1Department of Chemistry, S. K. University, Anantapur, A.P, India.
2Biomedical Engineering, Osmania University, Hyderabad, Telangana, India.
Received date: 20/10/ 2015 Accepted date: 23/11/ 2015 Published date: 05/01/2016
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The novel Organo Phospho Carbamates containing imidazole ureas/ Carboxamides derivatives are an important class of organophosphorus heterocycles, having potential biological importance due to their unique features. The conversion of acid azide to urethanes (carbamates) through isocyanate involves Curtius rearrangement is an important synthetic method for the preparation of substituted ureido/carboxamide carbamates. They have multifacted applications as important pharmacophores in agriculture, pharmaceuticals, chemical synthesis and diverse other potential biological areas. The compounds electron withdrawing group at position 4 of ureido/carboxamide carbamates increased the activity against bacteria and fungus.
Imidazole; Phospho ureas; Carboxamides;Antibacterial; Antifungal activity
The high therapeutic properties of the imidazole related drugs have encouraged the medicinal chemists to synthesize a largenumber of novel chemotherapeutic agents. Imidazole drugs have broadened scope in remedying various dispositions in clinicalmedicines. Numerous methods for the synthesis of imidazole and also their various structure reactions offer enormous scope inthe field of medicinal chemistry. Literature survey revealed that imidazole and its derivative are reported to have, antianthelminticactivity [1], cardiovascular activity [2], analgesic and anti-inflammatory activity [3], anti-neoplastic activity [4], anti-fungal activity [5],enzyme inhibition activity, anti-filarial agent, anti-viral activity and anti-ulcer activity [6].
The chemistry of phosphorus heterocyclic compounds containing nitrogen plays an important role in the development of newpharmaceutical materials with novel properties. The chemistry of organophosphorus compounds and their derivatives were foundto be the highlight of study in lead compound discovery and biological screening and study of their various biological activitiessuch as anti-bacterial [7], herbicides, insecticides, pesticides [8], anti-fungal agents [9], anti-HIV [10], anti-cancer [11], anti-viral andanti-inflammatory [12] including its application in the field of Agriculture, medicine and industry [13].
A good deal of importance was given to synthesized Imidazole possessing carbamate moiety besides dioxaphosphepinoureas/carboxamides screening for possible biological and pharmacological activities.
Solvents, reagents and conditions
(1-2) Isobutyl chloroformate, triethylamine stirred for 30 minutes and add NaN3 stirred for 20 minutes at 0°C (2-4). The reactionmixture was refluxed for 16 hrs. (4(a-d)-5(a-d)) Dry acetone, PTA, the reaction mixture stirred at R.T., under nitrogen atm for1 hr. (Step-1 and 2 [14]) Dry toluene, triethylamine, THF addition at 5°C, the reaction mixture slowly raised at R.T., stirred for 2 hrsand heated at 50-60°C and stirred for 4 hrs.
2-(6,6-dimethyl-4,8-dihydro-1H-[1,3]dioxepino[5,6-d]imidazole-1-yl) acetyl azide (2)
Yield 70%. m p: 94-96°C. IR (KBr): 2940 and 2895 (CH2 and CH3 of aliphatic-CH), 2400-2000 (N3), 1395 (C (CH3)2 stretching vibration), 1670, 1410 and 1285 cm-1 corresponding stretching vibrations of C=O, C-N of azide and C-O respectively. 1H-NMR (400MHz, DMSO-d6): PPM 1.27 (s, 6H, two geminial CH3 groups), 4.57 (s, 4H, two CH2 groups of acetals), 4.84 (s, 2H, N-CH2-CO), 7.57 (s,1H of imidazole ring). Anal.Calcd.For C10H13N5O3 C: 47.81, H: 5.22 and N: 27.87% Found: C: 47.01, H: 4.72 and N 27.27%.
Cyclohexyl ((6,6-dimethyl-4,8-dihydro-1H-[1,3] dioxepino [5,6-d]imidazol-1-yl) methyl) carbamate (4a)
Yield 68%. m p: 140-142°C. IR (KBr): 3418-3384 (N-H), 3050 (stretching of Ar-H), 2940 and 2895 (aliphatic C-H stretching),1715 (C=O), 1618 (C=N), 1416 (C-N), 1395 (C (CH3)2 bending vibration) and 1320 cm-1 (C-O) respectively. 1H-NMR (400 MHz,DMSO-d6): PPM 1.27 (s, 6H two geminial CH3 groups), 1.47-1.60 (m, 10H, CH2 of cyclohexyl), 3.91 (m, 1H, O-CH of cyclohexyl) 4.57(s, 4H two CH2 groups of acetals), 5.40 (d, 2H, N-CH2), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). Anal.Calcd.ForC10H13N5O4 C: 59.42, H: 7.79 and N 12.99% Found: C : 58.62, H: 7.29 and N: 12.39%.
Tetrahydro-2H-pyran-4-yl ((6,6-dimethyl-4,8-dihydro-1H-[1,3] dioxepino [5,6-d]imidazol-1-yl) methyl) carbamate (4b)
Yield 68%. m p: 142-144°C. IR (KBr): 3420-3386 (N-H), 3052 (stretching of Ar-H), 2940 and 2895 (aliphatic C-H stretching),1715 (C=O), 1620 (C=N), 1418 (C-N), 1395 (C (CH3)2 bending vibration) and 1324 cm-1 (C-O) respectively. 1H-NMR (400 MHz,DMSO-d6): PPM 1.27 (s, 6H two geminial CH3 groups), 1.47-1.60 (m, 10H, CH2 of cyclohexyl), 3.91 (m, 1H, O-CH of cyclohexyl) 4.57(s, 4H two CH2 groups of acetals), 5.40 (d, 2H, N-CH2), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). Anal.Calcd.ForC15H23N3O5 C: 55.37, H: 7.13 and N: 12.91% Found: C: 54.57, H: 6.63 and N 12.31%.
