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CAS No. : | 55477-80-0 | MDL No. : | MFCD03840371 |
Formula : | C9H15NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MGBHVVGQPZDMHA-UHFFFAOYSA-N |
M.W : | 201.22 | Pubchem ID : | 10932500 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.56 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.7 |
TPSA : | 64.63 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.48 cm/s |
Log Po/w (iLOGP) : | 2.59 |
Log Po/w (XLOGP3) : | 1.48 |
Log Po/w (WLOGP) : | 1.2 |
Log Po/w (MLOGP) : | 0.73 |
Log Po/w (SILICOS-IT) : | 0.4 |
Consensus Log Po/w : | 1.28 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.62 |
Solubility : | 4.78 mg/ml ; 0.0238 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.44 |
Solubility : | 0.724 mg/ml ; 0.0036 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.36 |
Solubility : | 8.8 mg/ml ; 0.0438 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.61 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | With silver(l) oxide In N,N-dimethyl-formamide Ambient temperature; | |
75% | Stage #1: methyl 2-[(tert-butoxycarbonyl)amino]acrylate; methyl iodide With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: methyl iodide In tetrahydrofuran at 0 - 20℃; for 18h; | |
With potassium carbonate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 4 A molecular sieve; toluene-4-sulfonic acid In Trichloroethylene for 8h; Heating; | |
68% | With toluene-4-sulfonic acid; hydroquinone In benzene for 3h; Heating; | |
47% | With trichlorophosphate In benzene at 70℃; for 0.25h; |
With toluene-4-sulfonic acid; 4-methoxy-phenol In toluene for 18h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrabutyl-ammonium chloride; sodium formate; sodium hydrogencarbonate ball-milling; | |
71% | With tetrabutyl-ammonium chloride; sodium hydrogencarbonate In N,N-dimethyl-formamide at 85℃; for 17h; | |
50% | With N-(4-carbethoxyphenyl)urea; palladium diacetate; potassium carbonate In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 100℃; for 16h; | 3 14d_proc_B General procedure: An appropriate alkene (1 equiv) was added to an NMP solution (enough solvent to attain an initial concentration ofalkene equal to ca. 0.1M) of aryl iodide (2 equiv), Pd(OAc)2 (1 mol %,delivered as a standard THF solution containing 1 mg/mL of compound),N-(4-carbethoxyphenyl)urea (CEPU, 2 mol %), and K2CO3(2 equiv) in a thick-walled glass reaction tube equipped witha magnetic stirring bar and fitted with a threaded Teflon cap. Thereaction tubewas sealed and immersed in an oil bath maintained at 100 C and stirring was started. After 16 h, the resulting black solution was cooled to rt, diluted with ethyl acetate, and washedsequentially with water and brine solution. The organic phase wasseparated, dried (Na2SO4), and concentrated under reduced pressure(rotary evaporator), and the residue was purified by flashcolumn chromatography. Procedure B using iodobenzene (36 mL, 0.32 mmol), K2CO3(44 mg, 0.32 mmol), Pd(OAc)2 (0.4 mL of THF solution containing1 mg/mL Pd(OAc)2, equivalent to 0.4 mg Pd(OAc)2), CEPU (0.9 mg),and methyl 2-((tert-butoxy- carbonyl)amino)acrylate (32 mg,0.16 mmol). Chromatography using 20% ether in hexanes gave 14das a colorless oil (22 mg, 50%). 1H: 7.54 (d, J6.8, 2H), 7.39e7.31 (m,3H), 7.25 (s, 1H), 6.18 (br s, 1H), 3.86 (s, 3H), 1.40 (s, 9H). 13C: 166.1,159.6, 134.12, 130.0, 129.7, 129.2, 128.5, 124.6, 81.0, 52.6, 28.1. IR:3323, 2979, 1705, 1644, 1483, 1442, 1363, 1257, 1157, 1048, 1026.APCI-MS: 276.2 (MH, 100%), 178.4 (MBoc, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris(triphenylphosphine)rhodium(I) carbonyl hydride; 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane; hydrogen In benzene at 80℃; for 70h; Yields of byproduct given. Title compound not separated from byproducts; | ||
86 % ee | With dicarbonylacetylacetonato rhodium (I); hydrogen; C77H77NO4P2 In toluene at 80℃; for 24h; Overall yield = 78 percent; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; copper(l) chloride; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; at 20℃; for 72h; | D. 2-tert-Butoxycarbonylaminoacrylic acid methyl ester. To a suspension of N-Boc-serine methyl ester (Cpd 15e, 2.19 g, 10 mmol) and EDC (2.01 g, 10.5 mmol) in DCM (70 mL) was added CuCl (1.04 g, 10.5 mmol). The reaction mixture was stirred at rt for 72 h. Upon removal of the solvent, the residue was diluted with EtOAc, washed sequentially with water and brine and then dried over MgSO4. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane ~1:4) to give Compound 15e (1.90 g, 94%) as a colorless oil. 1H NMR (300 MHz, CDCl3): delta 1.49 (9H, s), 3.83 (3H, s), 5.73 (1H, d, J=1.5 Hz), 6.16 (1H, s), 7.02 (1H, s). |
94% | With dmap; 1,8-diazabicyclo[5.4.0]undec-7-ene; p-toluenesulfonyl chloride; In acetonitrile; at 25℃; for 1h;Molecular sieve; | General procedure: 4-Toluenesulfonic chloride (TsCl) (2.0 eq) and 4-dimethylaminopyridine (DMAP) (0.2 eq) were added subsequently to the solution of N-Boc-DL-Ser-O-Me (1.0 eq) in acetonitrile (0.2 M, containing MS (4A) (40 mg/mmol)) at r.t., 1,8-diazobicyclo[5,4,0]undec-7-ene (DBU) (5.0 eq) was added dropwisely to the solution, whose color darkened during the addition, the reaction was monitored by thin layer chromatography (TLC). When starting material was consumed, the mixture was diluted with ethyl acetate, washed with saturated citric acid, followed by water, then by brine. The organic phase was dried over anhydrous sodium sulfate. Crude product was obtained after concentration, which was purified through flash chromatography. |
93% | With methanesulfonyl chloride; triethylamine; In dichloromethane; at -50 - 20℃; for 4.75h; | To a solution of methyl 2-[(tert-butoxyearbonyl) aminol-3-hydroxypropanoate (7.19 g) in CH2C12 (15 ml) are added 3.04 ml of mesyl chloride. NEt3 (13.64 ml) is then added at-50 C, under Argon. After 45 minutes at-50 C, the reaction warmed up to room temperature and stirred for 4 hours. The solution is poured into ice and the aqueous phase is extracted with CH2C12 (3 x 10 ml). The organic phases are dried over MgSO4 and evaporated to dryness. The residue is purified by silica gel chromatography using AcOEt/cyclohexane 20/80 as eluent to give 16 as oil. Yield: 93 %. MS (MH+) : 202. |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; copper(l) chloride; In dichloromethane; at 20℃; for 72h; | To a suspension of N-Boc-serine methyl ester (Compound 1e, 2.19 g, 10 mmol) and EDCl (2.01 g, 10.5 mmol) in DCM (70 mL) was added CuCl (1.04 g, 10.5 mmol). The reaction mixture was stirred at room temperature for 72 h. Upon removal of the solvent, the residue was diluted with EtOAc, washed sequentially with water and brine and then dried over MgSO4. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane1:4) to yield compound 1f as a colorless oil. 1H NMR (300 MHz, CDCl3): delta 1.49 (9H, s), 3.83 (3H, s), 5.73 (1H, d, J=1.5 Hz), 6.16 (1H, s), 7.02 (1 H, s). | |
With methanesulfonyl chloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.5h;Inert atmosphere; | Synthesis of intermediate CI. CI Methanesulfonyl chloride (2.29 mL, 29.649 mmol, 1.3 eq) was added to a mixture of <strong>[69942-12-7]methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate</strong> (5 g, 22.807 mmol, 1 eq) in N,N- dimethylformamide (57 mL) at 0C under Argon, followed by the addition of triethylamine (7.95 ml_, 57.016 mmol, 2.5 eq) dropwise over a period of 30 minutes. When the addition was complete, the cooling bath was removed and the yellow reaction was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ice-cold water and diethyl ether. The layers were separated, and the organic phase was washed with a saturated aqueous solution of NH4CI. The organic phase was dried over Na2S04, filtered and evaporated under vacuum to afford the desired intermediate as a pale yellow solid. The intermediate was used in the next step without further purification. HPLC-MS (method 4): Rt = 4.12, [M+H-Boc]+ 102.2. | |
