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CAS No. : | 171364-80-0 | MDL No. : | MFCD02179438 |
Formula : | C14H19BO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | REIZEQZILPXYKS-UHFFFAOYSA-N |
M.W : | 262.11 | Pubchem ID : | 2773500 |
Synonyms : |
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 74.2 |
TPSA : | 44.76 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.94 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.76 |
Log Po/w (WLOGP) : | 1.77 |
Log Po/w (MLOGP) : | 1.54 |
Log Po/w (SILICOS-IT) : | 1.77 |
Consensus Log Po/w : | 1.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.24 |
Solubility : | 0.151 mg/ml ; 0.000576 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.36 |
Solubility : | 0.116 mg/ml ; 0.000441 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.08 |
Solubility : | 0.022 mg/ml ; 0.0000839 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.86 |
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 |
---|---|---|
99% | With tris(trimethylphosphine)nickel(II) chloride; (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride In tetrahydrofuran at 100℃; for 12h; Inert atmosphere; | |
99% | With (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride; dichlorobis(trimethylphosphine)nickel In tetrahydrofuran at 100℃; for 12h; Inert atmosphere; Sealed tube; | 10; 11; 12; 3; 4; 5; 6; 13; 14; 15; 41 Example-10 Under an argon atmosphere, 1.4 mg (0.005 mmol) of dichlorobis (trimethylphosphine) nickel, 85.0 mg (0.5 mmol) of methyl 4-chlorobenzoate, 152 mg (1.0 mmol) of cesium fluoride, , 140 mg (0.55 mmol) of 5,5,4 ', 4', 5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolanyl) , 2-trifluoroethoxy) silane (180 mg, 1.05 mmol) and tetrahydrofuran (0.5 mL) were added and the mixture was sealed and stirred at 100 ° C. for 12 hours. After the reaction vessel was cooled to room temperature, 1 mL of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with 8 mL of ethyl acetate, and the obtained organic phases were combined. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: chloroform: ethyl acetate = 16: 4: 0 to 16: 4: 1)129 mg (white solid, yield 99%) of methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate was obtained. |
96% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); potassium acetate In 1,4-dioxane for 0.25h; Reflux; Inert atmosphere; |
96% | With potassium acetate; palladium diacetate; (1R,3S,5S,7R)-8-([1,1'-biphenyl]-2-yl)-1,3,5,7-tetramethyl-2,4,6-trioxa-8-phospha-adamantane In tetrahydrofuran at 25℃; for 12h; Inert atmosphere; Sealed tube; | General procedure for room temperature borylation (A). General procedure: An oven-dried ace pressure tube was evacuated and backfilled with argon. Pd(OAc)2 (0.005 - 0.02 mmol, 0.5 - 2 mol%) and ligand (0.0125 - 0.05 mmol, 1.25 - 5 mol%), were added and the tube was evacuated and backfilled with argon. THF (2.00 mL), aryl halide (1mmol), bis(pinacolato)diboron (2 - 3 mmol), KOAc (3 mmol), and n-decane (0.5 mmol, internal standard), were added to the tube. The tube underwent a final evacuation/backfill cycle, sealed with a screw cap, and allowed to stir at room temperature (25 °C) for the specified times (1 - 12 h). Conversion, selectivity and GC yield were quantified from an aliquot (0.20 mL) of the reaction mixture using GC-FID. Upon completion, the GC sample was transferred back into the main reaction mixture, an aqueous work-up was performed (EtOAc:H2O, 1:1). The organic layer was dried over MgSO4, filtered through a cotton wool plug and concentrated on a rotary evaporator. The isolated yield was obtained by purification of the crude product through column chromatography using silica gel (EtOAc-hexane). |
92% | With potassium phosphate tribasic heptahydrate; chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct; XPhos In ethanol at 20℃; for 15h; | 6.1 Example 1: Synthesis of 4-tert-butylphenylboronic acid pinacol ester General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1,1'-biphenyl) (1,1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2',4',6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98% |
91% | Stage #1: Methyl 4-chlorobenzoate; bis(pinacol)diborane With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; XPhos at 110℃; for 6h; Schlenk technique; Inert atmosphere; Stage #2: Inert atmosphere; | Palladium-Catalyzed Borylation of Aryl Chlorides in PEG-2000;General Procedure General procedure: To a dried Schlenk tube were added Pd2dba3 (4.6 mg, 0.005 mmol),XPhos (9.6 mg, 0.02 mmol), bis(pinacolato)diboron (190 mg, 0.75mmol), PEG-2000 (1.0 g), and KOAc (147 mg, 1.5 mmol). The Schlenktube was evacuated and backfilled with argon. The reaction mixturewas heated to 50 °C, followed by the addition of the aryl chloride (0.5mmol) via syringe (aryl chlorides that were solid were added withother reagents before evacuation). The reaction mixture was thenstirred at 110 °C under Ar for 6 h. After being cooled to 45 °C, the resultingmixture was extracted with cyclohexane (3 × 5 mL). The residueof the extraction was subjected to a second run of the borylationreaction by charging with the same substrates (aryl chloride, bis(pinacolato)diboron and KOAc) under the same conditions without furtheraddition of Pd2dba3 and XPhos. The combined cyclohexane layerwas concentrated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel using a mixture of petroleumether and EtOAc as eluent or by recrystallization from hexaneto afford the desired aryl boronates 2. |
90% | With p-phenylpyridine; sodium methylate In acetonitrile at 20℃; for 12h; Sealed tube; Inert atmosphere; Irradiation; | |
88% | With 10H-phenothiazine; caesium carbonate In acetonitrile for 48h; Irradiation; Sealed tube; Inert atmosphere; | |
86% | With tris-(dibenzylideneacetone)dipalladium(0); rac-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole; potassium acetate In N,N-dimethyl acetamide at 100℃; for 12h; Inert atmosphere; | |
85% | With potassium acetate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In tetrahydrofuran for 6h; Heating; | |
83% | With 3,7-di([1,1'-biphenyl]-4-yl)-10-(4-(trifluoromethyl)phenyl)-10H-phenoxazine; 1,8-diazabicyclo[5.4.0]undec-7-ene In dimethyl sulfoxide at 20℃; for 12h; Inert atmosphere; Irradiation; chemoselective reaction; | |
75% | With potassium acetate; palladium diacetate In benzene at 60℃; for 10h; Inert atmosphere; | |
75% | With catalyst: silica-SMAP/Pd(CH3COO)2; K(CH3COO) In benzene soln. of Pd complex in benzene and aryl halide added to mixt. of silica-SMAP, B compd., and KOAc in degassed benzene in glass tube with stirrer,tube sealed with screw cap, removed from glove box, mixt. stirred at 60 °C for 10 h; soln. filtered through Celite pad, filtrate evapd. under vac., column chromy. (silica gel, EtOAc/hexane 1/9); | |
70% | With pyridine-4-carbonitrile; potassium phosphate; sodium oxalate; 2,4,5-tri(9H-carbazol-9-yl)-6-(ethyl(phenyl)amino)isophthalonitrile In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Sealed tube; | |
61% | With p-phenylpyridine; potassium methanolate In tert-butyl methyl ether at 85℃; for 12h; Sealed tube; | |
61% | With p-phenylpyridine; potassium methanolate In tert-butyl methyl ether at 85℃; for 12h; | |
60% | With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; potassium acetate In benzene at 25℃; for 10h; Inert atmosphere; Sealed tube; | Typical Procedure for Miyaura Borylation of Chloroarenes (Figure 1 and Table 1) General procedure: In a nitrogen-filled glove box, Silica-3p-TPP ([P] 0.11 mmol/g, 45.5 mg, 0.005 mmol P, 1 mol % P), anhydrous, degassed benzene (0.8 mL), and a solution of [PdCl(η3-cinnamyl)]2 (0.65 mg, 0.00125 mmol, 0.5 mol % Pd) in benzene (0.2 mL) were placed in an oven-dried, 10-mL glass tube containing a magnetic stirring bar. After stirring of the mixture for 5 min, KOAc (147 mg, 1.5 mmol), bis(pinacolato)diboron (2, 140 mg, 0.55 mmol), and p-chlorotoluene (1a, 63.3 mg, 0.50 mmol) were added. The tube was sealed with a screw cap and was removed from the glove box. The mixture was stirred at 25 °C for 10 h, and was filtered through a Celite pad (eluting with Et2O). Solvent was removed under reduced pressure. An internal standard (1,1,2,2-tetrachloroethane) was added to a residue to determine the yield of the product by 1H NMR (95%). The crude material was then purified by silica gel chromatography to give arylboronate 3a (87.0 mg, 0.40 mmol, 80% yield). |
36% | With cerium(III) chloride; tetraethylammonium chloride In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Sealed tube; | |
27% | With C20H28Cl2CoFeNOP; potassium methanolate; methyllithium In tert-butyl methyl ether at 50℃; for 24h; Inert atmosphere; Schlenk technique; Sealed tube; | |
20% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In acetonitrile at 25℃; for 8h; Irradiation; Inert atmosphere; | |
87 % Chromat. | With potassium acetate; bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine In 1,4-dioxane at 80℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 100℃; | Production Example 51 methyl 4-(6-bromoimidazo[1,2-a]pyridin-3-yl)benzoate 2.3 g methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate prepared according to T. Ishiyama et al., J. Org. Chem., 60, 7508 (1995), 2.0 g <strong>[474706-74-6]6-bromo-3-iodoimidazo[1,2-a]pyridine</strong> (compound in Production Example 49), 2. 5 g potassiumphosphate, 360 mg tetrakistriphenyl phosphine palladium and 30 ML N, N-dimethylformamide were heated at 100C under nitrogen atmosphere.. Insolubles were filtered off, the solvent was removed, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give 1.39 g of the title compound (colorless crystals).1H-NMR (CDCl3) delta: 3.97(s, 3H), 7.32(dd, J=9.6, 2.0Hz, 1H), 7.62(d, J=9.6Hz, 1H), 7.65(dt, J=8.8, 2.0Hz, 2H), 7.79(br.s, 1H), 8.21(dt, J=8.8, 2.0Hz, 2H), 8.50(br.s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N,N,N′,N′-tetramethyldiaminomethane In lithium hydroxide monohydrate; propan-2-one; acetonitrile at -5℃; for 0.25h; UV-irradiation; Flow reactor; chemoselective reaction; | |
88% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In dimethyl sulfoxide at 50℃; for 8h; Inert atmosphere; | |
88% | With meso-tetra(p-tolyl)porphinato-palladium(II); anhydrous potassium acetate In 1,4-dioxane at 110℃; for 5.5h; chemoselective reaction; | General Procedure for Miyaura Borylation General procedure: Aryl/heteroaryl bromide 1 (1 mmol), B2pin2(2), B2npg2(4) orBpin (6, 1.2 mmol), and dioxane (5 mL) are taken into a 25 mLround-bottomed flask. KOAc (2 mmol) was added and stirredthe resultant mixture at room temperature for 5 min, PdII-TpTP(0.15 mol%) was added, and the contents were refluxed on preheatedoil bath at 110 °C under constant stirring in open-air.The reaction progress was ensured by TLC. After completion ofthe reaction, the mixture was cooled, dilute with water (20 mL)and extracted with tertbutylmethyl ether (3 × 10 mL). The combinedn-hexane layers were concentrated, and the crudeproduct obtained was purified by column chromatography (CC)on silica gel using a mixture of ethyl acetate and hexane (1:30)as eluent. |
87% | With bis(tri-tertiary-butylphosphine)palladium(0); anhydrous potassium acetate In lithium hydroxide monohydrate at 20℃; for 3h; Inert atmosphere; | |
87% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In N,N-dimethyl-formamide for 6h; Inert atmosphere; Reflux; | |
86% | With pyridine; C50H44CuN4OP2(1+)*F6P(1-); N-ethyl-N,N-diisopropylamine In lithium hydroxide monohydrate; acetonitrile at 20℃; for 12h; Inert atmosphere; Irradiation; | |
85% | With C37H51ClFeNPPd; anhydrous potassium acetate In 1,4-dioxane at 80℃; for 3h; Inert atmosphere; | |
85% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); anhydrous Sodium acetate In polyethylene glycol 600 at 90℃; for 6h; Inert atmosphere; | |
83% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In dimethyl sulfoxide at 85℃; for 72h; Inert atmosphere; | |
83% | With potassium polysulfide; lithium hydroxide monohydrate; 1,1,3,3-tetramethylguanidine In acetonitrile at 30℃; for 9h; Irradiation; Inert atmosphere; Sealed tube; | |
75% | With Pd(0)(dppf)2; anhydrous potassium acetate In dichloromethane; dimethyl sulfoxide at 80℃; for 3h; | |
75% | With fac-tris(2-phenylpyridinato-C<SUP>2</SUP>,N)iridium(III); tributyl-amine; lithium hydroxide monohydrate In acetonitrile at 25℃; for 36h; Schlenk technique; Inert atmosphere; Sealed tube; Irradiation; | |
75% | With anhydrous potassium acetate In N,N-dimethyl-formamide at 30℃; for 12h; Inert atmosphere; Irradiation; | 2.3. General procedure for photocatalytic reactions General procedure: Unless specified otherwise, all reactions were conducted in ambient Ar atmosphere at 30 °C. A mixture of aryl halides (1mmol), B2pin2 (1.2 mmol, 305 mg), base (1 mmol, 98 mg), andPd/SiC catalyst (40 mg) was suspended in 10 mL ofN,N-dimethylformamide (DMF) in an oven-dried 25 mL quartzvial equipped with a magnetic stirring bar. During the reaction,the mixture was stirred at 500 rpm using a magnetic stirrerand then exposed to a xenon lamp with a wavelength range of375 to 800 nm (the spectral output is shown in Fig. S1). Alow-pass optical filter was employed to block wavelengths below400 nm. The light intensity was maintained at 0.65 W/cm2.The effect of the light wavelength on the catalytic performancewas investigated using various light-emitting diode (LED)lamps with different wavelengths. After reaction, the mixture was diluted with dichloromethane(DCM, 10 mL). The organic phase was extracted andfiltered through a millipore filter (pore size: 0.22 μm). Then, 0.5mmol of n-dodecane was added as an internal standard. Theproduct yield was determined by gas chromatography-massspectrometry (GC-MS, Bruker Scion SQ 456) using n-dodecaneas the internal calibration standard. The reported values arethe average of two experiments. The yields were calculatedbased on the amount of aryl halide. The residue was purified bycolumn chromatography on silica gel (200-300 mesh; eluant:hexane/ethyl acetate) to isolate the desired product. |
75% | With tetrabutylammonium bromide; C55H46N4O4W; potassium carbonate In acetonitrile at 20℃; for 12h; Irradiation; | |
72% | With cerium(III) trichloride; Etamon chloride In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Sealed tube; | |
72% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate In N,N-dimethyl-formamide at 100℃; for 4h; | 1 Step 1: methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate A mixture of methyl 4-bromobenzoate (5.0 g, 23.25 mmol), Bis(pinacolato)diboron (7.67 g, 30.23 mmol), Pd(dppf)Cl2·CH2Cl2(950 mg, 1.16 mmol), and KOAc (6.84 g, 69.75 mmol) in DMF (50 mL) was stirred at 100 for overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous Na2SO4and concentrated under reduced pressure. Purification by silica gel column chromatography using ethyl acetate/hexane as the eluent to afford the title compound (4.4 g, 72%). |
66% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); anhydrous potassium acetate In neat (no solvent) at 110℃; for 24h; | 3.1. Miyaura borylation General procedure: Under atmospheric conditions, a 10-mL screwcap vial equipped with a magnetic stir bar was charged with Pd source (0.01 mmol, 0.02 equiv), base (0.6 mmol, 1.2 equiv), bis(pinacolato)diboron (0.525 mmol, 1.05 equiv) and aryl halide (0.5 mmol, 1 equiv). The reaction vial was transferred to a preheated oil bath. The reaction was stirred at 110 °C for the desired time to give a grey mixture. The reaction mixture was extracted with 10 mL of ethyl acetate, washed with water (2 × 15 mL), brine (10 mL), and dried over Na2SO4. The solvent was evaporated in vacuo to afford the crude product. The product yield was determined by GC-FID based on integration relative to hexamethylbenzene as an internal standard. The residue was purified by column chromatography on silica gel (eluting with 5:95 ethyl acetate in hexane) to give pure aryl boronic ester. |
65% | Stage #1: 4-methoxycarbonylphenyl bromide In 1,4-dioxane for 0.166667h; Inert atmosphere; Stage #2: 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4',4',5',5'-tetramethyl-1,3,2-dioxaborolane With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); anhydrous potassium acetate In 1,4-dioxane at 90℃; for 12h; | 22 Example 22: Synthesis of 4-(4-(2-(l-cyclopropyl-lH-pyrazol-3-yl)-6,7-dihydro-5H-pyrrolo[l,2- a]imidazol-3-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide (88) A solution of bromide lvii (5 g, 23.3 mmol) in l,4-dioxane (150 mL) is degassed under nitrogen atmosphere for 10 minutes. Potassium acetate (8 g, 81.6 mmol), (0278) bis(pinacolato)diboron (7 g, 27.6 mmol), and [1,1’- bis(diphenylphosphino)ferrocene]dichioropalladium(II) (Pd(dppf)Cl2) (1.7 g, 2.3 mmol) are added. The mixture is heated to 90 °C for 12 hours, then concentrated under vacuum. The residue is purified by flash column chromatography (15% ethyl acetate in petroleum ether) to give dioxaborolane lviii (4 g, 15.3 mmol) as an off-white solid in 65% yield. |
60% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); anhydrous potassium acetate In 1,4-dioxane at 80℃; for 4h; | |
With anhydrous potassium acetate In dimethyl sulfoxide | 12.A Step A. Step A. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester 4-Bromo benzoic acid methyl ester (20.0 g, 93.0 mmol), bis(pinacolato)diboron (26.0 g, 102 mmol), potassium acetate (27.4 g, 279 mmol) and dichloro[1,1'-bis(diphenylphosphino) ferrocene]palladium (II) dichloromethane adduct (2.28 g, 2.79 mmol) were combined in anhydrous dimethyl sulfoxide (465 mL) and heated to 80° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and filtered through silica gel. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (22 g) as an oil, which was recrystallized from pentane (-20° C.), m.p. 79° C. 1H NMR (CDCl3, 400 MHz): 8.03-8.01 (m, 2H), 7.88-7.86 (m, 2H), 3.92 (s, 3H), 1.36 (s, 12H). Anal. Calcd for C14H19BO4: C 64.15, H 7.31. Found: C 64.30, H 7.20. MS [EI, m/z]: 262 [M]+. Calcd. for C14H19BO4: 262.138. | |
With anhydrous potassium acetate In dimethyl sulfoxide | 7.A Step A. Step A. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic Acid Methyl Ester 4-Bromo benzoic acid methyl ester (20.0 g, 93.0 mmol), bis(pinacolato)diboron (26.0 g, 102 mmol), potassium acetate (27.4 g, 279 mmol) and dichloro[1,1'-bis(diphenylphosphino) ferrocene]palladium (II) dichloromethane adduct (2.28 g, 2.79 mmol) were combined in anhydrous dimethyl sulfoxide (465 mL) and heated to 80° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and filtered through silica gel. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (22 g) as an oil, which was recrystallized from pentane (-20° C.), m.p. 79° C. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.01 (m, 2H), 7.88-7.86 (m, 2H), 3.92 (s, 3H), 1.36 (s, 12H). Anal. Calcd for C14H19BO4: C, 64.15; H, 7.31. Found: C, 64.30; H, 7.20. MS [EI, m/z]: 262 [M]+. Calcd. for C14H19BO4: 262.138. | |
With anhydrous potassium acetate In N,N-dimethyl-formamide at 20 - 80℃; for 4.5h; | VI-3.1 A mixture of bis(pinacolato)diboron (0.35 g, 1.4 mmol), methyl 4-bromobenzoate (0.30 g, 1.4 mmol), palladium(II) acetate (0.01 g, 0.04 mmol), and KOAc (0.41 g, 4.2 mmol) in DMF (7.5 mL) was degassed with argon for 30 min at it. The mixture was then heated at 8O0C for 4 h. EPO After the mixture was cooled to rt, N-(4-bromophenyl)-6-fluoro-l,3-benzothiazol-2-amine (0.45 g, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.05 g, 0.04 mmol), and saturated aqueous NaHCO3 (5 mL) were added. The mixture was heated at 85°C overnight. Upon cooling to rt, the mixture was diluted with EtOAc. The combined organic phases were separated, dried over Na2SO4, and concentrated in vacuo. Purification by column chromatography (25% EtOAc in hexanes) yielded 0.094 g (18%) of the title compound. LC/MS m/z 379.3 (MH+); retention time 3.87 min. 1H NMR (400 MHz, CD3OD) δ 3.93 (s, 3H), 7.05 (t, IH), 7.39-7.81 (m, 8H), 8.03 (d, 2H). | |
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); anhydrous potassium acetate In dimethyl sulfoxide at 80℃; for 24h; Inert atmosphere; | ||
25 %Spectr. | With 1-(cyclopentadienyl)(4-benzyl-1-i-propyl-1,2,4-triazol-5-ylidene)nickel chloride; Cs2CO3 In tetrahydrofuran at 70℃; for 20h; Schlenk technique; Inert atmosphere; | |
2.01 g | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 90℃; for 6h; | 6.2 Step 2: The mixture of methyl 4-bromobenzoate (2.15 g, 10 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’- bi(1,3,2-dioxaborolane) (2.54 g, 10 mmol), Pd(dppf)C12 (816 mg, 1 mmol) and KOAc (1.96 g, 20 mmol) in Dioxane (150 mL) was stirred at 90°C for 6 hours. The mixture was diluted with DCM (200 mL), washed with water (50 mL x3) and brine (30 mL xl), dried over Na2SO4, filtered and concentrated. The cmde product was purified by silica gel column chromatography to afford the desired compound. Isolated weight: 2.01 g, yield: 77 % as a white solid. |
With tetrakis-(triphenylphosphine)-palladium; anhydrous potassium acetate | ||
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 100℃; for 16h; Inert atmosphere; | 206.1a Step la: Preparation of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate mixture of methyl 4-bromobenzoate (2.00 g, 9.30 mmol), Bispin (2.83 g, 11.2 mmol), Pd(dppf)Cl2 (680 mg, 0.930 mmol) and KOAc (2.74 g, 27.9 mmol) in anhydrous dioxane (20 mL) was degassed and purged with N2 for 3 times. And the resulting mixture was stirred at 100 °C for 16 hours under N2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 58% (Rt = 0.993 min; MS Calcd: 262.1 ; MS Found: 262.9 [M+H]+). The reaction mixture was filtered through a pad of celite, and the solid was washed with EtOAc (100 mL), the filtrate was concentrated under reduced pressure to give methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (crude), which was used for the next step without further purification. | |
