Advances in the stereoselective synthesis of antifungal agents and ...

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Chapter 8 193Synthetic method 7.11.1 16% yield; Synthetic method 7.11.216%yield1H-NMR (200 MHz, CDCl 3 ) δ =1.36 (t, J = 6.9 Hz, 3H), 4.34 (q, J =6.9 Hz, 2H), 6.58 (s, 1H), 7.16 (m, 4H), 7.54 (m, 12H).M.P.= 149-151 °C (EtOH).Elementary Analysis. calcd. for C 25 H 22 N 2 O 2 : C, 78.51; H, 5.80; N,7.33. Found: C, 78.73; H, 5.84; N, 7.19.(±)-1-[_-(4-Biphenylyl)benzyl]imidazole-5-carboxylic acid(±)-43.Synthetic method 7.121H-NMR (200 MHz, DMSO-d 6 ) δ =7.41 (m, 4H), 7.62 (m, 6H), 7.69(m, 7H). Anal. Calcd for C 23 H 18 N 2 O 2 : C, 77.95; H, 5.12; N, 7.91.Found: C, 78.12; H, 5.19; N, 7.83.IR (nujol mull) ν cm-1 =1740;M.P.= 163-166 °C (EtOH/H 2 O).(±)-5-Amino-1-(2-octyl)imidazole-4-carbonitrile (±)-46Synthetic method 7.13.1H-NMR (200 MHz, CDCl 3 ) δ =0.87 (t, J = 6.5 Hz, 3H), 1.26 (br s,8H), 1.46 (d, J = 6.7 Hz, 3H), 1.75 (m, 2H), 3.96 (m, 1H), 7.13 (s,1H).IR 3360, 2240 cm -1 ;M.P.=110 °C (cyclohexane).Elementary Analysis. calcd. for C 12 H 20 N 4 : C, 65.41; H, 9.15; N,25.44. Found: C, 65.67; H, 9.08; N, 25.25.(±)-5-Amino-1-(2-octyl)imidazole-4-carboxylic acid (±)-47Synthetic method 7.141H-NMR (200 MHz, DMSO-d 6 + D 2 O) δ =0.84 (t, J = 7.3 Hz, 3H),1.25 (br s, 8H), 1.37 (d, J = 7.4 Hz, 3H), 1.73 (m, 2H), 4.11 (m,1H), 7.18 (s, 1H).IR (nujol mull) ν cm-1 =3350, 1735;47 was not further purified and was directly used in the next step.(±)-5-Amino-1-(2-octyl)imidazole (±)-48Synthetic method 7.151H=NMR (200 MHz, CDCl 3 + D 2 O) δ = 0.88 (t, J = 6.8 Hz, 3H),1.30 (br s, 8H), 1.48 (d, J = 7.0 Hz, 3H), 1.75 (m, 2H), 4.04 (m, J =7.2 Hz, 1H), 4.75 (s, 1H), 7.21 (s, 1H).
Chapter 8 194IR (CHCl 3 ) ν cm-1 = 3350;M.P.= Colorless oil.Elementary Analysis. calcd. for C 11 H 21 N 3 : C, 67.64; H, 10.84; N,21.52. Found: C, 67.80; H, 10.72; N, 21.35.(±)-1-(2-Octyl)imidazole-4-carboxamide (±)-49Synthetic method 7.16.1H-NMR (200 MHz, CDCl 3 + D 2 O) δ =0.86 (t, J = 6.7 Hz, 3H), 1.32(m, 8H), 1.49 (d, J = 6.8 Hz, 3H), 1.75 (m, 2H), 4.17 (m, 1H), 7.59(s, 1H), 7.67 (s, 1H).IR (CHCl 3 ) ν cm-1 = 3540, 3420, 1670;Elementary Analysis. calcd. for C 12 H 21 N 3 O: C, 64.51; H, 9.51; N,18.81. Found: C, 64.84; H, 9.30; N, 18.48.(±)-N-[2,2-(Dimethoxy)ethyl]-2-octylamine (±)-52a:Synthetic method 7.17, 62% yield.1H-NMR (200 MHz, CDCl 3 ) δ =0.88 (t, J = 6.3 Hz, 3H), 1.04 (d, J =6.2 Hz, 3H), 1.27 (m, 8H), 2.05 (s, 1H), 2.72 (m, 4H), 3.85 (s, 6H),4.65 (t, J = 6.2 Hz, 1H).IR (CHCl 3 ) ν cm-1 = 3340;(S)-N-[2,2-(Dimethoxy)ethyl]-2-octylamine (S)-52a:Synthetic method 7.17, 65% yieldNo specific rotation could be measured at different wavelengths.Physical and spectral data were identical to those described above forthe racemate (±)-52a.(±)-N-[2,2-(Dimethoxy)ethyl]-1-phenyl-1-ethylamine(±)-52b:Synthetic method 7.17, 70% yield.1H-NMR (200 MHz, CDCl 3 ) δ =1.37 (d, J = 6.5 Hz, 3H), 1.65 (s, 1H,exchangeable with D 2 O), 2.55 (dd, J = 12.1, 6.3 Hz, 1H), 2.65 (dd, J= 12.1, 6.3 Hz, 1H), 3.29 (s, 3H), 3.34 (s, 3H), 3.76 (q, J = 6.5 Hz,1H), 4.45 (t, J = 6.5 Hz, 1H), 7.35 (m, 5H).IR (CHCl 3 ) ν cm-1 = 3345;(S)N-[2,2-(Dimethoxy)ethyl]-1-phenyl-1-ethylamine(S)-(-)-52b:Synthetic method 7.17[α] 20 D -31.0 (c 2.09, CHCl 3 ).Physical and spectral data were identical to those described above forthe racemate (±)-52b
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Advances in the stereoselectivesynt
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ACKNOWLEDGMENT:I would like to than
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Summary:Numerous drugs are chiral,
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IndexII2.2 Synthesis of enantiopure
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IndexIV4.4. Stereochemical Assignme
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IndexVImethyl amine 69 1446.6. Stud
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IndexVIII8.23.3.1 Desilylation usin
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Chapter 1 11.Introduction1.1. Chira
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Chapter 1 3The concept of stereoche
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Chapter 1 5switches is in the area
