reactor (R-2) was charged 4-nitrobenzenesulfonyl chloride (89.0 g, 402 mmol) and pyridine (200 mL). The contents of R-2 were transferred to R-l at a rate to maintain temperature range of -5 to -5°C. The batch in R-l was agitated at 5 to -5 °C for 15 to 45 minutes then warmed to 20 to 30°C for 45 to 75 minutes. Water (250 mL) was then added at a rate to maintain 20 to 30°C and agitated 5 to 15 minutes. The solids were filtered and the wet cake washed with water (100 mL x 3). The wet cake was dried in vacuum oven at 50°C to afford N-4-nitrobenzenesulfonyl-O-benzylhydroxylamine (113.3 g, 96% yield), m.p. 128.4-130.0 °C. 1H NMR (CDCls, 400 MHz) δ: 8.36 (d, J = 8.9 Hz, 2 H), 8.11 (d, J = 8.9 Hz, 2 H), 7.36 (m, 5H), 7.11 (s, 1H), 5.02 (s, 2H); 13C NMR (CDC13, 100 MHz) δ: 151.0, 142.5, 134.9, 130.2, 129.7, 129.3, 128.9, 124.5, 80.2.
Step C. Preparation of tert-butyl 4-((2S,5R)-5-((benzyloxy)amino)piperidine -2-carboxamido)piperidine- 1 -carboxylate (4)
Boc 
To a reactor (R-l) was charged tert-butyl 4-((2R,5R)-l-((2-nitrophenyl)sulfonyl)-5-(((2-nitrophenyl)sulfonyl)oxy)piperidine-2-carboxamido)piperidine-l -carboxylate (3) (110 g, 158 mmol), N-4-nitrobenzene sulfonyl-O-benzylhydroxylamine (58 g, 188 mmol), potassium carbonate (25.9 g, 187 mmol) and dimethylacetamide (440 mL). The stirred solution was heated to 60 to 70°C for 24 – 32 hours. The batch was cooled to 20 to 30°C and charged with toluene (660 mL). The batch was extracted with 1 N sodium hydroxide (3×220 mL) then washed with water (220 mL).
The toluene solution was azotropically distilled at ~50°C to about 1/3 volume. The solution was solvent-switched to MeOH at 45-55°C, adjusted to 237 mL.
The batch was cooled to 20-25°C, charged with thioglycolic acid (57.9 g, 629 mmol) at 10 °C, and then charged with K2CO3 anhydrous (172.0 g, 1225 mmol). The batch was agitated at 10-15°C for 0.5 h, warmed to 20-25°C, agitated at 20-25°C for 10-15 h, and heated at 48-53°C for 3-6 h.
The batch was charged with 10 wt% sodium chloride (1.10 L) and toluene (880 mL) at about 40°C. The layers were separated and the aq. layer back-extracted with toluene (3 x440 mL). The combined organic layer was washed with 10% NaHC03 (2 x220 mL). The batch was concentrated at 40-50°C to 165 mL, then cooled to 35-40°C. The batch was charged with seed (50 mg) and agitated for 1 h at 35-40°C. The batch was charged with heptanes (110 mL) at 35-40°C over 1 h, then slowly cooled to 15-20°C over 1 h. The batch was agitated for 3 h and the solids filtered. The wet cake was washed with toluene/heptanes (137.5 mL) then dried in vacuum oven at 30 °C for 3-8 h to affored 4. (47.3 g, 70% overall yield from 3), m.p. 117.5-118.0 °C. 1H NMR (CDC13, 500 MHz) δ: 7.37-7.29 (m, 5 H), 6.64 (d, J= 8.2 Hz, 1 H), 5.36 (brs, 1 H), 4.67 (s, 2 H), 4.00 (m, 2 H), 3.90 (m, 1 H), 3.28 (ddd, J= 11.8, 4.0, 1.7 Hz, 1 H), 3.12 (dd, J= 10.2, 3.2 Hz, 1 H), 2.95 (m, 1 H), 2.86 (m, 2 H), 2.46 (dd, J= 11.8, 9.5 Hz, 1 H), 2.10 (m, 1 H), 1.93-1.83 (m, 3 H), 1.58 (brs, 1 H), 1.45 (s, 9 H), 1.41 (m, 1 H), 1.35-1.23 (m, 3 H); 13C NMR (CDC13, 125 MHz) δ: 172.8, 154.7, 137.7, 128.4 (4 C), 127.9, 79.6, 76.9, 59.8, 57.0, 49.2, 46.1, 42.8 (br, 2 C), 32.0 (2 C), 28.4 (3 C), 28.3, 27.2.
Step D: Preparation of tert-butyl 4-((lR,2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1 ]octane-2-carboxamido)piperidine- 1 -carboxylate (5)
To a reactor (R-l) was charged tert-butyl 4-((2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxamido)piperidine-l-carboxylate (4) (46.3 g, 107 mmol), dichloromethane (463 mL), and Hunig’s base (58.0 mL). The batch was cooled to -18°C and then charged with triphosgene in four portions (25.1 g total; 85 mmol) at <-8°C. The batch was agitated at -5 to 0°C for 0.5 h then charged with 11.4 wt% aqueous H3P04 at -5 to 0 °C (347 g, 3541 mmol). The batch was agitated at 20-25°C for 15-20 h then phase cut. The aqueous layer was back-extracted with dichloromethane (138 mL). The combined organic layer was washed with 10% NaHC03 (115 mL), then water (115 mL). The organic solution was concentrated at atmospheric pressure to ~80
mL, then charged with MTBE (347 mL) at 35-45 °C over 0.5 h, then concentrated at 35-45 °C to 231 mL two times to form a slurry.
The slurry was charged with heptanes (139 mL) at 35-45 °C over 2 h, then slowly cooled to 15-20°C over 1 h. The batch was agitated at 15-20°C for 6-8 h. Solids were filtered and the wet cake washed with MTBE/heptanes (1.4 : 1 , 185 mL) then dried under vacuum at 25-30°C for 5-10 hours to afford 5 (43.7 g, 92% yield), m.p. 161.3-161.8 °C. 1H NMR (CDC13, 500 MHz) δ: 7.45-7.32 (m, 5 H), 6.55 (d, J= 8.2 Hz, 1 H), 5.05 (d, J= 11.6 Hz, 1 H), 4.90 (d, J= 11.6 Hz, 1 H), 4.02 (m, 2 H), 3.90 (m, 2 H), 3.30 (m, 1 H), 2.99 (dt, J= 11.7, 1.1 Hz, 1 H), 2.86 (m, 2 H), 2.64 (d, J = 11.7 Hz, 1 H), 2.37 (dd, J= 14.6, 6.9 Hz, 1 H), 2.04-1.82 (m, 4 H), 1.58 (m, 1 H), 1.45 (s, 9 H), 1.30 (m, 2 H); 13C NMR (CDC13, 125 MHz) δ: 168.3, 167.5, 154.7, 135.6, 129.2 (2 C), 128.8, 128.6 (2 C), 79.7, 78.3, 60.4, 57.8, 47.5, 46.8, 42.5 (br, 2 C), 32.0, 31.7, 28.4 (3 C), 20.8, 17.2.
Step E: Preparation of tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1|octane- 2-carboxamido) iperidine- 1 -carboxylate
tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-l -carboxylate (9.2 g, 20.1 mmol) was charged to a glass bottle, and the solids were dissolved in THF (150 mL). The solution was then charged to a hydrogenation reactor along with Pd/Al203 (10 wt%, 1.5 g). The reaction was purged three times with hydrogen and then set to a hydrogen pressure of 50 psi. The reaction temperature was adjusted to 25°C and the reaction was allowed to agitate for 22 hours. After the reaction was complete as determined by HPLC analysis, the solution was filtered through SOLKA-FLOC® (Interational Fiber Corporation, North Tonawanda, NY) to remove the catalyst and the filter cake was washed with THF. The filtrate and washes were then solvent switched by vacuum distillation to iPrOAc to a final volume of 40 mL. The resulting iPrOAc slurry was aged at room temperature for 1 hour. The solids were then filtered and washed with iPrOAc (20 mL) and dried under vacuum and N2 at 40°C to afford the title product (6.62 g., 17.97 mmol, 90% isolated yield). Spectral data matched the reference compound.
Preparation of (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide
tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-l-carboxylate (20 g, 54.3 mmol), THF (200 mL), 2-picoline (10.9 mL, 309 mmol) and pyridine-S03 complex (30.2 g, 190 mmol) were charged to a flask under nitrogen. The heterogeneous mixture was allowed to stir overnight (~15 h). The reaction mixture was cooled to -10°C then DCM (200 mL) was added. 0.5 M K2HP04 (168 mL, 84 mmol) was added over 10 minutes. Bu4NHS04 (19.4 g, 57 mmol) was then added over 10 minutes. The biphasic mixture was stirred for 30 minutes, phase cut and the water layer was back extracted with 40 ml of DCM. The combined DCM solution was washed with water (120 ml), phase cut and the organic solution was solvent-switched to MeCN (320 ml) by vacuum distillation with 3 bed volumes of MeCN (total 1.0 L) and used as is in the next step. The solution of Bu4N+ OSO3 salt 7 in MeCN solution was used with an assumed yield of 100% (37.5 g, 54.3 mmol). The reaction mixture was cooled in an ice bath, and TMSI (10.26 ml, 70.7 mmol) was added via addition funnel over 30 minutes between 0°C and 5°C. The resulting mixture was agitated for 1-2 h and then quenched with H20:MeCN (1 :1, 6 ml) to afford a slurry. The slurry was warmed to room temperature and agitated for 12 h and after this time the pH of the supernatant was about 3.0. Tetrabutylammonium acetate (13.6 ml, 13.59 mmol) was slowly added over 30 min. The slurry was agitated for 1 h and pH of the supernatant was about 4.0. Solids were collected by filtration. The solid was washed with 60 mL of aqueous MeCN to afford 19.5 g of the crude product 8 in a 93% isolated yield from compound 6 .
At this stage, all byproducts (including hydro lyzation products of TMS-carbonate) and impurities were soluble in the organic phase.
The product was dissolved back into 140 ml of MeCN:H20 (1 :2) at room temperature. 1-Butanol (390 ml) as antisolvent was slowly added into the solution to afford a slurry. The slurry was agitated overnight. The white crystalline solid was filtered and washed with 3:1 IPA: water (40 ml) and dried under vacuum and nitrogen at room temperature to afford the title product in the form of a crystalline hydrate. (Yield = 16.3 g, 82%). Spectral data matched reference compound.
Preparation of (2S,5R)-7-oxo-2-(piperidin- 1 -ium-4-ylcarbamoyl)- 1 ,6-diazabicyclo[3.2.1 ]octan-6-yl sulfate (1).
tert-Butyl 4-( {[(25*,5i?)-6-hydroxy-7-oxo- 1 ,6-diazabicyclo[3.2.1 ]oct-2-yl]carbonyl}amino)piperidine-l-carboxylate 16 (0.54 g, 1.5 mmol), THF (5.4 mL), 2-picoline (0.29 mL, 2.9 mmol) and pyridine-S03 complex (0.70 g, 4.4 mmol) were charged to a vial under nitrogen. The heterogeneous mixture was allowed to stir overnight (~15 hr). The reaction mixture was cooled to -10°C then dichloromethane (5.4 mL) was added. 0.5 M K2HPO4 (4.5 mL, 2.3 mmol) was added over 10 minutes. BU4NHSO4 (0.53 g, 1.54 mmol) was then added over 10 min. The biphasic mixture was stirred for 30 min, phase cut and the water layer was back extracted with 1 ml of DCM. The combined DCM solution was washed with water (2.0 mL), phase cut and the organic solution was solvent-switched to MeCN (3.2 mL) by vacuum distillation with 3 bed volumes of MeCN. The product was used as is in the next step (water content less than 1000 ppm).
The solution of Bu4N+S04~~ salt 8 in MeCN solution was used with an assumed yield of 100% (1.0 g, 1.47 mmol). The reaction mixture was cooled in an ice bath, and Ν,Ο-bis(trimethylsilyl)trifluoroacetamide (BSTFA) (0.4 lg, 1.59 mmol) was added into the reaction and was allowed to stir for 10 min. TMSI (0.06g, 0.27 mmol) was added between 0°C and 5°C. The resulting mixture was allowed to agitate for 2 hr and then quenched with H2O (0.07g, 4.1 mmol) and acetic acid (0.08g, 1.5 mmol) to afford a slurry. The slurry was warmed to room temperature and agitated for 12 hr. Filter to collect the solid. The solid was washed with MeCN/water (94:6, 1 mL X 4) to afford the crystalline product 1 (0.38 g) in a 75% yield.
If NO-bis(trimethylsilyl)acetamide (BSA) (0.32g, 1.59 mmol) was applied, the reaction needed 24 hr to achieve full conversion.
Patent
WO2015033191
Scheme 1.
Formula (V)
Formula (VI)
Formula (I)
Scheme – 1
Example -1
Preparation of (2S, 5R)-Sulfuric acid mono-{2-[N’-(4-aminopiperidinyl)-carbonyl]-7-oxo- l,6-diaza-bicyclo[3.2.1]oct-6-yl} ester (I).
Step-1: Preparation of (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (IV):
To a 250 ml round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-sodium 6-benzyloxy-7-oxo-l,6-diaza-bicyclo [3.2.1] octane-2-carboxylate (11.1 gm, 0.037 mol, prepared using a method disclosed in Indian Patent Application No 699/MUM/2013) in water (180 ml) followed by l-tert-butoxycarbonyl-4-amino-piperidine (7.8 gm, 0.039 mol), EDC hydrochloride (11 gm, 0.055 mol) and 1 -hydro ybenzotriazole (4.8 gm, 0.037 mol) at 30°C successively under stirring. The reaction mixture was stirred for 24 hours at 30°C to provide a suspension. The suspension was filtered under suction and washed with 45°C warm water (40 ml) to provide (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 12.7 gm quantity in 74% yield after drying under vacuum.
Analysis
NMR: (CDC13,) = 7.36-7.44 (m, 5H), 6.56 (d,lH), 5.06 (d,lH), 4.91 (d, 1H), 4.03 (br s, 1H), 3.88-3.97 (m, 2H), 3.29 (s, 1H), 3.00 (d, 1H), 2.86 (t, 2H), 2.64 (d, 1H), 2.37 (dd, 1H), 1.85-2.01 (m, 4H), 1.54-1.62 (m, 2H), 1.45 (s, 9H), 1.25-1.36 (m, 2H).
MS (ES+) C24H34N405 = 459.5 (M+l).
Step-2: Preparation of (2S, 5R)-tert-butyl { (6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (V):
To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (9 g, 19.5 mmol) in methanol (90 ml) followed by 10% palladium on carbon (2.7 g) at 35°C. The reaction mixture was stirred under 1 atm hydrogen pressure at 35°C for 2 hours. The catalyst was removed by filtering the reaction mixture under suction over a celite bed. The celite bed was washed with dichloromethane (50 ml). The combined filtrate was evaporated under vacuum below 35°C to provide (2S, 5R)-tert-butyl {(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 8.45 g quantity; it was used as such for the next reaction.
Analysis
NMR: (CDC13,) = 6.60 (d, 1H), 3.88-4.10 (m, 4H), 3.78 (s, 1H), 3.20 (d, 1H), 3.90 (t, 2H), 2.80 (d, 1H), 2.46 (dd, 1H), 2.1-2.2 (m, 1H), 2.85-2.20 (m, 4H), 1.70-1.80 (m, 1H), 2.47 (s, 9H), 1.30-1.41 (m, 3H).
MS (ES+) C17H28N405 = 369.4 (M+l).
Step-3: Preparation of Tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (VI):
To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-tert-butyl {(6-hydroxy-7-oxo-l,6-diaza-bicyclo [3.2.1 ]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (6.40 g, 7.6 mmol) in dichloromethane (90 ml), triethyl amine (9.3 ml), followed by pyridine – sulfur trioxide complex (5.4 g, 34.2 mmol) at 35°C under stirring. The reaction mixture was stirred for additional 4 hours at 35°C. The solvent was evaporated under vacuum below 40°C to provide a residue. The residue was stirred with 0.5N aqueous potassium dihydrogen phosphate solution (90 ml) for 1 hour. The resulting solution was extracted with dichloromethane (2 x 100 ml) to remove impurities. To the aqueous layer was added tetrabutyl ammonium hydrogen sulfate (6.9 g, 20.52 mmol) and the reaction mixture was stirred for 14 hours at 35°C. It was extracted with dichloromethane (3 x 30 ml). Combined organic layer was dried over sodium sulfate and evaporated under vacuum to provide tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 8.0 g quantity in 62% yield.
Analysis
NMR: (CDC13,) – 6.64 (d, 1H), 4.36 (br s, 1H), 4.05(br s, 2H), 3.90-4.00 (m, 1H), 3.87 (d, 1H), 2.28-3.34 (m, 10H), 3.80-3.95 (m, 2H), 3.74 (d, 1H), 2.42 (dd, 1H), 2.15-2.24 (m, 1H), 1.82-1.97 (m, 4H), 1.61-1.74 (m, 14 H), 1.41-1.52 (m, 10 H), 1.02 (t, 12H).
MS (ES-) C17H27N408S. N(C4H9)4 = 447.4 (M-l) as a free sulfonic acid.
Step-4: Synthesis of (2S, 5R)- Sulfuric acid mono-{ [(4-aminopiperidin-4-yl) carbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1]-oct-6-yl} ester (I):
To a 100 ml round bottom flask equipped with magnetic stirrer was charged a solution of tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (6.0 g) in dichloromethane (15 ml). The solution was cooled to -10°C under stirring and to it was added trifluoro acetic acid (15 ml) drop wise. The reaction mixture was stirred at -10°C for 1 hour. Solvents were evaporated under vacuum below 30°C to its 1/3 volume to provide a thick residue. The thick residue was stirred twice with diethyl ether (60 ml each time) to provide a precipitation. The solid obtained was filtered at suction and suspended in acetone (90 ml). To the suspension was added 10% solution of sodium-2-ethyl-hexanoate in acetone to adjust pH between 4.5 to 5.5. The suspension was stirred for 10 minutes and filtered under suction. The wet cake was washed with acetone and dried under vacuum below 40°C to provide 3 gm crude compound. The crude compound was stirred with aqueous isopropanol (3ml water: 21 ml iospropanol) for overnight to purify further. The resulting suspension was filtered under suction and washed with aqueous isopropanol (1 ml water: 7 ml IPA mixture). Finally the cake was dried under vacuum below 40°C to provide the title compound as a off-white solid in 1.8 g quantity in 65% yield.
Analysis
H1NMR (DMSO-d6, D20 exchange) = 8.19 (d, exchanges with D20), 3.99 (s, 1H), 3.82-3.92 (m, 1H), 3.72 (d, 1H), 2.24 (br d, 3H), 2.90-3.04 (m, 5H), 1.96-2.06 (m, 1H), 1.80-1.94 (m, 3H), 1.58-1.72 (m, 4H).
MS (ES+) C12H20N4O6S = 349.2 (M+l) as a free sulfonic acid;
Purity by HPLC: 99.2%
Specific rotation: [a] D -45.25 °, (c 0.3%, water)
///
C1CC(N2CC1N(C2=O)OS(=O)(=O)O)C(=O)NC3CCNCC3.O