Tetrahydro-2H-thiopyran-4-yl ((6,6-trimethyl-4,8-dihydro-1H-[1,3] dioxepino [5,6-d] imidazol-1-yl) methyl) carbamate (4c)
Yield 68%. m p: 144-146°C. IR (KBr): 3420-3390 (N-H), 3052 (stretching of Ar-H), 2940 and 2895 (aliphatic C-H stretching),1715 (C=O), 1620 (C=N), 1418 (C-N), 1395 (C(CH3)2 bending vibration), 1324 (C-O) and 715 cm-1 (C-S) respectively. 1H-NMR (400MHz, DMSO-d6): PPM 1.27 (s, 6H two geminial CH3 groups), 1.47-1.60 (m, 10H, CH2 of cyclohexyl), 3.91 (m, 1H, O-CH of cyclohexyl)4.57 (s, 4H two CH2 groups of acetals), 5.40 (d, 2H, N-CH2), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). Anal.Calcd.ForC15H23N3O4S C: 52.77, H: 6.79, N: 12.31 and S: 9.39% Found: C: 51.97, H: 6.29, N: 11.71 and S: 9.19%
Perfluorophenyl ((6,6-dimethyl-4,8-dihydro-1H-[1,3] dioxepino[5,6-d]imidazol-1-yl) methyl) carbamate (4d)
Yield 70%.m p: 142-144°C. IR (KBr): 3422-3392 (N-H), 3052 (stretching of Ar-H), 2940 and 2895 (aliphatic C-H stretching),1715 (C=O), 1620 (C=N), 1420 (C-N), 1395 (C (CH3)2 bending vibration), 1326 (C-O) and 1100 cm-1 (C-F) respectively. 1H-NMR(400 MHz, DMSO-d6): PPM 1.27(s, 6H two geminial CH3 groups), 4.57 (s, 4H two CH2 groups of acetals), 5.40 (s, 2H, N-CH2 ), 7.57(s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). Anal.Calcd.For C16H14F5N3O4 C: 47.18, H: 3.46, N: 10.32 and F: 23.32% Found:C: 46.38, H: 2.96, N: 9.72 and F: 22.52%.
Cyclohexyl ((4, 5-bis (hydroxymethyl)- 1H-imidazol-1-yl) methyl) carbamate (5a)
Yield 60%. m p: 164-166°C. IR (KBr): 3520 (νO-H, intramolecular H-bonding), 3020 (stretching of Ar-H), 3418-3384 (N-H),2940 and 2895 (CH2 of aliphatic C-H stretching), 1715 (C=O), 1618 (C=N), 1416 (C-N) and 1322 cm-1 (C-O) respectively. 1H-NMR(400 MHz, DMSO-d6): PPM 1.47-1.60 (m, 10H, CH2 of cyclohexyl), 3.91 (m, 1H, O-CH of cyclohexyl)), 4.25 (s, 2H two –OH havingintramolecular H-bonding), 4.73 (s, 4H two CH2 groups of dimethanols), 5.40 (s, 2H, N-CH2), 7.57 (s, 1H of imidazole ring) and 8.03(s, 1H, NH-CO). Anal.Calcd.For C13H21N3O4 C: 55.11, H: 7.47 and N: 14.83%. Found: C: 54.31, H: 6.97 and N: 14.23%.
Tetrahydro-2H-piran-4-yl ((4,5-bis (hydroxymethyl)- 1H -imidazol-1-yl) methyl) carbamate (5b)
Yield 65%. m p: 166-168°C. IR (KBr): 3520 (νO-H, intramolecular H-bonding), 3030 (stretching of Ar-H), 3418-3386 (N-H), 2940and 2895 (CH2 of aliphatic C-H stretching), 1715 (C=O), 1620 (C=N), 1418 (C-N) and 1324 cm-1 (C-O) respectively. 1H-NMR (400 MHz,DMSO-d6): PPM 1.72-1.97 (m, 4H CH2 of pyran), 3.55-3.65 (t, 4H, CH2-O of pyran), 4.20 (s, 2H two –OH having intramolecular H-bonding),4.07 (m, 1H, O-CH of pyran), 4.73 (s, 4H two CH2 groups of dimethanols), 5.40 (s, 2H, N-CH2), 7.57 (s, 1H of imidazole ring) and 8.03 (s,1H, NH-CO). For C12H19N3O5 C: 55.11, H: 7.47 and N: 14.83%. Found: C: 54.31, H: 6.97 and N: 14.23%.
Tetrahydro-2H-thiopiran-4-yl ((4,5-bis (hydroxymethyl)- 1H -imidazol-1-yl) methyl) carbamate (5c)
Yield 62%. m p: 165-168°C. IR (KBr): 3520 (νO-H, intramolecular H-bonding), 3045 (stretching of Ar-H), 3418-3388 (NH),2940 and 2895 (CH2 of aliphatic C-H stretching), 1715 (C=O), 1620 (C=N), 1418 (C-N), 1324 cm-1 (C-O) and 715 cm-1(C-S)respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 1.81-2.06 (m, 4H, CH2 of thiopyran), 2.47-2.57 (t, 4H, -CH2 –S of thiopyran), 4.20 (s,2H two –OH having intramolecular H-bonding), 4.17 (m, 1H, O-CH of thiopyran), 4.73 (s, 4H two CH2 groups of dimethanols), 5.40(s, 2H, N-CH2), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). For C12H19N3O4S C: 47.83, H: 6.35, N: 13.94 and S: 10.64%.Found: C: 47.03, H: 5.85, N: 13.34 and S: 10.44%.
Perfluorophenyl ((4, 5-bis(hydroxymethyl)- 1H-imidazol-1-yl) methyl) carbamate (5d)
Yield 75%. m p: 169-171°C. IR (KBr): 3520 (νO-H, intramolecular H-bonding), 3035 (stretching of Ar-H), 3422-3390 (N-H),2940 and 2895 (CH2 of aliphatic C-H stretching), 1715 (C=O), 1620 (C=N), 1420 (C-N), 1326 cm-1 (C-O) and 1100 cm-1(C-F)respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 4.20 (s, 2H two –OH having intramolecular H-bonding), 4.73 (s, 4H two CH2 groupsof dimethanols), 5.40 (s, 2H, N-CH2), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). For C13H10F5N3O4 C: 42.52, H: 2.74, N:11.44 and F: 25.87%. Found: C: 41.72, H: 2.24, N: 10.84 and F: 25.07%.
Cyclohexyl ((6-oxide-6-(3-phenylureido)-4,8-dihydro-H-[1,3,2] dioxaphosphepino[5,6-d] imidazole-1-yl) methyl) carbamate 7(a)
The obtained product of 7a is 0.88 g, Yield 64%. m p: 149-151°C. IR (KBr): 3416-3382 (γ P-NH), 3040 (Ar-H), 2940 and 2895(aliphatic C-H stretching), 1705 (C=O of ester group), 1675 (C=O of urea), 1618 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250(γP=O)and 950 cm-1 (γP-O) respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 1.47-1.60 (m, 10H, CH2 of cyclohexyl), 3.91 (m, 1H, O-CH ofcyclohexyl), 5.23 (s,4H, two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 2H, NH-of urea moiety), 7.19-7.61 (m, 5H, C6H5 attached to urea moiety),7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). 13C-NMR(75 MHz, DMSO-d6):PPM137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 76.8, 30.8, 24.1, 25.7, 152.0, 137.5, 120.8, 129.0 and 133.3 corresponding toC1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12, C11, C14, C15, C16 and C20, C17 and C19 and C18. 31P-NMR (161.89 MHz, DMSO-d6):PPM -6.90, -6.45. For C20H26N5O6P C: 51.83, H: 5.65, N: 15.11 and P: 6.68%. Found: C: 51.03, H: 5.15, N: 14.51 and P: 5.98%.