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; | 73 Synthesis of 73.1. To a stirred solution of methyl 4- bromobenzoate (500mg, 2.32mmol, l.Oeq) and Bis(pinacolato)diboron (1.47g, 5.81mmol, 2.5eq) in dioxane (8mL) and H2O (2mL) (4: 1) was added potassium acetate (1.3g, 13.9mmol, 6.0eq). The reaction mixture was degassed for lOmin under argon atmosphere. Then PdChdppf (340mg, 0.46mmol, 0.2eq) was added to the reaction mixture and degassed for another lOmin. The reaction mixture was heated at 90°C for 16h. After completion of the reaction, the reaction mixture was filtered through celite bed and the filtrate was diluted with ethyl acetate. Combined organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to provide 73.1 (600mg, crude) as a brown sticky solid. MS(ES): m/z 263.1 [M+H]+, LCMS purity 80% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A. 3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic Acid Methyl Ester 4-Bromo-3-methyl benzoic acid methyl ester (5.00 g, 21.8 mmol) and bis(pinacolato)diboron (6.09 g, 24.0 mmol) were reacted in the manner of Example 7, Step A. Recrystallization from pentane (-20 C.) afforded the title compound (5.59 g), m.p. 53-54 C. 1H NMR (CDCl3, 400 MHz): delta 7.83-7.81 (m, 1H), 7.80-7.79 (m, 2H), 3.91 (s, 3H), 2.57 (s, 3H), 1.36 (s, 12H). Anal. Calcd. for C15H21BO4: C, 65.24; H, 7.67. Found: C, 65.67; H, 7.54. MS [(+)-ESI, m/z]: 294.0 [M+NH4]+. Calcd, for C15H25BNO4: 294.191. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With sodium carbonate In ethanol; water; toluene at 100℃; for 18h; | 1.E Part E. Preparation of methyl 5'-(tert-butoxycarbonylamino)-3'-tert-butyl-2'-methoxy biphenyl-4-carboxylate.; [00722] Toluene (2ml) and ethanol (2ml) were combined with the product from Part E (281mg,0.78mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (411mg, 1.57mmol) and IM sodium carbonate (0.78ml, 0.78mmol) and de-gassed for 20min with N2. Tetrakis(triphenyl- phosphine)palladium(O) (18mg, O.Olβmmol) was added and de-gassing continued for 5-10min. Heated at1000C in a sealed tube for 18h, cooled and concentrated under vacuum. Purification by silica gel column chromatography eluting with EtOAc/hexanes gave the title compound (182mg, 56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate In 1,2-dimethoxyethane at 130℃; for 0.75h; Microwave irradiation; Saturated solution; | Synthesis of methyl 4-(3-formyl-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzoate; In a 20 ml microwave vial was combined 4-bromo-1-methyl-1-H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.5 g, 2.1 mmole), dimethoxyethane (8 mL), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.1 g, 4.2 mmole), saturated sodium carbonate (4.6 mL) and polymer supported triphenylphosphine palladium (0.38 g, 0.042 mmole; Biotage, 0.11 mmol/g). The mixture was then heated to 130° C. under microwave irradiation for 45 minutes, cooled then filtered through Celite and rinsed with warm methanol and water. The solution was concentrated to half the volume when solids formed. The solids were filtered, washed with water, dried in vacuo to afford 0.46 g (75%) of an off white solid. (M+H)+ 295.4. |
75% | With sodium carbonate In 1,2-dimethoxyethane at 130℃; for 0.75h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In tetrahydrofuran for 6h; Reflux; Inert atmosphere; | |
95% | In tetrahydrofuran for 5h; Inert atmosphere; Reflux; | |
92% | In diethyl ether at 20℃; for 18h; |
85% | In tetrahydrofuran for 2h; Reflux; | |
83% | In tetrahydrofuran at 70℃; for 5h; | |
76% | In acetone at 20℃; for 24h; | |
In diethyl ether at 20℃; Molecular sieve; | ||
In tetrahydrofuran at 70℃; for 2h; | 2.3.2 Synthesis of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 4-(Methoxycarbonyl)phenylboronic acid (20.5g, 114mmol), 2,3-dimethyl-2,3-butanediol (14.0g, 118mmol), and 500mL of dry THF were added into a 1000mL round-bottomed flask, and then the mixture was refluxed at 70°C for 2h. The solvent was evaporated under a reduced pressure, and the residue was purified by passing through an Al2O3 column with THF as the eluent. 1H NMR (400MHz, CDCl3, δ, ppm): 3.89 (s, 3H), 5.34 (d, 2H), 5.44 (d, 2H), 7.24-7.446 (d, 1H), 7.57 (q, 1H), 7.66 (d, 1H). | |
In ethyl acetate at 40℃; | ||
In diethyl ether at 20℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With potassium carbonate In ethanol; water; toluene at 100℃; for 12h; Inert atmosphere; | Synthesis of 4-(2-(2-Chloro-6-fluorophenyl)-5-cyano-lH-imidazol-4-yl)-N-(3- fluorophenvDbenzamide (Ex-168)[000306] To A solution of 4-bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazole-5- carbonitrile (1-10) (1.0 mmol) in a 2 : 1 : 1 toluene : ethanol : water solution (3.5 mL) was added methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (R-53) (1.45 mmol), Pd(PPh3)4 (0.017 mmol) and K2CO3 (2.0 mmol). The resulting suspension was bubbled with nitrogen and then heated at 100 0C for 12 hours. After cooled down to room temperature, the reaction mixture was extracted with EtOAc (3x 30 mL). The organics were combined and washed with water and brine, then dried over MgSO4. Purification by preparative ΗPLC (MeCN gradient 10 to 90 %) gave 4-(2-(2-chloro-6-fluorophenyl)-5-cyano-lH-imidazol-4- yl)benzoic acid (1-43) as white solid (20% yield). MS (m/z) (M+l)+: 342.0. [000307] To a solution of 4-(2-(2-chloro-6-fluorophenyl)-5-cyano-lH-imidazol-4- yl)benzoic acid (1-43) (0.03 mmol) in DMF (1 mL) was added ΗATU (0.06 mmol) and aniline (R-54) (0.04 mmol). The resulting solution was stirred at room temperature for 6 hours. After purification by preparative HPLC (MeCN gradient 10 - 90%) 4-(2-(2-chloro-6- fluorophenyl)-5-cyano- lH-imidazol-4-yl)-N-(3-fluorophenyl)benzamide (EX-171) was obtained as a white solid. 1H NMR (400MΗz, d6-OMSO) δ 10.6 (s, 1H),8.15 (m, 2H), 8.01 (m, 2H), 7.78 (dt, J = 12.0 , 2.4 Hz, IH), 7.70 (m, IH), 7.60 (m, 2H), 4.50 (m, IH), 7.41 (m, IH), 6.96 (m, IH). MS (m/z) (M+l)+: 435.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetrakis(triphenylphosphine) palladium(0); silver carbonate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; regioselective reaction; | 4.2.19. 4-Bromo-2',2,5’,5-tetramethoxy-4-methoxycarbonyl-(hexa-p-phenylene) (15) The reaction was carried out by following the rt-12 h procedure, using 12 (0.20 g, 0.30 mmol), 4-(methoxycarbonyl)phenyl boronic acid pinacol ester (3f, 0.052 g, 0.20 mmol), silver carbonate (0.11 g, 0.40 mmol), Pd(PPh3)4 (0.018 g, 0.016 mmol), and tetrahydrofuran (50 mL). Compound 15 was isolated by column chromatography (silica gel, cyclohexane/AcOEt 9.2/0.8) as a white solid (0.30 g, 78% yield), mp: 230 °C dec; 1H NMR (400 MHz, CDCl3) δ: 8.10 (d, 2H, J=8.4 Hz, ArH), 7.73-7.66 (m, 12H, ArH), 7.61 (d, 2H, J=8 Hz, ArH), 7.19 (s, 1H, ArH), 7.04 (s, 1H, ArH), 6.99 (s, 1H, ArH), 6.95 (s, 1H, ArH), 3.94 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3) ppm; 13C NMR (100 MHz, CDCl3) δ: 168.5 (CO), 150.9 (C), 150.8 (C), 150.7 (C), 150.4 (C), 143.0 (C), 139.9 (C), 139.7 (C), 139.6 (2×C), 137.2 (2×C), 136.8 (2×C), 129.9 (2×CH), 129.8 (C), 129.5 (3×CH), 129.4 (3×CH), 127.5 (3×CH), 126.8 (3×CH), 117.0 (CH), 114.8 (2×CH), 114.7 (2×CH), 114.5 (C), 57.0 (2×OCH3), 56.5 (OCH3), 56.5 (OCH3), 52.1 (OCH3) ppm; IR (KBr) ν: 1729 νCO cm-1; HRMS calcd for C42H35BrO6Na: 737.1515, Found: 737.1520. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With tetrakis(triphenylphosphine) palladium(0); silver carbonate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; regiospecific reaction; | 4.2.20. 4-Bromo-2',2,5’,5-tetramethyl-4-methoxycarbonyl-(hexa-p-phenylene) (16) The reaction was carried out by following the rt-12 h procedure, using 11 (0.46 g, 0.77 mmol), 4-(methoxycarbonyl)phenyl boronic acid pinacol ester (3f, 0.135 g, 0.51 mmol), silver carbonate (0.28 g, 1.02 mmol), Pd(PPh3)4 (0.047 g, 0.041 mmol), and tetrahydrofuran (50 mL). Compound 16 was isolated by column chromatography (silica gel, cyclohexane/CH2Cl2 9/1) as a white solid (0.18 g, 54% yield), mp: >300 °C dec; 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, 2H, J=8.6 Hz, ArH), 7.75 (s, 4H, ArH), 7.71-7.70 (m, 4H, ArH), 7.48-7.43 (m, 5H, ArH), 7.37 (d, 2H, J=8.6 Hz, ArH), 7.22 (s, 1H, ArH), 7.17 (s, 1H, ArH), 7.14 (s, 1H, ArH), 3.94 (s, 3H, COOCH3), 2.39 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.26 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3) δ: 168.4 (CO), 142.0 (C), 139.5 (C), 138.9 (C), 138.7 (C), 138.5 (C), 136.1 (2×C), 135.70 (C), 135.69 (C), 133.9 (2×C), 132.8 (C), 131.7 (C), 130.2 (2×CH), 129.9 (C), 129.8 (3×CH), 129.0 (3×CH), 128.1 (3×CH), 126.1 (3×CH), 119.5 (CH), 117.8 (2×CH), 114.9 (2×CH), 114.5 (C), 52.0 (OCH3), 29.2 (CH3), 23.5 (CH3), 19.5 (CH3), 14.2 (CH3) ppm; IR (KBr) ν: 1730 νCO cm-1; HRMS calcd for C42H35BrO2Na: 673.1718, Found: 673.1720. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 56% 2: 5% | With tetrakis(triphenylphosphine) palladium(0); silver carbonate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; regioselective reaction; | 4.2.13. 4-Bromo-4-methoxycarbonyl-p-terphenylene (5f) The reaction was carried out by following the rt-12 h procedure, using p-dibromobiphenyl (1, 0.40 g, 1.28 mmol), 4-(methoxycarbonyl)phenyl boronic acid pinacol ester (3f, 0.22 g, 0.85 mmol), silver carbonate (0.47 g, 1.70 mmol), Pd(PPh3)4 (0.08 g, 0.07 mmol), and tetrahydrofuran (40 mL). Compound 5f was isolated by column chromatography (silica gel, cyclohexane/AcOEt 9.8/0.2) as a white solid (0.17 g, 56% yield), mp: 120-123 °C; 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, 2H, J=8.2 Hz, ArH), 7.70-7.46 (m, 10H, ArH), 3.93 (s, 3H, COOCH3) ppm; 13C NMR (100 MHz, CDCl3) δ: 167.0 (CO), 142.2 (C), 140.1 (C), 140.0 (2×C), 131.3 (2×CH), 127.3 (C), 127.2 (2×CH), 127.0 (2×CH), 126.9 (4×CH), 121.0 (C), 120.8 (2×CH), 58.0 (OCH3); IR (KBr) ν: 1734 νCO cm-1; HRMS calcd for C20H15BrO2: 366.0255, Found: 366.0257. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydrogencarbonate In 1,4-dioxane at 100℃; for 1h; Inert atmosphere; Microwave irradiation; | 107 Intermediate 107Methyl 4-[(2S,4/?)-1 -acetyl-2-methyl-4-([(1 -methylethyl)oxy]carbonyl}amino)- tetrahydro-6-quinolinyl]benzoateA flask was charged with methyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (0.355 g, 1 .354 mmol), 1 -methylethyl [(2S,4R)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4- tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.5 g, 1 .354 mmol), a saturated NaHC03 aqueous solution (1 .5 mL, 1 .354 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(ll)-DCM adduct (0.1 1 1 g, 0.135 mmol) then filled with 1 ,4-dioxane (7 mL). The resulting mixture was degassed by bubbling nitrogen in to it, stirred at 100°C for 1 hr under microwave irradiation then cooled to room temperature. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was partitioned between EtOAC (30 mL) and water (30 mL) and the layers were separated. The organic phase was washed with brine (25 mL) dried over MgS04 and concentrated in vacuo to give methyl 4-[(2S,4/?)-1 -acetyl-2-methyl-4-([(1 - methylethyl)oxy]carbonyl}amino)-1 ,2,3,4-tetrahydro-6-quinolinyl]benzoate (0.47 g, 1.1 1 mmol, 82%) which was used in the next step without further purificationLCMS (method A): Retention time 1.09 min, [M+H]+ = 425.19 |
