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TRANS-SULFURIC ACID MONO-{2-[5-(3-AZETIDINYLAMINO)-METHYL-[1,3,4]- OXADIAZOL-2-YL]-7-OXO-1,6-DIAZABICYCLO[3.2.1] OCT-6-YL} ESTER TRIFLUOROACETATE
trans-sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[1,3,4]- oxadiazol-2-yl]-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl}ester trifluoroacetate
PCT International Patent Application No. PCT/US2013/034562.
Indian Patent Application No. 1635/MUM/2014
Molecular Weight: 488.3 and Molecular Formula:
Scheme 1. Typically, compound of Formula (I) is prepared from sodium salt of 6-benzyloxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (III).
The sodium salt of 6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid
(III) is reacted with 3-(ier^butoxycarbonyl-hydrazinocarbonylmethyl-amino)-azetidine-1-carbamic acid tert-buty\ ester (II) in presence of coupling agent at a temperature ranging from -15°C to 60°C for about 1 hour to about 24 hours to provide an intermediate compound of Formula (IV). Typical, non-limiting examples of coupling agent include EDC hydrochloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide (DIC), (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(benzotriazol- 1 -yl)-N,N,N’ ,Ν’ -tetramethyluroniumhexafluorophosphate (HBTU), O-(benzotriazol-l-yl)- Ν,Ν,Ν’,Ν’-tetramethyluroniumtetrafluoroborate (TBTU), 0-(7-azabenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(6-ahlorobenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU), 0-(3,4-dihydro-4-oxo-l,2,3-benzotriazine-3-yl)-N,N,N’,N’-tetramethyl uronium tetrafluoroborate(TDBTU), 3-(diethylphosphoryloxy)- 1 ,2,3-benzotriazin-4(3H)-one (DEPBT), carbonyldiimidazole (CDI), pivalyl chloride, HOBt and the like. In some embodiments, compound of Formula (II) is reacted with a compound of Formula (III) in presence of EDC hydrochloride and HOBt at a temperature of about 25°C to about 35°C for about 15 hours to provide an intermediate compound of Formula (IV). In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (III) in presence of suitable solvent such as dimethylformamide, water or a mixture thereof.
The compound of Formula (IV) is cyclized to provide a compound of Formula (V). The cyclization of a compound of Formula (IV) is effected by treating with a reagent such as p-toluene sulfonyl chloride, p-nitrobenzene sulfonyl chloride, methane sulfonyl chloride or triphenylphosphine in a suitable solvent such as toluene, chloroform, dichloromethane, or N,N-dimethyl formamide at a temperature ranging from about -10° C to about 70°C for about 15 minutes to about 4 hours to provide 1,3,4-oxadiazole intermediate compound of Formula (V). In some embodiments, a compound of Formula
(IV) is cyclized in presence of triphenylphosphine, iodine and triethylamine, at a temperature of about -10°C to about 0°C for about 30 minutes to provide a compound of Formula (V). In some embodiments, compound of Formula (IV) is cyclized to a compound of Formula (V) in presence of dichloromethane as solvent.
Sulfonation
Scheme 1
Example 1
Synthesis of traras-sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[l,3,4]- oxadiazol-2-yl]-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl]ester trifluoroacetate (I)
Step 1; Preparation of traras-{3-[N-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1] octane-2-carbonyl)-hydrazinocarbonyl]-2-oxo-ethyl}-tert-butoxycarbonyl-amino)-azetidine-l-carboxylic acid tert-butyl ester (IV):
A solution of 3-(ier^butoxycarbonyl-hydrazinocarbonylmethyl-amino)-azetidine-1-carbamic acid tert-butyl ester (II) (2.8 g, 0.008 mol) in dimethylformamide (7 ml) was added to a stirred solution of sodium salt of 6-benzyloxy-7-bicyclo [3.2.1] octane-2-carboxylic acid (III) (2.43 g 0.008 mol) in water (41 ml). To this EDC.HCl (2.32 g, 0.012 mol) and HOBt (1.09 g, 0.008 mol) was added and stirred for 15 hours. Dichloro methane (50 ml) was added and layers were separated. Organic layer was dried over sodium sulfate and concentrated. The residue (6.1 gm) was purified by silica gel column chromatography using mixture of acetone and hexane as eluent to afford 3.4 g of ir ns-3-({2-[N-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazino]-2-oxo-ethyl}-teri-butoxy carbonyl-amino)-azetidine-l -carboxylic acid tert-butyl ester (IV) in 70% yield.