With methanesulfonyl chloride; triethylamine; In dichloromethane; at -50 - 20℃;Inert atmosphere; | To a solution of <strong>[69942-12-7]methyl 2-(tert-butoxycarbonylamino)-3-hydroxy-propanoate</strong> (10.02 g, 45.6 mmol) in DOM (100 mL) was added MsCl (6.27 g, 54.73 mmol) at -50 00 under N2 followed by TEA (13.85 g, 136.83 mmol). The reaction mixture was stirred at the same temperature for 45 mm, and then left at room temperature overnight. The mixture was poured into water (50 mL) and the resulting mixturewas extracted with DOM (3x50 mL). The combined organic phases were dried over anhydrous Mg504, and concentrated to afford crude 19.1 (9.02 g, 98% yield), which was used in the next step without further purification. 1H NMR (400 MHz, 0D013): 67.02 (m, 1H), 6.16 (m, 1H), 5.73 (d, J= 1.6 Hz, 1H), 3.83 (s, 3H), 1 .49 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With methanesulfonyl chloride; triethylamine In dichloromethane at 20℃; for 3h; Inert atmosphere; | |
95% | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; copper chloride (I) In chloroform for 5h; Ambient temperature; | |
88% | With tris-(2-chloro-ethyl)-amine; triphenylphosphine; diethylazodicarboxylate In toluene at 0℃; for 3h; |
86% | With methanesulfonyl chloride; triethylamine | |
84% | With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 3h; | |
83% | With triethylamine; 1,1'-carbonyldiimidazole In tetrahydrofuran for 6h; Ambient temperature; | |
81% | With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; copper chloride (I) In chloroform for 32h; Ambient temperature; | |
72% | With N,N-phenylbistrifluoromethane-sulfonimide; TEA In dichloromethane for 17h; Ambient temperature; | |
63% | With triphenylphosphine; diethylazodicarboxylate; phenol In toluene | |
With Chlorodifluoromethane; hexaethyltriamido-N-methylimidophosphate In dichloromethane at -70℃; | ||
With copper chloride (I); diisopropyl-carbodiimide In dichloromethane | ||
With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 2h; | ||
Multi-step reaction with 2 steps 1: 68 percent 2: 1.) CuI / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 3 h | ||
Multi-step reaction with 2 steps 1: 68 percent 2: 90 percent / diethylcuprate (Et2CuLi) / diethyl ether / 3 h / -60 °C | ||
Multi-step reaction with 3 steps 1: 68 percent 2: 76 percent / I(1-) / acetone 3: 1.) CuI / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 5 h | ||
Multi-step reaction with 3 steps 1: 68 percent 2: 76 percent / I(1-) / acetone 3: 1.) CuI / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 3 h | ||
Multi-step reaction with 3 steps 1: 68 percent 2: 76 percent / I(1-) / acetone 3: 1.) CuI, butyl sulfide / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 3 h | ||
Multi-step reaction with 3 steps 1: 68 percent 2: 76 percent / I(1-) / acetone 3: 1.) CuI, butyl sulfide / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 18 h | ||
Multi-step reaction with 3 steps 1: 68 percent 2: 76 percent / I(1-) / acetone 3: 1.) CuI / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -10 deg C, 5 h | ||
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 0 °C 2: 87 percent / Et3N / tetrahydrofuran | ||
Multi-step reaction with 5 steps 1: pyridine / 4 °C 2: CsCO3 / dimethylformamide 3: NaOMe / methanol 4: triethylbenzylammonium chloride, KOH 5: 1. NaH 2. NaI / 1. dimethoxyethane, -10 deg C -> room temp. | ||
With methanesulfonyl chloride; triethylamine In dichloromethane at -15 - -5℃; for 0.5h; | ||
Multi-step reaction with 2 steps 1.1: pyridine / dichloromethane / 0.25 h / -50 °C 1.2: 20 h / -50 - 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 65 °C | ||
Multi-step reaction with 2 steps 1: dmap / acetonitrile / 8 h / 22 °C / Inert atmosphere 2: 1,1,3,3-tetramethylguanidine / acetonitrile / 8 h / 22 °C / Inert atmosphere; Darkness | ||
With N-ethyl-N,N-diisopropylamine In acetonitrile at 45℃; for 2h; | A716.1 Synthesis of (3S)-1-acryloyl-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-21,22,23,26,61,62,63,64,65,66-decahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(5,1)-pyridinacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N-methylpyrrolidine-3-carboxamide Step 1. To a solution of methyl (tert-butoxycarbonyl)-L-serinate (10 g, 45 mmol) in anhydrous MeCN (150 mL), was added DIPEA (17 g, 137 mmol). The reaction mixture was stirred at 45° C. for 2 h to give methyl 2-((tert-butoxycarbonyl)amino)acrylate in solution. LCMS (ESI): m/z [M+Na] calc'd for C9H15NO4 201.1; found 224.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 73% 2: 9% | With tris-(2-chloro-ethyl)-amine; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; benzene 1.) -78 deg C, 1 h, 2.) RT, 16 h; | |
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0.5 h / 0 °C 2: sodium azide / N,N-dimethyl-formamide / 0.5 h / 50 °C | ||
Multi-step reaction with 2 steps 1: trimethylamine hydrochloride; triethylamine; dmap / dichloromethane / 2 h / 0 °C 2: sodium azide / N,N-dimethyl-formamide / 0.17 h / 70 °C |
Multi-step reaction with 2 steps 1: triphenylphosphine; 1H-imidazole; iodine / dichloromethane / 0 - 20 °C 2: sodium azide / N,N-dimethyl-formamide; chloroform / 3 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With lithium diethylcuprate In diethyl ether at -60℃; for 3h; | |
With thiophenol; triethylamine | ||
Multi-step reaction with 3 steps 1.1: NaBr 2.1: lithium selenolate / diethyl ether / 0 °C 2.2: 49 percent / diethyl ether / 20 h / 20 °C 3.1: H2O2 |
Multi-step reaction with 3 steps 1: NaBr 2: LiBEt3H 3: H2O2 | ||
Multi-step reaction with 2 steps 1: 76 percent / I(1-) / acetone 2: 1.) CuI / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 5 h | ||
Multi-step reaction with 2 steps 1: 76 percent / I(1-) / acetone 2: 1.) CuI / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 3 h | ||
Multi-step reaction with 2 steps 1: 76 percent / I(1-) / acetone 2: 1.) CuI, butyl sulfide / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 3 h | ||
Multi-step reaction with 2 steps 1: 76 percent / I(1-) / acetone 2: 1.) CuI, butyl sulfide / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -60 deg C, 18 h | ||
Multi-step reaction with 2 steps 1: 76 percent / I(1-) / acetone 2: 1.) CuI / 1.) Et2O, -60 deg C, 30 min; 2.) Et2O, -10 deg C, 5 h | ||
Multi-step reaction with 2 steps 1: NaI 2: 70 percent / diethyl ether / 5 h / -10 °C | ||
Multi-step reaction with 2 steps 1: NaI 2: 70 percent / diethyl ether / 5 h / -10 °C | ||
Multi-step reaction with 2 steps 1: NaI 2: 63 percent / diethyl ether / 5 h / -60 °C | ||
Multi-step reaction with 2 steps 1: NaI 2: 48 percent / diethyl ether / 3 h / -60 °C | ||
Multi-step reaction with 2 steps 1: NaI 2: 42 percent / diethyl ether / 3 h / -60 °C | ||
Multi-step reaction with 2 steps 1: NaI 2: 10 percent / diethyl ether / 3 h / -60 °C | ||
Multi-step reaction with 2 steps 1: NaI 2: 9 percent / diethyl ether / 3 h / -60 °C | ||
Multi-step reaction with 4 steps 1: CsCO3 / dimethylformamide 2: NaOMe / methanol 3: triethylbenzylammonium chloride, KOH 4: 1. NaH 2. NaI / 1. dimethoxyethane, -10 deg C -> room temp. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With palladium diacetate; chloranil; sodium hydrogencarbonate In 1,2-dichloro-ethane at 83℃; for 8h; | |
76% | With palladium diacetate; chloranil; sodium hydrogencarbonate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap In acetonitrile at 20℃; for 16h; | |
85% | With dmap In acetonitrile at 40℃; for 4h; | |
82% | With dmap In acetonitrile at 20℃; for 9.5h; |
65% | With dmap In acetonitrile at 0℃; for 6h; | A716.2 Step 2. To a solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (12 g, 60 mmol) in anhydrous MeCN (150 mL) at 0° C., was added 4-DMAP (13 g, 90 mmol) and (Boc)2O (26 g, 120 mmol). The reaction was stirred for 6 h, then quenched with H2O (100 mL) and extracted with DCM (200 mL*3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-(bis(tert-butoxycarbonyl)amino)acrylate (12.5 g, 65% yield) as solid. LCMS (ESI): m/z [M+Na] calc'd for C14H23NO6 301.2; found 324.1. |