81% | With potassium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; | To a solution of isopropyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1 ,2,3,4-tetrahydroquinolin- 4-yl)carbamate (5 g, 13.54 mmol) and methyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (3.90 g, 14.89 mmol) in DME (50 mL) and water (10.0 mL) were successively added palladium tetrakis(triphenylphosphine) (1.565 g, 1.354 mmol) and potassium carbonate (5.61 g, 40.6 mmol). The resulting mixture was stirred at 100 °C for 1 h, whereupon it was allowed to cool down to room temperature and was filtered through Celite. The filtrated was concentrated in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (x3) and the combined organic layers were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The crude compound was purified by flash chromatography on a silica gel cartridge (50g) eluting with EtOAc in cyclohexane (5-60%). The appropriate fractions were combined and concentrated under reduced pressure to give methyl 4-((2S,4R)-1- acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1 ,2,3,4-tetrahydroquinolin-6-yl)benzoate (4.64 g, 81 %) as a white gum. LCMS (Formate, 2min), Rt=1 .09min, MH+ = 425. |
81% | With potassium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; | To a solution of isopropyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1 ,2,3,4-tetrahydroquinolin- 4-yl)carbamate (5 g, 13.54 mmol) and methyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzoate (3.90 g, 14.89 mmol) in DME (50 mL) and water (10.0 mL) were successively added palladium tetrakis(triphenylphosphine) (1.565 g, 1.354 mmol) and potassium carbonate (5.61 g, 40.6 mmol). The resulting mixture was stirred at 100 °C for 1 h, whereupon it was allowed to cool down to room temperature and was filtered through Celite. The filtrated was concentrated in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (x3) and the combined organic layers were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The crude compound was purified by flash chromatography on a silica gel cartridge (50g) eluting with EtOAc in cyclohexane (5-60%). The appropriate fractions were combined and concentrated under reduced pressure to give methyl 4-((2S,4R)-1- acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1 ,2,3,4-tetrahydroquinolin-6-yl)benzoate (4.64 g, 81 %) as a white gum. LCMS (Formate, 2min), Rt=1 .09min, MH+ = 425. |
81% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 100℃; for 1h; | 19 Intermediate 19 Methyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate Intermediate 19 Methyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate [0201] [0202] To a solution of isopropyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (5 g, 13.54 mmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.90 g, 14.89 mmol) in DME (50 mL) and water (10.0 mL) were successively added palladium tetrakis(triphenylphosphine) (1.565 g, 1.354 mmol) and potassium carbonate (5.61 g, 40.6 mmol). The resulting mixture was stirred at 100° C. for 1 h, whereupon it was allowed to cool down to room temperature and was filtered through Celite. The filtrated was concentrated in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified by flash chromatography on a silica gel cartridge (50 g) eluting with EtOAc in cyclohexane (5-60%). The appropriate fractions were combined and concentrated under reduced pressure to give methyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (4.64 g, 81%) as a white gum. LCMS (Formate, 2 min), Rt=1.09 min, MH+=425. |
With sodium hydrogencarbonate In 1,4-dioxane at 100℃; for 1h; Inert atmosphere; Microwave irradiation; | 107 A flask was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.355 g, 1.354 mmol), 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.5 g, 1.354 mmol), a saturated NaHCO3 aqueous solution (1.5 mL, 1.354 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM adduct (0.111 g, 0.135 mmol) then filled with 1,4-dioxane (7 mL). The resulting mixture was degassed by bubbling nitrogen in to it, stirred at 100° C. for 1 hr under microwave irradiation then cooled to room temperature. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was partitioned between EtOAC (30 mL) and water (30 mL) and the layers were separated. The organic phase was washed with brine (25 mL) dried over MgSO4 and concentrated in vacuo to give methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-([(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (0.47 g, 1.11 mmol, 82%) which was used in the next step without further purificationLCMS (method A): Retention time 1.09 min, [M+H]+=425.19 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane; water for 3h; Inert atmosphere; Reflux; | |
40% | With sodium carbonate In 1,4-dioxane for 2h; Reflux; | 1-1.5 To a dioxane (100 mL) solution of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5.24 g, 20 mmol), 3-bromo-8-(methylthio)imidazo[1,2-a]pyrazine (119 mg, 1.00 mmol) and sodium carbonate (4.24 g, 40 mmol), PdCl2(dppf) (1.60 g, 2.0 mmol) was added and stirred for 2 hours while heating under reflux. To the reaction solution, water and ethyl acetate were added to separate phases. The water phase was extracted with ethyl acetate and organic phases were combined, washed with saturated sodium bicarbonate water and saturated saline, and dried over magnesium sulfate. The organic phase was filtrated and then concentrated under reduced pressure. The resultant residue was purified by medium-pressure silica gel chromatography (hexane:ethyl acetate=4:1) to obtain the titled compound (2.39 g, 40%) as a white solid substance.MS (ESI) m/z=300 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tert.-butylnitrite; eosin In acetonitrile at 20℃; for 2h; Irradiation; | General experimental procedure for the synthesis of aryl and hetero-aryl boronates.representative procedure for the synthesis of 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: General procedure: tert-Butyl nitrite (155 mg, 1.1 mmol) wasadded drop wise to a mixture of bis(pinacolato)diborane (127 mg, 0.5 mmol),4-anisidine (61 mg, 0.5 mmol) and eosin Y (0.01 mmol) in acetonitrile (3 mL).The resulting mixture was stirred at room temperature under irradiation withblue LED for 2 h (TLC). This mixture after being diluted with ethyl acetate(5 mL) was ltered through celite and the ltrate was extracted with ethylacetate (3 10 mL). The extract was washed with brine, dried over anhydrousNa 2 SO 4 , and evaporated to leave the crude product which was puried bycolumn chromatography over silica gel with hexane-ethyl acetate (98:2) aseluent to furnish pure 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a light yellow viscous liquid (3d, 208 mg, 88%); IR (neat)2978, 2933, 2839, 2526, 2050, 1950, 1911, 1724, 1605, 1570 cm1;1H NMR(500 MHz, CDCl 3 ) d 1.33 (s, 12H), 7.82 (s, 3H), 6.89 (d, J = 8.0 Hz, 2H), 7.75 (d,J = 8.0 Hz, 2H);13C NMR (125 MHz, CDCl 3 ) d 24.9 (4C), 55.2, 83.6 (2C), 113.4(2C), 136.6 (2C), 162.3. The spectroscopic data is in full agreement with thosereported for an authentic sample.14This procedure was followed for all thereactions listed in Table 2. All of these products (3a,143b,143c,16a3d,143e,143f,8a3g,143h,143i,143j,8a3k,8a3l,8a3m,143n,8c3o,16b) are known compounds,and their spectroscopic data are in agreement with those previously reported. |
72% | Stage #1: 4-methoxycarbonyl aniline With hydrogenchloride; sodium nitrite In water at 0 - 5℃; Stage #2: With sodium tetrafluoroborate In water at 5℃; Stage #3: bis(pinacol)diborane With copper(I) bromide In water; acetonitrile at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tris-(dibenzylideneacetone)dipalladium(0); water; cesium fluoride; copper(l) chloride; XPhos In N,N-dimethyl-formamide at 65℃; for 16h; Inert atmosphere; | |
40% | With tris-(dibenzylideneacetone)dipalladium(0); cesium fluoride; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; copper(l) chloride In 1,4-dioxane; water at 65℃; Inert atmosphere; | INTERMEDIATE C11 Synthesis of methyl 4-(2,2,2-trifluoroethyl)benzoate (Intermediate Cll) A mixture of (4-carbomethoxyphenyl)boron pinacolate (1.0 g, 3.82 mmol), 1,1,1-trifluoro-2-iodoethane (1.6 g, 7.6 mmol), Pd2(dba)3 (175 mg, 191 umol), xantphos (221 mg, 382 umol), CuCl (38 mg, 382 umol) and CsF (1.74 g, 1 1.5 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred under N2 atmosphere at 65°C overnight. The mixture was cooled to rt and filtered; the filtrate was concentrated in vacuo. The residue was dissolved in DCM (100 mL), washed with FLO (50 mL), and brine (50 mL), then dried over Na2S04. The solution was concentrated in vacuo, and purified by silica gel column chromatography (pet. ether / EtO Ac = 10 /l) to afford Intermediate Cll (330 mg, 40 % yield) as a light yellow solid. TLC: EtOAc/pet. ether =l/5(v/v), Rf=0.82 1H NMR: (400 MHz, DMSO-d6) d 7.97 (d, J= 8.1 Hz, 2H), 7.52 (d, J= 7.9 Hz, 2H), 3.86 (s, 3H), 3.78 (q, J= 11.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 6-chloro-3-fluoro-4-iodo-9H-pyrrolo[2,3-b:5,4-c']dipyridine; methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate With caesium carbonate In 1,4-dioxane; water for 18 - 20h; Reflux; Stage #2: With water; sodium hydroxide In 1,4-dioxane for 1h; Reflux; | 97 625 mg of 6-chloro-3-fluoro-4-iodo-9H-dipyrido[2,3-b:4',3'-d]pyrrole 96, 1.415 g of 4-methoxycarbonylphenylboronic acid pinacol ester, 208 mg of tetrakis(triphenyl-phosphine)palladium(0), 1.76 g of caesium carbonate in 40 ml of 1,4-dioxane and 8 ml of water are placed in a three-necked flask, and the mixture is then refluxed for 18-20 hours. 4 ml of aqueous 1N sodium hydroxide solution are added to the reaction medium, and the resulting mixture is refluxed for a further one hour. After cooling, the reaction medium is poured into a mixture of water and ethyl acetate with vigorous stirring. The phases are separated and the pH of the aqueous phase is then brought to 4 by adding aqueous hydrochloric acid solution. The precipitate that forms during this acidification is filtered off, drained by suction and dried under vacuum. 