2
Tazobactam

Tazobactam.svgTazobactam.png

Tazobactam; Tazobactam acid; 89786-04-9; Tazobactamum; YTR-830H; CL-298741
(2S,3S,5R)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
CAS 89785-84-2 SODIUM SALT
TAIHO Innovator
Molecular Formula:C10H12N4O5S
Molecular Weight:300.29108 g/mol
Tazobactam is a beta Lactamase Inhibitor. The mechanism of action of tazobactam is as a beta Lactamase Inhibitor.
Tazobactam is a penicillanic acid sulfone derivative and beta-lactamase inhibitor with antibacterial activity. Tazobactam contains a beta-lactam ring and irreversibly binds to beta-lactamase at or near its active site. This protects other beta-lactam antibiotics from beta-lactamase catalysis. This drug is used in conjunction with beta-lactamase susceptible penicillins to treat infections caused by beta-lactamase producing organisms.
Tazobactam is a pharmaceutical drug that inhibits the action of bacterial β-lactamases, especially those belonging to the SHV-1 and TEM groups. It is commonly used as its sodium salt, tazobactam sodium.
Tazobactam is combined with the extended spectrum β-lactam antibiotic piperacillin in the drug piperacillin/tazobactam, one of the preferred antibiotic treatments for nosocomial pneumonia caused by Pseudomonas aeruginosa.[citation needed] Tazobactam broadens the spectrum of piperacillin by making it effective against organisms that express β-lactamase and would normally degrade piperacillin.[1]
Tazobactam is a heavily modified penicillin and a sulfone.

