经典合成反应标准操作—钯催化的插羰反应 药明康德新药开发有限公司
Ph-I+CO+Et2NHPdCl2(MePh2P)2100oC, 95%PhCOCONEt2+2-6386 : 14PhCONEt2
HaON.1I+NHAcCO+Et2NHPdCl2(MePh2P)2COCONEt2NHAcN2-64OONH2-65MeCOe2.M93%
Cl+CO+Et2NHCr(CO)32-66PdCl2(MePh2P)2PhMe, 100oC51.7F.6%COCONEt2+CONEt2
α-酮酯2-67能够通过碘苯和大位阻二级胺的二次羰基化反应形成，但是这个反应的选择性非常低。对于二次插羰反应来说，烯基溴化物比芳基卤化物的反应活性更低。α-酮酰胺能够通过芳基和烯基溴化物的二次羰基化反应得到，而α-酮酯是不能够通过他们在相应醇中的羰基化反应得到。
PhI+CO+sec-BuOHPdCl2(PCy3)2Et3N, 91% conv.PhCOCO2Bu+2-6764 : 36PhCO2Bu
3. 插羰反应制备羧酸实验操作
NHCOMeBr+CO+H2OPdCl2(Ph3P)2(0.1 wt%), Ph3PBu3N, 120oC, 3 atm., 85%2-11CO2HNHCOMe
A 200-mL glass pressure bottle equipped with two valves and a pressure gauge was charged
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经典合成反应标准操作—钯催化的插羰反应 药明康德新药开发有限公司
with 8 mg of Pd(PPh3)(Cl)2, 40 mg of triphenylphosphme, and 2.0 g of 2-(acetylamino)-5-(1-methylethyl) phenylbromide. The bottle was then evacuated, refilled with argon three times, and charged further with 2.2 mL of deoxygenated tri-n-butylamine and 0.5 mL of deoxygenated water. The apparatus was then pressurized with 3 atm of carbon monoxide, sealed, heated 18 h with stirring at a bath temperature of 120-125 °C, and then allowed to cool. The final pressure was 1.1 atm at 23 °C. Hydrochloric acid (2.4 M) was added to the viscous orange-brown reaction mixture in four 2-mL portions with constant agitation. The crude yield of 2-11 which separated (95% pure by NMR) was 1.63 g (94%). Recrystallization from ethanol-water gave 1.35 g (78%) of a light yellow solid.
4. 插羰反应制备羧酸酯实验操作
OMeI+MeOSPh2-12-2CO+OHOOIPdCl2, K2CO3, PhH120oC, 12 atm., 70%OMeOOMeOISPh2-3OOMeOOMeOOO2-4
A mixture of the iodobenzene 2-1 (0.46 mmol), w-indo alcohol 2-2 (0.83 mmol), K2CO3 (1.38 mmol), and PdCl2 (0.04 mmol) in dry benzene (6 mL) was heated at 120℃ with stirring in an autoclave under carbon monoxide (12 atm) for 16 h. The reaction mixture was filtered and the easter 3 was isolated by column chromatography in 70% yield.
FONNOONNNFBrFFCO, Pd(OAc)2, dppfEt3N, EtOH, 90oCOONFFONNNONFFFOFFF
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经典合成反应标准操作—钯催化的插羰反应 药明康德新药开发有限公司
（2R,4S）
-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-bromopyrimidin-2-yl)}-amino-2-ethyl-6-methoxy-3,4-dihyfro-2H-[1,5]naphthridine-1-carboxylic acid ethyl ester (18 g) is dissolved in N,N-dimethylformamide (60 mL), and thereto are added palladium acetate (611 mg), 1,1’-bis(diphenylphosphino)-ferrocene (3.02 g), ethane (31.7 mL) and triethylamine (37.9 mL). The mixture is purged by carbon monoxide at room temperature for 10 minutes, then is heated at 90 oC and stirred overnight under 40 psi of carbon monoxide. The reaction solution is cooled to room temperature, and thereto is added saturated brine and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography
(silica
gel;
hexane:ethyl
acetate
=
8:1)
to
give
(2R.4S)-4-{[3,5-bis(triflouromethyl)benzyl]-(5-ethoxycarbonylpyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (12.4 g).
OCO, Pd(PPh3)2Cl2NHINONH2Et3N, EtOH, 80oCONONHONH2O
To a stirred solution of 3-(aminocarbonyl)-4-{[3-(methyloxay)penyl]amino}-6-iodoquinoline (1
g)
in
ethanol
(50
mL)
was
added
triethylamine
(0.63
mL)
and
dichlorobis(triphenylphosphine)palladium (II) (0.08 g). The flask was evacuated and refilled with nitrogen three times and then evacuated and refilled with carbon monoxide two times. The mixture was heated at 80oC under an atmosphere of carbon monoxide for 16 h. the mixture was cooled to 20oC and the solvent removed in vacuo. Purification by column chromatography on silica gel, eluting with 9:1 ethyl acetate: cyclohexane, gave the title compound as a pale yellow solid (0.8 g).
