Kamagra enthält Sildenafilcitrat als pharmakologisch aktiven Bestandteil. Dieser hemmt selektiv die Phosphodiesterase-5 und erhöht dadurch die Konzentration von cGMP im Corpus cavernosum. Der Effekt ist zeitlich begrenzt, da die Halbwertszeit von Sildenafil etwa vier Stunden beträgt. In der galenischen Form als Mundgel erfolgt die Resorption besonders rasch, was zu einem schnelleren Wirkeintritt führt. Der Abbau erfolgt überwiegend hepatisch über CYP3A4, wobei ein aktiver Metabolit entsteht, der zur Gesamtwirkung beiträgt. Typische Nebenwirkungen ergeben sich aus der Vasodilatation, darunter leichte Kopfschmerzen und nasale Kongestion. In klinischen Beschreibungen wird kamagra oral jelly im Zusammenhang mit der schnelleren Absorption erwähnt.
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Cross-Coupling Reaction catalyst Tamao-Kumada-Corriu Murahashi Suzuki-Miyaura Migita-Kosugi-Stille Al, Zr, In, Bi. Reaction Mechansim oxidative transmetallation reductive addition elimination Tamao-Kumada-Corriu Coupling NiCl2(dppp) R = Ar, vinyl, benzyl R' = Ar, vinyl, ally, alkyl X = I, Br, Cl
還元的脱離 R R' The first reports NiCl2(dppe) Et2O reflux, 20 h Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374. Ni(acac) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun. 1972, 144. Mg (12.2 g, 0.50 mol) Et2O (200 mL) 1-bromobutane (68.5 g, 0.5 mol) in Et2O (50 mL) NiCl2(dppp) 0 °C → reflux (30.0-31.5 g) NiCl2(dppp) (0.25 g, 0.5 mmol) 1,2-dichlorobenzene (29.5 g, 0.21 mol) Et2O (150 mL) Kumada, M.; Tamao, K.; Sumitani, K. Org. Synth. 1988, Coll. Vol. 6, 407. cf. Buck, J. R.; Park, M.; Wang, Z.; Prudhomme, D. R.; Rizzo, C. J. Org. Synth. 1999, Vol. 77, 153. Organic Synthesis Website: http://www.orgsyn.org/ NiCl2/L* Et2O 0 °C, 2 d (-)-DIOP R = iPr (S)-(R)-PPFA t-Leuphos <16% ee R = tBu (R) (S) Hayashi, T.; Konishi, M.; Fukushima, M.; Kanehira, K.; Hioki, T.; Kumada, M. J. Org. Chem. 1983, 48, 2195. Et2O, 0 °C ibuprofen 81%ee Hayashi, T.; Konishi, M.; Fukushima, M.; Mise, T.; Kagotani, M.; Tajika, M.; Kumada, M. J. Am. Chem. Soc. 1982, 104, 180. PhMgBr/LiBr Et2O/toluene - 30 °C, 40 h 87% (93%ee) Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc. 1995, 117, 9101. NiCl2/1,3-butadiene C10H21 Br + C10H21 Bu THF, 0 °C, 30 min Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2002, 124, 4222. + tBuMgCl C8H17 But 25 °C, 6 h Br > F > Cl Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646. NiCl2(PPh3)2 C6H6 rt, 72 h Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org. Chem. 1984, 49, 4894. NiCl2(PPhCy2)2 tAmOMe/Et2O 23 °C, 15 h Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428. cf. Dallaire, C.; Kolber, I.; Gingras, M. Org. Synth. 2000, Vol. 78, 42. Iron-Catalyzed Grignard Cross-Coupling Fe(acac)3 RMgBr 0 °C → rt, 5 min PhMgBr (28%) 6H13MgBr (91%) X = Cl (91%) OTf (87%) OTs (83%) Br, I (<40%) 6H13MgBr: Fe(acac) 0 °C → rt, 5 min 14H29MgBr (95%) PhMgBr (73%) Furstner, A.; Leitner, A.; Mendez, M.; Krause, K. J. Am. Chem. Soc. 2002, 124, 13856. Furstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. NiCl2(dppp) C4H9MgBr reflux, 6 h Fe(acac)3 C6H13MgBr 0 °C, 5 min Fe(acac)3 1) Me2CHCH2MgBr 2) C14H29MgBr THF/NMP, 0 °C 1) 3 min 2) 5 min RCH2CH2CH2CH2R 4 RCH2CH2MgX [R Fe(MgX)] [Fe(MgX) [R Fe(MgX)2] Negishi Coupling R = Ar, vinyl, alkyl R' = Ar, vinyl, alkyl generaion of Zn reagents inert to ketone, esters, amino and R'MgX + ZnCl cyano goups R'Li + ZnCl2 R'3Al + ZnCl2 I + Zn(Cu) iodine-zinc exchange Pd(PPh3)4 tBuLi THF, rt, 1 h THF, rt, 5 h -78 °C, 1 h