Tetrahydro-2H-pyran-4-yl ((6-oxide-6-(3-phenylureido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl)carbamate 7(b)
The obtained product of 7b is 0.93 g Yield 67%. m p: 150-152°C. IR (KBr): 3420-3384 (γ P-NH), 3040 (Ar-H), 2940 and 2895(aliphatic C-H stretching), 1705 (C=O of ester group), 1675 (C=O of urea), 1618 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250(γP=O) and950 cm-1 (γP-O) respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 1.72-1.97(m, 4H, CH2 of pyran), 3.55-3.65 (t, 4H, CH2-O of pyran),4.07 (m, 1H, O-CH of pyran), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 2H, NH-ofurea moiety), 7.19-7.61 (m, 5H, C6H5 attached to urea moiety),7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). 13C-NMR(75MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 72.5, 33.4, 63.2, 152.0, 139.4, 121.6, 128.9 and 128.0corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14, C15 and C19, C16 and C18 and C17. 31P-NMR (161.89MHz, DMSO-d6): PPM -6.95, -6.53. For C19H24N5O7P C: 49.03, H: 5.20, N: 15.05 and P: 6.66%. Found: C: 48.23, H: 4.70, N: 14.45and P: 5.96%.
Tetrahydro-2H-thiopyran-4-yl ((6-oxide-6-(3-phenylureido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl)carbamate 7(c)
The obtained product of 7c is 0.93 g Yield 65%. m p: 152-154°C. IR (KBr): 3425-3386 (γ P-NH), 3040 (Ar-H), 2940 and 2895(aliphatic C-H stretching), 1705 (C=O of ester group), 1675 (C=O of urea), 1620 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250(γP=O),950 (γP-O) and 715 cm-1(C-S) respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 1.81-2.06 (m, 4H, CH2 of thio pyran), 2.47-2.57 (t, 4H,CH2-S of thiopyran), 4.17 (m, 1H, O-CH of thiopyran), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H,N-CH2), 6.0 (s, 2H, NH-of urea moiety), 7.19-7.61 (m, 5H, C6H5 attached to urea moiety),7.57 (s, 1H of imidazole ring) and 8.03 (s,1H, NH-CO). 13C-NMR(75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 69.5, 33.2, 25.5, 152.0, 139.4, 121.6,128.9 and 128.0 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14, C15 and C19, C16 and C18 and C17.31P-NMR (161.89 MHz, DMSO-d6) PPM -7.04, -6.42. For C19H24N5O6PS C: 47.40, H: 5.02, N: 14.55, P: 6.43 and S: 6.66%. Found: C:46.60, H: 4.52, N: 13.95, P: 5.73 and S: 6.46%.
Perfluorophenyl ((6-oxide (3-phenylureido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate (7d)
The obtained product of 7d is 0.95 g Yield 70%. m p: 156-158°C. IR (KBr): 3430-3388 (γ P-NH), 3040 (Ar-H), 2940 and 2895(aliphatic C-H stretching), 1705 (C=O of ester group), 1675 (C=O of urea), 1622 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250(γP=O),1100 (C-F) and 950 cm-1 (γP-O) respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 5.23 (s, 4H two CH2 groups attached to phosphorusmoiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 2H, NH-of urea moiety), 7.19-7.61 (m, 5H, C6H5 attached to urea moiety), 7.57 (s, 1H ofimidazole ring) and 8.03 (s, 1H, NH-CO). 13C-NMR(75 MHz, DMSO-d6): PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 155.0, 142.0,139.3, 142.4, 140.1, 152.0, 139.4, 121.6, 128.9 and 128.0 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12,C11, C14, C15, C16 and C20, C17 and C19 and C18. 31P-NMR (161.89 MHz, DMSO-d6) PPM -8.48. For C20H15F5N5O6P C: 43.89, H: 2.76, F:17.36, N: 12.80 and P: 5.66%. Found: C: 43.09, H: 2.26, F: 16.56, N: 12.20 and P: 4.96%.
Cyclohexyl ((6-(3-(4-methoxyphenyl) ureido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate7(e)
The obtained product of 7e is 0.94 g Yield 64%. m p: 150-152°C. IR (KBr): 3416-3382 (γ P-NH), 3025 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1705 (C=O of ester group), 1670 (C=O of urea), 1616 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250(γP=O) and 950 cm-1 (γP-O) respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 1.49-1.80 (m, 10H, CH2 of cyclohexyl), 3.83 (s, 3H, CH3of methoxyphenyl), 3.91 (m, 1H, O-CH of cyclohexyl), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H,N-CH2), 6.0 (s, 2H, NH-of urea moiety), 6,97-7.51 (m, 4H, C6H4 attached to urea moiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s,1H, NH-CO). 13C-NMR(75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 76.8, 30.8, 24.1, 25.7, 152.0, 131.7,119.8, 114.5, 158.9 and 56.8 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12, C11, C14, C15, C16 and C20, C17and C19, C18 and C21. 31P-NMR (161.89 MHz, DMSO-d6): PPM -6.08, -5.16. For C21H28N5O7P C: 51.11, H: 5.72, N: 14.19 and P: 6.28%.Found: C: 50.31, H: 5.52, N: 13.59 and P: 5.58%.
Tetrahydro-2H-pyran-4-yl ((6-(3-(4-chlorophenyl)ureido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate 7(f)
The obtained product of 7f is 1.01 g Yield 68%. m p: 152-154°C. IR (KBr): 3420-3384 (γ P-NH), 3027 (Ar-H), 2940 and 2895 (aliphatic C-H stretching), 1705 (C=O of ester group), 1680 (C=O of urea), 1618 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O),950 (γP-O) and 730 cm-1 (C-Cl) respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 1.72-1.97(m, 4H, CH2 of pyran), 3.65 and 3.55 (t,4H, CH2-O of pyran), 4.07 (m, 1H, O-CH of pyran), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2),6.0 (s, 2H, NH-of urea moiety), 7.47-7.57 (m, 4H, C6H4 attached to urea moiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NHCO).13C-NMR(75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 72.5, 33.4, 63.2, 152.0, 139.4, 121.6, 128.9and 128.0 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14, C15 and C19, C16 and C18 and C17. 31P-NMR(161.89 MHz, DMSO-d6): PPM -8.32. For C19H23ClN5O7P C: 45.66, H: 4.64, Cl: 7.09, N: 14.09 and P: 6.20%. Found: C: 44.86, H: 4.14,Cl: 6.29, N: 13.41 and P: 5.50%.