PAPER
Synthesis 
PATENT
CN 104031065
[2S- (2 α, 2 β, 5 α)] -3- methyl _7_ oxo _3_ (1Η-1,2,3_ triazol-1-ylmethyl) -4- thia-1-azabicyclo - [3,2, O] - heptane-2-carboxylic acid 4,4-dioxide.
The structural formula:
Figure CN104031065AD00041
The first from 6-aminopenicillanic acid (6-APA) prepared by starting from the Hall TW et al., Its structure is to add a triazole ring on the basis of sulbactam to improve the effect of inhibiting the enzyme, which is currently lactam best clinical results β_ inhibitor, with high stability, low activity, low toxicity, inhibiting activity and other characteristics. 1992, tazobactam combination drug tazobactam / piperacillin (1: 8) for the first time in France the market, used to treat a variety of bacterial infections.
The literature related to the different synthesis Tazobactam triazole ring according to the introduction, there are two main ways of preparation methods: the azide cycloaddition synthetic triazole five-membered ring and the side chains directly added triazole ring .
Preparation Method One: the azide cycloaddition method, as shown below:
Figure CN104031065AD00051
The azide cycloaddition preparation method, which is penicillanic acid diphenylmethyl ester sulfoxide as raw material, open-loop, chloride, azide, oxidation, alkyne cycloaddition, deprotection steps to obtain cilostazol Batan, although each step is quite simple and easy for industrial production, at present most manufacturers use this route, but its route is longer, and there is the azide reaction byproducts generated a large number of six-membered ring, the total yield compared low.
Preparation Method two: direct plus side chains triazole ring
Direct plus side chains triazole ring Preparation mainly disulfide nucleophilic ring was open and IH-1,2,3- triazole occurred directly in acetic acid in the presence of mercury or mercury oxide substituted rings (US4898939) or directly with the IH-1,2,3- triazole silver salt catalyzed reaction of iodine (Synthesis, 2005,3,442-446), as shown below:
Figure CN104031065AD00052
And the use of methyl chloride in an alkaline environment and iodine catalyzed substitution to generate the target product (CN200810238479 with 1H-1,2,3- triazole; Shanghai Second Medical University, Shanghai 2009/20 (5): 388- 391), as shown below:
Figure CN104031065AD00061
Direct plus side chains triazole ring preparation method because of its short synthetic route, avoiding the risk of high temperature and pressure addition is currently a hot tazobactam drug synthesis research. Since the compound (4) the sulfur atom lone pair of electrons more of a halogen atom (Cl, Br,
I) have a role to leave, under alkaline action by 1H-1,2,3- triazole nucleophilic attack IH ions generated carbocations prone to rearrangement to form a six-membered ring by-products higher probability, if the sulfur atom is oxidized to a sulfone, a sulfur atom, provided no lone pair of electrons, although able to increase its stability, but at the same time a halogen atom (Cl, Br, I) leaving passivation effect, such that the nucleophilic replace hardly occurs while using the expensive raw mercury and silver salts of heavy metals, higher costs, greater environmental pollution, which greatly restricted the industrial scale production.
Synthetic route of the present invention are as follows:
Figure CN104031065AD00071
Example 1: Preparation of 3-methyl - [2-oxo-4- (2-benzothiazolyl dithio) -1-azetidinyl] -3-butene diphenylmethyl ester (Compound 3) Preparation of
In penicillanic acid diphenylmethyl ester sulfoxide (compound 2) as a raw material, according to the literature (Synthesis, 2005,3,442-446) preparation, to give a pale yellow crystalline solid from acetone powder at a yield of 95%.
[0019] Examples of 2: 2 β- bromomethyl -2 α- methyl - penicillanic acid diphenylmethyl ester (Compound 4) Preparation of the solid obtained in Example I (Compound 3) 26g (0.05mol) dissolved in 300mL of methylene chloride, cooled to 0 ° C
The following is added 33.5g (0.075mol) of anhydrous copper bromide, after increases in (T5 ° C the reaction was stirred 10-ΐ2 hours, TLC sample testing of raw materials point disappears, and the filter cake was rinsed with 50mL methylene burn, The filtrate was respectively 200mL water, 200mL saturated sodium bicarbonate, 200mL water washing, containing 2β- bromomethyl -2α- methyl - penicillanic acid diphenylmethyl ester (compound 4) in methylene chloride was used directly in the next step reaction.
Examples 3 [0020]: 2 β - bromomethyl -2 α - methyl - penicillanate _1 β _ oxide diphenylmethyl ester (Compound 5) Preparation of
Of Example 2 was 2 β - bromomethyl -2 α - methyl - penicillanic acid diphenylmethyl ester (Compound 4) in dichloromethane was added 30mL of methanol, cooled to -5 ° C or less, dropwise 30mL50 % hydrogen peroxide / sodium tungstate mixture for about 30 minutes after the dripping, and the temperature at (T5 ° C incubation for 4 hours, then heated to 1 (T15 ° C incubation for 4 flying hours, TLC sample testing of raw materials (Compound 4) disappear , was added 200mL 7jC, stirred for five minutes, standing layer, the liquid layer was then washed with dichloromethane material 200mL 5% aqueous sodium bicarbonate to give comprising 2β - bromomethyl -2 α - methyl - di penicillanate phenylmethyl ester -1 β - oxide (Compound 5) in methylene chloride was used directly in the next reaction.
[0021] Example 4: 2 @ - (! 1 1-1,2,3- triazole group) -20- methyl - penicillanic acid diphenylmethyl ester 1 @ - oxide (compound 6) Preparation
Of Example 3 was 2 β - bromomethyl -2 α - methyl - penicillanic acid diphenylmethyl ester -1 β - oxide (Compound 5) in dichloromethane was added 60mL methanol, 30mL water and 10.35g (0.15mol) 1H-1,2,3- triazole, cooled to below 5 ° C, was added 26g anion resin, temperature 5 ~ 10 ° C and stirred overnight (more than 24 hours), samples of raw materials by TLC (Compound 5) disappears, filtered, and the filtrate was added 200mL of water, standing layered material liquid dichloromethane layer was added anhydrous magnesium sulfate and activated carbon decolorization dehydration process, concentrated and dried under reduced pressure, the residue was added 60mL of methanol was dissolved by heating, stirring slowly cooled to (T5 ° C crystallization, precipitation continued until most of the solids after cooling to below -10 ° C for about 4 hours, filtered, and the cake was rinsed with cold methanol and vacuum dried to give a white solid (compound 6) Hg, yield 82% (Compound 3 by meter), mp: V; ESI (m / z):. 450 ,; IHNMR (CDl3) Examples 5: 2β- (1Η-1,2, 3- triazole-yl) -2α- methyl - penicillanic acid diphenylmethyl ester 1,1-dioxide (Compound 7) Preparation of
The 9g (0.02πιο1) 2β - (1H-1,2,3- triazole group) _2 α - methyl - penicillanic acid diphenylmethyl ester 1-oxide (compound 6) was dissolved in 225mL dichloro methane, adding 45mL glacial acetic acid, cooled to below 0 ° C, was added in portions
3.8g (0.024mol) of potassium permanganate. After the addition was completed in 5 ~ 10 ° C incubated overnight (more than 16 hours), sampled by HPLC completion of the reaction, insolubles were removed by filtration, the filtrate was added to 200mL water, stirred for five minutes, allowed to stand The layers were separated and then washed with 200mL saturated aqueous sodium bicarbonate, methylene chloride stock solution layer was dehydrated by adding anhydrous magnesium sulfate and decolorizing charcoal treatment, the remaining concentrated under reduced pressure to about 50mL volume, slowly with stirring to a cooled (TC hereinafter Crystallization 2 hours, filtered, rinsed with a small amount of methylene chloride, dried in vacuo to give a white solid (Compound 7) 8.85g, yield 95%, mp: 201-206 ° C; ESI (m / z): 466, .; IHNMR (CDl3) Example 6: Preparation of tazobactam he (Compound I),
The 1g (0.021mol) 2 β - (1H-1,2,3- triazole group) _2 α - methyl - penicillanate 1,1-diphenyl ester (compound 7) was dissolved in 10mL m-cresol at 50 ~ 55 ° C incubated for 2 hours, cooled to O ~ 5 ° C, was added 200mL of methyl isobutyl ketone, extracted twice with 10mL saturated sodium bicarbonate solution, the combined aqueous layers were dried 10mL ethyl acetate extract miscellaneous twice, and the aqueous layer was added active carbon filtration, and the filtrate was cooled to O ~ 5 ° C, dropping 6mol / L hydrochloric acid to precipitate a solid no longer far, filtered cake was washed with cold water and dried under vacuum to give a white solid tazobactam 5.9g, yield 92%, mp: 136-1380C; ESI (m / z): 300; IHNMR (CDl3) ο