→ rt, 1h o-iodotoluene (26.2 g, 120 mmol) Pd(PPh3)4 (1.16 g, 1 mmol) Et2O (60 mL) THF (100 mL) 1.56M tBuLi in hexane (154 mL, 240 mmol) 1-bromo-4-nitrobenzene (20.2 g, 100 mmol) THF (80 mL) ZnCl2 (16.3 g, 120 mmol) THF (60 mL) Negishi, E.; Takahashi, T.; King, A. O. Org. Synth. 1993, Col. Vol. 8, 430. Pd(PPh3)4, LiCl t THF, reflux, 18 h -78°C, 30 min 1.75M tBuLi in pentane (52 mL, 91.0 mmol) THF (80 mL) 2-bromopyridine (7.13 g, 45.1 mmol) ZnCl2 (13.3 g, 97.4 mmol) 5-methylpyridyl triflate (8.95 g, 37.1 mmol) LiCl (3.18g, 75.2 mmol) Pd(PPh3)4 (1.75 g, 1.5 mmol) Smith, A. P.; Savage, S. A.; Love, J. C.; Fraser, C. L. Org. Synth. 2000, Vol. 78, 51. Zn(Cu) (1.71 g, 26 mmol) C6H6 (60 mL) HMPA (7.7 mL) 4-iodo-1-phenylbutan-1-one (5.48 g, 20 mmol) Pd(PPh3)4 40 °C, 1 h (E)-1-iodohexene (3.88 g, 18.5 mmol) Pd(PPh3)4 (711 mg, 0.62 mmol) C6H6 (30 mL) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Angew. Chem., Int. Ed. Eng. 1987, 26, 1157. iPr2Zn (1.1 equiv) Li(acac) (10 mol%) Pd(0) or Cu(I) (FG Ar)2Zn Et2O/NMP (1:10) 25 °C, 12 h high functional group compatibility ester, ketone, cyano, aldehyde, isothiocyanate Pd(dba)2/TFP Kniesel, F. F.; Dochnahl, M.; Knochel, Angew. Chem. Int. Ed. 2004, 43, 1017. decyne (22.6 mL, 125 mmol) hexane (80 mL) HAl(iBu)2 HAl(iBu) hexane, 50-60 °C, 6 h 2 (22.3 mL, 125 mmol) Pd(PPh3)4 Al(Bui)2 (Z)-hezenyl iodide (21.0 g, 100 mmol) (14.5-15.8 g) ZnCl2 (13.6 g, 100 mmol) Pd(PPh3)4 (1.15 g, 1 mmol) THF (100 mL) Negishi, E.; Takahashi, T.; Baba, S. Org. Synth. 1993, Coll. Vol.8, 295. Cp2ZrCl2 (7.01 g, 24 mmol) ClCH2CH2Cl (100 mL) 1-buten-3-yne (12.48 g, 120 mmol) in xylene Cp2ZrCl2 2M Me3Al (120 mL, 240 mmol) in toluene Me3Al ClCH2CH2Cl rt, 12 h Pd(PPh3)4 THF rt, 6 h 16.70 g (83%) geranyl chloride (17.25 g, 100 mmol) Pd(PPh3)4 (1.15 g, 1 mmol) THF (100 mL) Negishi, E.; Matsushita, H. Org. Synth. 1990, Coll. Vol.7, 245. Suzuki-Miyaura Coupling R = Ar, vinyl, alkynyl, alkyl R' = Ar, vinyl, ally, alkyl X = I, Br, Cl, OTs high functional group compatibility non-toxicity of boronic acids stability of boronic acids to heat, air, and moisture easy separation of inorganic boron from reaction mixture Reaction Mechansim oxidative transmetallation reductive addition elimination role of base ate complex The first paper cat. Pd(PPh3)4 NaOEt benzene/EtOH reflux, 2 h Miyaura, N.; Yamada K.; Suzuki, A. Tetradedron Lett. 1979, 3437. Alkyl-Alkyl coupling Pd(PPh3)4 K3PO4 dioxane 60 °C, 24 h Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691. Pd(OAc)2, PPh3 PrOH, H2O, reflux, 45 min 4-bromobenzaldehyde (50.0 g, 0.270 mol) benzeneboronic acid (34.6 g, 0.284 mol) 1-propanol (485 mL) Pd(OAc)2 (0.182 g, 0.811 mmol) PPh3 (0.638 g, 2.43 mmol) 1M Na2CO3 (162 mL, 0.324 mol) H2O (95.0 mL) Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, A. Org. Synth. 1997, Col. Vol. 75, 53. Pd(OAc)2, K2CO3 acetone, H2O reflux, 2 h o-tolylboronic acid (10.0 g, 73.6 mmol) 4-iodoanisole (16.8 g, 71.8 mmol) acetone (200 mL) K2CO3 (25.0 g, 0.180 mol) in H2O (200 mL) Pd(OAc)2 (3.30 mg, 0.02 mmol) in acetone (10 mL) Goodson, F. E.; Wallow, T. I.; Novak, B. M. Org. Synth. 1997, Vol. 75, 61. 