Tetrahydro-2H-thiopyran-4-yl ((6-(3-(4-bromophenyl)ureido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate 7(g)
The obtained product of 7g is 1.12 g Yield 67%. m p: 154-156°C. IR (KBr): 3425-3386 (γ P-NH), 3029 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1705 (C=O of ester group), 1680 (C=O of urea), 1618 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250(γP=O), 950 (γP-O) and 715 cm-1 (C-S) respectively. 1H-NMR (400 MHz, DMSO-d6): PPM 1.81-2.06 (m, 4H, CH2 of thio pyran), 2.57 and2.47 (t, 4H, CH2-S of thiopyran), 4.17 (m, 1H, O-CH of thiopyran), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety),5.40 (s, 2H, N-CH2), 6.0 (s, 2H, NH-of urea moiety), 7.58-7.70 (m, 4H, C6H4 attached to urea moiety), 7.57 (s, 1H of imidazole ring)and 8.03 (s, 1H, NH-CO). 13C-NMR(75 MHz, DMSO-d6): PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 69.6, 32.2, 25.5, 152.0,138.4, 121.9, 131.8 and 122.3 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14, C15 and C19, C16 andC18 and C17. 31P-NMR (161.89 MHz, DMSO-d6) PPM -10.45. For C19H23BrN5O6PS C: 40.72, H: 4.14, Br: 14.26, N: 12.50, P: 5.53 andS: 5.72%. Found: C: 40.03, H: 3.69, Br: 13.66, N: 11.60, P: 4.93 and S: 5.52%.
Perfluorophenyl ((6-(3-(4-nitrophenyl) ureido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl)carbamate 7(h)
The obtained product of 7h is 1.06 g Yield72%. m p: 158-1600C. IR (KBr): 3430-3388 (γ P-NH), 3030 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1705 (C=O of ester group), 1685 (C=O of urea), 1622 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250(γP=O), 950 (γP-O) and 1100 cm-1 (C-F) respectively. 1H-NMR (400 MHz, DMSO-d6): δ PPM: 5.23 (s, 4H two CH2 groups attached tophosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 2H, NH-of urea moiety), 7.82-8.24 (m, 4H, C6H4 attached to urea moiety), 7.57(s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). 13C-NMR(75 MHz, DMSO-d6): PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 155.0,142.0, 139.3, 142.4, 140.1, 152.0, 145.5, 119.9, 124.1 and 143.5 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13,C10 and C12, C11, C14, C15, C16 and C20, C17 and C19 and C18. 31P-NMR (161.89 MHz, DMSO-d6): PPM -7.85, -7.50. For C20H14F5N6O8P C:40.55, H: 2.38, F: 16.04, N: 14.19 and P: 5.23%. Found: C: 39.75, H: 1.88, F: 15.84, N: 13.59 and P: 4.53%.
Cyclohexyl ((6-(morpholine-4-carboxamido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl)carbamate (7i)
The obtained product of 7i is 0.91 g. Yield : 67%. M p: 163-165°C. IR (KBr): 3416-3382 (γ P-NH), 3030 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1650 (C=O), 1616 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O) and 950 cm-1 (γP-O) respectively.1H NMR (400 MHz, DMSO-d6) δ PPM: 1.49-1.80 (m, 10H, CH2 of cyclohexyl), 3.31 (t, 4H, N-CH2 of morpholine ring J=7.1Hz), 3.65(t, 4H, -CH2-O of morpholine ring J=7.1Hz), 4.30 (m, 1H, CH of cyclohexyl ring attached to oxygen), 5.23 (s, 4H two CH2 groupsattached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-of carboxamide moiety), 7.57 (s, 1H of imidazole ring) and8.03 (s, 1H, NH-CO).
13C-NMR(75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 76.8, 30.8, 24.1, 25.7, 158.5, 139.4, 46.3and 65.7 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12, C11, C14, C15 and C18 and C16 and C17.
31P-NMR (161.89 MHz, DMSO-d6) PPM: -6.95.
Anal. Calcd(%) For C18H28N5O7P C: 47.26, H: 6.17, N: 15.31 and P: 6.77%. Found: C: 46.66, H: 5.67, N: 14.71 and P: 6.77%.
Tetrahydro-2H-pyran-4-yl ((6-(morpholine-4-carboxamido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate (7j)
The obtained product of 7j is 0.96 g, Yield : 70%.m p: 165-167°C. IR (KBr): 3420-3384 (γ P-NH), 3034 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1650 (C=O), 1618(C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O) and 950 cm-1 (γP-O) respectively.1H NMR (400 MHz, DMSO-d6) δ PPM: 1.70-1.90 (m, 4H, CH2 pyran of carbamate), 3.31 (t, 4H, N-CH2 of morpholine ring), 3.65 (t, 4H,-CH2-O of morpholine ring J=7.1Hz), 3.85 (t, 4H, CH2-O pyran of carbamate J=7.1Hz), 4.17 (m, 1H, O-CH pyran of carbamate), 5.23(s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-of carboxamide moiety), 7.57 (s, 1H ofimidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 72.5, 33.4, 63.2, 158.5, 46.3 and 65.7corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14 and C17 and C15 and C16.
Anal.Calcd (%) For C17H26N5O8P C: 44.45, H: 5.70, N: 15.24 and P: 6.74%. Found: C: 43.65, H: 5.20, N: 14.64 and P: 6.04%.
Tetrahydro-2H-thiopyran-4-yl ((6-(morpholine-4-carboxamido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate (7k)
The obtained product of 7k is 0.98 g, Yield: 69%.m p: 167-169°C. IR (KBr): 3425-3386 (γ P-NH), 3010 (Ar-H), 2940 and 2895(aliphatic C-H stretching), 1650 (C=O), 1618(C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O), 950 (γP-O) and 715 cm-1 (C-S) respectively.
1H NMR (400 MHz, DMSO-d6) δ PPM: 1.81-2.06 (m, 4H, CH2 thio pyran of carbamate), 2.57 (t, 4H, CH2-S thiopyran of carbamate),3.31 (t, 4H, N-CH2 of morpholine ring J=7.1Hz), 3.65(t, 4H, -CH2-O of morpholine ring J=7.1Hz), 4.10 (m, 1H, O-CH thiopyran ofcarbamate), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-of carboxamidemoiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 69.5, 32.2, 25.5, 158.5, 46.3 and 65.7corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14 and C17 and C15 and C16.