PATENT

WO 2014037893
improved process for the preparation of Tazobactam of formula (I).
Figure imgf000003_0001
(I)
Tazobactam is chemically known as 2a-methyl-2 -(l,2,3-triazol-l-yl)- methylpenam-3a-carboxylate- 1,1 -dioxide and has a very low antibacterial activity. On the other hand, it exhibits a beta-lactamase inhibitory activity when irreversibly bonded to beta-lactamases produced by microorganisms. For this reason, Tazobactam may be used in combination with known antibiotics prone to be inactivated by beta-lactamases to allow them to exhibit their inherent antibacterial activity against beta-lactamase producing microorganisms. Tazobactam as a product is disclosed in US Patent No. 4,562,073.
Considering the importance of Tazobactam there are several literatures available which disclose various processes for the preparation of Tazobactam, some of which are described below.
US patent No. 4,562,073 provides Tazobactam of formula (I) and its derivatives. This patent also describes a process for their preparation as shown in Scheme - 1.
Figure imgf000004_0001
(I )
Scheme - 1
wherein R is hydrogen or trialkylsilyl; R is hydrogen, trialkylsilyl or COOM wherein M is hydrogen, C1-18 alkyl, C2-7 alkoxymethyl, etc., R has the same meaning as M and R represents carboxyl protecting group.
US patents 4,891,369 and 4,933,444 disclose an approach, which involves the preparation of 2a-methyl-2 -triazol lmethylpenam derivative of formula (V)
Figure imgf000004_0002
(V)
wherein R is a carboxy protecting group, by treatment of a β-halomethyl penam derivative of formula (IV), wherein X is chlorine or bromine and R is a carboxy protecting group, with 1,2,3-triazole.
Figure imgf000004_0003
(IV) US patent No. 4,507,239 provides a process which involves the preparation of 2a-methyl-2 -azidomethylpenam derivatives of formula (VII) by treatment of compound of formula (IV) with sodium azide in aqueous aprotic solvents.
Figure imgf000005_0001
In yet another method disclosed in US patent No. 4,895,941, penam sulfoxide of formula,
Figure imgf000005_0002
(II)
wherein R represents a carboxy protecting group, is treated with 2-trimethylsilyl- 1,2,3-triazole in a sealed tube at elevated temperatures to give a mixture which upon column chromatography purification yields 2a-methyl-2 -triazolylmethyl penam derivative of formula (V).
US patent 4,518,533 provides a process for the preparation of intermediate of formula (III)
Figure imgf000005_0003
(HI) wherein the ester of penicillanic acid- 1 -oxide [compound of formula (II)] is reacted with 2-mercaptobenzothiazole in aliphatic hydrocarbon or aromatic hydrocarbon followed by isolation using column chromatographic method.
US patent 7,273,935 provides a process for the preparation of compound of formula (VIII) by reacting compound of formula (III) with cyclising agents like HCl or HBr and sodium nitrite.
Figure imgf000006_0001
(VIII)
wherein R is carboxyl protecting group and L is a leaving group like CI or Br.
US patent 6,936,711 provides a process for the preparation of protected tazobactam [compound of formula (VI)] by reacting compound of formula (VIII) with 1,2,3-triazole using a base.
In addition, US patent namely US 6,660,855, US 7,692,003, and US 7,547,777 claim process for the preparation of crystalline intermediates useful in the preparation of Tazobactam.
In general, de-protection of p-nitrobenzyl/ diphenylmethyl group in penem/penicillin core like Meropenem, Imipenem, Doripenem, Ertapenem, Faropenem, tazobactam and the like utilizes 1-10% of palladium on carbon, like commercially available 1.0%, 2.5%, 5.0%, 7.5% or 10%, which requires high pressure reactor. US patent 4,925,934 provides a de-protection method for 2a-methyl-2 - triazolylmethylpenam derivative of formula (VI) by reaction with m-cresol
Figure imgf000007_0001
(VI)
wherein R is selected from p-methoxybenzyl, diphenylmethyl (benzhydryl), 3,4,5- tirmethoxybenzyl, 2,4-dimethoxybenzyl, 3,5-dimethoxy-4-hydroxybenzyl, 2,4,6- trimethylbenzyl, ditolylmethyl, dianisylmethyl or tert-butyl. The isolated product contains higher amount of m-cresol as an impurity.
US patent 7,674,898 provides a process for the isolation of tazobactam by heating the aqueous solution containing Tazobactam before adjusting the pH. Before adjusting the pH of the aqueous solution containing tazobactam, the said solution was treated with ion-exchange resin column to purify the product. The use of ion-exchange resin and eluting the product is cumbersome on commercial scale.
Considering the importance of Tazobactam in healthcare treatment, the present inventors diligently worked to identify a robust and high yield process for the preparation of Tazobactam having cresol content below 5 ppm. A further purpose of the invention is to provide a manufacturing method that yields Tazobactam and its related intermediates with high purity and productivity.
Scheme:
Figure imgf000009_0001
Preparation of Tazobactam (I)
Into m-cresol was added benzhydryl 3-methyl-7-oxo-3-(lH-l,2,3-triazol-l- ylmethyl)-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide (VI) (5 g) and heated at 50-55°C till the completion of the reaction. The reaction mass was diluted with methyl isobutyl ketone. The reaction mass was extracted with sodium bicarbonate solution. The aqueous extract was acidified with hydrochloric acid to pH 3.0-4.0 and washed with methyl isobutyl ketone. Activated carbon was added, stirred and filtered. The filtrate was cooled to 0-5°C, and isopropyl alcohol (20 mL) was added followed by adjusting the pH to 1.0-2.0 using hydrochloric acid. The crystallized product was filtered, washed with water and dried.
Yield: 2.7 g
Purity: 99.9%
m-cresol content: 0.7 ppm
Example 5
Preparation of Tazobactam (I)
Into m-cresol was added benzhydryl 3-methyl-7-oxo-3-(lH-l,2,3-triazol-l- ylmethyl)-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide (VI) (5 g) and heated at 70-75 °C till the completion of the reaction. The reaction mass was diluted with dichloromethane. The reaction mass was extracted with potassium carbonate solution. The aqueous extract was acidified with hydrochloric acid to pH 3.0-4.0 and washed with dichloromethane. Activated carbon was added, stirred and filtered. To the filtrate, methanol (20 mL) was added followed by adjusting the pH to 1.0-2.0 using hydrochloric acid at 22-27° C. The crystallized product was filtered, washed with water and dried.
Yield : 2.6g
Purity: 99.9%
m-cresol content : 0.24 ppm
Example 6
Preparation of Tazobactam (I)
Into m-cresol was added benzhydryl 3-methyl-7-oxo-3-(lH-l,2,3-triazol-l- ylmethyl)-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide (VI) (5 g) and heated at 60-65 °C till the completion of the reaction. The reaction mass was diluted with dichloromethane. The reaction mass was extracted with potassium carbonate solution. The aqueous extract was acidified with hydrochloric acid to pH 3.0-4.0 and washed with dichloromethane. Activated carbon was added, stirred and filtered. To the filtrate, ethanol (20 mL) was added followed by adjusting the pH to 1.0-2.0 using hydrochloric acid at 22-27° C. The crystallized product was filtered, washed with water and dried.
Yield : 2.6g
Purity: 99.9%
m- ere sol content : 0.31
Reference example- 1
The process disclosed (example-1) in US 4,925,934 was repeated to get Tazobactam
Figure imgf000021_0001
• The above table clearly indicates that the use of water-miscible solvents helps to reduce the m-cresol content to less than 1 ppm.
• The present process obviates the use of ion-exchange resin for the purification (Refer example-1 of US 7,674,898) and provides a robust process for the industrial production of Tazobactam having less than 5ppm, preferably less than lppm. The m-cresol content in tazobactam acid is determined using HPLC with the following parameters
Colum Zorbax SB C8 (150 x 4.6mm, 3.5μ).
Mobile phase Phosphate buffer: Acetonitile
Detector UV at 200 nm
Column temperature 30°C
Flow rate 0.8 mL/min
Run time 15 min.

PATENT

CN 102020663
Example 8:
 (I) in a three-necked flask were added CH2Cl2 300mL IOOOmL and 1. 5mol. [1H2SO4 lOOmL, stirring was added 81. 3g (0. 508mol) of bromine was cooled to 0 ° C after, Ilg sixteen burning trimethylammonium ammonium bromide and 35g (0. 508mol) sodium nitrite to the reaction mixture, with continuous stirring, was added portionwise 6-APA 55g (0. 254mol) and dissolved, and stirred at 0~5 ° C Ih, a solution of lmol . L-1 NaHSO3 to K1- starch paper test solution does not change color. And then allowed to stand separated, the aqueous layer was combined organic layer was extracted twice IOOmL CH2Cl2, washed successively with water, 7% aqueous NaHCO3, saturated sodium chloride aqueous solution, to give 6,6-dibromo-containing penicillanic acid in CH2Cl2 solution was used directly in the next reaction.
 (2) in IOOOmL three flask, 6,6_-dibromo penicillanic acid in CH2Cl2 solution (about 400ml), cooled to 5 ° C after the addition of benzhydrol 47g (254mmol), DCC (N, N- dicyclohexyl carbodiimide) 52. 3g (254mmol), 1. 8g of concentrated sulfuric acid was added and dissolved with stirring, at 5~10 ° C under stirring for 30min the reaction product was filtered off D⑶ DCC dehydrated to form the (N, N- two cyclohexylurea), liquor spotting, TLC [developing solvent V (cyclohexane): V (ethyl acetate) = 6: 4] to display all the raw materials after completion of the reaction on a rotary evaporator at 30~40 ° C steam dichloromethane, to give the 6,6-dibromo-penicillanic acid diphenylmethyl ester concentrate was used directly in the next reaction.
[0120] (3) obtained in the above Step 6,6-dibromo-penicillanic acid diphenylmethyl ester concentrate was added 500mL three flask, cooled with stirring to (TC, was added 0. 5g cobalt acetate Co (AC) 2 at 0~5 ° C dropping 50mL 30% H202, finished in 30min drip, drip completed at 0~5 ° C thermal reaction, TLC [developing solvent V (cyclohexane): V (ethyl acetate) = 6: 4] track to complete the reaction (about 4h). Still stratification, the organic layer was successively washed with water three times, after 7% NaHC03 was washed twice, the solvent was distilled off under reduced pressure to give 6,6-dibromo-penicillanic alkylene acid diphenylmethyl ester sulfoxide The crude product without purification, was used directly in the next reaction.
 (4) the 6,6-dibromo-penicillanic acid diphenylmethyl ester sulfoxide The crude product was dissolved in 4001 ^ tetrahydrofuran, at 101: add 150mL 10% NH4Cl solution, zinc powder was added in four portions 82. 5g (127mol), at intervals IOmin, about 50min addition was completed, plus complete response at 0~10 ° C 30min. Plus zinc filtered through Celite, standing stratified rotating concentrated organic layer recovered tetrahydrofuran. Ethyl acetate was added to dissolve the concentrated solution, washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure (45 ° C or less) to just precipitate a solid, 0~5 ° C curing crystallization 3h, suction and the filter cake was dried in vacuo to give white crystals of 6,6-dihydro-penicillanic acid sulfoxide, diphenylmethyl ester 70g, 72% yield [6-APA to calculate, yield = weight of dry product / (6-APA was mass X 383)], mp 145 ~147 ° C (literature value of 145 ~148 ° C).
 (5) containing 6,6-dihydro-penicillanic acid sulfoxide, diphenylmethyl ester (70g, 0. 182mol), 2- trimethylsilyl-1,2,3-triazole (25. 7g, the 0. 182mol) and toluene (500mL) autoclave purged with nitrogen, then heated to 110~120 ° C, the reaction 4.5h. After cooling, toluene was evaporated, extracted with ethyl acetate (700mL), water (250mL) washed with saturated sodium chloride solution (250mL), dried over anhydrous magnesium sulfate, the solvent was evaporated, and recrystallized from ethanol to give 2a- A yl 23- (1,2,3-triazol-1-yl) methyl penicillanate -3 a- carboxylic acid, diphenylmethyl ester (white solid) 43.48g, 55% yield [yield = dry product Weight / (() • 182X434. 4)], mp 140 ~142 ° C (literature values ​​141 ~143 ° C).
 (6) The 2a- methyl 2 P - (1,2,3`_ triazol _1_ yl) methyl penicillanate _3 a - carboxylic acid diphenylmethyl ester 43. 48g (0.1OOmoI ) was dissolved in 35mL of acetone, was added 70mL of water and 105mL of glacial acetic acid, cooled to 0~5 ° C, was added with stirring a mixture of KMnO4 (23. 7g KMnO4,16. 5g of concentrated phosphoric acid, and 520ml water), with 5mol. L- phosphate, pH was adjusted to 1 6.5, the reaction was stirred at room temperature for 3h. 30% hydrogen peroxide was added dropwise to the reaction solution colorless, filtered, and the resulting crude product was recrystallized from methanol to give 40. 6g as a white solid (2 a- methyl 2 ¢ - (1, 2,3- triazol-1-yl) methylpenicillanate _3 a - carboxylic acid diphenylmethyl ester-dioxide), 87% yield [yield = weight of dry product / (0 100X466.7).]. mp 205~207 ° C (206 ~208 literature values ​​..).
 (7) in 500ml reaction flask was added 2 a- methyl 2 ¢ - (1, 2,3- triazol-1-yl) methyl penicillanate _3 a- two carboxylic acid diphenylmethyl ester oxide 40. 6g (0. 087mol) and 200mL (2mol) between A sprinkle, stirred until solid was completely dissolved, 80 ° C the reaction was kept 4h, cooled to room temperature, was added 600mL of methyl isobutyl ketone, with IOOmL 7% carbonate solution of sodium hydroxide wash, the aqueous layer was separated, the organic layer was washed twice with 150ml, the combined aqueous layer was cooled to 0~5 ° C, with 6mol. L-1 hydrochloric acid to adjust the pH to I~1. 8, white crystals precipitated, pumping filter, 80 ° C drying, dry goods tazobactam 15. 2g, 58% yield [yield = dry goods weight / (0. 087X300. 3)] o mp 136 ~137 ° C (literature value of 136 ~ 138 ° C).
Figure CN102020663BD00061