With dmap In acetonitrile at 20℃; for 16h; | Synthesis of intermediate CM. Synthesis of intermediate CM. CM Di-tert-butyl dicarbonate (4.83 g, 22.1 15 mmol, 1 eq) was added to a mixture of intermediate CI (4.45 g, 22.115 mmol 1 eq) in acetonitrile (44 ml_) at room temperature, followed by the addition of 4-dimethylaminopyridine (540 mg, 4.423 mmol, 0.2 eq). The reaction mixture was stirred at room temperature for 16 hours. After removal of volatiles in vacuo, the residue was diluted with AcOEt. The organic layer was washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of NaCI, dried over Na2S04, filtered, and concentrated in vacuo to give the desired intermediate as a beige solid. The intermediate was used in the next step without further purification. HPLC-MS (method 4): Rt = 4.44, [M+H-2Boc]+ 102.2. 1 H NMR (300 MHz, DMSO) δ 6.28 (d, J = 0.8 Hz, 1 H), 5.86 (d, J = 0.8 Hz, 1 H), 3.74 (s, 3H), 1.40 (s, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With tetrabutyl-ammonium chloride; sodium hydrogencarbonate In N,N-dimethyl-formamide at 80℃; for 8h; | |
43% | With tetrabutyl-ammonium chloride; sodium hydrogencarbonate In N,N-dimethyl-formamide at 60℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tetrabutyl-ammonium chloride; sodium hydrogencarbonate In N,N-dimethyl-formamide at 85℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With N-Bromosuccinimide In dichloromethane at 20℃; Stage #2: With erythritol tetranitrate In dichloromethane at 20℃; for 3h; Further stages.; | |
Stage #1: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With N-Bromosuccinimide In dichloromethane at 20℃; for 1h; Stage #2: With triethylamine In dichloromethane at 0 - 6℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 3h; | |
80% | With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tert.-butylhydroperoxide In chloroform-d1 at 20℃; for 50h; | |
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / methanol / 0.08 h / 0 °C / Inert atmosphere 2: tetrahydrofuran; methanol / 0 - 27 °C / Inert atmosphere 3: dihydrogen peroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tetrabutyl-ammonium chloride; sodium formate; sodium hydrogencarbonate ball-milling; | |
68% | With N-(4-carbethoxyphenyl)urea; palladium diacetate; potassium carbonate In tetrahydrofuran; 1-methyl-pyrrolidin-2-one at 100℃; for 16h; | 3 14a_proc_B General procedure: An appropriate alkene (1 equiv) was added to an NMP solution (enough solvent to attain an initial concentration ofalkene equal to ca. 0.1M) of aryl iodide (2 equiv), Pd(OAc)2 (1 mol %,delivered as a standard THF solution containing 1 mg/mL of compound),N-(4-carbethoxyphenyl)urea (CEPU, 2 mol %), and K2CO3(2 equiv) in a thick-walled glass reaction tube equipped witha magnetic stirring bar and fitted with a threaded Teflon cap. Thereaction tubewas sealed and immersed in an oil bath maintained at 100 C and stirring was started. After 16 h, the resulting black solution was cooled to rt, diluted with ethyl acetate, and washedsequentially with water and brine solution. The organic phase wasseparated, dried (Na2SO4), and concentrated under reduced pressure(rotary evaporator), and the residue was purified by flashcolumn chromatography. Procedure B using 4-iodoanisole (300 mg, 1.29 mmol), K2CO3(177 mg, 1.29 mmol), Pd(OAc)2 (1.4 mL of THF solution containing1 mg/mL Pd(OAc)2, equivalent to 1.4 mg Pd(OAc)2), CEPU (2.6 mg),and methyl 2-((tert-butoxycarbonyl)amino)acrylate (129 mg,0.63 mmol). Chromatography using 40% ether in hexanes gave 14aas a pale yellow oil, which crystallized upon standing (132 mg,68%). Mp 103e106 C (lit.51 107e108 C). 1H (acetone-d6): 7.67 (d,J8.8; 2H), 7.47 (br s, 1H), 7.23 (s, 1H), 6.97 (d, J8.8, 2H), 3.83 (s,3H), 3.76 (s, 3H), 1.42 (s, 9H). 13C (acetone-d6): 166.1, 160.6, 153.7,131.8, 126.6, 124.1, 113.9, 79.1, 54.8, 51.5, 27.6. IR: 3205, 3098, 2974,2930, 1698, 1637, 1603, 1514, 1443, 1356, 1255, 1163, 1054, 1029. ESIMS:330.3 (MNa, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: 4-bromo-2-iodoaniline; methyl 2-[(tert-butoxycarbonyl)amino]acrylate With tetrabutyl-ammonium chloride; sodium formate; sodium hydrogencarbonate for 1h; Stage #2: With acetic anhydride for 12h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrabutyl-ammonium chloride; triethylamine In tetrahydrofuran at 70℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrabutyl ammonium fluoride In tetrahydrofuran at 28℃; for 0.166667h; | |
80% | With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 1h; | |
3 g | With potassium carbonate In N,N-dimethyl-formamide at 20 - 65℃; for 3.08h; | 52-0 To a solution of Compound 55-1 (6.00 g, 16.989 mmol) in N,N-dimethylformamide (60 mL), K2CO3 (4.695 g, 33.979 mmol) was added slowly over a period of 5 minutes at room temperature. The reaction was then stirred at 65° C. for 3 hours. The reaction mixture was diluted with H2O (500 mL) and extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine solution (300 mL), dried over Na2SO4 and concentrated in vacuo. The product was purified by normal phase chromatography with a running gradient of 10% EtOAc/hexane to afford 3.00 g of Compound 55-2 as a colourless liquid. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.46-7.32 (m, 1H), 5.65 (s, 1H), 5.49 (s, 1H), 3.72 (s, 3H), 1.41 (s, 9H). LC-MS=102.1 [M-100]+ (De-Boc), retention time=1.28 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With mesitylenesulfonylhydroxylamine; potassium carbonate In water; N,N-dimethyl-formamide at 20℃; for 0.05h; | |
80% | With 1,4-Diiodobutane; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h; | |
54% | With 1,4-Diiodobutane; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h; |
Multi-step reaction with 3 steps 1: Me3(PhCH2)N(+)OH(-) 2: m-CPBA 3: toluene / 110 °C | ||
Multi-step reaction with 3 steps 1: 80 percent / Me3(PhCH2)NOH / methanol; tetrahydrofuran / 0.5 h / -20 °C 2: m-CPBA / CH2Cl2 / 0.33 h / -50 °C 3: 2-methyl-1-buten-3-yne / toluene / 1 h / 110 °C | ||
Multi-step reaction with 2 steps 1: triethylbenzylammonium chloride, KOH 2: 1. NaH 2. NaI / 1. dimethoxyethane, -10 deg C -> room temp. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With triethylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 110℃; for 24h; | 15.E E. (Z)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)acrylic acid methyl ester. A flask charged with Compound 15d (0.46 g, 2.0 mmol), Compound 15f (0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol), DMF (8 mL) was purged with N2 (g) 3 times. After the addition of tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31 mL, 2.2 mol), the reaction mixture was heated at 110° C. for 24 h. At that time, the reaction was quenched by addition of water, and then extracted with EtOAc. The organic phase was washed with 1 N HCl, saturated aqueous NaHCO3, brine, and dried over MgSO4. The mixture was concentrated to a residue, which was purified by flash column chromatography (eluent: EtOAc:hexane~1:1 to EtOAc only) to give Compound 15g (0.40 g, 57%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1H, s), 7.56 (2H, s); 13C NMR (75 MHz, DMSO-d6): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4, 128.3, 131.2, 135.2, 135.5, 152.8, 164.3,169.6; MS (ES+) (relative intensity): 349.1 (38%)(M+1). |