540 mg (88%) of 4-[3-fluoro-6-chloro-9H-pyrrolo[2,3-b:5,4-c']dipyridin-4-yl]benzoic acid 97 are thus obtained,UPLC-MS-DAD-ELSD: Tr (min)=0.73; [M-H]- m/z 340.08 and 342.02 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium carbonate; XPhos In 1,4-dioxane; water at 100℃; for 16h; Inert atmosphere; | 60.4 Step 4 (S)-Methyl 4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate Procedure The mixture of (S)-5-chloro-N-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.53 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (153 mg, 0.585 mmol), Pd2(dba)3 (61 mg, 0.11 mmol), X-Phos (102 mg, 0.21 mmol) and Na2CO3 (169 mg, 1.6 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford (S)-methyl 4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (121 mg, 48%) as yellow oil. LC-MS: 476 [M+H]+, tR=1.999 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 0.0833333h; Inert atmosphere; | 6 (Comparative Example 6); In Comparative Example 6, synthesis of p-[18F]fluoromethyl benzoic acid methyl (2) was carried out using [18F]FCH2I as the fluorine source according to the following synthesis route (Formula 5). The details are shown below. [Show Image] 18F]FCH2I> Synthesis of [18F]FCH2I that is the substrate of [18F]fluoromethylation was carried out as follows using a labeling synthesis device (manufactured by Sumitomo Heavy Industries, Ltd.) shown in Fig. 10. Water containing [18F] fluorine ions was produced by irradiating 12 MeV electron beam (current value 30 µA, irradiation time 10 minutes) to [18O] water (manufacture by TAIYO NIPPON SANSO CORPORATION, about 2 mL), using an accelerator cyclotron (HM-12S, manufactured by Sumitomo Heavy Industries, Ltd.) not shown. The aqueous [18O] solution containing about 10 GBq of [18F] fluorine ions thus obtained was transferred into the labeling synthesis device shown in Fig. 10, which was arranged in a hot cell not shown, and adsorbed to an anion exchange resin cartridge (Sep-Pak light Accell plus QMA Cartridges, manufactured by Waters). [18F]KF was eluted into this cartridge through an aqueous acetonitrile solution (acetonitrile:water = 700 µL: 200 µL solution, 1 mL) containing Kryptofix 222 (K.222) (about 20 mg) and potassium carbonate (about 5 mg) and added to the primary reaction container. This solution was heated from 100 to 130°C under reduced pressure with flowing a N2 gas and solidified with drying. Subsequently, acetonitrile (1 mL) was added to azeotropically dry remaining water. An acetonitrile (0.6 mL) solution containing CH2I2 (about 50 µL) was added to the obtained residue, and [18F]FCH2I was synthesized with paying attention not to bumping under heating at 130°C. While the evaporated gas under the heating was pushed away with a N2 gas, CH2I2 being the raw material, acetonitrile being the solvent, and the desired [18F] FCH2I were separated through a three-connected ion liquid vials (1-butyl-3-methylimidazolium trifluoromethanesulfonate 2 mL×2, 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide 1.5 mL×1). Almost all of CH2I2 being the raw material and acetonitrile being the solvent could be removed according to the operation. Note that the time for the serial operations of synthesis of [18F]FCH2I was about 40 minutes until separation and purification of [18F]FCH2I starting from supply of [18F]F- from the cyclotron. Then, [18F] FCH2I (about 126 MBq: generally 100 to 300 MBq) was blown into 0.5 mL of a DMF solution that has been contained in the secondary reaction container in advance, and the obtained solution was transferred into the third reaction container containing the organoboron compound 1 (32 µmol), Pd2(dba)3(3.2 µmol), P(o-CH3C6H4)3 (19 µmol), and K2CO3 (3.6 µmol) and reacted at 65°C for 5 minutes. A part of the reaction solution was extracted to carry out a HPLC analysis. As a result, as shown in Fig. 1, a HPLC analytical yield of the desired product 2 was as low as 23%, and peaks of by-products (indicated with small arrows) were large. HPLC analysis conditions: COSMOSIL AR-II 4.6 x 150 mm column manufactured by NACALAI TESQUE, INC., column temperature at 30°C, eluate CH3CN:H2O=45:55, 1 mL/min flow rate, retention time of the desired product 2 for 6.5 to 7.5 minutes. | |
23 %Chromat. | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 65℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In 1,4-dioxane; water at 20 - 96℃; Inert atmosphere; | 11.1 Step 1Methyl 4-(8-bromo-[1,2,4]-triazolo[1,5-a]pyridin-6-yl)benzoate Procedure:To a stirred solution of 8-bromo-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (1.29 g, 3.98 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.05 g, 4 mmol) and sodium carbonate (1.53 g, 14.4 mmol) in water (10 mL) and dioxane (150 mL) at room temperature under nitrogen was added Pd(PPh3)4 (0.46 g, 0.37 mmol) in one portion. Then the reaction mixture was degassed by bubbling nitrogen for six minutes and then stirred at 96° C. for 24 h. The solvent was evaporated at 40° C. at reduced pressure and the residue was filtered through a plug of silica gel. The filter cake was washed with ethyl acetate/petroleum ether (1:2, v/v) and the combined filtrates concentrated to give crude methyl 4-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzoate (0.818 g, 61.9%) as a solid. This was used directly without further purification. LC/MS: 331.8 [M+H]+. | |
With sodium carbonate In 1,4-dioxane; water at 96℃; for 24h; Inert atmosphere; | 11.1 To a stirred solution of 8-bromo-6-iodo-[l,2,4]triazolo[l,5-a]pyridine (1.29 g, 3.98 mmol), methyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzoate (1.05 g, 4 mmol) and sodium carbonate (1.53 g, 14.4 mmol) in water (10 mL) and dioxane (150 mL) at room temperature under nitrogen was added Pd(PPh3)4 (0.46 g, 0.37 mmol) in one portion.Then the reaction mixture was degassed by bubbling nitrogen for six minutes and then stirred at 96°C for 24 h. The solvent was evaporated at 40°C at reduced pressure and the residue was filtered through a plug of silica gel. The filter cake was washed with ethyl acetate / petroleum ether (1 :2, v/v) and the combined filtrates concentrated to give crude methyl 4-(8-bromo-[l,2,4]triazolo[l,5-a]pyridin-6-yl)benzoate (0.818 g, 61.9 %) as a solid. This was used directly without further purification. LC/MS: 331.8 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; XPhos In 1,4-dioxane; water at 10 - 97℃; for 16.16h; Inert atmosphere; | 14.1 Step 1Methyl 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzoate Procedure:To a stirred solution of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (0.126 g, 0.38 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.151 g, 0.57 mmol), X-Phos (0.052 g, 0.11 mmol), sodium carbonate (0.120 g, 1.13 mmol) in water (1 mL) and dioxane (15 mL) was added Pd2(dba)3 (0.026 g, 0.028 mmol) in one portion under nitrogen at room temperature. Then the reaction mixture was degassed by bubbling nitrogen for 10 minutes and then stirred at 97° C. for 16 h under nitrogen. The solvent was evaporated at 40° C. at reduced pressure and the residue filtered through a plug of silica gel. The cake was washed with ethyl acetate/petroleum ether (1:3, v/v) then the combined filtrates concentrated to give crude methyl 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)benzoate (0.150 g, 91.4%) as a yellow solid. This was used directly without further purification. LC/MS: 429.1 [M+H]+. | |
With sodium carbonate; XPhos In 1,4-dioxane; water at 97℃; for 16h; Inert atmosphere; | 14.1 To a stirred solution of 6-chloro-N-(6-(2-methylpyrrolidin-l-yl)pyridin-2-yl)- [l,2,4]triazolo[l,5-a]pyridin-8-amine (0.126 g, 0.38 mmol), methyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (0.151 g, 0.57 mmol), X-Phos (0.052 g, 0.11 mmol), sodium carbonate (0.120 g, 1.13 mmol) in water (1 mL) and dioxane (15 mL) was added Pd2(dba)3 (0.026 g, 0.028 mmol) in one portion under nitrogen at room temperature. Then the reaction mixture was degassed by bubbling nitrogen for 10 minutes and then stirred at 97°C for 16 h under nitrogen. The solvent was evaporated at 40°C at reduced pressure and the residue filtered through a plug of silica gel. The cake was washed with ethyl acetate / petroleum ether (1:3, v/v) then the combined filtrates concentrated to give crude methyl 4-(8-(6-(2-methylpyrrolidin-l-yl)pyridin-2-ylamino)- [l,2,4]triazolo[l,5-a]pyridin-6-yl)benzoate (0.150 g, 91.4 %) as a yellow solid. This was used directly without further purification. LC/MS: 429.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With caesium carbonate In 1,4-dioxane; water at 120℃; for 0.333333h; Microwave irradiation; | 23 Example 23. Synthesis of 4H-[l,2,4]triazolo[4,3-a][l,5]benzodiazepine,5,6- dihydro-l-methyl-8- (4-carboxy-phenyl)-6-(4-chloro-phenyl) (Compound 20). A mixture of 4H-[l,2,4]triazolo[4,3-a][l,5]benzodiazepine,5,6-dihydro-l-methyl-8-bromo -6-(4-chloro- phenyl) (Compound 13; 60 mg, 0.15 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzoate (81 mg, 0.30 mmol), and cesium carbonate (98 mg, 0.30 mmol) in dioxane (2 mL) and water (1 mL) was heated at 120°C for 20 minutes under microwave (pressure: 17.2 bar, equipment power : 150W). The solid was filtered and the filtrate was concentrated to give a residue. To the residue, ethyl acetate (30 mL) was added and the mixture was washed with brine (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give a residue, which was purified by column chromatography (silica gel, dichloromethane/methanol = 10:1) to afford 4H-[l,2,4]Triazolo[4,3-a][l,5]benzodiazepine, 5,6-dihydro-l-methyl-8- (4-carboxy- phenyl)-6-(4-chloro-phenyl) as a white solid (30 mg, 47 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; XPhos In 1,4-dioxane; water at 100℃; for 4h; Inert atmosphere; | 14.1 Step 1 Methyl 4-(6-aminopyridazin-3-yl)benzoate A mixture of 6-chloropyridazin-3-amine (3.24 g, 25 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (9.8 g, 37.4 mmol), Pd2(dba)3 (0.72 g, 1.25 mmol), X-phos (1.19 g, 2.5 mmol) and Na2CO3 (7.95 g, 75 mmol) in dioxane (150 mL) and water (15 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give methyl 4-(6-aminopyridazin-3-yl)benzoate (2.8 g, 48%) as a white solid. LC-MS: [M+H]+, 230.1, tR=1.213 min. |
48% | With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; XPhos In 1,4-dioxane; water at 100℃; for 4h; Inert atmosphere; | 14.1 Methyl 4-f6-aminopyridazin-3-yl)benzoate A mixture of 6-chloropyridazin-3 -amine (3.24 g, 25 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (9.8 g, 37.4 mmol), Pd2(dba)3 (0.72 g, 1.25 mmol), X-phos (1.19 g, 2.5 mmol) and Na2C03 (7.95 g, 75 mmol) in dioxane (150 mL) and water (15 mL) was heated to 100 °C with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200 - 300 mesh, CH2C12 : MeOH = 20 : 1) to give methyl 4-(6-aminopyridazin-3-yl)benzoate (2.8 g, 48 %) as a white solid. LC-MS: [M+H]+, 230.1, tR = 1.213min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; C50H44CuN4OP2(1+)*F6P(1-); N-ethyl-N,N-diisopropylamine In water; acetonitrile at 20℃; for 12h; Inert atmosphere; Irradiation; | |
85% | With fac-tris(2-phenylpyridinato-N,C2')iridium(III); tributyl-amine; water In acetonitrile at 25℃; for 24h; Schlenk technique; Inert atmosphere; Sealed tube; Irradiation; | |
83% | With potassium acetate In N,N-dimethyl-formamide at 30℃; for 3h; Inert atmosphere; Irradiation; | 2.3. General procedure for photocatalytic reactions General procedure: Unless specified otherwise, all reactions were conducted in ambient Ar atmosphere at 30 °C. A mixture of aryl halides (1mmol), B2pin2 (1.2 mmol, 305 mg), base (1 mmol, 98 mg), andPd/SiC catalyst (40 mg) was suspended in 10 mL ofN,N-dimethylformamide (DMF) in an oven-dried 25 mL quartzvial equipped with a magnetic stirring bar. During the reaction,the mixture was stirred at 500 rpm using a magnetic stirrerand then exposed to a xenon lamp with a wavelength range of375 to 800 nm (the spectral output is shown in Fig. S1). Alow-pass optical filter was employed to block wavelengths below400 nm. The light intensity was maintained at 0.65 W/cm2.The effect of the light wavelength on the catalytic performancewas investigated using various light-emitting diode (LED)lamps with different wavelengths. After reaction, the mixture was diluted with dichloromethane(DCM, 10 mL). The organic phase was extracted andfiltered through a millipore filter (pore size: 0.22 μm). Then, 0.5mmol of n-dodecane was added as an internal standard. Theproduct yield was determined by gas chromatography-massspectrometry (GC-MS, Bruker Scion SQ 456) using n-dodecaneas the internal calibration standard. The reported values arethe average of two experiments. The yields were calculatedbased on the amount of aryl halide. The residue was purified bycolumn chromatography on silica gel (200-300 mesh; eluant:hexane/ethyl acetate) to isolate the desired product. |