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Chapter 1 7-bonds 9 . It is now wid
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Chapter 1 914CH 3Cyt P-450 DMOH3O 2
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Chapter 1 11piperazine) is also the
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Chapter 1 13The four stereoisomers
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Chapter 1 15single enantiomers and
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Chapter 1 17was synthesized by the
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Chapter 1 19HOHODesmolaseHOCholeste
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Chapter 1 21formic acid results in
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Chapter 1 23inactivation. 113 . Bec
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Chapter 1 25Two newer compounds whi
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Chapter 1 2715 is an advanced repre
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Chapter 1 29transformation of the a
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Chapter 1 31Enantioselective synthe
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Chapter 1 33+R,S DRUG ANCHOR R MOLE
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Chapter 1 35solubilized in hot etha
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Chapter 2 37RsORmRmRsRLRL RRRLH - A
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Chapter 2 39The stereochemistry and
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Chapter 2 41An asymmetric reducing
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Chapter 2 43This approach clearly e
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Chapter 2 45PhaxeqP 1MP 2axeqPhP 2M
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Chapter 2 47pyrrolidine ] 20 , LAH-
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Chapter 2 49Enzymatic reactions are
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Chapter 2 51As [ES] in equation 4 c
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Chapter 2 53E+AK 1AK -1AEAK 2AE+PE+
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Chapter 2 552.2.4 Lipases.Most lipa
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Chapter 2 57enzyme intermediate can
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Chapter 2 59projecting above the pl
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Chapter 2 612.3.1.1. Step 1: Adduct
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Chapter 2 63A -+ ROHRO - + AH'RO 2
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Chapter 2 65There are various effec
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Chapter 2 67The reactions were foun
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Chapter 2 69Yamanaka and coworkers
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Chapter 2 71sodium or potassium car
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Chapter 3 73The reaction is quite s
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Chapter 3 75literature as the best
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Chapter 3 77dry solvents and, is ch
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Chapter 3 79XXOH+ H 2 NDry K 2 CO 3
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Chapter 3 81substituents are the mo
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Chapter 3 83induces a rotation of t
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Chapter 3 85very sharp and it was p
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Chapter 3 87Raney NickelOH Br MeOH;
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Chapter 4 8933a-m were hydrolysed t
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Chapter 4 91benzo[b]furane (entries
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Chapter 4 93hydroxy or amine groups
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Chapter 4 95the products with ethyl
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Chapter 4 97NCO 2 HNCO 2 H(±)34c(-
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Chapter 4 99NNH37CO2EtOH(±)-27a(+)