Anal.Calcd (%) For C17H26N5O7PS C: 42.94, H: 5.51, N: 14.73, P: 6.51 and S: 6.74%. Found: C: 42.14, H: 5.01, N: 14.13, P:5.81 and S: 6.54%.
Perfluorophenyl ((6-(morpholine-4-carboxamido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl)carbamate (7l)
The obtained product of 7l is 1.01 g, Yield: 75%.m p: 169-171°C. IR (KBr): 3430-3388 (γ P-NH), 3020 (Ar-H), 2940 and 2895(aliphatic C-H stretching), 1650 (C=O), 1618(C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O), 1100 (C-F) and 950 cm-1 (γP-O) respectively.
1H NMR (400 MHz, DMSO-d6) δ PPM: 3.31 (t, 4H, N-CH2 of morpholine ring J=7.1Hz), 3.65 (t, 4H, -CH2-O of morpholine ringJ=7.1Hz), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-of carboxamide moiety),7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 155.0, 142.0, 139.3, 142.4, 140.1, 46.3, 65.7 and46.3 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12, C11, C14, C15 and C18 and C16 and C17.
Anal.Calcd (%) For C18H17F5N5O7P C: 39.94, H: 3.17, F: 17.55, N: 12.94 and P: 5.72% Found: C: 39.14, H: 2.67, F: 16.75, N:12.34 and P: 5.02%.
Cyclohexyl ((6-oxido-6-(piperidine-1-carboxamido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl)carbamate (7m)
The obtained product of 7m is 0.88 g, Yield: 65%. m p: 162-164°C. IR (KBr): 3416-3382 (γ P-NH), 3025 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1650 (C=O), 1618(C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O) and 950 cm-1 (γP-O) respectively.1H NMR (400 MHz, DMSO-d6) δ PPM: 1.49-1.80 (m, 10H, CH2 cyclohexyl of carbamate), 1.53-1.59 (m, 6H, CH2 piperidine ofcarboxamide), 3.77 (t, 4H, N-CH2 piperidine of carboxamide J=7.1Hz), 3.91 (m, 1H, O-CH cyclohexyl of carbamate), 5.23 (s, 4H twoCH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-of carboxamide moiety), 7.57 (s, 1H of imidazolering) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 76.8, 30.8, 24.1, 25.7, 156.5, 49.0, 24.9 and23.8 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12, C11, C14, C15 and C19, C16 and C18 and C17.
31P-NMR (161.89 MHz, DMSO-d6) PPM: -5.05.
Anal.Calcd (%) For C19H30N5O6P C: 50.11, H: 6.64, N: 15.38 and P: 6.80% Found: C: 49.31, H: 6.14, N: 14.78 and P: 6.10%.
Tetrahydro-2H-pyran-4-yl ((6-oxido-6-(piperidine-1-carboxamido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate (7n)
The obtained product of 7n is 0.96 g, Yield: 70%. m p: 164-166°C. IR (KBr): 3420-3384 (γ P-NH), 3027 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1650 (C=O), 1618(C=N), 1416 (C-N),1320 (γC-O/δC-O), 1250 (γP=O) and 950 cm-1 (γP-O) respectively.
1H NMR (400 MHz, DMSO-d6) δ PPM: 1.53-1.59 (m, 6H, CH2 piperidine of carboxamide), 1.72-1.97 (m, 4H, CH2 pyran ofcarbamate), 3.77 (t, 4H, N-CH2 piperidine of carboxamide J=7.1Hz), 3.55-3.65 (m, 4H, CH2-O pyran of carbamate), 4.07 (m, 1H,O-CH pyran of carbamate), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-ofcarboxamide moiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 72.5, 33.4, 63.2, 156.5, 49.0, 24.9 and 23.8corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14 and C18, C15 and C17 and C16.
Anal.Calcd (%) For C18H28N5O7P C: 47.26, H: 6.17, N: 15.31 and P: 6.77%. Found: C: 46.46, H: 5.67, N: 14.71 and P: 6.07%.s
Tetrahydro-2H-thiopyran-4-yl ((6-oxido-6-(piperidine-1-carboxamido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate (7o)
The obtained product of 7o is 0.89 g, Yield: 63%.m p: 166-168°C. IR (KBr): 3425-3386 (γ P-NH), 3029 (Ar-H), 2940 and 2895 (aliphatic C-H stretching), 1650 (C=O), 1620 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O), 950 (γP-O) and 715 cm-1 (C-S)respectively.
1H NMR (400 MHz, DMSO-d6) δ PPM: 1.53-1.59 (m, 6H, CH2 piperidine of carboxamide), 1.81-2.06 (m, 4H, CH2 thio pyran ofcarbamate), 2.57 (t, 4H, CH2-S thio pyran of carbamate J=7.1Hz), 3.77 (t, 4H, N-CH2 piperidine of carboxamide J=7.1Hz), 4.17 (m,1H, O-CH thio pyran of carbamate), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H,NH-of carboxamide moiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO). 13C-NMR (75 MHz, DMSO-d6) PPM 137.3, 132.9,127.7, 63.4, 60.6, 61.8, 156.2, 69.5, 32.2, 25.5, 156.5, 49.0, 24.9 and 23.8 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 andC12, C10 and C11, C13, C14 and C18, C15 and C17 and C16.
Anal.Calcd (%) For C18H28N5O6PS C: 45.66, H: 5.96, N: 14.79, P: 6.54 and S: 6.77%. Found: C: 44.86, H: 5.46, N: 14.19, P:5.84 and S: 6.57%.
Perfluorophenyl ((6-oxido-6-(piperidine-1-carboxamido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl)carbamate (7p)
The obtained product of 7p is 1.0 g, Yield: 75%. m p: 168-170°C. IR (KBr): 3430-3388 (γ P-NH), 3030 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1650 (C=O), 1622 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O), 1100 (C-F) and 950 cm-1 (γP-O)respectively.
1H NMR (400 MHz, DMSO-d6) δ PPM: 1.53-1.59 (m, 6H, CH2 piperidine of carboxamide), 3.77 (t, 4H, N-CH2 piperidine ofcarboxamide J=7.1Hz), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-ofcarboxamide moiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 155.0, 142.0, 139.3, 142.4, 140.1, 156.5, 49.0,24.9 and 23.8 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12, C11, C14, C15 and C19, C16 and C18 and C17.
Anal.Calcd (%) For C19H19F5N5O6P C: 42.51, H: 3.55, F: 17.61, N: 12.98 and P: 5.74% Found: C: 41.31, H: 3.05, F: 16.81, N:12.38 and P: 5.04%.