With tris-(dibenzylideneacetone)dipalladium(0); triethylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 110℃; for 24h; | 1.E A flask charged with compound 1d (0.46 g, 2.0 mmol), compound 1f (0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol) and DMF (8 mL) was purged with N2(g) 3 times. After the addition of tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31 mL, 2.2 mol), the reaction mixture was heated at 110° C. for 24 h. At that time, the reaction was quenched by addition of water, and then extracted with EtOAc. The organic phase was washed with 1N HCl, saturated aqueous NaHCO3, brine, and dried over MgSO4. The mixture was concentrated to a residue, which was purified by flash column chromatography (eluent: EtOAc:hexane1:1 to EtOAc only) to yield compound 1g as a white solid. 1H NMR (300 MHz, CD3OD): δ 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1H, s), 7.56 (2H, s); 13C NMR (75 MHz, DMSO-d6): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4, 128.3, 131.2, 135.2, 135.5, 152.8, 164.3, 169.6; MS (ES+) (relative intensity): 349.1 (38%)(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine In methanol at 55℃; for 16h; | 9 3-{2-[4-(4-Benzyloxycarbonylaminobutyl)phenoxy]ethylamino}-2-N,N'-di-(tert-butoxycarbonyl)aminopropionic acid methyl ester (21) A mixture of {4-[4-(2-aminoethoxy)phenyl]butyl}carbamic acid benzyl ester hydrochloride (141 mg, 0.372 mmol), 2-[N,N-di(tert-butoxycarbonyl)]aminoacrylic acid methyl ester (102 mg, 0.338 mmol), and triethylamine (0.16 mL, 1.11 mmol) in methanol (3 mL) was stirred at 55° C. (oil bath) for 16 h. It was then cooled to room temperature. The solvent was removed by rotary evaporation. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The organic layer was concentrated in vacuo and purified by flash silica gel column chromatography using ethyl acetate/hexanes (gradient 1:10, 1:6, 1:4, and 1:2, v/v) to give the desired Michael adduct 21 (110 mg, 51% yield). 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H), 1.43-1.50 (m, 9H), 1.50-1.65 (m, 4H), 2.50-2.60 (m, 2H), 3.12-3.25 (m, 2H), 3.49-3.72 (m, 4H), 3.75 (s, 3H), 3.98-4.10 (m, 2H), 4.45-4.65 (m, 1H), 4.79 (br s, 1H), 5.09 (s, 2H), 5.50 (m, 1H), 6.81 (d, J=8.5 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 7.28-7.38 (m, 5H). m/z (ESI) 644 [C34H49N3O9+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 2-(2,6-dichlorophenyl)-6-quinolinyl trifluoromethanesulfonate; methyl 2-[(tert-butoxycarbonyl)amino]acrylate With tetrabutyl-ammonium chloride; triethylamine In N,N-dimethyl-formamide at 90℃; for 0.333333h; Stage #2: In N,N-dimethyl-formamide for 3h; Heating / reflux; | 1.9.4 To a solution of 2- (2, 6-dichlorophenyl)-6-quinolinyl trifluoromethanesulfonate 21 (0.67 g) in DMF (15 ml) are added 0.8 g of freshly prepared methyl-2-N- (tert- butoxycarbonyl)-acrylate 16, tetrabutylammonium (0.57 g) and NEt3 (0.3 ml). The solution is degassed for 20 minutes and Pd (OAc) 2 (36 mg, 10 % mol) is added. The solution is heated at 90 °C for 3 h, then water (10 ml) is added. The aqueous phase is extracted with AcOEt (3 x 10 ml), and the organic phases are washed with water (2 x 10 ml), brine and dried over MgSO4. After evaporation under vacuum, the residue is purified over silica gel using AcOEt/petroleum ether 20/80 as eluent. Yield: 77 %. MS (MH+): 473. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With N-Methyldicyclohexylamine In 1,4-dioxane at 20℃; for 16h; | (Z)-Methyl 3-(4-amino-3-(benzyloxy)-5-methylphenyl)-2-(tert-butoxycarbonyl)acrylate. To a flame dried 500 mL of Schlenck flask, was added Pd(PtBu3)2 (308 mg, 0.60 mmol, 0.025 equiv) and Pd(dba)2 (346 mg, 0.60 mmol, 0.025 equiv), it was degassed and purged with N2 5 times. The dioxane (53 mL) solution of the bromide (7.05 g, 24.1 mmol, 1 equiv), the enamide (5.33 g, 26.5 mmol, 1.1 equiv) and Cy2NMe (5.61 mL, 26.5 mmol, 1.1 equiv), after it was degassed by a flow of N2 for 45 min, was cannulated into the Schlenck flask. The resulting mixture was degassed and purged with N2 5 times and it was stirred at r.t. for 16 h. The mixture was diluted with EtOAc (500 mL) and filtered through a pad of SiO2 and rinsed with EtOAc (300 mL). Solvents were removed and the residue was subjected to flash chromatography (SiO2) using EtOAc/hexanes (1:3 and 1:2) as eluent to afford the title compound as an orange solid (8.04 g, 81% yield). The orange solid was recrystalized using MeOH (110 mL) and acetone (20 mL), a tan solid (5.65 g, 57% yield) was obtained, which was used directly for the asymmetric hydrogenation reaction. Solvents were removed from the mother liquor and the residue was subjected to flash chromatography (SiO2) using EtOAc/hexanes (1:3 and 1:2) as eluent to afford an orange solid (2.40 g, 24% yield). For the recrystalized product: 1HNMR (CDCl3, 500 MHz) δ 7.44-7.37 (m, 4H), 7.35-7.32 (m, 1H), 7.12 (d, J=1.0 Hz, 1H), 6.99 (d, J=1.0 Hz, 1H), 6.08 (br s 1H), 5.06 (s, 2H), 4.08 (br s, 2H), 3.81 (s, 3H), 2.16 (s, 3H), 1.45 (br s, 9H); 13CNMR (CDCl3, 125 MHz) δ 166.7, 145.4, 137.0, 136.9, 133.6, 128.7, 128.2, 127.8, 126.8, 123.0, 121.7, 111.3, 80.6, 70.6, 52.4, 28.4, 17.3; Mass Spec. 413.23 (MH30 ), Calc. for C23H28N2O5 412.20 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tetrabutylammonium triphenyldifluorosilicate In tetrahydrofuran at 23℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With tetrabutylammonium triphenyldifluorosilicate In tetrahydrofuran at 23℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-methoxy-phenol In toluene at 110 - 115℃; for 20h; Title compound not separated from byproducts.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-methoxy-phenol In toluene at 110 - 115℃; for 20h; Title compound not separated from byproducts.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-methoxy-phenol In toluene at 110 - 115℃; for 20h; Title compound not separated from byproducts.; | ||
With 2-methoxy-phenol In toluene at 110 - 115℃; for 20h; Title compound not separated from byproducts.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-methoxy-phenol In toluene at 110 - 115℃; for 20h; Title compound not separated from byproducts.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With mesitylenesulfonylhydroxylamine; potassium carbonate In water; N,N-dimethyl-formamide at 20℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 45% 2: 48% | With oxygen; mesitylenesulfonylhydroxylamine; potassium carbonate In water; N,N-dimethyl-formamide at 20℃; for 0.0333333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.75h; Inert atmosphere; Stage #2: 5-iodo-3-(methoxymethoxy)pent-1-ene In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.75h; Inert atmosphere; Stage #2: tert-butyl(5-iodopent-1-en-3-yloxy)dimethylsilane In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.75h; Inert atmosphere; Stage #2: 5-iodo-3-methylpent-1-ene In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.75h; Inert atmosphere; Stage #2: bromopentene With lithium iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With bis(tri-tert-butylphosphine)palladium(0); N-Methyldicyclohexylamine; bis(dibenzylideneacetone)-palladium(0) In 1,4-dioxane at 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 2-phenoxy-6-quinolinyl trifluoromethanesulfonate In N,N-dimethyl-formamide for 0.5h; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With tetrabutyl-ammonium chloride; triethylamine at 90℃; for 2h; | 1.8.7 To a solution of 2-phenoxy-6-quinolinyl trifluoromethanesulfonate 15 (0. 782 g) in DMF (20 ml) is added palladium acetate (0.0285 g). The solution is degassed with Argon for 30 minutes. Methyl-2-N- (tert-butoxycarbonyl)-acrylate 16 (1.065 g), tetrabutyl ammonium chloride (0.706 g) and NEt3 (0.342 ml) are then added. The solution is heated at 90 °C for 2 h and then poured in ice. The aqueous phase is extracted with AcOEt (3 x 15 ml). The organic phases are dried over MgSO4 and evaporated to dryness. The residue is purified by silica gel chromatography using AcOEt/ether petroleum 10/90 then 40/60 as eluent. Yield: 91 %. MS (MH+): 421. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With Hexamethylphosphorous triamide In tetrahydrofuran at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With Rh(1+)*2CH4O*C4H12B(1-)*C34H40O2P2; hydrogen In methanol at 22℃; for 0.0666667h; Inert atmosphere; enantioselective reaction; | |