2(PhCN)2, AsPh3 THF/H2O, 25°C, 1 h 2-iodo-2-cyclohexen-1-one (10.69 g, 70.4 mmol) 4-methoxyphenylboronic acid (16.72 g, 72.1 mmol) Ag2O (0.85 g, 2.8 mmol) AsPh3 (0.53 g, 1.4 mmol) PdCl2(PhCN)2 (0.53 g, 1.4 mmol) THF (200 mL) H2O (25 mL) Ruel, F. S.; Braun, M. P.; Johnson, C. R. Org. Synth. 1997, Vol. 75, 69. hexyne (4.9 g, 60 mmol) 60-70 °C catecholborane (6.7 mL, 60 mmol) 2(PPh3)2 reflux, 3 h (Z)-β-bromostyrene (8.4 g, 46 mmol) 2M NaOEt in EtOH (50 mL) PdCl2(PPh3)2 (0.28 g, 0.4 mmol) Miyaura, N.; Suzuki, A. Org. Synth. 1993, Col. Vol. 8, 532. Pd2(dba)3 aq. KOH, THF -78 °C → rt Yasuda, N.; Xavier, L.; Rieger, D. L.; Li, Y.; DeDamp, A. E.; Dolling, U. H. Tetrahedron Lett. 1993, 34, 3211. TESO H H Me Pd(dba)2 THF, H2O, Et3N 30 °C, 2-3 h Yasuda, N.; Huffman, M. A. et al J. Org. Chem. 1998, 63, 5438. 2.00 kg (70%) Palytoxin caboxylic acid Kishi, Y. et.al. J. Am. Chem. Soc. 1989, 111, 7525. Recent Advances in Cross-Coupling Reactions Design of Ligand bulky and electron-rich phosphine N-heterocyclic carbene For a review on Pd-catalyzed coupling reactions of aryl chlorides: Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176. For a review on monoligated Pd species: Christmann, U.; Vilar, R. Angew. Chem. Int. Ed. 2005, 44, 366. Pd2(dba)3/PBut3 THF, KF rt intermolecular competition experiment : kAr-Cl / kAr-OTf >20 Pd(OAc)2/PCy3 THF, KF rt Pd2(dba)3/PBut3 Littke, A. F.; Dai, C.; Fu, G.C. J. Am. Chem. Soc. 2000, 12 Pd(OAc)2 K3PO4 toluene 90 °C, 12 min increases steric bulk oxygen lone pair may stabilize Pd complex prevents cyclometalation increases electron density in biaryl backbone Pd(OAc)2 K3PO4 toluene 110 °, 18 h Walker, S. D.; Barder, T. E.; Martineli, J. R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2004, 43, 1871. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. iPr Pri t Pri t THF, K3PO4 80 °C, 3 h Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. Ni(cod)2/PCy3 THF, K3PO4 rt, 8 h Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058. NiCl2(dppe)/PPh3 toluene, K3PO4 80 °C, 14 h Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, J. Org. Chem. 2004, 69, 3447. Gstottmayr, C. W. K.; Bohm, V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann, W. A. Angew. Chem. Int. Ed. 2002, 41, 1363. Pd(OAc)2 K3PO4 THF/toluene 110 °C, 16 h Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc. 2004, 126, 15195. NaOBut iPrOH rt, 75 min Ar = 2,6-(iPr)2C6H3 i [IPrPd(0)] Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem. Soc. 2003, 125, 16194.35 Migita-Kosugi-Stille Coupling R = Ar, vinyl, ally, alkyl R' = Ar, vinyl, allyl X = I, Br, Cl, OTf R' = alkynyl > vinyl > aryl > benzyl, allyl > acetonyl > CH3 SE2 (cyclic) SE2 (open) Espinet, P. et. al. J. Am. Chem. Soc. 2000, 122, 11771. Angew. Chem. Int. Ed. Engl. 2004, 43, 4704. The first papers + Bu3SnBr benzene 100 °C, 20 h Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 301. Pd(PPh3)4 + Me3SnCl benzene 140 °C, 5 h Kosugi, M.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 1423. 