 PATENT

  • methods of producing β-substituted methyl penam derivatives. For instance, US 4,529,592 discloses a process which involves the treatment of 2α-methyl-2β-azidomethyl penam derivatives of formula (c):
    Figure imgb0003
    wherein R is a carboxy-protecting group, with acetylene, an acetylene derivative or a vinyl derivative under high pressure in a sealed reactor and at elevated temperatures, followed by deprotection with a suitable reagent to get the β-lactamase inhibitor of formula (a).
  • The 2α-methyl-2β-azidomethyl penam derivative of formula (c) is in turn prepared from the 2α-methyl-2β-halomethyl penam derivatives of formula (d)
    Figure imgb0004
    wherein R is a carboxy-protecting group and X is chloro or bromo, by treating with sodium azide in aqueous polar aprotic solvents, followed by oxidation.
  • US 4,891,369 and US 4,933,444 disclose a different approach, which involves the preparation of 2α-methyl-2β-triazolylmethylpenam derivatives of formula (e) wherein R is a carboxy protecting group and n is 0, by the treatment of a β-halomethyl penam derivative of formula (d), wherein X is chlorine or bromine and R is a carboxy-protecting group, with 1H-1,2,3-triazole.
    Figure imgb0005
    The product obtained can be oxidized and deprotected to get the 2β-substituted methyl penam compound (a).
  • US 4,912,213 discloses a reduction method employing lead salts in catalytic amounts to prepare a 2α-methyl-2β-triazolylmethyl penam derivative of formula (e) (n=0-2) from 6-halo or 6,6-dihalo-2α-methyl-2β-triazolylmethyl penam derivatives of formula (f)
    Figure imgb0006
    where X may be Cl, Br, I; Y may be Cl, Br, I or a hydrogen atom; and R is a carboxy-protecting group.
  • In yet another method disclosed by US 4,895,941, penam sulfoxide of formula (g), wherein R represents a carboxy-protecting group, is treated with 2-trimethylsilyl-1,2,3-triazole in a sealed tube at elevated temperatures to give a mixture which requires purification by column chromatography to isolate the 2α-methyl-2β-triazolylmethyl penam derivative of formula (e) (n=0).
    Figure imgb0007
  • As an alternative to the hydrogenation, US 4,925,934 discloses a deblocking method for a 2α-methyl-2β-triazolylmethyl penam derivative of formula (h) by reaction with cresol
    Figure imgb0008
    where R is selected from p-methoxybenzyl, 3,4,5-trimethoxybenzyl, 2,4-dimethoxybenzyl, 3,5-dimethoxy-4-hydroxybenzyl, 2,4,6-trimethylbenzyl, diphenylmethyl, ditolylmethyl, dianisylmethyl or tert-butyl.
  • [0009]
    Published application US 2003/232983 discloses a complete different route of synthesis for 2α-methyl-2β-triazolylmethyl-penam derivatives starting from cepham derivates of formula (i) by substitution and rearrangement
    Figure imgb0009
    where R represents a carboxy-protecting group and L a leaving group.
  • In most of the methods involved, 2α-methyl-2β-halomethyl penam of formula (d) is used as the key intermediate. This is true with both the azide/acetylene combo and the triazole route discussed above. However, the 2α-methyl-2β-halomethyl penam of formula (d) itself is an unstable intermediate and therefore manufacturing and storage of this intermediate in large quantities is always cumbersome. This intermediate has been found to degrade on storage even at low temperatures in isolated form as well as in the solution from which it is isolated. Thus, all the operations related to preparation of the intermediate have to be done rapidly, and the isolated intermediate has to be converted to the final product immediately. As a result of these limitations, in-plant scale up always yields by-products which ultimately require purification demands.
Example 1: Preparation of Tazobactam Sodium by route A. (Fig. 1)Step 1.
      Production of 6α-Bromopenicillanic acid (BPA) (compound II)
    • 2.5 L of 1.24 molar sulphuric acid (3.125 mol) was stirred at 4°C in a 6 L flask. 218.4 g (1.0 mol) of 6-APA (99%) (compound I) following 601 g (5.05 mol) of potassium bromide and 2000 mL of ethanol were added, maintaining the temperature between 4 to 8°C. Inorganic salts were removed by filtration. The resulting cake was washed by 2 x 1.25 L of cooled dichloromethane. The aqueous phase was extracted twice using the previous washing liquor and 3 x 500 mL of cooled dichloromethane. The organic phases were combined (approx. 4.0 L) and washed with 2 x 200 mL of 30% brine at 4°C. The greenish-brown solution was concentrated to 700 mL in vacuum. The precipitate was removed by filtration and the solution was kept below 0°C and used without further purification in the next reaction step.
      Yield: 90% (by titration)
      TLC (thin layer chromatography; detection by UV and phosphomolybdic acid, eluent: acetone - methanol 2:1 v/v): Rf 0.65 (BPA), (eluent: acetone - methanol 4:1 v/v) Rf 0.35 (BPA)
Step 2
      . Production of 6α-Bromopenicillanic acid-S-oxide (BPO) (compound III)
    • 1.8 mol of BPA in 1400 mL of dichloromethane was placed in a 4 L flask. The temperature of the solution was maintained between 0 to 2°C. 2.0 mol peracetic acid in acetic acid solution (342 mL, 40 wt.-% peracetic acid) was added within 100 to 120 minutes, maintaining the temperature of the solution between 0 to 8°C. The color of the solution changed to yellowish-brown. The solution was stirred further 1 hour at 0 to 8°C. The product crystallizes. The slurry was cooled to -10 to -15°C and stirred further 30 minutes then filtered. The cake was washed with 2 x 400 mL of dichloromethane at -10°C. The product was dried at 20 - 25°C in vacuum. The crude product was kept below 0°C and used without further purification immediately (storage time 1 to 2 days) in the next reaction step.
      Yield: 314 - 331g (58,9 - 62.1 %)    Mp: 130 °C (decomp.)
      Cumulative yield of 1st and 2nd steps: 51- 52%
      TLC (detection by UV and phosphornolybdic acid, eluent: acetone - methanol 2:1 v/v)
      Rf 0.65 (BPA), Rf 0.45 (BPO)
      The yield can be improved using higher concentrated peracetic acid.
Step 3
      . Production of 6α-Bromopenicillanic acid-S-oxide p-nitrobenzyl ester (BPE) (compound IV)
    • In a 4 L flask 272.44 g (0.92 mol) of BPO was dissolved in 120 mL DMF at 25°C. 100.8 g (1,2 mol) of sodium hydrogencarbonate and 229.0 g (1.06 mol) of p-nitrobenzylbromide (PNM) were added portionwise. The slurry was cooled and stirred at 0 to 5°C for one hour. The product was filtered and washed with 2 x 800 mL of cold water. The wet product was placed in a 2 L flask and 1200 mL of methanol was added. The slurry was refluxed for one hour, cooled to -10°C and filtered. The cake was washed with 2 x 800 mL of methanol at -10°C. The product was dried at 25 - 30°C in vacuum and stored at 0°C without further purification in the next reaction step.
      Yield: 334.8 g (84.4%)    Mp: 130 °C (decomp.)
      Cumulative yield of 1st, 2nd and 3rd steps: 46%
      TLC (detection by UV, eluent: acetone - methanol 2:1 v/v) Rf 0.75 (BPE), Rf 0.65 (BPO);
      (eluent: ethyl acetate - hexane 2:1 v/v) Rf 0.50 (BPE), Rf 0.00 (BPO)
Step 4.
      Production of 2-(2-Benzothiazolyldithio)-3-bromo-α-(1-methylethylidene)-4-oxo-1-azetidincacetic acid p-nitrobenzyl ester (BBE) (compound V)
    • In a 4 L flask 140.84 g (0.826 mol) of 95% 2-mercaptobenzothiazole (MBT) and 345.0 g BPE (0.8 mol) were dissolved in 1360 mL toluene when the solution was heated to 86 - 90°C and an azeotropic mixture of toluene-water was distilled at 450 to 500 mbar. After 3 to four hours, 14 to 16 mL of water was removed using a Dean-Stark apparatus maintaining the temperature between 86 to 90°C. If unreacted BPE could be detected by TLC, a small amount of 2 to 8 g of MBT was added. The solution was refluxed until no starting material could be detected by TLC.
    • The solution was evaporated in vacuum between 60 to 70°C. The residual oil was dissolved in 1200 mL of ethyl acetate. After cooling the product crystallizes. The slurry was concentrated in vacuum below 50 °C to 800 mL and 1200 mL isopropyl ether was added to give a well-filterable crystalline slurry that was cooled below 20°C and stirred for additional 24 hours. Subsequently, the product was filtered and washed with 2 x 500 mL cooled isopropyl ether. The product was dried in vacuum between 25 - 30°C.
      Yield: 412.8 g (88.9%)    Mp.: 116-119°C
      Cumulative yield of 1st, 2nd, 3rd and 4th steps: 41%
      TLC (detection by UV, eluent: isopropyl ether - ethyl acetate 99:1 v/v) Rr 0.65 (BBE)
Step 5
      . Production of 6α-Bromo-2β-bromomethyl-2α-methylpenam-3α carboxylic acid p-nitrobenzyl ester (DBPE) (compound VI)