Cyclohexyl ((6-(4-methylpiperazine-1-carboxamido)-6-oxido-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl)methyl) carbamate (7q)
The obtained product of 7q is 0.91 g, Yield: 65%. m p: 164-166°C. IR (KBr): 3416-3382 (γ P-NH), 3025 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1650 (C=O), 1616 (C=N), 1416 (C-N),1320 (γC-O/δC-O), 1250 (γP=O) and 950 cm-1 (γP-O) respectively.1H NMR (400 MHz, DMSO-d6) δ PPM: 1.49-1.80 (m, 10H, CH2 cyclohexyl of carbamate), 2.26 (s, 3H, N-CH3), 2.27 (t, 4H, CH2-Npiperazine of carboxamide J=7.1Hz), 3.40 (t, 4H, N-CH2 piperazine of carboxamide J=7.1Hz), 3.91 (m, 1H, O-CH of cyclohexyl ofcarbamate), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-of carboxamidemoiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 76.8, 30.8, 24.1, 25.7, 158.5, 51.4, 51.0 and46.6 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12, C11, C14, C15 and C18, C16 and C17 and C19.
31P-NMR (161.89 MHz, DMSO-d6) PPM: -7.10.
Anal.Calcd (%) For C19H31N6O6P C: 48.51, H: 6.64, N: 17.86 and P: 6.58% Found: C: 47.71, H: 6.14, N: 17.26 and P: 5.88%.
Tetrahydro-2H-pyran-4-yl ((6-(4-methylpiperazine-1-carboxamido)-6-oxido-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d]imidazole-1-yl) methyl) carbamate (7r)
The obtained product of 7r is 0.9 g, Yield: 70%. m p: 166-168°C. IR (KBr): 3420-3384 (γ P-NH), 3027 (Ar-H), 2940 and 2895(aliphatic C-H stretching), 1650 (C=O), 1618 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O) and 950 cm-1 (γP-O) respectively.
1H NMR (400 MHz, DMSO-d6) δ PPM: 1.72-1.97(m, 4H, CH2 pyran of carbamate), 2.26 (s, 3H, N-CH3), 2.27 (t, 4H, CH2-Npiperazine of carboxamide J=7.1Hz), 3.40 (t, 4H, N-CH2 piperazine of carboxamide J=7.1Hz), 3.85 (t, 4H, CH2-O pyran of carbamateJ=7.5Hz), 4.07 (m, 1H, O-CH pyran of carbamate), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2),6.0 (s, 1H, NH-of carboxamide moiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 72.5, 33.4, 63.2, 158.5, 51.4, 51.0 and 46.6corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14 and C17, C15 and C16 and C18.
Anal.Calcd (%) For C18H29N6O7P C: 45.76, H: 6.19, N: 17.79 and P: 6.56%. Found: C: 44.96, H: 5.69, N: 17.19 and P: 5.86%.
Tetrahydro-2H-thiopyran-4-yl ((6-(4-methylpiperazine-1-carboxamido)-6-oxido-4,8-dihydro-1H-[1,3,2]dioxaphosphepino[5,6-d]imidazole-1-yl) methyl) carbamate (7s)
The obtained product of 7s is 0.98 g, Yield: 67%. m p: 168-170°C. IR (KBr): 3425-3386 (γ P-NH), 3029 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1650 (C=O), 1620 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O), 950 (γP-O) and 715 cm-1 (C-S)respectively.
1H NMR (400 MHz, DMSO-d6) δ PPM: 1.81-2.06 (m, 4H, CH2 thio pyran of carbamate), 2.26 (s, 3H, N-CH3), 2.27 (t, 4H,CH2-N piperazine of carboxamide J=7.1Hz), 2.57 (t, 4H, CH2-S thiopyran of carbamate J=7.1Hz), 3.40 (t, 4H, N-CH2 piperazine ofcarboxamide J=7.5Hz), 4.17 (m, 1H, O-CH thiopyran of carbamate), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety),5.40 (s, 2H, N-CH2), 6.0 (s, 1H, NH-of carboxamide moiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM: 137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 156.2, 69.5, 33.2, 25.5, 158.5, 51.4, 51.0 and 46.6corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C12, C10 and C11, C13, C14 and C17, C15 and C16 and C18.
Anal.Calcd (%) For C18H29N6O6PS C: 44.26, H: 5.98, N: 17.20, P: 6.34 and S: 6.56%. Found: C: 43.46, H: 5.48, N: 16.60, P:5.64 and S: 6.36%.
Perfluorophenyl ((6-(4-methylpiperazine-1-carboxamido)-6-oxido-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate (7t)
The obtained product of 7t is 1.00 g, Yield: 73%. m p: 170-172°C.IR (KBr): 3430-3388 (γ P-NH), 3030 (Ar-H), 2940 and2895 (aliphatic C-H stretching), 1650 (C=O), 1622 (C=N), 1416 (C-N), 1320 (γC-O/δC-O), 1250 (γP=O), 1100 (C-F) and 950 cm-1 (γP-O)respectively.
1H NMR (400 MHz, DMSO-d6) δ PPM: 2.26 (s, 3H, N-CH3), 2.27 (t, 4H, CH2-N piperazine of carboxamide J=7.1Hz), 3.40 (t, 4H,N-CH2 piperazine of carboxamide J=7.1Hz), 5.23 (s, 4H two CH2 groups attached to phosphorus moiety), 5.40 (s, 2H, N-CH2), 6.0(s, 1H, NH-of carboxamide moiety), 7.57 (s, 1H of imidazole ring) and 8.03 (s, 1H, NH-CO).
13C-NMR (75 MHz, DMSO-d6) PPM137.3, 132.9, 127.7, 63.4, 60.6, 61.8, 155.0, 142.0, 139.3, 142.4, 140.1, 158.5, 51.4,51.0 and 46.6 corresponding to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C13, C10 and C12, C11, C14, C15 and C18, C16 and C17 and C19.
Anal.Calcd (%) For C19H20F5N6O6P C: 41.16, H: 3.64, F: 17.14, N: 15.16 and P: 5.59% Found: C: 40.36, H: 3.14, F: 16.34, N:14.56 and P: 4.89%.