Analysis:
Mass: 603.3 (M+l); for Molecular Weight: 602.6; Molecular Formula: 
1H NMR (400 MHz, CDC13): δ 8.45. (bs, IH), 8.20 (bs, IH) 7.38-7.45 (m, 5H), 5.04 (d, IH), 4.91 (d, IH), 4.13 (m, 2H), 3.97-4.04 (m, 5H), 3.30 (s, IH), 3.07 (s, 2H), 2.91 (d, IH), 2.31 (m, IH), 2.20 (d, IH), 1.93-2.00 (m, 2H), 1.45 (s, 18H).
Step 2: Preparation of tr «s-{2-[5-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-2-oxo-ethyl}-tert-butoxycarbonyl-amino)-azetidine-l-carboxylic acid tert-butyl ester (V):
Triethyl amine (3.6 ml, 0.026 mol) was added to a cooled (0 °C) solution of iodine (1.62 gm, 0.0063 mol) and triphenylphosphine (1.67 g, 0.0063 mol) in dichloromethane (64 ml). After stirring for 15 minutes a solution of 3-({2-[N-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazino]-2-oxo-ethyl}-fert-butoxycarbonyl- amino)-azetidine-l-carboxylic acid tert-butyl ester (IV) (3.2 g, 0.0053 mol) in dichloromethane (16 ml) was added. Reaction mixture was stirred at -10°C to 0°C for another 30 minutes. Dichloromethane was concentrated and ethyl acetate (35 ml) was added; stirred and filtered to remove triphenylphosphine oxide. Filtrate was concentrated and purified by silica gel column chromatography using a mixture of methanol and chloroform as eluent to obtain 4.5 g of 3-{ [5-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4] oxadiazol-2-yl-methyl]-tert-butoxycarbonyl-amino}-azetidine- 1 -carboxylic acid tert-buty\ ester (V).
Analysis:
Mass: 585.4 (M+l); for Molecular Weight: 584.6 and Molecular Formula: 
1H NMR (400 MHz, CDC13): δ 7.64-7.68 (m, 6H), 7.52-7.56 (m, 3H) 7.42-7.48 (m, 7H), 7.36-7.38 (m, 2H), 5.07 (d, IH), 4.92 (d, 2H), 4.72 (s, IH), 4.68 (s, 2H), 4.15 (s, 2H), 4.01 (s, 2H), 3.36 (s, IH), 2.91 (d, IH), 2.79 (d, IH), 2.27-2.30 (m, 2H), 2.11-2.14 (m, IH), 1.97-1.99 (m, IH), 1.42 (s, 18H).
Step 3: Preparation of tr «s-{2-[5-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]-oxadiazole-2-yl]-methyl}-tert-butoxycarbonyl-amino)-azetidine-l-carboxylic acid tert-butyl ester (VI):
Palladium on carbon (10%) was added to a stirred solution of 3-{ [5-(6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl-methyl]-feri-butoxy carbonyl-amino}-azetidine-l -carboxylic acid tert-butyl ester (V) (4.5 g) in methanol (45 ml). Resulting suspension was stirred under hydrogen gas pressure of about 50 psi for 15 hours at 25°C. The reaction mixture was filtered through celite bed and washed using additional methanol (5 ml). The filtrate was concentrated to obtain 3.5 g of ir ns-{2-[5-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]-oxadiazole-2-yl]-methyl}-teri-butoxy carbonyl-amino)-azetidine-l -carboxylic acid tert-butyl ester (VI) in 92% yield.
Analysis:
Mass: 495.4 (M+l); for Molecualr Weight: 494.5 and Molecular Formula: 
1H NMR (400 MHz, DMSO): δ 9.86 (s, 1H), 7.51-7.62 (m, 12H), 4.70 (s, 2H), 4.58 (d, 1H), 3.99 (d, 2H), 3.65 (s, 2H), 2.92 (d, 1H), 2.67 (d, 1H), 2.31 (s, 1H), 2.00-2.11 (m, 2H), 1.84 (m, 1H), 1.31 (s, 18H).