    • In a 4 L flask 290.24 g (0.5 L) of BBE was dissolved in 1500 mL dichloromethane. The solution was cooled to -2°C. 540 mL of 30% aqueous solution of hydrogen bromide (2.52 mol) was added, keeping the temperature below 0°C. A solution of 103.5 g (1.5 mol) sodium nitrite in 300 mL was added keeping the temperature between 0 to 3 °C. Meanwhile the colour of the organic phase turned to brown. The reaction mixture was stirred about 90 min at 0 to 5 °C until the starting material could not be detected by TLC. 80 g of sodium carbonate (0.75 mol) was added, adjusting the pH to between 6 and 7. The reaction mixture was filtered using perlite as a filter aid. The precipitate was washed with 3 x 100 mL dichloromethane. The combined organic layer was separated and concentrated to 700 mL. The solution was cooled to 20 °C and two litres of isopropyl ether were added slowly. The crystalline suspension was stirred 16 hours at 20 °C and two hours at 0 °C. It was filtered and the product was washed with 2 x 300 mL of cooled isopropyl ether. The product was dried at 20 to 25 °C in vacuum.
      Yield: 235.84 g (95.5%)    Mp.: 80 °C (decomp.)
      Purity: min. 95 %
      Cumulative yield of 1st - 5th steps: 39%
      The product is sensitive to light and decomposes on silica gel to give cepham.
      TLC (detection by UV, eluent: isopropyl ether - ethyl acetate 99:1 v/v) Rf 0.72 (DBPE),
      Rf 0.65 (BBE), Rf 0.57 (cepham)
Step 6
      . Production of 6α-Bromo-2β-azidomethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester (BTPE) (compound VII)
    • In a 2 L flask 292.3 g (342 mL, 2.664 mol) trimethylsilylchloride was dissolved in 1300 mL of toluene. 210.1 g (3.20 mol) sodium azide was added and the suspension was stirred and refluxed. The reaction was traced by GC. After 10 to 16 hours less than 0.1% of the starting material could be detected. The suspension was cooled to -5 to 0°C and was filtered (or decanted). The solution (1580 mL) contains 2.40 mol of trimethylsilylazide, which is volatile (Bp: 95°C) and a toxic compound.
    • In a 2 L flask 52.63 g (23.7 mL, 0.2 mol) tin(IV) chloride was added to a toluene solution of 2.4 mol of trimethylsilylazide between 20 - 25°C. The solution was stirred 24 hours at 20 - 25 °C while some white precipitate appeared. 197.7 g (0.4 mol) DBPE was added. The suspension was stirred 40 to 70 hours while brown gum appeared. The formation of azide was traced by TLC (eluent isopropyl ether - ethyl acetate 99:1 v/v) Rf 0.72 (DBPE), Rf 0.61 (BAPE), Rf 0.58 (cephambromide) Rf 0.40 (cephamazide).
    • Conversion of the starting material to product was less than 50% after 40 hours. Additionally, 0.2 mol of tin (IV) chloride was added, which accelerated the formation of BAPE.
    • After no starting material could be detected by TLC, the reaction mixture was quenched with 1200 mL of saturated sodium carbonate solution at 5-10°C. The insoluble material was dissolved by 400 mL ethyl acetate and added to the sodium carbonate solution. The biphasic reaction mixture was stirred 15 minutes, The pH of the lower aqueous phase was between 8 and 9. Perlite (50 g) as a filter aid was added and the suspension was filtered. The cake was washed with 2 x 200 mL of ethyl acetate.
    • The combined filtrates were poured into a 5 L separating funnel and the lower aqueous phase was removed and extracted with 2 x 200 mL ethyl acetate. The combined organic phases were washed by 200 mL saturated sodium bicarbonate solution and 200 mL brine. The solvent was removed in vacuum and the residue was suspended in 1000 mL methanol at 0 - 5 °C. The crystalline suspension was stirred 2 to 3 hours at 0 - 5 °C and filtered. The product was washed with 200 mL diisopropyl ether and dried in vacuum at 20 - 25 °C.
      Yield: 153.8 g (84.3%)
      Purity: 68 ― 70% (by HPLC: mobile phase 0.05 M KH2PO4 - acetonitrile 1:1, pH 6,
      Rf 14.33 min)
      Cumulative yield of 1st - 6th steps: 33%
Step 7
      . Production of 6α-Bromo-2β-[(1,2,3-triazol-1-yl)methyl]-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester (BTPE) (compound VIII)
    • In a 1 L autoclave 7.6 g (50 mmol) BAPE was dissolved in 640 mL 2-butanone. The solution was cooled down to 0 - 5 °C. The autoclave was pressured three times with nitrogen gas up to six bar. The autoclave was filled with acetylene gas up to 1.5 bar pressure and approx. 36 g acetylene gas was dissolved. The autoclave was heated gradually from 0 °C up to 84 - 94 °C, keeping the pressure between 5 - 6 bar. The reaction mixture was stirred in the autoclave 14 - 20 hours at 84 to 94 °C and pressure of 5 to 6 bar. No starting material was detected by TLC (eluent hexane - ethyl acetate 1:2 v/v) Rf> 0.9 (BAPE), Rf 0.51 (BTPE), Rf 0.32 (cephamtriazole).
    • The autoclave was cooled down to -20 to -25 °C and 7.6 g BAPE in 50 mL 2-butanone solution was added. The autoclave was heated again to 84 - 94 °C and the reaction mixture was stirred 14 to 20 hours at 84 - 94 °C. The autoclave was cooled and the procedure was repeated with 7.6 g BAPE. The autoclave was cooled down to 20 - 25 °C and opened. The reaction mixture was poured into a 1 L flask and was concentrated in vacuum up to 140 mL. The solution was cooled to 0 - 5°C. The crystalline suspension was stirred for 1 hour and was filtered. The product was washed with 40 mL cool 2-butanone. The product was dried in vacuum at 25 - 30 °C.
      Yield: 13.51 g (56.0%)    Mp.: 180-182°C (decomp.)
      Purity: 98.6% (by HPLC: mobile phase 0.05 M KH2PO4 - acetonitrile 1:1, pH 6,
      Rf 8.40 min)
      Cumulative yield of 1st- 7th steps: 18%
Step 8
      . Production of p-Nitrobenzyl 6α-bromo-2α-methyl-2β-(1,2,3-triazol-1-yl)methylpenam-3α -carboxylate-1,1-dioxide (compound. IX)
    • To a solution of 4.82 g (10.00 mmol) of BTPE in a mixture of 210 ml of acetic acid and 27 ml of water, 3.79 g (23.6 mmol) of KMnO4 was added in 30 minutes at room temperature. The progress of the reaction was monitored by TLC. When the reaction was complete, the excess of KMnO4 was destroyed by 30 % H2O2 solution. The reaction mixture was poured into 930 mL of cold water, the precipitated product was filtered and washed with cold water and dried over P2O5, giving compound IX.
      Yield: 4,12 g (80 %)
      Purity: more than 95 % (HPLC)    Mp.: 122-124°C
      TLC (detection by UV, eluent: ethyl acetate - hexane 2:1 v/v) Rf 0.51 (VIII), Rf 0.23 (IX)
Step 9
      . Production of Tetrabutylammonium 2α-methyl-2β-(1,2,3-triazol-1-yl)methylpenam-3α -carboxylate-1,1-dioxide (compound Xa)
    • A stainless steel stirred autoclave with a total volume of 1 L was charged with 5.1 g (10 mmol) of compound IX, 2.5 g (30 mmol) of NaHCO3, 1.0 g of 10 % Pd on charcoal, 100 mL of water and 100 mL of ethyl acetate. The autoclave was sealed and flushed with argon, then pressured with hydrogen up to 14 bars. The hydrogenation was carried out at room temperature for 5 h. Completion of the reaction was checked by TLC. The mixture was filtered and the filter washed with water. The aqueous phase was separated, washed with ethyl acetate (2 × 10 mL) and Bu4NNaSO4 solution (prepared from 340 mg (1 mmol) of Bu4NHSO4 and 84 mg (1 mmol) of NaHCO3 in 5 mL of water) added. The aqueous solution was extracted with dichloromethane (5 x 10 ml). The combined dichloromethane phases were dried over Na2SO4 and concentrated under reduced pressure to dryness keeping the temperature of the water bath below 20 °C.
      Yield: 0.39 g (75 %)
      Purity: 95.5 % (HPLC)
      HPLC mobile phase: 0.05 M KH2PO4 buffer, pH 2.3
      Eluent A: 95 % of 0.05 M KH2PO4 buffer (pH 2.3) plus 5 % acetonitrile
      Eluent B: 40 % of 0.05 M KH2PO4 buffer (pH 2.3) plus 60 % acetonitrile
      Retention time: 11.53 min
      Column: RP-18 endcapped (5µm, 250 mm)
      TLC (detection by UV and 1 % AgNO3 in ethanolic solution, eluent: ethyl acetate - hexane 2:1 v/v) Rf 0.23 (IX); (eluent: acetone -methanol 2:1 v/v) Rf 0.48 (Xa)
Step 10.
    Production of Sodium 2α-methyl-2β-(1,2,3-triazol-1-yl)methylpenam-3α-carboxylate-1,1-dioxide (Tazobactam sodium)
  • The residue containing compound Xa (0.40 g) was eluted with water on a column of Amberlite-Na+ cation-exchange resin. The appropriate fractions were concentrated under reduced pressure and finally lyophilized, yielding Tazobactam sodium.
    Yield: 0.21 g (85 %)
    Purity: 99.5 % (HPLC)
    HPLC mobile phase: 0.05 M KH2PO4 buffer, pH 2.3
    Eluent A: 95 % of 0.05 M KH2PO4 buffer (pH 2.3) plus 5 % acetonitrile
    Eluent B: 40 % of 0.05 M KH2PO4 buffer (pH 2.3) plus 60 % acetonitrile
    Retention time: 11.53 min
    Column: RP-18 cndcapped (5µm, 250 mm)

PATENT

Tazobactam arginine can be a salt consisting of the conjugate base of (2S,3S,5R)-3-((1H-1,2,3-triazol-1-yl)methyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (tazobactam) and the conjugate acid of (S)-2-amino-5-guanidinopentanoic acid (L-arginine) in a 1:1 ratio, as represented by the structure below.
Figure US08476425-20130702-C00001