Synthesis of 2-(6,6-dimethyl-4,8-dihydro-1H-[1,3] dioxepino[5,6-d] imidazole-1-yl) acetyl azide (2) [15]
To a solution of 2-(6,6-dimethyl-4,8-dihydro-1H-[1,3] dioxepino [5,6-d] imidazol-1-yl-acetic acid (4.5 g, 0.02 mol) (1) inacetone was added triethyl amine (0.50 ml) and stirred for 30 minutes. To the reaction mixture aqueous NaN3 (0.6 mol) was addedand stirred for 20 minutes at 0°C. After completion, reaction mixture was poured in ice cold water (20 ml), extracted with diethylether (10 ml). The organic layer was separated, washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporatedunder vacuum to give crude product. The crude product was purified by column chromatography (60-120 mesh silica gel, eluent:10 % EtoAc-pet ether), to give pure acid azide (3.51 g) (2). This was collected by filtration and recrystallized from ethanol, mp 94-96°C, yield 70%.
Synthesis of Cylohexyl/tetrahydro-2H-pyran/tetrahydro-2H-thiopyran/perfluoro phenyl (6,6-dimethyl-4,8-dihydro-1H-[1,3] dioxepino[5,6-d] imidazol-1-yl) methyl carbamates 4(a-d) [16]
To the solution if acid azide (2) (1.09 g 0.0039 mol), in Cyclohexanol (15 ml, 0.1 mol) (3a) was added and reaction mixturewas refluxed for 16 hours. After completion of the reaction, solvent was evaporated under vacuum to give crude residue, which waspurified by column chromatography (60-120 mesh silica gel). The reaction was monitored with TLC using hexane and ethylacetate(7:3) as an eluent. Ethylacetate and petroleum ether (3:7) solvent mixture was used as an eluent. Finally the product compoundcyclohexyl ((6,6-dimethyl-4,8-dihydro-1H-[1,3] doxepin [5,6-d] imidazol-1-yl) methyl) carbamate (0.87 g) (4a) was purified fromaqueous dimethyl formamide. Yield 68%, m p 140-142°C. The similar experimental procedure was adopted to synthesize 4(b-d)(4b-0.88 g with 68%, 4c-0.87 g with 68%, 4d-0.79 g with 70%) from 2 and Tetrahydro-2H-pyron-4-ol (3b-1.5 ml, 0.0174 mol),Tetrahydro-2H-pyron-4-ol (3c-1.5 ml, 0.0147 mol) and 2, 3, 4, 5, 6-pentafluorophenol (3d-1.5 ml, 0.0118 mol).
Synthesis of Cyclohexyl/tetrahydro-2H-pyran-4-yl/tetrahydro-2H-thiopyran-4-yl/pefluorophenyl ((4, 5-bis (hydroxymethyl)- 1Himidazol-1-yl) methyl) carbamates 5(a-d)
The isopropylidenation of 1, 2-diols was carried out by a procedure as reported in the literature. A suspension of the cyclohexyl((6,6-dimethyl-4,8-dihydro-1H-[1,3] doxepin [5,6-d] imidazol-1-yl) methyl) carbamate (0.85 g, 0.0026 mol) (4a) (1 m mol) in dryacetone and to this 5 mol% of phosphotungstic acid was added and the reaction mixture was stirred at room temperature undernitrogen atmosphere for 1 hour The progress of the reaction was monitored by TLC using cyclohexane and ethyl acetate (7:3)solvent mixture as an eluent. After completion of the reaction, the solvent was removed under reduced pressure. The residue wasextracted with dichloromethane (3×20 ml) and water and the combined organic layer was dried with Na2SO4 and concentratedin vacuum to give the crude product (5a). The crude product was purified by column chromatography on silica gel (60-120 mesh)with 15-30% ethyl acetate in cyclohexane as an eluent. The m p of (0.81 g) (5a) was 164-166°C with yield of 60%.
The similar procedure was adopted to synthesize 5(b-d) (5b-0.84 g with 65%, 5c-0.86 g with 62%, and 5d-0.77 gr with 75%)from (4b-0.85 g, 0.0026 mol, 4c-0.85 g, 0.0024 mol and 4d-0.77 g, 0.0017 mol).
Synthesis of Cyclohexyl/terahydro-2H-pyran/tetrahydro-2H-thiopyran/perfluorophenyl ((6-oxide-6-(3-phenylureido)/(4-methoxyphenyl)/(4-chlorophenyl)/(4-bromophenyl)/(4-nitrophenyl) ureido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazol-1-yl) methyl) carbamates 7(a-h)
A solution of (phenyl carbamoyl) phosphoramidic dichloride (5.0 g, 0.019 mol)[17] (6a) (2 mmol) in 25 ml of dry toluenewas added drop wise over a period of 20 minutes to a stirred solution of Cyclohexyl ((4, 5-bis (hydroxymethyl)-1H-imidazol-1-yl) methyl) carbamate (0.80 g, 0.003 mol) (5a) and triethylamine in 30 ml of dry toluene and 10 ml of tetrahydrofuran at 5°C.After completion of the addition, the temperature of the reaction mixture was slowly raised to room temperature and stirred for2 hours. Later on the reaction mixture was heated to 50-60°C and maintained for 4 hours with stirring. The completion of thereaction was monitored by TLC analysis. Triethyl amine hydrochloric acid was filtered from mixture and solvent was removed underreduced pressure. The residue was washed with water and then recrystallized from aqueous 2-propanol to get pure compoundcyclohexyl ((6-oxide-6-(3-phenylureido)-4,8-dihydro-1H-[1,3,2] dioxaphosphepino [5,6-d] imidazole-1-yl) methyl) carbamate (0.80g, 0.0019 mol) (7a), yield 64%, m p 149-151°C. The similar procedure was adopted to synthesize 7(b-d) (0.83 g-7b; 0.83 g-7c;0.76 g-7d) by the reaction between 5(b-d) (0.83 g, 0.003 mol-5b; 0.85 g, 0.003 mol-5c; 0.75 g, 0.0025 mol-5d) with (phenylcarbamoyl) phosphoramidic dichloride (5.0 g, 0.019 mol) (6a), 7(e-h) (0.84 g-7e; 0.91 g-7f; 0.99 g-7g; 0.96 g-7h) were preparedby condensation of 5a (0.84 g, 0.003 mol) + 6b (5.0 g, 0.017 mol), 5b (0.85 g, 0.003 mol) + 6c (5.0 g, 0.017 mol), 5c (0.90 g,0.003 mol) + 6d (5.0 g, 0.015 mol) and 5d (0.91 g, 0.0025 mol) + 6e (5.0 g, 0.016 mol) respectively.