With methanol; bis(norbornadiene)rhodium(l)tetrafluoroborate; (Rp,Rp)-1,2-bis[(2-isopropoxyphenyl)(phenyl)phosphino]ethane; hydrogen at 20℃; for 0.0833333h; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.3% | With triethylamine In dichloromethane at 20℃; for 3h; | Synthesis of methyl 2-(tert-butoxycarbonylamlno)acrylate (compound 1) At 0 °C, methylsulfonyl chloride (81.1 g, 0.71 mo.) was added to a solution of Boc-Ser-O e (77.5 g, 0.35 mol) and TEA (141.4 g, 1.4 mol) In dichloromethane (1 L). The reaction was stirred for 3 h at ambient temperature, then quenched with 5% NaHC03 solution (300 ml). The organic phase was collected, dried over anhydrous Na2504, and concentrated under vacuum. The residue was purified by HPFC (PE: EA » 10: 1) to afford methyl 2-(tert- butoxycarbonylamlno)acrylate (63.5 g, 90.3%). LC- S: 202.3 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: p-bromobenzaldehyde tosylhydrazone With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With N-benzyl-N,N,N-triethylammonium chloride In tetrahydrofuran; toluene at 50℃; for 96h; Inert atmosphere; | 5 (1R, 2R plus IS, 2S)-Methyl-2-(4-bromophenyl)-1-(tert-butoxycarbonyl- amino)cydopropanecarboxylate (3)A solution of N,-(4-bromobenzylidene)-4- methyl benzenesulfono-hydrazide (2, 56.4 g, 0.16 mol) In THF (1 L) was kept at -78 °C. n-Butyllithlum (64 ml, 0.16 mol) was added dropwlse to the solution. The reaction was stirred for 1 h at -78 °C, and the solvent was removed under vacuum. To the residue was added a mixture of methyl 2-(tert- butoxycarbonylamino)acryiate (1, 32.2 g, 0.16 mol), benzyltriethylammonlum chloride (0.91 g, 4 mmol), and catalyst CIFeTPP (0.56 g, 0.4 mmol) in toluene (1 L). The reaction was stirred for 4 days at 50 °C under N2 protection. The solvent was removed under vacuum and the residue was partitioned between dichloromethane (500 ml) and water (500 ml). The organic layer was collected, and the water layer was extracted with dichloromethane (500 ml x 2). The organic phases were combined, dried over anhydrous Na2S04, and concentrated. The crude product was purified by HPFC (PE: EA = 10: 1) to afford a mixture of (1R, 2R)- and (IS, 2S)- 3 (29.1 g, yield 49%). LC-MS: 371.2 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N'-((4'-trifluoromethylbiphenyl-4-yl)methyl)sulfonic hydrazide With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With N-benzyl-N,N,N-triethylammonium chloride In toluene at 50℃; for 96h; Inert atmosphere; | 2 (iR,2R)- methyl l-amino-2-(4'- trifiuoromethyl blphenyl-4-yl)cyclopropane-carboxylate(Compound 27)At -78 0C, n-butylllthium (69 ml, 0.17 mo.) was added dropwise to a solution of N'-((4'- tr1fluoromethyl-4-y1)methyl)sulfonic hydrazlde (72 g, 0.17 mol) In THF (1 L). The reaction was stirred for 1 h at -78 OC and the solvent was removed under vacuum. Then to the flask, was added a mixture of toluene, methyl 2-(tert-butoxycarbonylamlno)acrylate (34.7 g, 0.17 mol), benzyltriethylammonium chloride (0.98 g, 4.3 mmol), and catalyst CIFeTPP (0.61 g, 0.43 mmol). The reaction was stirred for 4 days at 50 °C under N2 protection. The solvent was removed under vacuum and the residue was partitioned between dlchloromethane and water. The organic phase was collected, and the water phase was extracted withdichloromethane for two more times. The organic phases were combined, dried over anhydrous Na2S04, and concentrated. The crude product was purified by HPFC (PE: EA » 10: 1) to afford (lR,2R)-methyl l-(tert-butoxycartx3nylamino)-2-(4*-(trifluoromethyl)biphenyl-4- yl)cyclopropanecarboxylate, which was treated with 6 HCl/EA solution (50 ml) for 30 min at ambient temperature to give the title compound (5.9 g, 10.3%). LC-MS: 336.1 ( +i), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N'-((4'-fluorobiphenyl-4-yl)methyl)sulfonyl hydrazide With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With N-benzyl-N,N,N-triethylammonium chloride In toluene at 50℃; for 96h; Inert atmosphere; | 1 (lR,2R)-methyl l-amino-2-(4'-fluoroblpheny.-4~yi)cyciopropanecarboxyiate (Compound 22)At -78 °C, BuLi (34.8 ml, 87 mmol) was added dropwlse to a solution of N'-((4'- fluoroblphenyl-4-yl)methyl)sulfonic hydrazJde (32 g, 87 mmol) In THF. The reaction was stirred for 1 h at -78 °C and the solvent was removed under vacuum. Then to the flask, was added a mixture of toluene, methyl 2-(tert-butoxycarbonylamlno)acrylate (17.5 g, 87 mmol), benzy.triethylammonlum chloride (0.5 g, 2.2 mmol), and catalyst CIFeTPP (0.31 g, 0.22 mmol). The reaction was stirred for 4 days at 50 °C under N2 protection. The solvent was removed under vacuum and the residue was partitioned between dlchloromethane and water. The organic phase was collected, and the water phase was extracted with dlchloromethane for two more times. The organic phases were combined, dried over anhydrous Na2504, and concentrated. The crude product was purified by HPFC (PE: EA = 10: 1) to afford Boc protected (lR,2R)-methyl l-amlno-2-(4'-fluorobiphenyl-4-yl)cyclopropanecarboxylate which was treated with 6 M HCl/EA solution (10 ml) for 30 mln at ambient temperature to give the title compound (2.7 g, 10.9%). LC- S: 286.1 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetrabutyl-ammonium chloride; sodium hydrogencarbonate; tris-(o-tolyl)phosphine; palladium dichloride In N,N-dimethyl-formamide at 70℃; for 19h; Inert atmosphere; | (Z)-Methyl-3-(2-(bis(tert-butoxycarbonyl)-amino)pyrimidin-5-yl)-2-(tertbutoxycarbonylamino)acrylate (3b) N, N-di-tert-butoxycarbonyl-5-iodopyrimidin-2-amine (2b) (0.53 g, 1.25 mmol, 1.0 eq.), methyl-2-(tert-butoxycarbonylamino)acrylate (0.36 g, 1.80 mmol, 1.4 eq.), NaHCO3 (0.21 g, 2.50 mmol,2.0 eq.), Bu4NCl (0.45 g, 1.62 mmol, 1.3 eq.), PdCl2 (0.06 g, 0.25 mmol, 20 mol%) and tri-otolylphosphine(0.08 g, 0.25 mmol, 20 mol%) were mixed with DMF (anhydrous, 6 mL) and stirredfor 19 h at 70 °C under nitrogen. The reaction was quenched with sat. aq. NaHCO3-solution (20 mL)and ethyl acetate (20 mL) was added. The org. layer was separated, washed with water (2 × 20 mL),dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the brown solidwas purified via column chromatography (hexane/ethyl acetate, 3:1, Rf = 0.26) to give (Z)-methyl-3-(2-(bis(tert-butoxycarbonyl)-amino)pyrimidin-5-yl)-2-(tert-butoxycarbonylamino)acrylate 3b (0.19 g,30%) as a colorless solid (m.p.: 143 °C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrabutyl-ammonium chloride; sodium hydrogencarbonate; tris-(o-tolyl)phosphine; palladium dichloride In N,N-dimethyl-formamide at 70℃; for 19h; Inert atmosphere; | (Z)-Methyl-2-(tert-butoxycarbonylamino)-3-(2-(dibenzylamino)pyrimidin-5-yl)acrylate (3a) N, N-Dibenzyl-5-iodopyrimidin-2-amine (2a) (0.50 g, 1.25 mmol, 1.0 eq.), methyl-2-(tertbutoxycarbonylamino)acrylate (0.33 g, 1.62 mmol, 1.3 eq.), NaHCO3 (0.21 g, 2.50 mmol, 2.0 eq.),Bu4NCl (0.45 g, 1.62 mmol, 1.3 eq.), PdCl2 (0.06 g, 0.25 mmol, 20 mol%) and tri-o-tolylphosphine(0.08 g, 0.25 mmol, 20 mol%) were mixed with DMF (anhydrous, 4 mL) and stirred for 19 h at 70 °Cunder nitrogen. The reaction was quenched with sat. aq. NaHCO3 (20 mL) and ethyl acetate (20 mL)was added. The org. layer was separated, washed with water (2 × 20 mL), dried over MgSO4 andfiltered. The solvent was removed under reduced pressure and the brown solid was purified viacolumn chromatography (hexane/ethyl acetate, 5:1, Rf = 0.26) to give (Z)-methyl-2-(tert-butoxycarbonylamino)-3-(2-(dibenzylamino)pyrimidin-5-yl)acrylate 3a (0.415 g, 70%) as a light yellowsolid (m.p.: 122 °C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-(4-carbethoxyphenyl)urea; palladium diacetate; potassium carbonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 100℃; for 16h; | General procedure: An appropriate alkene (1 equiv) was added to an NMP solution (enough solvent to attain an initial concentration ofalkene equal to ca. 0.1M) of aryl iodide (2 equiv), Pd(OAc)2 (1 mol %,delivered as a standard THF solution containing 1 mg/mL of compound),N-(4-carbethoxyphenyl)urea (CEPU, 2 mol %), and K2CO3(2 equiv) in a thick-walled glass reaction tube equipped