References

  1. Yang Y, Rasmussen BA, Shlaes DM (1999). "Class A beta-lactamases—enzyme-inhibitor interactions and resistance". Pharmacol Ther. 83: 141–151. doi:10.1016/S0163-7258(99)00027-3.
CN1037514AMar 1, 1989Nov 29, 1989大鹏药品工业株式会社Process for preparing 2 alpha-methyl-2 beta-(1,2,3-triazole-1-yl) methylpenam-3 alpha-carboxylic acid derivatives
US7674898 *Jul 23, 2001Mar 9, 2010Otsuka Chemical Co., Ltd.Anhydrous crystal of β-lactam compound and method for preparation thereof
Reference
1*LI YANG ET AL.: 'Synthesis of Tazobactam, [beta- Lactamase Inhibitor' TRANSACTIONS OF TIANJIN UNIVERSITY vol. 8, no. 1, March 2002, pages 33 - 36

Tazobactam
Tazobactam.svg
Tazobactam ball-and-stick.png
Systematic (IUPAC) name
(2S,3S,5R)-3-Methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide
Clinical data
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • B
Legal status
  •  (Prescription only)
Routes of
administration
Intravenous
Identifiers
CAS Number89786-04-9 Yes
ATC codeJ01CG02
PubChemCID: 123630
DrugBankDB01606 Yes
ChemSpider110216 Yes
UNIISE10G96M8W Yes
KEGGD00660 Yes
ChEBICHEBI:9421 Yes
ChEMBLCHEMBL404 Yes
Chemical data
FormulaC10H12N4O5S
Molecular mass300.289 g/mol
PatentSubmittedGranted
2-OXO-1-AZETIDINE SULFONIC ACID DERIVATIVES AS POTENT BETA-LACTAMASE INHIBITORS [EP0979229]2000-02-162002-10-23
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Antimicrobial composition comprising a vinyyl pyrrolidinon derivative and a carbapenem antibiotic or a beta-lactamase inhibitor [EP0911030]1999-04-282005-04-13
7-alkylidene-3-substituted-3-cephem-4-carboxylates as beta-lactamase inhibitors [US7488724]2006-04-062009-02-10
Sustained release of antiinfectives [US7718189]2006-04-062010-05-18
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ENGINEERED BACTERIOPHAGES AS ADJUVANTS FOR ANTIMICROBIAL AGENTS AND COMPOSITIONS AND METHODS OF USE THEREOF [US2010322903]2009-01-122010-12-23
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Citing PatentFiling datePublication dateApplicantTitle
CN102304139A *Jul 12, 2011Jan 4, 2012景德镇市富祥药业有限公司Method for preparing 2 beta-methyl penicillanate benzhydryl dioxide
CN102304139BJul 12, 2011Jun 4, 2014江西富祥药业股份有限公司Method for preparing 2 beta-methyl penicillanate benzhydryl dioxide
CN102382123A *Mar 10, 2011Mar 21, 2012海南美好西林生物制药有限公司Preparation method of tazobactam sodium
CN102827189A *Sep 18, 2012Dec 19, 2012山东罗欣药业股份有限公司Tazobactam sodium compound and pharmaceutical composition thereof
US8476425Sep 27, 2012Jul 2, 2013Cubist Pharmaceuticals, Inc.Tazobactam arginine compositions
US8906898May 28, 2014Dec 9, 2014Calixa Therapeutics, Inc.Solid forms of ceftolozane
US8968753May 22, 2014Mar 3, 2015Calixa Therapeutics, Inc.Ceftolozane-tazobactam pharmaceutical compositions
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/////////
O=S2(=O)[C@]([C@@H](N1C(=O)C[C@H]12)C(=O)O)(Cn3nncc3)C
or
CC1(C(N2C(S1(=O)=O)CC2=O)C(=O)O)CN3C=CN=N3









3

NXL104, Avibactam


NXL-104, Avibactam
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt (e.g., NXL-104)
CAS 396731-20-7, 1192491-61-4
AVE-1330
AVE-1330A
PHASE 1 a broad-spectrum intravenous beta-lactamase inhibitor, was under development for the treatment of infections due to nosocomial drug resistant Gram-negative bacteria
SANOFI  INNOVATOR
Novexel holds exclusive worldwide development and commercialization rights from Sanofi.
NXL104; Avibactam; UNII-7352665165;
Molecular Formula:C7H11N3O6S
Molecular Weight:265.24374 g/mol
CAS 1192500-31-4, 396731-14-9
[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate
Avibactam is a non-β-lactam β-lactamase inhibitor antibiotic being developed by Actavis jointly with AstraZeneca. A new drug application for avibactam in combination with ceftazidime was approved by the FDA on February 25, 2015, for treating complicated urinary tract and complicated intra-abdominal Infections caused by antibiotic resistant-pathogens, including those caused by multi-drug resistant gram-negative bacterial pathogens.[2][3][4]
Increasing resistance to cephalosporins among Gram-(-) bacterial pathogens, especially among hospital-acquired infections, results in part from the production of beta lactamase enzymes that deactivate these antibiotics. While the co-administration of a beta lactamase inhibitor can restore antibacterial activity to the cephalorsporin, previously approved beta lactamase inhibitors such astazobactam and Clavulanic acid do not inhibit important classes of beta lactamase including Klebsiella pneumoniae carbapenemases (KPCs), metallo-beta lactamases, and AmpC. Avibactam inhibits KPCs, AmpC, and some Class D beta lactamases, but is not active aganist NDM-1.[5]
U.S. Pat. No. 7,112,592 discloses novel heterocyclic compounds and their salts, processes for making the compounds and methods of using the compounds as antibacterial agents. One such compound is sodium salt of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide. Application WO 02/10172 describes the production of azabicyclic compounds and salts thereof with acids and bases, and in particular, trans-7-oxo-6-sulphoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and its pyridinium, tetrabutylammonium and sodium salts. Application WO 03/063864 and U.S. Patent Publication No. 2005/0020572 describe the use of compounds including trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt, as β-lactamase inhibitors that can be administered alone or in, combination with β-lactamine antibacterial agents. These references are incorporated herein by reference, in their entirety.