2Pd(PPh3)2Cl + Me3SnCl HMPA, 65 °C, 10 min Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. Removal of R3Sn-X Pd(PPh3)4 0.23 g (0.20 mmol) toluene (20 mL) reflux, 4 h (10.1 mmol) (11.0 mmol) pyridine (4.4 mL), 1.2 N pyridinium fluoride solution (9.3 mL) stirred for 16 h at rt extraction by Et2O McKean, D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J. K. J. Org. Chem. 1987, 52, 422. PdCl2(PPh3), LiCl DMF, 100-105 °C, 2.5 h DMF (300 mL) 4-nitrophenyl trifluoromethanesulfonate (15.0 g, 55.4 mmol) tributyl(4-methoxyphenyl)stannane (27.8 g, 70.0 mmol) LiCl (7.5 g) PdCl2(PPh3)2 (1.6 g) vaccum-filterd through the pad of Celite 521, washed with EtOAc removal of EtOAc, the brown liquid is slowly poured into H2O (1.5 L) and collect the preciptate after standing for 8 h the solid is dissolved in CH3CN (500 mL), washed with hexane (3 x 300 mL), 24 g of crude product as a brown solid column chromatography (Rf = 0.26, hexane:EtOAc = 95:5), 6.9 g (a yellow solid) dissolved in EtOAc and stirred over saturated, aqueous KF for 24 h recrystalization from EtOH, 6.1 g (yellow needles) Stille, J. K.; Echavarren, A. M.; Williams, R. M. Org. Synth. 1998, Col. Vol. 9, 553. Pd/C, Cul, AsPh NMP, 95°C, 24 h 4-iodoacetophenone (10.0 g, 40. 6 mmol) CuI (770 mg, 4.1 mmol) 1-methyl-pyrroldinone (150 mL) 2-(tributylstannyl)thiophene (14.1 mL, 44.7 mmol) 10% Pd/C (215 mg, 0.2 mmol) EtOAc (300 mL), saturated aqueous NaF (200 mL), stirred vigorously for 30 min the green-yellow hetergeneous mixture is passed through a sand pad Liebeskind, L. S.; Pena-Cabrera, E. Org. Synth. 1999, Vol. 77, 135. (-)-Macrolactine A Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935. (-)-Macrolactine A Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935. Sanglifehrin A (SFA) Nicolau, K. C. et. al. J. Am. Chem. Soc. 2000, 122, 3830. Hiyama Coupling Y = Cl, F, H, OMe, cyclobutyl, thienyl, OH . R = Ar, vinyl, alkynyl, allyl R' = Ar, vinyl, allyl, alkynyl X = I, Br, OTf [(η3-C3H5)PdCl]2 (Et 2N)3S+Me3SiF2 (TASF) HMPA, 50 °C, 2 h Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. Alkyl-Alkyl Coupling undesired
β-hydride elimination Alkyl-Alkyl Coupling Pd(OAc)2/PCy3 K THF, rt, 16 h Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099. Pd2(dba)3/PCy3 CsOH.H2O dioxane, 90 oC Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 1945. Pd2(dba)3/P(cC5H9)3 THF/NMP, NMI 80 °C, 14 h Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527. Pd(acac)2 55 °C, 24 h Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 82. PMetBu2 Si(OMe)3 THF, r.t. Lee, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616. [(π-ally)PdCl]2 PCy(pyrrolidinyl)2 Tang, H.; Menzel, K.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 5079. sBu-Pybox Bus Bus Ni(cod)2 DMA, r.t., 20 h Zhou, J.; Fu. G. C. J. Am. Chem. Soc. 2003, 125, 14726. Ni(cod)2 sbutanol, KOBut 60 oC, 5 h Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340. Si: Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788. Sn: Powell, D. A.; Maki, T.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 510.
IMMUNIZATION HISTORY Circle semester of FIRST Enrollment and specify year: Fall (year)_______ Spring (year)_______ Summer (year)_______ ¾ Exemption Note: Individuals born before 1957 are exempt from further documentation and need only complete the above section of the form, as well as the Medical History form. However, completion of the sections below may be useful in providing care.
Commission des courses Commission de l’Ontario July 12, 2007 Notice to the Industry Medication Control Task Force asks: “What’s inside your vehicle? Know the rules and your responsibility.” Recent seizures of medications at Ontario tracks indicate some licensees are unaware of medication control rules and their responsibilities under the Rules of Rac