witha magnetic stirring bar and fitted with a threaded Teflon cap. Thereaction tubewas sealed and immersed in an oil bath maintained at 100 C and stirring was started. After 16 h, the resulting black solution was cooled to rt, diluted with ethyl acetate, and washedsequentially with water and brine solution. The organic phase wasseparated, dried (Na2SO4), and concentrated under reduced pressure(rotary evaporator), and the residue was purified by flashcolumn chromatography. Procedure B using tert-butyl (4-iodophenyl)carbamate (102 mg,0.32 mmol), K2CO3 (44 mg, 0.32 mmol), Pd(OAc)2 (0.4 mL of THFsolution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mgPd(OAc)2), CEPU (0.9 mg), and methyl 2-((tert-butoxycarbonyl)amino) acrylate (32 mg, 0.16 mmol). Chromatography using 40%ether in hexanes gave 14c as a pale yellow solid (36 mg, 57%); mp138e141 C. 1H: 7.50 (d, J8.6, 2H), 7.37 (d, J8.6, 2H), 7.24 (s, 1H),6.63 (br s, 1H), 6.13 (br s, 1H), 3.84 (s, 3H), 1.52 (s, 9H), 1.42 (s, 9H).13C: 166.2, 152.4, 139.4, 131.0, 130.7, 128.6, 117.9, 80.9, 52.5, 28.3,28.1. IR: 3295, 2980, 1696, 1592, 1524, 1366, 1322, 1241, 1154, 1051.APCI-MS: 391.0 (MH, 100%). ESIeHRMS: calcd for C20H28N2O6Na[MNa] 415.1845; found: 415.1839. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With N-(4-carbethoxyphenyl)urea; palladium diacetate; potassium carbonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 100℃; for 16h; | General procedure: An appropriate alkene (1 equiv) was added to an NMP solution (enough solvent to attain an initial concentration ofalkene equal to ca. 0.1M) of aryl iodide (2 equiv), Pd(OAc)2 (1 mol %,delivered as a standard THF solution containing 1 mg/mL of compound),N-(4-carbethoxyphenyl)urea (CEPU, 2 mol %), and K2CO3(2 equiv) in a thick-walled glass reaction tube equipped witha magnetic stirring bar and fitted with a threaded Teflon cap. Thereaction tubewas sealed and immersed in an oil bath maintained at 100 C and stirring was started. After 16 h, the resulting black solution was cooled to rt, diluted with ethyl acetate, and washedsequentially with water and brine solution. The organic phase wasseparated, dried (Na2SO4), and concentrated under reduced pressure(rotary evaporator), and the residue was purified by flashcolumn chromatography. Procedure B using 4-iodo-N,N-dimethylaniline (300 mg,1.20 mmol), K2CO3 (168 mg, 1.20 mmol), Pd(OAc)2 (1.35 mL of THFsolution containing 1 mg/mL Pd(OAc)2, equivalent to 1.35 mgPd(OAc)2), CEPU (2.5 mg), and methyl 2-((tert-butoxycarbonyl)amino)acrylate (123 mg, 0.60 mmol). Chromatography using 40%ether in hexanes gave 14b as an orange solid (85 mg, 44%); mp118e120 C. 1H: 7.51 (d, J8.9, 2H), 7.30 (s, 1H), 6.66 (d, J8.9, 2H),5.99 (br s, 1H), 3.82 (s, 3H), 3.01 (s, 6H), 1.46 (s, 9H). 13C: 166.7, 153.5,151.0, 133.3, 132.0, 121.5, 120.0, 111.6, 80.4, 52.2, 40.1, 28.2. IR: 3332,2955, 1695,1601, 1483,1437, 1366, 1280,1239,1155, 1124,1054,1028.APCI-MS: 321.4 (MH, 100%), 265.4 (MtBu, 60%). ESIeHRMS: calcdfor C17H25N2O4 [MH] 321.1814; found; 321.1815. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: methyl 2-[(tert-butoxycarbonyl)amino]acrylate; phenylboronic acid With 5,5’-bis(diphenylphosphino)-2,2,2’,2’-tetrafluoro-4,4’-bi-1,3-benzodioxole; chlorobis(ethylene)rhodium(I) dimer; sodium hydrogencarbonate for 0.166667h; Inert atmosphere; Stage #2: In isopropyl alcohol at 25℃; for 20h; Inert atmosphere; enantioselective reaction; | 1 General Procedure 1; synthesis of (R)-methyl 2-tert-butoxycarbonylamino-3-phenylpropanoate General procedure: The following are introduced successively into a 90-mL tubular reactor under an argon atmosphere: 3 mmol of α-aminoacrylate, two equivalents of boronic acid RB(OH)2, 1.5 mol % of dimer of chlorobis(ethylene)rhodium(I) [RhCl(═)2]2 (17.7 mg), 3.3 mol % of (S)-Difluorphos (69.7 mg) and one equivalent of NaHCO3 (252 mg). The mixture is stirred under vacuum for about ten minutes and is then placed under argon. 12 mL of isopropanol is then introduced. After a succession of two vacuum/argon cycles, the reactor is immersed in a bath preheated to 25° C. After stirring for 20 hours, the mixture is concentrated under vacuum. The addition product is then purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane | To a 10mL flame--dried flask was added 3(125μmol,1.0equiv.)and dissolved in the given solvent(2.5mL).To this solution was the nadded base(500μmol,4.0equiv.).The solution turned from yellow to dark green and into dark blue with successful elimination.The reaction course was monitored byTLC analysis at2,5,10,and every 5 mins afterwards until the reaction was complete.The reaction mixture was then concentrated directly before purification,except for DMF and DMSO which under went aqueous work--up;thereaction was diluted with5%KHSO4(aq,5mL),extracted withEt2O(3x10mL),dried(Na2SO4),filteredandconcentrated.Theresultingresiduewaspurifiedbyflashcolumnchromatography(DCM),yielding4asacolorlessoil.Rf0.48(CH2Cl2).1H--NMR(CDCl3,400MHz):δ(ppm)7.01(s,1H,NH),6.14(s,1H),5.71(d,J=1.4Hz,1H),3.82(s,3H),1.47(s,9H).13C--NMR(CDCl3,100MHz):δ(ppm)164.6,152.7,131.4,105.3,80.8,53.0,28.4.HRMS(ES)m/z:[M+H--C(O)OC(CH)3+H]+calcd.forC4H8NO2+:102.0550;found:102.0550.IR(neat)vmax/cm--13429,2985,1736,1716,1635,1508,1442,1395,1369,1324,1245,1204,1155,1065,1001,967,887,847,808,712,599. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 39% 2: 37% | With sodium azide In N,N-dimethyl-formamide at 70℃; for 0.166667h; | preparation of (S)-3 and 10 To a solution of (S)-9a (0.518 g, 1.39 mmol) in DMF (19 mL) was added sodium azide (0.285g, 4.38 mmol). The resulting solution was heated to 70°C during 10 minutes. The hot mixturewas transferred into a beaker that contains 100 mL of cold water (4-5°C). The reactionmixture was stirred at 4-5°C during 2 minutes and extracted with ethyl acetate (3*40 mL).The organic phases were combined, washed with aqueous saturated NaCl (4*80 mL), driedover MgSO4, filtered and concentrated under reduced pressure. The residue was purified byflash chromatography (silica gel, EtOAc/PE, 0/100 ramping to 100/0, v/v) to give compound(S)-3 (0.131 g, 0.54 mmol) in 39% yield as a colorless oil and compound 10 in 37% yield as ayellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 25% 2: 29% | With sodium azide In N,N-dimethyl-formamide at 50℃; for 0.5h; | preparation of (S)-3 and 10 This product was synthesized using the conditions described by Shetty et al.2To a solution of (S)-9b (1.554 g, 5.23 mmol) in DMF (35 mL) was added sodium azide (0.852g, 13.10 mmol). The resulting solution was heated to 50°C during 30 minutes. The hotmixture was transferred into a beaker that contains 100 mL of cold water (4-5°C). Thereaction mixture was stirred at 4-5°C during 2 minutes and extracted with ethyl acetate (3*60mL). The organic phases were combined, washed with aqueous saturated NaCl (8*80 mL),dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purifiedby flash chromatography (silica gel, EtOAc/PE, 0/100 ramping to 100/0, v/v) to givecompound (S)-3 (0.325 g, 1.33 mmol) in 25% as a colorless oil and compound 10 in 29% as ayellow oil. This products exhibit the same characteristics that we described above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.0 g | With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 1h; | b To a stirred solution of methyl O-((benzyloxy)carbonyl)-N-(tert-butoxycarbonyl)-L-serinate (22.0 g, 62.3 mmol) in DMF (150 ml) was added K2CO3(17.2 g, 124.6 mmol) at rt and the reaction mixture was stirred at 65°C for 1 h. The mixture was cooled to rt, poured into water (2000 ml) and extracted with EtOAc (2 x 500 ml). The combined organic phase was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc in hexane) yielding methyl 2-((tert-butoxycarbonyl)amino)acrylate (11.0 g, 54.726 mmol). 