82% | With potassium methanolate; [1,3-bis(2,4,6-trimethylphenyl)imidazol]-2-ylidene; zinc dibromide In tert-butyl methyl ether at 20℃; for 8h; Inert atmosphere; Glovebox; Schlenk technique; Green chemistry; | |
81% | With copper(l) iodide; palladium diacetate; caesium carbonate; triphenylphosphine In acetonitrile at 20℃; for 24h; chemoselective reaction; | |
81% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere; | Methyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (27) Methyl 4-iodobenzoate (1.57 g, 6.00 mmol), B2Pin2 (1.68 g, 6.60 mmol), KOAc (1.77 g, 18.0 mmol) and Pd(dppf)Cl2.CH2Cl2(0.147 g, 0.18 mmol) were added to anhydrous DMSO (12 mL, degassed via freeze-pump-thaw) under Ar. The resultant suspension was then stirred at 80 °C overnight. The mixture was cooled, diluted with H2O and extracted with EtOAc (3×). The organics were washed with H2O and brine, dried (MgSO4) and evaporated to give a crude solid (2.0 g). The crude solid was distilled under vacuum using a Kugelrohr (130-140 °C, 0.64 Torr) to give a white solid which was then recrystallised from MeOH at -20 °C to give compound 27 as a colourless crystalline solid (1.27 g, 81%); m.p. 77-78 °C; 1H NMR (700 MHz; CDCl3) δ 1.35 (s, 12H) 3.91 (s, 3H), 7.85-7.89 (m, 2H), 8.00-8.04 (m, 2H); 13C NMR (176 MHz; CDCl3) δ 25.1, 52.3, 84.4, 128.8, 132.5, 134.9, 167.3; 11B NMR (128 MHz, CDCl3) δ 30.63; IR (neat) max/cm-12980w, 2955w, 2935w, 1719s, 1507m, 1398s, 1359s, 1267s, 707s; MS(EI): m/z = 262.1 [M]+; Found: C, 64.32; H, 7.27. Calc. for C14H19BO4: C, 64.15; H, 7.31% [10]. |
81% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium acetate In 1,4-dioxane for 24h; Inert atmosphere; Sealed tube; chemoselective reaction; | |
75% | With silver fluoride In acetonitrile at 20℃; Sealed tube; UV-irradiation; Inert atmosphere; | 2.3. General procedure for the photo-driven reactions General procedure: To a 10 mL Pyrex reaction vial were added 20 mg of organichalide, 2.5 eq of B2pin2, 20 mg of silver(I) salt and 2.0 mL of MeCN. n-C12H26 was added as an internal standard of GC as necessary. Thevial was sealed with a butyl rubber stopper and then purged withN2. The vial was half immersed in a water bath to maintain roomtemperature and irradiated from the side. After every certain interval,ca. 1.0 μL of the solution was withdrawn and analysed with GCor GC-MS to check the products and the reaction kinetics. To isolatethe products, the dispersion was filtered with celite and thenthe filtrate was purified by column chromatography. For thegram-scale reaction, 1.0 g of 1, 2.5 eq of B2pin2 and 1.0 g of AgFwere dispersed in 60 mL of MeCN. The reaction was performedon the building roof for sunlight irradiation from 10:00 to 15:00.The ambient temperature was 25 - 35 °C. |
74% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | synthesis of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (12) To a solution of methyl-4-iodobenzoate (500 mg, 1.91 mmol) in anhydrous dimethylformamide (5mL) were added PdCl2(dppf)2 (0.191 mmol), potassium acetate (5.73 mmol) andbis(pinacolato)diboron (2.10 mmol) under argon atmosphere. The reaction mixture was heated to80oC and stirred overnight. The reaction mixture was diluted with ethyl acetate and filtered throughCelite. The filtrate was washed with 0.1 M Na2S2O3, saturated NaHCO3, and brine. The organiclayer was dried with anhydrous MgSO4 and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel (ethyl acetate : hexane = 1 : 30 to 1: 20 to 1 : 10) to give 12 (74%). 1H-NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H), 7.86 (d, J= 8.2 Hz, 2H), 3.92 (s, 3H), 1.35 (s, 12H) 13C NMR (101 MHz, CDCl3) δ 167.21, 134.76, 132.42,128.69, 84.27, 52.22, 24.98. |
68% | With caesium carbonate In methanol for 34h; Reflux; Inert atmosphere; | |
63% | Stage #1: bis(pinacol)diborane With diethylzinc; sodium t-butanolate In tetrahydrofuran; hexane at 0 - 20℃; for 0.5h; Schlenk technique; Glovebox; Inert atmosphere; Stage #2: methyl 4-iodobenzoate In tetrahydrofuran; hexane at 20 - 75℃; for 24h; Schlenk technique; Glovebox; Inert atmosphere; Sealed tube; | |
62% | With p-phenylpyridine; potassium methanolate In tert-butyl methyl ether at 85℃; for 12h; Sealed tube; | |
61% | With lithium tert-butoxide In tetrahydrofuran at 60℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dichloro-ethane at 80℃; for 42h; Inert atmosphere; | 12.1 Stage 1. Methyl 4-{5-amino-6-[(2,6-dichlorobenzyl)am ino]pyrazin-2-yl}benzoate Stage 1. Methyl 4-{5-amino-6-[(2,6-dichlorobenzyl)am ino]pyrazin-2-yl}benzoate To a solution of Intermediate 1 (3.82 g, 11.0 mmol) in DME (75 mL) was added methyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (4.48 g, 16.5 mmol) and 2N Na2003 (13.7 mL, 27.4 mmol) and the solution was degassed by bubbling nitrogen through the reaction mixture. Dichlorobis (triphenylphosphine) palladium (II) (385 mg, 0.5 mmol) was added and the reaction was stirred at 80°C under a nitrogen atmosphere for 18 hrs. Another 0.05 eq of dichlorobis (triphenylphosphine) palladium (II) (385 mg, 0.5 mmol) was added and the reaction was stirred at 80°C under a nitrogen atmosphere for 24 hrs for complete reaction. The reaction mixture was filtered through Celite and the filter cake was washed with EtOAc (2 x 50 mL). The combined filtrates were washed with water (50 mL), brine (50 mL), dried over Mg504, filtered and concentrated in vacuo before purification by column chromatography (60% EtOAc/heptane) to give the title compound as a yellow/green solid (3.88 g,88%).LCMS: m/z 403/405 [M+H].1H NMR (300 MHz, CD3OD) ö ppm: 8.09-8.02 (4H, m), 7.82 (1H, 5), 7.47-7.44 (2H,m), 7.36-7.29 (1H, m), 5.00 (2H, 5), 3.92 (3H, 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With Pd(OTf)<SUB>2</SUB>(CH<SUB>3</SUB>CN)<SUB>4</SUB>; sodium hydrogencarbonate; N-acetyl-D-tert-leucine; silver carbonate; p-benzoquinone In tert-Amyl alcohol; water; dimethyl sulfoxide at 100℃; for 18h; Inert atmosphere; Schlenk technique; regioselective reaction; | Methods General procedure: In a 50 ml Schlenk tube, starting material 1 (49.8 mg, 0.2 mmol), 4-methoxycarbonylphenylboronic acid pinacol ester (2) (104.8 mg, 0.4 mmol),Pd(OTf)2(MeCN)4 (11.4 mg, 0.02 mmol), Ac-D-tLeu-OH (3) (6.9 mg, 0.04 mmol),NaHCO3 (100.8 mg, 1.2 mmol), Ag2CO3 (110.3 mg, 0.4 mmol) and 1,4-benzoquinone (10.8 mg, 0.1 mmol) were combined. The flask was evacuated and backfilled with N2 three times, before a solution of dimethylsulfoxide (DMSO,6.0 mg, 0.076 mmol), water (20 mg, 1.1 mmol) and t-amyl-OH (1 ml, 0.2 M) was added. The reaction mixture was then stirred at 100 8C for 18 hours. After being allowed to cool to room temperature, the mixture was diluted with a 1:1 mixture of hexanes:ethyl acetate, and filtered through a pad of celite. The filtrate was concentrated in vacuo, and the resulting residue purified by column chromatography using an eluent of hexanes:ethyl acetate. The product, 1b, was obtained as a light-yellow liquid (62.9 mg, 82%).The above procedure to prepare 1b is generally representative for all the products shown in Tables 3 and 4. Any deviations from this protocol are specified in the footnotes of the tables. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 0.333333h; Microwave irradiation; | 152 Example 152 : Compound 745[1243]methyl 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-(trifluoromethyl)biphenyl-4-carboxylate Example 152 : Compound 745[1243]methyl 3'-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-5'-(trifluoromethyl)biphenyl-4-carboxylate[1244]Starting material6d(0.050 g, 0.081 mmol), methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-yl)benzoate (0.043 g, 0.163 mmol), sodium carbonate (0.026 g, 0.244 mmol) and Pd(dbpf)Cl2(0.003 g, 0.004 mmol) were added to dimethylformamide (0.8 mL)/water (0.4 mL) and stirred with microwave irradiation at 100 for 20 minutes. Then, the reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate to remove water, and then concentrated under reduced pressure. The residue was purified by MPLC (SiO2, EtOAc/hexane = 0% ~ 20%) to obtain desired compound745(0.050 g, 86.0 %) as a white foam solid.[1245]1H NMR(400 MHz, CDCl3); δ 8.13 (m, 2H), 7.88 (m, 1H), 7.77-7.74 (m, 3H), 7.67-7.63 (m, 2H), 7.56 (s, 1H), 7.28 (m, 1H), 5.63 (d, 1H,J=7.7Hz), 4.13 (m, 1H), 3.97 (m, 4H), 3.66 (d, 1H,J=14.9Hz), 2.47-2.33 (m, 2H), 2.00 (s, 2H), 1.57 (t, 2H,J=6.2Hz), 1.07 (d, 6H,J=14.6Hz), 0.44 (d, 3H,J=6.3Hz)[1246]MS (ESI) m/z 714.2 (M++ H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I) In tetrahydrofuran at 70℃; for 16h; Inert atmosphere; Sealed tube; | Carboxylation of Arylboronic Esters with PMC; Typical Procedure General procedure: In a glovebox, Cu(IPr)Cl catalyst and PMC (62.8 mg, 0.55 mmol,1.1 equiv) were charged to a glass reaction tube. A solution of 3(0.50 mmol) in THF (1.5 mL) was added, the tube was sealed, taken out of the glovebox, and heated at 70 °C for 16 h. After cooling tor.t., H2O (2 mL) was added and the reaction mixture was acidified with aqueous HCl (1 M), and saturated with sodium chloride. After extraction with EtOAc (3 × 5 mL), the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuo. The product was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
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62% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; | 3.2 Preparation of methyl 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (Compound 3) Step 2. A microwave vial was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (147 mg, 0.561 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, the reaction vial was capped, and the reaction was heated at 140° C. for 30 min in a Biotage Initiator microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. A white solid formed, which was filtered and air-dried to give the title compound as a white solid (146 mg, 62%): mp 192-195° C.; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 8.19-8.12 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 7.45-7.38 (m, 2H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -85.90, -87.86; ESIMS m/z 414 ([M+H])+. |
62% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; | 3.2 Preparation of methyl 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (Compound 3) A microwave vial was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (147 mg, 0.561 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, the reaction vial was capped, and the reaction was heated at 140° C. for 30 min in a Biotage Initiator microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. A white solid formed, which was filtered and air-dried to give the title compound as a white solid (146 mg, 62%): mp 192-195° C.; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 8.19-8.12 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 7.45-7.38 (m, 2H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -85.90, -87.86; ESIMS m/z 414 ([M+H])+. |
62% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation; | 3.2 Preparation of methyl 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (Compound 3) A microwave vial was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (147 mg, 0.561 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, the reaction vial was capped, and the reaction was heated at 140° C. for 30 min in a Biotage Initiator microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. A white solid formed, which was filtered and air-dried to give the title compound as a white solid (146 mg, 62%): mp 192-195° C., 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 8.19-8.12 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 7.45-7.38 (m, 2H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -85.90, -87.86; ESIMS m/z 414 ([M+H])+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In tetrahydrofuran; water at 70℃; for 0.833333h; | 45A.5 Step 5 - Preparation of methyl 4-[6-(3,5-dimethylisoxazol-4-yl)-l-[phenyl(2- pyridyl)methyl]pyrrolo[3,2-b]pyridin-3-yl]benzoate (P-0610): To 4-[3-iodo- l-[phenyl(2- pyridyl)methyl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole (35, 0.45 g, 0.89 mmol) in THF (25 ml) were added [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 g, 0.07 mmol), methyl 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzoate (0.38 g, 1.45 mmol), and 1M potassium carbonate in water (10 ml). The reaction was heated to 70 °C for 50 minutes. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated, and purified by flash chromatography eluting with 20 - 100% ethyl acetate in hexane to give product (P-0610, 0.32 g, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In tetrahydrofuran; water at 70℃; for 2h; | 49.2 Step 2 - Preparation of methyl 4-[6-(3,5-dimethylisoxazol-4-yl)-l-[(lS)-l-(2- pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl]benzoate (P-0509): To 4-[3-iodo-l-[(l S)- l-(2- pyridyl)ethyl]pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole (46, 0.5 g, 1.13 mmol) in THF (16 ml) was added methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (0.38 g, 1.46 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 g, 0.07 mmol), and 1M aqueous potassium carbonate (8 ml). The reaction was allowed to stir for 2 hours at 70 °C. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel flash chromatography eluting with 20-100% ethyl acetate in hexane to give product (P-0509, 0.37 g, 72.7%) MS (ESI) [M+FT ] = 453.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water; N,N-dimethyl-formamide; acetonitrile at 120℃; for 3h; | 7 [00480j (R,E)-Methyl 4-(4-amino- 1 -(1 -(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin- 3- yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzoate (25) (620 mg, 61%) was obtained as a yellow solid from (R,E)- 1 -(3-(4-amino-3-iodo- 1H-pyrazolo[3 ,4-d]pyrimidin- 1 -yl) pyrrolidin- 1 -yl)-4- (cyclopropyl(methyl)amino)but-2-en- 1-one (1 g, 2.14 mmol) and methyl 4-(4,4,5 ,5 -tetramethyl1,3,2-dioxaborolan-2-yl)benzoate (673 mg, 2.56 mmol). LC-MS (ESI): m/z (M+1) 476.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate In tetrahydrofuran; water at 70℃; for 2h; | 1.4 Step 4-Preparation of methyl 4-[5-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-(3,5-dimethylisoxazol-4-yl)pyrrolo[2,3-b]pyrazin-7-yl]benzoate (P-2043): Step 4-Preparation of methyl 4-[5-[dideuterio-(4,4-difluorocyclohexyl)methyl]-3-(3,5-dimethylisoxazol-4-yl)pyrrolo[2,3-b]pyrazin-7-yl]benzoate (P-2043): To 4-[5-[dideuterio-(4,4-difluorocyclohexyl)methyl]-7-iodo-pyrrolo[2,3-b]pyrazin-3-yl]-3,5-dimethyl-isoxazole (P-2039, 0.07 g, 0.15 mmol) in THF (18 ml) was added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.05 g, 0.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.02 g, 0.03 mmol), and 1 M potassium carbonate in water (8 ml). The reaction was allowed to stir for 2 hours at 70° C. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give product P-2043 (0.05 g, 70%) MS (ESI) MH(+)=483.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.3% | Stage #1: methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate With ammonium hexafluorophosphate; palladium(II) trifluoroacetate; 2-[(S)-4,5-dihydro-4-tert-butyl-1,3-oxazol-2-yl]pyridine In 1,2-dichloro-ethane at 20℃; for 0.0833333h; Stage #2: 1-benzopyran-4(4H)-one With water In 1,2-dichloro-ethane at 60℃; | 120A Example 120 A (i?)-methyl 4-(4-oxochroman-2-yl)benzoate Example 120 A (i?)-methyl 4-(4-oxochroman-2-yl)benzoate A mixture of bis(2,2,2-trifluoroacetoxy)palladium (0.341 g, 1.026 mmol), (5)-4-(tert- butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.252 g, 1.232 mmol), ammonium hexafluorophosphate(V) (1.004 g, 6.16 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (4.04 g, 15.40 mmol) and dichloroethane (8 mL) in a 20 ml vial was stirred at room temperature for 5 minutes, followed by the addition of 4H-chromen-4-one (CAS 11013-97-1, 1.5 g, 10.26 mmol) and water (0.256 mL, 14.19 mmol). The vial was capped and the mixture was stirred at 60 °C overnight. The reaction mixture gradually turned to black with Pd plated out on the sides of the vial. The mixture was filtered through a plug of celite and eluted with ethyl acetate to give a red solution, which was washed with water and dried over MgS04. After filtration, the solvent was removed in vacuo. The crude material was chromatographed using a 100 g silica gel cartridge and eluted with a gradient of 5-40 % ethyl acetate in heptane to yield title compound (1.66 g, 57.3 % yield). 1H NMR (400 MHz, CDC13) δ 8.16 - 8.06 (m, 2H), 7.94 (dd, J = 8.0, 1.7 Hz, 1H), 7.62 - 7.47 (m, 3H), 7.14 - 7.02 (m, 2H), 5.56 (dd, J = 13.1, 3.1 Hz, 1H), 3.94 (s, 3H), 3.13 - 2.86 (m, 2H); LC/MS (ESI+) = 283 (M+l)+. |
57.3% | Stage #1: methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate With ammonium hexafluorophosphate; palladium(II) trifluoroacetate; 2-[(S)-4,5-dihydro-4-tert-butyl-1,3-oxazol-2-yl]pyridine In 1,2-dichloro-ethane at 20℃; for 0.0833333h; Stage #2: 1-benzopyran-4(4H)-one In water; 1,2-dichloro-ethane at 60℃; | 23.23A Example 23A methyl 4-[(2R)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate Example 23A methyl 4-[(2R)-4-oxo-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate A mixture of bis(2,2,2-trifluoroacetoxy)palladium (0.341 g, 1.026 mmol), (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (0.252 g, 1.232 mmol), ammonium hexafluorophosphate(V) (1.004 g, 6.16 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4.04 g, 15.40 mmol) and dichloroethane (8 mL) in a 20 mL vial was stirred at room temperature for 5 minutes, followed by the addition of 4H-chromen-4-one (CAS 11013-97-1, 1.5 g, 10.26 mmol) and water (0.256 mL, 14.19 mmol). The vial was capped, and the mixture was stirred at 60° C. overnight. The mixture was filtered through a plug of diatomaceous earth eluted with ethyl acetate. The filtrate was washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was chromatographed using a 100 g silica gel cartridge eluted with a gradient of 5-40% ethyl acetate in heptane to yield the title compound (1.66 g, 57.3% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.16-8.06 (m, 2H), 7.94 (dd, J=8.0, 1.7 Hz, 1H), 7.62-7.47 (m, 3H), 7.14-7.02 (m, 2H), 5.56 (dd, J=13.1, 3.1 Hz, 1H), 3.94 (s, 3H), 3.13-2.86 (m, 2H); LC/MS (ESI+) 283 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrakis(triphenylphosphine) palladium(0); cesium fluoride In 1,2-dimethoxyethane at 100℃; for 24h; Inert atmosphere; Sealed tube; | 1 example 1 A solution of 5.00 g (10.35 mmol) of 1,3,6,8-tetrabromo-9H-carbazole, 14.91 g (56.93 mmol)Methyl 4-formate phenylborate,10.00 g (66.22 mmol) of cesium fluoride, 0.60 g (0.520 mmol) of tetrakistriphenylphosphine palladium, 320 mL of ethylene glycol dimethyl etherWas added into a 500 mL three-necked flask, sealed, evacuated and nitrogen-shielded, and reacted at 100 ° C for 24 hours. After the reaction was stopped,Dichloromethane extraction, washing, anhydrous sodium sulfate drying, filtration, vacuum distillation, separation and purification by silica gel column chromatography, 1,Methyl-9H-carbazole (5.60 g) in a yield of 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In water; dimethyl sulfoxide at 80℃; for 16h; Inert atmosphere; | Methyl 4-[4,4-dimethyl-1-(propan-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]benzoate (28) Compound 21 (0.0925 g, 0.281 mmol) was dissolved in DMSO/H2O (6 mL, 5:1), and the resultant solution was degassed via freeze-pump-thaw. Under Ar, compound 27 (0.081 g, 0.309 mmol), K3PO4(0.12 g, 0.562 mmol) and Pd(dppf)Cl2(6 mg, 0.00843 mmol) were added, and the resultant suspension was stirred at 80 °C for 16 h. The solution was cooled, diluted with H2O, and extracted with EtOAc (3×). The organics were washed with H2O and brine, dried (MgSO4) and evaporated to give a crude solid. This was purified by SiO2chromatography (hexane/EtOAc 92:8, with 1% Et3N as eluent) to givecompound 28 as a light yellow crystalline solid (0.065 g, 68%): m.p. 103-104 oC; 1H NMR (700 MHz; CDCl3) δ 1.24 (d, J = 6.6 Hz, 6H), 1.34 (s, 6H), 1.69-1.79 (m, 2H), 3.18-3.29 (m, 2H), 3.92 (s, 3H), 4.19 (sept, J = 6.7 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 8.6, 2.3 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.56-7.69 (m, 2H), 8.00-8.13 (m, 2H); 13C NMR (176 MHz; CDCl3) δ 19.1, 30.4, 32.4, 36.7, 37.1, 47.4, 52.2, 111.2, 124.8, 125.8, 126.0, 126.2, 127.2, 130.2, 132.2, 144.7, 146.3, 167.5; IR (neat) max/cm-12978w, 2953w, 2909w, 2847w, 1708s, 1596m, 1492m, 1434m, 1260s, 775s, MS(ES): m/z = 338.7 [M+H]+; HRMS (ES) calcd. for C22H28NO2 [M+H]+: 338.2120, found 338.2121. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 80℃; for 16h; Inert atmosphere; | 162 Methyl 4-(pyridin-2-yl)benzoate Methyl 4-(pyridin-2-yl)benzoate (0523) In a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was combined a solution of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (5 g, 0.019 mol, 1.00 equiv) in dioxane (50 mL), Na2CO3 (6.04 g, 0.057 mol, 3.00 equiv), 2-bromopyridine (4.5 g, 0.028 mol, 1.50 equiv), and Pd(Ph3P)4 (1.1 g, 0.001 mmol, 0.05 equiv). The resulting solution was stirred for 16 h at 80° C. The resulting solution was quenched by water/ice and extracted with 3×50 ml EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by flash chromatography with EtOAc/petroleum ether (1:5) to afford 3.5 g (86%) of the product as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; potassium carbonate In toluene at 100℃; for 24h; Inert atmosphere; | Synthesis of Intermediate 1 Add in a 500mL three-necked flask with a spherical condenser4,7-dibromo-2,1,3-benzothiadiazole (4.20 g, 14 mmol),4-methoxybenzoylboronic acid pinacol ester (3.60 g, 14 mmol), then 160 mL of toluene,Stir at room temperature, add K2CO3 (2M, 14mL) under N2 protection,TBAB (0.45 g, 1.4 mmol) and Pd (PPh3) 4 (0.48 g, 0.42 mmol) were stirred at 100 ° C for 24 h.After the system was cooled to room temperature, 100 mL of distilled water was added to the reaction solution for dilution.Then, it was extracted with CH2Cl2 (100 mL×3), and washed with saturated brine (100 mL×3).Dry over anhydrous magnesium sulfate, filter, and remove the solvent.The residue was subjected to silica gel column chromatography [eluent, V ( petroleum ether): V (dichloromethane) = 2:1],Purification of the pale yellow solid intermediate 1 (3.20 g), yield 67%. |