Synthesis of Cyclohexyl/tetrahydro-2H-pyran-4-yl/tetrahydro-2H-thiopyran-4-yl/perfluorophenyl ((6-(morpholine-4-carboxamido)/(piperidine-1-carboxamido)/(4-methylpiperazine-1-carboxamido)-6-oxide-4,8-dihydro-1H -[1,3,2] dioxaphosphepino[5,6-d]imidazole-1-yl) methyl) carbamates 7(i-t)
A solution of morpholino carbamoyl phosphoramidic dichloride [18] (6a) (15 ml, 0.060 mole) in 25 ml of dry toluene wasadded drop wise over a period of 20 minutes to a stirred solution of Cyclohexyl ((4, 5-bis (hydroxymethyl)-1H-imidazol-1-yl) methyl)carbamate (0.84 g, 0.003 mol) (5a) and triethylamine (6 ml, 0.004 mole) in 30 ml of dry toluene and 10 ml of tetrahydrofuran at5°C. After completion of the addition, the temperature of the reaction mixture was slowly raised to room temperature and stirredfor 2 hours. Later the reaction mixture was heated to 50-60°C and maintained for 4 hours with stirring. The completion of thereaction was monitored by TLC analysis. Triethyl amine hydrochloric acid was filtered from mixture and solvent was removed underreduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh) with 30% of ethylacetate incyclohexane as anelutent to afford Cyclohexyl ((6-(morpholine-4-carboxamido)-6-oxide-4,8-dihydro-1H-[1,3,2] dioxaphosphepino[5,6-d] imidazole-1-yl) methyl) carbamate (0.91 g) of (7i) with yield 67%, m p 163-165°C.
The similar procedure was adopted to synthesize 7(j-t) by the reaction between 5(b-d) (5b-0.85 g, 0.003 mol; 5c-0.90 g,0.003 mol; 5d-0.91 g, 0.0025 mol) with morpholino carbamoyl phosphoramidic dichloride (15 ml, 0.06 mol) (6a), 7(j-t) (7j-0.96g, 7k-0.98 g, 7l-1.01 g, 7m-0.88 g, 7n-0.96 g, 7o-0.89 g, 7p-1.0 g, 7q-0.91 g, 7r-0.99 g, 7s-0.98 g, 7t-1.0 g) were prepared bycondensation of 5(a-d) with (piperidene-1-carbonyl) phosphoramidic dichloride (15 ml, 0.061 mol) (6b) and 4-methylpiperazine-1-carbamoyl phosphoramidic dichloride (15 ml, 0.056 mol) (6c).
The determine both the antibacterial and antifungal activity, these newly synthesized compounds was performed accordingto disc diffusion method, as recommended by the National Committee for Clinical Laboratory. The synthesized compounds wereused at the concentration of 250μg/ml DMF as a solvent [18].
Antibacterial assay
The antibacterial activity of Carbamates containing imidazole ureas/caboxamides dioxaphosphepinoes 7(a-t) were screenedagainst the Staphylococcus aureus NCCS 2079 and Bacillus cerus NCCS 2106 (gram positive) and Escherichia coli NCCS 2065Antifungal activity of Carbamates containing imidazole ureas/carboxamides dioxaphosphepinoes 7(a-t) were screened againstAspergillus niger NCCS 1196 and Candida albicans NCCS 3471. Here Ketoconazole is tested as reference compound to comparethe activity. and Pseudomonasaeruginosa NCCS 2200 (gram negative) organisms. Here Amoxicillin is tested as referencecompound to compare the activity.
Antifungal assay
Most of the compounds exhibit good antibacterial and antifungal activity against both given microorganism. The presence ofnitro, chloro and bromo were showed more activity than other substituted compounds.
The Anti-bactterial and anti-fungal activity of 7(a-t) was shown in Table 1.
| S.NO | COMP | R | X | Zone of inhibition(mm) 250 (µg/disc) | |||||
|---|---|---|---|---|---|---|---|---|---|
| Anti-bacterial activitya | Anti-fungal activityb | ||||||||
| S.a | B.c | E.c | P.a | A.n | C.a | ||||
| 1 | 7a | H | - | 8 | 7 | 9 | 10 | 10 | 8 |
| 2 | 7b | H | - | 8 | 6 | 7 | 8 | 11 | 9 |
| 3 | 7c | H | - | 7 | 5 | 6 | 7 | 8 | 6 |
| 4 | 7d | H | - | 6 | 5 | 6 | 7 | 7 | 6 |
| 5 | 7e | OCH3 | - | 15 | 14 | 13 | 15 | 15 | 16 |
| 6 | 7f | *Cl | - | 19 | 18 | 19 | 17 | 19 | 18 |
| 7 | 7g | *Br | - | 18 | 17 | 18 | 17 | 18 | 17 |
| 8 | 7h | *NO2 | - | 20 | 21 | 19 | 20 | 20 | 22 |
| 9 | 7i | - | O | 6 | 5 | 7 | 8 | 10 | 6 |
| 10 | 7j | - | O | 7 | 4 | 5 | 6 | 11 | 7 |
| 11 | 7k | - | O | 5 | 3 | 4 | 5 | 8 | 4 |
| 12 | 7l | - | O | 4 | 3 | 4 | 5 | 7 | 4 |
| 13 | 7m | - | CH2 | 15 | 16 | 15 | 13 | 15 | 17 |
| 14 | 7n | - | CH2 | 13 | 12 | 13 | 12 | 14 | 16 |
| 15 | 7o | - | CH2 | 13 | 15 | 12 | 14 | 17 | 20 |
| 16 | 7p | - | CH2 | 10 | 9 | 7 | 8 | 13 | 14 |
| 17 | 7q | - | *NCH3 | 17 | 18 | 17 | 15 | 18 | 16 |
| 18 | 7r | - | *NCH3 | 15 | 14 | 15 | 14 | 17 | 15 |
| 19 | 7s | - | *NCH3 | 18 | 20 | 18 | 17 | 20 | 18 |
| 20 | 7t | - | *NCH3 | 15 | 17 | 16 | 14 | 15 | 13 |
| Amoxicillin | 21 | 27 | 24 | 22 | - | - | |||
| Ketoconazole | - | - | - | - | 22 | 25 | |||
Table 1: Anti-bacterial and anti-fungal activity of Carbamates containing imidazole ureas/carboxamides dioxaphosphepinoe 7(a-t).
In conclusion, we have demonstrated the synthesis of Organo Phospho Carbamates containing imidazole ureas/Carboxamidesof 7(a-t) involving the four more synthetic steps was required. In case of Organo phosphoimidazole derivatives which are provedto be having great potential for the different pharmacological activities (Scheme 1).
Figure 1: Synthesis of organo phospho carbamates containing imidazole ureas/Carboxamides.
The author V.Esther Rani thanks to U G C-S A P and U G C-B S R, New Delhi for financial assistance. They are also thankfulto IICT Hyderabad and CDRI Lucknow for spectral and analytical data.
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