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Chapter 4 101As already outlined ab
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Chapter 4 103(+)-(S)-2-octylimidazo
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Chapter 4 105CNNH N2 NCN nC 6 H 13N
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Chapter 4 107key step is the conver
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Chapter 4 109reverse addition in th
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Chapter 4 111which was eliminated e
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Chapter 4 113separate (±)-57a and
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Chapter 5 115to avoid this side rea
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Chapter 5 117Complete degradation o
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Chapter 5 119Entry R T °C Product
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Chapter 5 1212:1:3 in weight. All t
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Chapter 5 123reaction conditions we
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Chapter 5 125Entry Substrate R Time
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Chapter 5 127experiments. But it wa
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Chapter 5 129OClOSAM IIPH=7; R.T.OH
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Chapter 5 131OHOXHOHRHK 2 CO 3 ; Me
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Chapter 6 133HCuSO 4 .5H 2 O,NH 4 O
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Chapter 6 1356.2.1 Heteroannullatio
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Chapter 6 137This discovery allowed
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Chapter 6 139OH(±)-62OHFigure 6.1
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Chapter 6 141Entry Substrate R Time
Page 158 and 159: Chapter 6 143HOH58-a-c,e,h-lRPdCl 2
Page 160 and 161: Chapter 6 145afforded the benzo[b]f
Page 162 and 163: Chapter 6 147RR[P(Ph) 3 ]Pd°OHOPh
Page 164 and 165: Chapter 6 149H2-IodophenolOHOH(±)-
Page 166 and 167: Chapter 6 151presence of base as de
Page 168 and 169: Chapter 7 153A chiral lithium alumi
Page 170 and 171: Chapter 7 155derivatives were tried
Page 172 and 173: Chapter 7 157Finally an hypothesis
Page 174 and 175: Chapter 8 159were washed with a sat
Page 176 and 177: Chapter 8 16145 min, the mixture wa
Page 178 and 179: Chapter 8 1638.9 Decarboxylation of
Page 180 and 181: Chapter 8 165Alcohol 27a (0.2 mmol)
Page 182 and 183: Chapter 8 167for 48 h. After coolin
Page 184 and 185: Chapter 8 169room temperature for t
Page 186 and 187: Chapter 8 171in CH 2 Cl 2 and washe
Page 188 and 189: Chapter 8 1738.26 Screening of lipa
Page 190 and 191: Chapter 8 175Na 2 SO 4 . After remo
Page 192 and 193: Chapter 8 177NMR and MS analysis we
Page 194 and 195: Chapter 8 179Argon was bubbled thru
Page 196 and 197: Chapter 8 181IR (CHCl 3 ): ν cm-1=
Page 198 and 199: Chapter 8 183GC-MS: 305 M + (68%),
Page 200 and 201: Chapter 8 185[α] 20 D -5.7 (c 1.75
Page 202 and 203: Chapter 8 187Synthetic method 7.7.1
Page 204 and 205: Chapter 8 189(R,S)-(±)-1-(2-Octyl)
Page 206 and 207: Chapter 8 191M.P. = oil.Elementary
Page 210 and 211: Chapter 8 195(±)-N-1-(2-Octyl)-2-t
Page 212 and 213: Chapter 8 197IR (CHCl 3 ) ν cm-1 =
Page 214 and 215: Chapter 8 199(±)-1-(4-Fluorophenyl
Page 216 and 217: Chapter 8 201Physical and spectral
Page 218 and 219: Chapter 8 203(±)-1-(Phenyl)-2-prop
Page 220 and 221: Chapter 8 205128.61, 128.87, 130.39
Page 222 and 223: Chapter 8 207min.Physical and spect
Page 224 and 225: Chapter 8 20913C J MOD NMR (CDCl 3
Page 226 and 227: Chapter 8 211(±)-2'-Methylphenyl-2
Page 228 and 229: Chapter 9 213References chapter 1:1
Page 230 and 231: Chapter 9 21531) De Felice, R.; Joh
Page 232 and 233: Chapter 9 21768) Brodie, A.M.H. in
Page 234 and 235: Chapter 9 219112) Brodie, A. M. H.;
Page 236 and 237: Chapter 9 2214) Karabatsos, M.C. J.
Page 238 and 239: Chapter 9 22334c) Blow D. Nature 19
Page 240 and 241: Chapter 9 22567a) Kundu, N.G.; Pal,
Page 242: Chapter 9 22712) Thompson,A.S.; Hum
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