PATENT
In some embodiments, sulphaturamide or tetrabutylammonium salt of (1R,2S,5R)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide may be prepared by chiral resolution of its racemic precursor trans-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, the preparation of which is described in Example 33a Stage A in Application WO 02/10172. In exemplary embodiments, injection of 20 μl of a sample of 0.4 mg/mL of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, eluted on a Chiralpak ADH column (5 25 cm×4.6 mm) with heptane-ethanol-diethylamine mobile phase 650/350/0.05 vol at 1 mL/min makes it possible to separate the (1R,2S,5R) and (1S,2R,5S) enantiomers with retention times of 17.4 minutes and 10.8 minutes respectively. The sulphaturamide is then obtained by conversion according to the conditions described in Example 33a Stage B then Stage C and finally in Example 33b of Application WO 02/10172.
In other embodiments, the sulphaturamide can be prepared from the mixture of the oxalate salt of (2S)-5-benzyloxyamino-piperidine-2-carboxylic acid, benzyl ester (mixture (2S,5R)/(2S,5S) ˜50/50) described in application FR2921060.
For example, the preparation may proceed in the following stages:
Figure US08835455-20140916-C00006
EXAMPLES Example 1 Preparation and characterization of amorphous trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt
Amorphous trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide can be prepared as described in U.S. Pat. No. 7,112,592. The XRD pattern was obtained by mounting samples on a sample holder of Rigaku Miniflex X-ray diffractometer with the Kβ radiation of copper (λ=1.541 Å). The samples, without grinding, were put on a glass plate and were analyzed at ambient temperature and humidity. Data were collected at 0.05° interval, 2°/minute from 3°-40° 2θ. FIG. 1shows the X-ray diffraction (XRD) pattern for amorphous trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt.
A solution, in a water-acetone mixture (1-1), of the sodium salt of the racemic trans-7-oxo-6-(sulphoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide described in Example 33c of Application WO 02/10172 is evaporated under reduced pressure, under the conditions of concentration described in said example. The salt is obtained in crystallized form. The X-ray spectra (“XRPD diffraction patterns”) of the polymorphic Forms were compared. The diffraction pattern of the racemic form obtained according to the prior art is different from each of those of the polymorphic Forms.
Example 2 Preparation and characterization of Form I of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt
Method I
A solution of the 5.067 g (10 mmoles) of the tetrabutylammonium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide in 12.5 ml of 200 proof ethanol and 12.5 ml of 190 proof ethanol was filtered through a 1.6 μm filter and added to a 100 ml jacketed-reactor equipped with magnetic stirrer. The solution was warmed to an internal temperature of 35° C. Separately, a solution of 3.3 g (20 mmoles) of sodium 2-ethylhexanoate in 25 ml 200 proof ethanol was filtered through a 1.6 μm filter. 2.5 ml of this solution was added to the reactor and the mixture was stirred for 1 h at 35° C. Crystallization occurred during this time. The remainder of the sodium 2-ethylhexanoate solution was added over 20 min. The mixture was stirred for an additional 1 h at 35° C., followed by 12 h at 25° C. The mixture was cooled to 0° C. for 2 h. The crystals were isolated by filtration and washed with 10 ml ethanol. The crystals were dried under vacuum at 35° C. for 16 h. 2.72 g of the sodium salt of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide (Form I) was obtained, corresponding to a yield of 95%
PATENT
Example -1
Preparation of sodium salt of (2S, 5R)-sulfuric acid mono-{2-carboxamido-7-oxo-l,6-diaza- bicyclo Γ3.2.11 octane
Step-1: Preparation of (2S, 5R)-2-Carboxamido-6-benzyloxy-7-oxo-l,6-diaza- bicyclo [3.2.1] octane:
Method-1:
The starting compound ((2S, 5R)-sodium 6-benzyloxy-7-oxo-l,6-diaza-bicyclo [3.2.1] octane-2-carboxylate; compound of Formula (II)) was prepared according to a procedure disclosed in Indian Patent Application No. 699/MUM/2013. To a 100 ml round bottom flask equipped with magnetic stirrer was charged (2S, 5R)-sodium 6-benzyloxy-7- oxo-l,6-diaza-bicyclo [3.2.1] octane-2-carboxylate (10.0 gm, 0.033 mol), followed by freshly prepared HOBt. ammonia complex (10.0 gm, 0.066 mol), EDC hydrochloride (9.62 gm, 0.050 mol) and 1-hydroxy benzotriazole (4.51 gm, 0.033 mol). To this mixture of solids, water (30 ml) was added at about 35°C, and stirring was started. Precipitation occurred after 30 minutes. The reaction mixture was stirred for additional 20 hours at about 35°C. Dichloro methane (150 ml) was added to the suspension and the reaction mass was allowed to stir for 10 minutes. The layers were separated. Aqueous layer was washed with additional dichloro methane (50 ml). Combined organic layer was evaporated under vacuum to provide a residue (21 gm). The residue was stirred with acetone (21 ml) for 30 minutes and filtered under suction to provide (2S, 5R)-2-carboxamido-6-benzyloxy-7-oxo-l,6-diaza- bicyclo [3.2.1] octane as a white solid in 5.5 gm quantity in 60% yield after drying under vacuum at about 45 °C.
Analysis
H!NMR (DMSO-de)
7.35 -7.45 (m, 6H), 7.25 (bs, 1H), 4.89 - 4.96 (dd, 2H), 3.68 (d, 1H), 3.62 (s, 1H), 2.90 (s, 2H), 2.04 - 2.07 (m, 1H), 1.70-1.83 (m, 1H), 1.61-1.66 (m, 2H).
MS (ES+) C14H17N3O3 = 276.1 (M+l) Purity: 93.95% as determined by HPLC Specific rotation: [a]25 D - 8.51° (c 0.5%, CHC13) Method-2:
Alternatively, the above compound was prepared by using the following process. To a 50 ml round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)- sodium 6-benzyloxy-7-oxo-l,6-diaza-bicyclo [3.2.1] octane-2-carboxylate (1 gm, 0.003 mol) in water (15 ml) followed by EDC hydrochloride (1 gm, 0.005 mol) and 1- hydroxybenzotriazole (0.39 gm, 0.003 mol) at 35°C under stirring. The reaction mass was stirred for 1 hour to obtain a white suspension. At this point, aqueous ammonia was added (2 ml, 40% w/v), under stirring. The reaction mixture was stirred for additional 5 hours. The suspension was filtered, washed with additional water (10 ml) to provide (2S, 5R)-2- carboxamido-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] after drying under vacuum at 45°C in 0.21 gm quantity.
Step-2: Preparation of Tetrabutyl ammonium salt of (2S, 5R)-2-carboxamido-6-sulfooxy-7- oxo-l,6-diaza-bicyclo [3.2.1] octane:
To a Parr shaker bottle, was charged (2S, 5R)-2-carboxamido-6-benzyloxy-7-oxo-l,6- diaza-bicyclo [3.2.1] octane (7.0 gm, 0.025 mol) followed by a 1:1 mixture of N,N- dimethylformamide and dichloro methane (35 ml: 35 ml). To the clear solution was added 10% palladium on carbon (1.75 gm) and hydrogen pressure was applied up to 50 psi. The suspension was shaken for 3 hours at 35°C. The catalyst was removed by filtering the reaction mixture over celite bed. The catalyst bed was washed with dichloro methane (30 ml). Combined filtrate was evaporated under vacuum at a temperature below 40°C to obtain an oily residue. The oily residue (4.72 gm) was dissolved in N,N-dimethylformamide (35 ml) and to the clear solution was added sulfur trioxide.DMF complex at 10°C under stirring in one lot. The mixture was allowed to stir at 35°C for additional 2 hours. As TLC showed complete conversion, 10% aqueous solution of tetrabutyl ammonium acetate (9.44 gm, 0.031 mol, in 30 ml water) was added under stirring and the reaction mixture was stirred for overnight and then subjected to high vacuum distillation on rotavapor by not exceeding temperature above 40°C to obtain a residue. Xylene (50 ml) was added to the residue and similarly evaporated to remove traces of DMF. The dry residue thus obtained was stirred with water (70 ml) and extracted with dichloro methane (70 ml x 2). Combined organic extract was dried over sodium sulfate and solvent was evaporated under vacuum below 40°C to obtain oily residue in 7 gm quantity as a crude product. It was stirred with methyl isobutyl ketone (21 ml) for 30 minutes at about 35°C to obtain a white solid in 5.9 gm quantity as a tetrabutyl ammonium salt of (2S, 5R)-2-carboxamido-6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane in pure form in 46% yield.
Analysis
NMR: (CDC13)
6.63 (s, 1H), 5.48 (s, 1H), 4.34 (br s, 1H), 3.90 (d, 1H), 3.27-3.40 (m, 9H), 2.84 (d, 1H), 2.38 (dd, 1H), 2.21-2.20 (m, 1H), 1.60-1.71 (m, 12H), 1.40-1.50 (m, 8H), 1.00 (t, 12H).
MS (ES-) C7H10N3O6S. N(C4H9)4 = 264.0 (M-l) as a free sulfonic acid.
Purity: 98.98% as determined by HPLC.
Specific rotation: [a]25 D - 30.99° (c 0.5%, MeOH)
Step-3: Synthesis of Sodium salt of (2S, 5R)-2-carboxamido-6-sulfooxy-7-oxo-l,6-diaza- bicyclo [3.2.1] octane
To a 100 ml round bottom flask equipped with magnetic stirrer was charged tetrabutyl ammonium salt of (2S, 5R)-2-carboxamido-6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane ( 5.5 gm, 0.0108 mol) followed by ethanol (28 ml) to provide a clear solution under stirring at about 35°C. To the reaction mixture was added a solution of sodium 2-ethyl hexanoate (3.6 gm, 0.021 mol) dissolved in ethanol (28 ml) in one lot under stirring to provide precipitation. The suspension was stirred for additional 2 hours to effect complete precipitation at about 35°C. The reaction mixture was filtered under suction and the wet cake was washed with acetone (30 ml x 2). The wet cake was dried at 40°C under vacuum to provide sodium salt of (2S, 5R)-2-carboxamido-6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane as a white solid in 2.6 gm quantity in 83% yield.
Analysis
H!NMR (DMSO-d6)
7.39 (s, 1H), 7.24 (s, 1H), 3.98 (s, 1H), 3.68 (d, 1H), 3.02 (d, 1H), 2.92 (d, 1H), 2.00- 2.10 (m, 1H), 2.80-2.90 (m, 1H), 1.55-1.70 (m, 2H).
MS (ES-) C7H10N3O6SNa = 264.0 (M-l) as a free sulfonic acid;
Purity: 97.98% as determined by HPLC
Specific rotation: [a]25 D - 49.37° (c 0.5%, water)
Powder X-ray diffractogram: (degrees 2 theta):

PATENT

References

  1.  "Full Prescribing Information: AVYCAZ™ (ceftazidime-avibactam) for Injection, for intravenous use". ©2015 Actavis. All rights reserved. Retrieved 1 June 2015.
  2.  Zhanel, GG (2013). "Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination"Drugs 73 (2): 159-77.doi:10.1007/s40265-013-0013-7PMID 23371303.
  3.  "Actavis Announces FDA Acceptance of the NDA Filing for Ceftazidime-Avibactam, a Qualified Infectious Disease Product"Actavis—a global, integrated specialty pharmaceutical company—Actavis. Actavis plc. Retrieved 1 June 2015.
  4. Ehmann, DE; Jahic, H; Ross, PL; Gu, RF; Hu, J; Durand-Réville, TF; Lahiri, S; Thresher, J; Livchak, S; Gao, N; Palmer, T; Walkup, GK; Fisher, SL (2013). "Kinetics of Avibactam Inhibition against Class A, C, and D β-Lactamases"The Journal of biological chemistry 288 (39): 27960–71. doi:10.1074/jbc.M113.485979PMC 3784710PMID 23913691.
  5.  "www.accessdata.fda.gov" (PDF).

External links


ChemSpider 2D Image | Avibactam | C7H11N3O6S
PatentSubmittedGranted
NOVEL CRYSTALLINE FORMS OF TRANS-7-OXO-6-(SULPHOOXY)-1,6-DIAZABICYCLO[3,2,1]OCTANE-2-CARBOXAMIDE SODIUM SALT [US2014349967]2014-08-072014-11-27
PROCESS FOR PREPARING A COMPOUND USEFUL FOR PRODUCING AN OPTICALLY ACTIVE DIAZABICYCLOOCTANE COMPOUND [US2014303375]2014-05-272014-10-09
QUICK METHOD FOR DETECTING ENYZMES AND MICROORANISMS [US2013089883]2011-03-012013-04-11
Crystalline forms of trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt [US8835455]2013-05-242014-09-16
WO2009091856A2 *Jan 15, 2009Jul 23, 2009Merck & Co IncBeta-lactamase inhibitors
WO2012086241A1 *Jun 30, 2011Jun 28, 2012Meiji Seika Pharma Co., Ltd.Optically-active diazabicyclooctane derivative and method for manufacturing same
INMU06992013ATitle not available
US7112592Jul 24, 2001Sep 26, 2006Aventis Pharma S.A.Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
Avibactam
Avibactam structure 2.svg
Avibactam ball-and-stick model.png
Systematic (IUPAC) name
[(2S,5R)-2-Carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate
Clinical data
Trade namesAvycaz (formulated with ceftazidime)
Legal status
Routes of
administration
intravenous
Pharmacokinetic data
Bioavailability100% (intravenous)
Protein binding5.7–8.2%[1]
Metabolismnil
Onset of actionincreases in proportion to dose
ExcretionRenal (97%)
Identifiers
CAS Number1192500-31-4
ATC codeJ01
PubChemCID: 9835049
ChemSpider8010770
ChEBICHEBI:85984 Yes
ChEMBLCHEMBL1689063
Chemical data
FormulaC7H11N3O6S
Molecular mass265.24 g/mol
////////
[Na+].NC(=O)[C@@H]2CC[C@@H]1CN2C(=O)N1OS([O-])(=O)=O
C1CC(N2CC1N(C2=O)OS(=O)(=O)O)C(=O)N



4

Zidebactam, WCK 5107

Figure imgf000036_0001
2D chemical structure of 1436861-97-0
Zidebactam,  WCK 5107
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)
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
(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
2D chemical structure of 1706777-46-9UNII-NHY7N0Y9DG.png
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.


http://chem.sis.nlm.nih.gov/chemidplus/structure/1436861-97-0?maxscale=30&width=300&height=300
PATENT
Figure imgf000022_0001
Scheme-1
Figure imgf000023_0001
function with Boc group)
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
Figure imgf000036_0001
Step-1: Preparation of trans-3-[N'-(6-benzyloxy-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-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-)
Figure imgf000037_0001
as a salt = 490.0 (M-l) as a free sulfonic acid;
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
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
PATENT
WO 2015110885
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
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, 2012Mar 7, 2013Wockhardt Limited1,6- diazabicyclo [3,2,1] octan-7-one derivatives and their use in the treatment of bacterial infections
WO2014135931A1 *Oct 12, 2013Sep 12, 2014Wockhardt LimitedA 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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