NNNNNCO, Pd(dppf)Cl2NaOAc, Methanol, 90oCNONONBr
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经典合成反应标准操作—钯催化的插羰反应 药明康德新药开发有限公司
6-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-B]pyrazol-3-yl]-quinoline (22.7 g, 45 mmol) is added to a mixture of sodium acetate (19 g, 230 mmol) and the palladium catalyst [1,1’-bis (diphenylphosphimo) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (850 mg, 1.04 mmol) in 130 mL methanol. Place the mixture under 50 psi carbon monoxide atmosphere and stir while warming to 90oC over 1 hour and with constant charging with additional carbon monoxide. Allow the mixture to cool over 8 hours, recharge again with carbon monoxide and heat to 90oC. The pressure may rise to about 75 psi. The reaction is complete in about an hour when the pressure is stable and TLC (1:1 toluene/acetaone) shows no remaining bromide. Partition the mixture between methylene chloride (600 mL) and water (1 L). Extract the aqueous portion with an additional portion of methylene chloride (400 mL). Filter the organic solution through a 300 mL silica plug and wash with 500 mL methylene chloride, 1200 mL ethyl acetate and 1500 mL acetone. Discard the acetone portion. Combine appropriate fractions and concentrate to yield 18.8 g (87.4%) of the desired subtitled intermediate as a pink powder.
ClHNOOHNCO, Pd(OAc)2, dpppIEt3N, CH3OH, DMFOOHOClHNNO
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (30.0 g), Et3N (19.1 mL), MeOH (110.6 mL), Pd(OAc)2 (431 mg), and 1,3-bis(diphenylphosphino)propane (791.9 mg) in 375 mL anhydrous DMF is stirred at room temperature until everything dissolves. CO (g) is slowly bubbled through for 2 days and the reaction is maintained at 70oC. The reaction is cooled to room temperature. The product is precipitated by adding 160 mL 1 N HCl into the reaction mixture. An orange solid precipitates is collected. The solid is triturated with EtOAc, filtered, and washed with CH2Cl2 to afford 23.8 g (93 % yield) of the title compound as an off-white solid.
NBocICO, Pd(PPh3)4, Et3NMeOH,CH3CN, 50Psi, 50oCCO2MeNBoc
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经典合成反应标准操作—钯催化的插羰反应 药明康德新药开发有限公司
A mixture of 2-(3-iodo-2-methyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (26 g, 0.067 mol), Pd(PPh3)4 (2.4 g, 0.002 mol), Et3N (14.3 mL, 0.1 mol), 110 mL of acetonitrile and 50 mL of methanol was stirred under 50 Psi of carbon monoxide at 50 ?C for 8 h. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 250 mL of ethyl acetate, then washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product, which was purified by column chromatography (petroleum ether: ethyl acetate 30:1 to 10:1) to afford the title product (20 g, 93%) as a gray solid.
OONCO, PdCl2, BINAPEt3N, CH3OH, CH3CNNBrCO2CH3
PdCl2 (18.4 g, 0.104 mol) and BINAP (27.6 g, 0.044 mol) were added to a solution of 5-(2-bromo-phenyl)-oxazole (331.0 g, 0.44 mol) and Et3N (242.2 g, 2.22 mol) in 6 L CH3OH/CH3CN (2:1) in steel bomb. The mixture was stirred at 100 ?C under CO (1 atm) for 48 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography (EtOAc/petroleum = 1:10) to give 2-oxazol-5-yl-benzoic acid methyl ester (210.0 g, 70 %) as brown oil.
5. 插羰反应制备酰胺实验操作
OTsOEtONBrONHOR+COPd(Ph3P)4, Bu3N110oC, 69%TsOEtOONNO2-52OOR2-52-A
A mixture of 2-52-A (6.3 mg, 11 rmnol), Pd(PPh3)4 (1.27 g, 1.1 mmol) and n-Bu3N (4.47 g, 24.2 mmol) in toluene (20 mL) was heated under carbon monoxide(10 atm) at 1l0oC for 24 h. Ethyl acetate was added to the reaction mixture and the organic layer was washed with 5% HCl, 5% Na2S2O3, sat. NaHCO3 and then brine, dried over Na2SO4 and evaporated. The
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