1HNMR (400 MHz, DMSO-d6) δ ppm: 8.39 (s, 1 H), 5.60 (s, 1 H), 5.49 (s, 1 H), 3.72 (s, 3 H), 1.42 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.80 g | With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 30.25h; | c To a solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (10.3 g, 51.24 mmol) in DCM (103 ml) was added TFA (0.26 ml) at 0°C. N-(Methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (13.35 g, 56.37 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 15 min and then stirred at rt for 15 h. After 15 h unreacted starting material was observed so again N-(Methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (3.64 g, 15.373 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was stirred at rt for a further 15 h. The resulting reaction mixture was poured into water (250 ml) and basified using Na2C03. The resulting mixture was extracted with DCM (2 x 150 ml) and the combined organic phase was washed with brine solution (50 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (20% EtOAc in hexane) yielding methyl 1- benzyl-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylate (13.80 g, 41.294 mmol). LCMS: Method 3, 4.68 min, MS: ES+ 335.3; 1HNMR (400 MHz, DMSO-d6) δ ppm: 7.59 (s, 1H), 7.21 - 7.33 (m, 5H), 3.57 - 3.62 (m, 5H), 2.99 (d, J=10 Hz, 1 H), 2.67 (d, J=10 Hz, 1 H), 2.50 -2.61 (m, 2H), 2.14 - 2.18 (m, 1H), 1.98 - 1.99 (m, 1H), 1.35 (s, 9H). |
1.9 g | With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16.08h; | 52-0 To a solution of Compound 55-2 (3.7 g, 18.398 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (4.36 g, 18.398 mmol) in DCM (30 mL), TFA (0.1 mL) was added slowly over a period of 5 minutes at 0° C. Then the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with H2O (50 mL) and extracted twice with DCM (50 mL). The combined organic layers were washed with aqueous NaHCO3 and brine (50 mL), the organic layer was dried over Na2SO4 and concentrated in vacuo. The product was purified by normal phase chromatography with a running gradient of 20% EtOAc/n-hexane to afford 1.90 g of Compound 55-3 as a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 3.73 (s, 3H), 3.64 (q, J=13.0 Hz, 2H), 2.88 (s, 1H), 2.81 (d, J=10.3 Hz, 1H), 2.67-2.52 (m, 2H), 2.08-1.93 (m, 1H), 1.58 (s, 1H), 1.42 (s, 9H). LC-MS=335.2 [M+H]+, retention time=1.04 minutes. |
With trifluoroacetic acid In dichloromethane at 0 - 30℃; for 18h; | Intermediate 1 : Methyl (R)-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylate To a solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (430 g, 2.14 mol) and N- benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (533 g, 2.2 mol) in DCM (5.5 L) was added trifluoroacetic acid (24.4 g, 214 mmol) slowly at 0 °C. The reaction mixture was stirred at 30 °C for 18 hrs. The mixture was quenched with aq.NaHCO3 (5 L). The crude product was extracted with DCM (2.5 L). The organic layer was washed with brine (3.0 L), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE/EtOAc = 10/1 to 0/1) to afford methyl 1-benzyl-3-((tert- butoxycarbonyl)amino)pyrrolidine-3-carboxylate as a yellow solid (INT-1A). 1H NMR (400 MHz, CDCI3) d 7.35-7.31 (m, 4H), 7.27-7.23 (m, 1 H), 5.12 (s, 1 H), 3.75 (s, 3H), 3.67-3.61 (m, 2H), 2.95-2.87 (m, 2H), 2.82 (d, J = 9.2 Hz, 1 H), 2.67-2.53 (m, 2H), 2.06-1.94 (m, 1 H), 1.43 (s, 9H). LC-MS: [M+H]+ = 335.1 , 336.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(II) bis(trifluoromethanesulfonate); ammonium chloride; zinc In ethanol at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(II) bis(trifluoromethanesulfonate); ammonium chloride; zinc In ethanol at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(II) bis(trifluoromethanesulfonate); ammonium chloride; zinc In ethanol at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With copper(II) bis(trifluoromethanesulfonate); ammonium chloride; zinc In ethanol at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With copper(II) bis(trifluoromethanesulfonate); ammonium chloride; zinc at 20℃; | |
42% | With triisobutylamine In water; acetonitrile at 20℃; for 16h; Irradiation; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With triisobutylamine In water; acetonitrile at 20℃; for 16h; Irradiation; chemoselective reaction; | |
14% | With copper(II) bis(trifluoromethanesulfonate); ammonium chloride; zinc at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With triisobutylamine In water; acetonitrile at 20℃; for 16h; Irradiation; chemoselective reaction; | |
13% | With copper(II) bis(trifluoromethanesulfonate); ammonium chloride; zinc at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: p-bromobenzaldehyde tosylhydrazone With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With iron(III) meso-tetraphenylporhinato chloride; N-benzyl-N,N,N-triethylammonium chloride In toluene at 50℃; for 96h; Inert atmosphere; | 2.1.1.2 (1R,2R and 1S,2S)-methyl-2-(4-bromophenyl)-1-(tert-butyloxycarbonylamino)cyclopropanecarboxylate (IIIa and IIIb) A solution of N’-(4-bromobenzylidene)-4-methylbenzenesulfonohydrazide (56.4g, 0.16mol) in THF (1 L) was kept at -78°C. To the solution dropwise n-Butyllithium (64mL, 0.16mol) was added. The reaction was stirred for 1h at -78°C, and the solvent was removed under vacuum. To the residue was added a mixture of methyl 2-(tert-butyloxycarbonylamino)acrylate (I) (32.2g, 0.16mol), benzyltriethylammonium chloride (0.91g, 4mmol), and catalyst ClFeTPP (0.56g, 0.4mmol) in toluene (1 L). The reaction was stirred for 4days at 50°C under N2 protection. The solvent was removed under vacuum and the residue was partitioned between dichloromethane (500mL) and water (500mL). The organic layer was collected, and the water layer was extracted with CH2Cl2 (500mL×2). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by HPFC (PE:EA=10:1) to afford a mixture of (1R,2R)-(IIIa) and (1S,2S)-methyl-2-(4-bromophenyl)-1-(tert-butoxycarbonyl-amino)cyclopropanecarboxylate (IIIb) (29.1g, yield 49%). LC-MS: 371.2 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triisobutylamine In water; acetonitrile at 20℃; for 16h; Irradiation; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutyl-ammonium chloride; palladium diacetate; triethylamine In N,N-dimethyl-formamide at 90℃; for 6.5h; Sealed tube; Inert atmosphere; | 143 Synthesis of methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-(ethoxymethyl)- 2.6-dimethoxyphenyl)-1 -methyl-1H-indazol-7-yl)acrylate (143D): To a sealed tube was added 60B (127 mg, 0.31 mmol) and DMF (3 mL). This solution was degassed with nitrogen for 30 min. To this, methyl 2-((tert-butoxycarbonyl)amino)acrylate (189 mg, 0.94 mmol), tetrabutylammonium chloride (TBACI, 105 mg, 0.38 mmol), TEA (0.05 mL, 0.36 mmol) and palladium acetate (35 mg, 0.16 mmol) were added. The tube was sealed and heated to 90 °C for 6 h. Reaction mixture was cooled to RT and purified by silica gel chromatography using 0- 100% EtOAc in hexanes to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-bromo-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)isoquinoline With palladium diacetate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With tetrabutyl-ammonium chloride; triethylamine In N,N-dimethyl-formamide at 90℃; Inert atmosphere; Sealed tube; | 160 Synthesis of methyl (Z)-2-((tert-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl)- 2,6-dimethoxyphenyl)isoquinolin-5-yl)acrylate (160C): To a solution of 5-bromo-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)isoquinoline (160B, 401 mg, 997 pmol) in DMF (10 ml_) was added palladium acetate (1 1 mg, 50 pmol), and the mixture was flushed with N2 for 30 min. To the resulting mixture were added methyl 2-((tert-butoxycarbonyl)amino)acrylate (501 mg, 2.49 mmol), tetrabutylammonium chloride (332 mg, 1 .20 mmol), and triethylamine (161 uL, 1 .16 mmol), and the mixture was flushed with N2 for an additional 2 min. The reaction vial was then sealed and stirred at 90 °C overnight. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with 10% aqueous citric acid solution, sat. NaHC03, and brine. The organic layer was concentrated under reduced pressure. The resulting material was purified by silica gel chromatography using 0-100% EtOAc in hexanes to afford the title compound. MS (m/z) 523.