Step-4: Preparation of traras-tetrabutyl ammonium salt-methyl-{2-[5-(7-oxo-6-sulphooxy-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-methyl}-tert-butoxycarbonyl-amino )-azetidine-l-carboxylic acid fert-butyl ester (VII):
Sulfur trioxide-pyridine complex (3.17 g, 0.019 mol) and triethyl amine (4.5 ml, 0.033 mol) was added to a stirred solution of ir ns- {2-[5-(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]-oxadiazole-2-yl]-methyl}-ieri-butoxycarbonyl-amino)-azetidine- 1 -carboxylic acid tert-butyl ester (VI) (2.62 g, 0.0066 mol) in dichloromethane (20 ml). The reaction mixture was stirred for 2 hours. Aqueous solution of 0.5 N potassium dihydrogen phosphate (50 ml) followed by ethyl acetate (40 ml) was added, stirred for 10 minutes and aqueous layer was separated. Aqueous layer was again extracted with the mixture of dichloromethane (10 ml) and ethyl acetate (20 ml). Combined organic layers were concentrated. The residue was dissolved in water (50 ml), washed with diethyl ether (2 x 25 ml) to remove triphenylphosphine oxide (a side product carried from the step-2) and extracted with dichloromethane (2 x25 ml). Dichloromethane was dried over sodium sulfate and concentrated to give 2.7 g of residue (87%). This residue was again dissolved in dichloromethane (50 ml) followed by addition of triethylamine (5.70 ml, 0.042 mol). Tetrabutylammonium hydrogen sulphate (1.27 g, 0.0037 mol) was added and stirred for 2 hours. Water (30 ml) was added to the reaction mixture and layers were separated. Dichloromethane layer was dried on sodium sulfate and solvent was concentrated under vacuum. The residue (2.7 g) was purified by silica gel column chromatography using methanol and chloroform as eluent to get 2.1 g of irans-tetrabutyl ammonium salt-methyl- {2-[5-(7-oxo-6-sulphooxy- 1 ,6-diaza-
bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-methyl}-ieri-butoxycarbonyl-amino)-azetidine- 1 -carboxylic acid tert-buty\ ester (VII) in 48% yield.
Analysis:
Mass: 575.4 (M+l) as free sulfonic acid; for Molecular Weight: 816.6 and Molecular Formula: C22H34N6O10S. Ci6H36N;
1H NMR (400 MHz, CDC13): δ 4.63-4.69 (m, 5H), 4.40 (s, 2H), 4.16 (s, 2H), 4.02 (s, 2H), 3.28-3.32 (m, 12H), 3.23 (s, 1H), 2.84 (d, 1H), 2.24-2.32 (m, 2H), 2.02-2.04 (m, 1H), 1.63-1.71 (m, 12H), 1.46-1.56 (m, 12H), 1.44 (s, 18H), 0.99-1.02 (m, 18H).
Step 5: Preparation of traras-sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diazabicyclo[3.2.1]oct-6-yl]ester trifluoroacetate (I)
irans-Tetrabutyl ammonium salt-methyl- {2-[5-(7-oxo-6-sulphooxy- 1 ,6-diaza-bicyclo[3.2.1]oct-2-yl)-[l,3,4]oxadiazol-2-yl]-methyl}-ieri-butoxycarbonyl-amino)-azetidine- 1 -carboxylic acid tert-butyl ester (VII) (2.1 g, 0.003 mol) was cooled to 0°C and to this was added trifluoro acetic acid cooled at 0°C in 15 minutes and the reaction mixture was stirred for 3 hours. The obtained reaction mixture was concentrated under high vacuum. Diethyl ether (20 ml) was added and solid precipitated was stirred and diethyl ether was decanted. This treatment was repeated twice. Solid separated was dried and dichloromethane (20 ml) was added and stirred; solid was allowed to settle and dichloromethane was decanted. Again this treatment was repeated twice and the solid was dried to get 1 g of irans-sulfuric acid mono-{2-[5-(3-azetidinylamino)-methyl-[l,3,4]-oxadiazol-2-yl]-7-oxo-l,6-diazabicyclo [3.2.1]oct-6-yl]ester trifluoroacetate (I) in 76% yield.
Analysis:
Mass: 375.2 (M+l) as free sulfonic acid; for Molecular Weight: 488.3 and Molecular Formula:
CF3COOH;
1H NMR (400 MHz, DMSO): δ 4.64 (d, IH), 4.06 (s, 3H), 3.92 (s, 2H), 3.81-3.86 (m, IH), 3.73 (s, 2H), 2.94-2.97 (d, IH), 2.70 (d, IH), 2.16 -2.19 (m, IH), 1.88-2.14 (m, 2H), 1.86-1.88 (m, IH);
19F NMR (DMSO-d6): δ -74.41 (CF3COOH);
1 C NMR (DMSO-de as a TFA salt): δ 165.4, 165.1, 164.9, 159.2-158.2 (TFA-C), 57.7, 52.6 (2C), 52.3, 49.3, 46.1, 40.4, 20.1, 19.7.
Mr Habil Khorakiwala, Chairman, Wockhardt Ltd.
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