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-bromo-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinoline With palladium diacetate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With tetrabutyl-ammonium chloride; trimethylamine at 90℃; for 3h; Sealed tube; Inert atmosphere; | 31 Synthesis of methyl 2-((te/f-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl)-2,6- dimethoxyphenyl)-2-methylquinolin-5-yl)acrylate (31C): To a stirred solution of 31B (190 mg, 0.46 mmol) in DMF (4.7 ml_) was added palladium(ll) acetate, and the reaction was degassed with nitrogen for 30 minutes. To this, methyl 2-((te/f-butoxycarbonyl)amino)acrylate (230 mg, (0921) 1.1 mmol), tetrabutylammonium chloride (152 mg, 0.55 mmol), and trimethylamine (0.074 ml_, 0.53 mmol) were added, and the reaction was sealed and heated to 90 °C for 3 hours. It was cooled to RT, diluted with ethyl acetate, and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified via flash chromatography, eluting with a linear gradient of 5-100% ethyl acetate/hexanes, to yield compound 31 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-bromo-8-(2,6-dimethoxyphenyl)isoquinoline With palladium diacetate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate With tetrabutyl ammonium fluoride; triethylamine In N,N-dimethyl-formamide at 90℃; for 16h; | 106 Synthesis of methyl (Z)-2-((te/f-butoxycarbonyl)amino)-3-(8-(2,6-dimethoxyphenyl) isoquinolin-5-yl)acrylate (106B): To a stirred solution of 106A (250.0 mg, 0.726 mmol) in DMF (2.70 ml_) was added palladium(ll) acetate (24.5 mg, 0.109 mmol). This was degassed with N2 for 30 minutes. In a separate vessel, methyl 2-((te/f-butoxycarbonyl)amino)acrylate (292.3 mg, 1.45 mmol) and tetrabutylammonium chloride (242.2 mg, 0.872 mmol) were stirred in DMF (2 ml_). The bromide solution was added to the acrylate solution and triethylamine was added (0.12 ml_, 0.843 mmol). The reaction vessel was sealed and heated to 90 °C for 16 hours. The material was loaded directly onto silica and was purified by silica gel chromatography using 10- 100% EtOAc in hexanes to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 93% 2: 7% | Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere; Stage #2: With 3-bromofurane; 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0) at 25 - 50℃; for 25h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 71% 2: 22% 3: 7% | Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere; Stage #2: 3-bromofurane With tris-(dibenzylideneacetone)dipalladium(0); XPhos In N,N-dimethyl-formamide at 25 - 50℃; for 25h; Inert atmosphere; chemoselective reaction; | Activated zinc dust (4.00 g, 60.8 mmol, 4.0 eq.) was heated under vacuum for 20 min, then the flask wasfilled with argon and cooled down to 70 °C. Anhydrous DMF (15 mL) and I2 (389 mg, 1.52 mmol, 0.1 eq.)were added and the resulting light grey suspension was stirred at 70 °C for a further 20 min. The reactionmixture was cooled to 50 °C and then added a solution of iodoalanine 3 (5.00 g, 15.2 mmol, 1.0 equiv.) inDMF (12 mL). The mixture was stirred under argon for another 20 min. and then treated sequentially with3-bromofuran (4.47 g, 45.6 mmol, 3.0 eq.), Pd2(dba)3 (1.37 g, 1.52 mmol, 0.1 eq.) and XPhos (2.86g, 6.08mmol, 0.40 eq.). The reaction mixture was stirred for 5 h at 50 °C, and for 20 h at room temperature priorto be filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc/hexanes =1: 25) to provide 4 (2.91 g, 71%) as a yellow oil. |
1: 66% 2: 20% 3: 14% | Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere; Stage #2: 3-bromofurane With tris-(dibenzylideneacetone)dipalladium(0); tert-butyl XPhos at 25 - 50℃; for 25h; Inert atmosphere; | |
1: 58% 2: 17% 3: 17% | Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere; Stage #2: 3-bromofurane With tris-(dibenzylideneacetone)dipalladium(0); ruphos at 25 - 50℃; for 25h; Inert atmosphere; |
1: 30% 2: 30% 3: 41% | Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere; Stage #2: 3-bromofurane With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine at 25 - 50℃; for 25h; Inert atmosphere; | |
1: 40% 2: 33% 3: 20% | Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere; Stage #2: 3-bromofurane With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) at 50℃; for 25h; Inert atmosphere; | |
1: 34% 2: 18% 3: 15% | Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With iodine; zinc In N,N-dimethyl-formamide at 50℃; for 0.333333h; Inert atmosphere; Stage #2: 3-bromofurane With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0) at 25℃; for 25h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.03% | Stage #1: 4-(3-bromophenyl)-2-aminothiazole With trimethylaluminum In toluene at 100℃; for 0.5h; Stage #2: methyl 2-[(tert-butoxycarbonyl)amino]acrylate In toluene at 100℃; for 0.5h; | 76.1 Step 1: Preparation of tert-butyl (3-((4-(3-bromophenyl)thiazol-2-yl)amino)-3-oxoprop-1-en-2- yl)carbamate (Intermediate C) To a solution of 4-(3-(pyridin-4-yl)phenyl)thiazol-2-amine [prepared according to the method in Example 4] (1.27 g, 4.97 mmol) in toluene (8 mL) was added AlMe3 (2 M, 2.48 mL). The reaction mixture was stirred at 100 °C for 0.5 h. Methyl 2-(tert-butoxycarbonylamino)prop-2-enoate (1 g, 4.97 mmol) was added at 100 °C. The reaction mixture was stirred at 100 °C for 0.5 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by silica gel chromatography column (PE~PE/EA=1/1) and concentrated to give Intermediate C (450 mg, 896.16 mmol, 18.03% yield) as yellow solid. LCMS (ESI) m/z [M+H]+ = 423.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With C115H106CoN8O4; caesium carbonate In chlorobenzene at 4℃; for 12h; Schlenk technique; Inert atmosphere; Sealed tube; Overall yield = 88 percent; Optical yield = 30 percent de; | 6.1. Supplemental Experimental Procedure for [Co(Por)]-Catalyzed Cyclopropanation General procedure: An oven-dried Schlenk tube was charged with 1.0 equivalent of olefin (0.1 mmol), 1.2equivalents of hydrazone (0.12 mmol), [Co(Por)] (2 mol %) and 2.4 equivalents of Cs2CO3(0.24 mmol). The Schlenk tube was then evacuated and back filled with nitrogen for 3times. The Teflon screw cap was replaced with a rubber septum, and PhCl (1 mL) wasadded. The Schlenk tube was then purged with nitrogen for 30 s and the rubber septum wasreplaced with a Teflon screw cap. The mixture was stirred at 4 C. After 12 h, the reactionmixture was filtered through a plug of silica and then concentrated in vacuo. The residuewas purified via a flash chromatography to afford the compound as a mixture of Z/Ediastereomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile In N,N-dimethyl acetamide; acetonitrile at 20℃; for 0.833333h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile In N,N-dimethyl acetamide; acetonitrile at 20℃; for 0.833333h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 28% 2: 17% | With potassium carbonate; 1,3-bis(mesityl)imidazolium chloride In tetrahydrofuran at 20℃; for 72h; | 5 The applied general procedure (GP3) was as follows: General procedure: 1 ,3-bis(2,4,6-trimethylphenyl)-1 H-imidazole-3-iumchloride (1.02 g, 3.00 mmol, 1.5 eq) and potassium carbonate (1.24 g, 9.00 mmol, 4.5 eq) were mixed in tetrahydrofuran (80 mL). Afterwards disulfide (549 mg, 2.00 mmol, 1 .0 eq) was added and the reaction was stirred until completion of the reaction (usually 24 h) at rt. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to obtain the sulfide. Minor impurities as disulfide residues were removed for analytical samples by HPLC, if indicated. |
Tags: 55477-80-0 synthesis path| 55477-80-0 SDS| 55477-80-0 COA| 55477-80-0 purity| 55477-80-0 application| 55477-80-0 NMR| 55477-80-0 COA| 55477-80-0 structure
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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