67% | With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; potassium carbonate In toluene at 20 - 100℃; for 24h; Inert atmosphere; Darkness; | 1 Synthesis of Intermediate 1 4,7-dibromo-2,1,3-benzothiadiazole (4.20 g, 14 mmol) was sequentially added to a 500 mL three-necked flask equipped with a spherical condenser.4-methoxybenzoylboronic acid pinacol ester(3.60g, 14mmol),Then add 160 mL of toluene,Stir at room temperature,Add K2CO3 (2M, 14mL) under N2 protection,TBAB (0.45 g, 1.4 mmol) and Pd (PPh3) 4 (0.48 g, 0.42 mmol),Stir at 200 ° C for 24 h in the dark.After the system is cooled to room temperature,Add 100 mL of distilled water to the reaction solution for dilution.Then extracted with CH2Cl2 (100 mL×3),Washed with saturated brine (100 mL×3), dried over anhydrous magnesium sulfate.Filtration, solvent removal, the residue was subjected to silica gel column chromatography [eluent, V ( petroleum ether): V (dichloromethane) = 2:1]Purified to light yellow solid intermediate 1 (3.20g)The yield was 67%. |
67% | With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; potassium carbonate In toluene at 100℃; for 24h; Inert atmosphere; Darkness; |
63% | With tetrabutylammomium bromide; potassium carbonate; palladium In water; toluene at 105℃; for 24h; Inert atmosphere; Darkness; | 1.4 (4) Synthesis of intermediates of chemical formula d: (2.94 g, 10 mmol) of benzothiadiazole,(2.62 g, 10 mmol) of borate,(2.76 g, 20 mmol) of K2CO3,Appropriate amount of water and tetrabutylammonium bromide,0.1 g palladium catalyst,80 mL of toluene was added,Immediately vacuum,N2 protection, dark,The temperature was raised to 105 ° C for 24 hours.Cooled to room temperature, extracted with CH2Cl2 and water,Anhydrous MgSO4 dried,Filter, spin dry.Finally, petroleum ether / dichloromethane as eluent for column chromatography,A dark yellow solid was obtained in 63% yield. |
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran at 80℃; for 8h; | |
40% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran for 12h; Inert atmosphere; Reflux; | 4 (4) Synthesis of Intermediate 8: Add 50mL of tetrahydrofuran to a 100mL two-necked flask; weigh 4,7-dibromo-2,1,3-benzothiadiazole (2.20g, 7.60mmol), 4 -Methoxycarbonylphenylboronic acid pinacol ester (1.00g, 3.80mmol) was added to a two-necked flask and stirred to dissolve, protected by argon. Add palladium tetrakistriphenylphosphorus (86.60 mg, 0.08mmol) and potassium carbonate (6mL, 2M), heat and reflux for 12h, track the reaction with thin-layer chromatography until the concentration of the reactant is basically unchanged, and stop the reaction. Post-treatment: cooling, spin-drying, dissolving in dichloromethane, washing with water, extracting, collecting the organic phase, spin-drying, separation by silica gel column chromatography (dichloromethane/petroleum ether=1:1, gradient elution), collecting product 8, spin Dried to white powder, vacuum drying oven to dry to constant weight (0.53g, 40%). |
40% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran for 12h; Inert atmosphere; Reflux; | 4 (4) Synthesis of Intermediate 7: Measure 50mL of tetrahydrofuran and add it to a 100mL two-necked flask; weigh 4,7-dibromo-2,1,3-benzothiadiazole (2.2g, 7.6mmol), 4-methoxycarbonylphenylboronic acid pinacol ester (1.0g, 3.8mmol) was added to a two-neck flask and stirred to dissolve, protected by argon. Add tetrakistriphenylphosphoruspalladium (86.6mg, 0.075mmol) and potassium carbonate (6mL, 2M), heat and reflux for 12h, Follow the reaction with thin-layer chromatography until the concentration of the reactants is basically unchanged, stop the reaction; post-processing: cooling, spin-drying, dissolving in dichloromethane, washing with water, extracting, collecting the organic phase, Rotate to dry, separate by silica gel column chromatography (dichloromethane/petroleum ether=1:1, gradient elution), collect product 7, and spin dry to obtain white powder, and dry it in a vacuum drying oven to constant weight (0.53g, 40%). |
40% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran for 12h; Inert atmosphere; Reflux; | 4 (4) Synthesis of Intermediate 8: Add 50mL of tetrahydrofuran to a 100mL two-necked flask; weigh 4,7-dibromo-2,1,3-benzothiadiazole (2.20g, 7.60mmol), 4 -Methoxycarbonylphenylboronic acid pinacol ester (1.00g, 3.80mmol) was added to a two-neck flask and stirred to dissolve, protected by argon. Add palladium tetrakistriphenylphosphorus (86.60 mg, 0.08 mmol) and potassium carbonate (6 mL, 2M), heat and reflux for 12 hours, track the reaction with thin-layer chromatography until the concentration of the reactants is basically unchanged, and stop the reaction. Post-treatment: cooling, spin-drying, dissolving in dichloromethane, washing with water, extracting, collecting the organic phase, spin-drying, separation by silica gel column chromatography (dichloromethane/petroleum ether=1:1, gradient elution), collecting product 8, spin It was dried to obtain a white powder, which was dried in a vacuum drying oven to a constant weight to obtain Intermediate 8 (0.53 g, 40%). |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.7% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 100℃; for 24h;Inert atmosphere; | A mixture of 3,6-bis(5-bromothiophen-2-yl)-2,5-bis(2-ethylhexyl)-2,5-dihydropyrrolo[3,4-c] pyrrole-1,4-dione (5) (1.97 g,2.90 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6) (0.76 g, 2.90 mmol), K2CO3 (1.60 g, 11.60 mmol),Pd(PPh3)4 (0.17 g, 5 mol%) and toluene/H2O (60 mL, 3/1, V/V) wasadded to the reaction flask under a N2 atmosphere and then stirred at100 C for 24 h. After cooling to the room temperature, the reactionmixture was extracted with CH2Cl2, washed with water and brine,and dried over MgSO4. The crude product was purified by columnchromatography (CH2Cl2/petroleum ether, 1/4, V/V) on silica gel toyield a purplish red solid (1.55 g, yield 72.7%). 1H NMR (400 MHz,CDCl3, delta/ppm): 8.97 (d, J = 4.2,1H), 8.11 (d, J = 8.5, 3H), 7.76 (d, J = 4.5,3H), 7.58 (d, J = 4.3, 1H), 4.11-4.04 (m, 3H), 3.96 (s, 4H), 1.93 (s, 2H),1.42-1.26 (m, 16H), 0.94-0.83 (m, 12H). MALDI-TOF MS (m/z): calcdfor (C76H75N3O4S3): 736.2004; Found: 736.2350. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 18h;Inert atmosphere; | Example 79A methyl 4-(6-aminopyridin-2-yl)benzoate A mixture of 6-chloropyrid-2-amine (255.1 mg, 1.984 mmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (611.2 mg, 2.332 mmol) in dimethoxyethane (5 mL) and water (2.5 mL) was degassed under a N2 flow for 15 minutes. Potassium carbonate (581.9 mg, 4.21 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (87.5 mg, 0.120 mmol) were added, and the mixture stirred at 80 C. for 18 hours. Water was then added to the reaction mixture (35 mL), and it was extracted with ethyl acetate (3*35 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with 5% ethyl acetate in dichloromethane (Rf=0.28), to provide the title compound (344.5 mg, 76%). 1H NMR (400 MHZ), DMSO-d6) delta 8.16-8.09 (m, 2H), 8.05-7.96 (m, 2H), 7.50 (dd, J=8.2, 7.5 Hz, 1H), 7.18-7.11 (m, 1H), 6.49 (d, J=8.3 Hz, 1H), 6.08 (s, 2H), 3.87 (s, 3H): MS (ESI+) m/z 229 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium phosphate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) In 1,4-dioxane; water at 90℃; for 2h; Sealed tube; | Step 2: methyl 4-[6-[(E)-but-2-enyl]-7-oxo-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-4-yl]benzoate (19) To an 8 mL vial was added 4-bromo-6-[(E)-but-2-enyl]-1-(ptolylsulfonyl)pyrrolo[2,3-c]pyridin-7-one (250 mg. 0.59 mmol), 1,4-dioxane (2 mL), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (233 mg, 0.89 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (21 mg, 0.030 mmol), and potassiumphosphate tribasic (2.0 M in water, 0.89 mL, 1.8 mmol). The reaction was capped and shaken for2h at 90 °C. The reaction was cooled to room temperature, and extracted with ethyl acetate. Theaqueous was further extracted with ethyl acetate, then the combined organics were dried oversodium sulfate and concentrated under reduced pressure. The crude was purified by flash column(30-80% ethyl acetate : heptanes) yielding desired product (185 mg, 65% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tetrabutylammomium bromide; potassium carbonate; palladium; In water; toluene; for 24h;Inert atmosphere; Reflux; | (0.82 g, 2.5 mmol) of fluorinated benzothiadiazole,(0.65 g, 2.5 mmol) of borate,(0.7 g, 5 mmol) of K2CO3,Appropriate amount of water and tetrabutylammonium bromide,0.1 g palladium catalyst,Add 50 mL of toluene,N2 under reflux for 24 hours.Cooled to room temperature,Extracted with CH2Cl2 and water,Anhydrous MgSO4 dried,Filter, spin dry.Finally, petroleum ether / dichloromethane as eluent for column chromatography,To give a pale yellow solid,Yield 55%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate; silver(l) oxide In 1,2-dichloro-ethane at 120℃; for 6h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With Wilkinson's catalyst In toluene at 160℃; for 15h; Inert atmosphere; | |
52% | With tributylphosphine; Ni(1,5-cyclooctadiene)2; lithium carbonate In 1,4-dioxane; toluene at 160℃; for 36h; Inert atmosphere; Sealed tube; Glovebox; | Procedure II : In a nitrogen-filled glovebox, a 10-mL oven-dried sealed tube containing a stirring bar was charged with amide 6 (0.20 mmol, 1.0 equiv), yellow Ni(COD)2 (5.5 mg, 10 mol%) and lithium carbonate(22.2 mg, 0.30 mmol, 1.5 equiv). Subsequently, freshly distilled toluene (1.0 mL) was added, and then bis(pinacolato)diboron 9 (76.2 mg, 0.30 mmol, 1.5 equiv) and tri-n-butylphosphine ligand (20 μL, 40mol%) were added respectively via microsyringe. The tube with the mixture was sealed and removed from the glovebox. After stirring at 160 °C for 36 h, the mixture was then allowed to cool to room temperature, diluted with EtOAc (5 mL) and filtered through a celite plug, eluting with additionalEtOAc (10 mL). The filtrate was concentrated and purified by column chromatography on silica gel toyield the title product 10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N,N,N,N,-tetramethylethylenediamine; copper(II) sulfate; cesium fluoride In methanol at 50℃; for 24h; Inert atmosphere; | A typical procedure for copper-catalyzed thiolation of boronic acid pinacol esters withthiosulfonates General procedure: To a mixture of S-(4-(tert-butoxycarbonylamino)phenyl) 4-toluenethiosulfonate (2e) (94.8mg, 0.250 mmol, 1.0 equiv), copper sulfate (2.0 mg, 13 μmol, 5.0 mol %), and cesiumfluoride (77.2 mg, 0.508 mmol, 2.0 equiv) were added a solution of TMEDA (1.72 mg, 14.8μmol, 5.9 mol %) and phenylboronic acid pinacol ester (1c) (77.9 mg, 0.382 mmol, 1.5equiv) dissolved in MeOH (2.5 mL), and the mixture was stirred at 50 °C for 24 h. Aftercooling to room temperature, the mixture was filtered through a pad of Celite, and then thefiltrate was concentrated under reduced pressure. To the residue was added EtOAc (20 mL)and the mixture was washed with aqueous saturated solution of sodium bicarbonate (20 mL ×2) and brine (20 mL), and then dried (Na2SO4). After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by preparative TLC (n-hexane/EtOAc =10/1) to give 4-(tert-butoxycarbonylamino)phenyl phenyl sulfide (3n) (61.9 mg, 0.205 mmol,82.2%) as a colorless solid. According to the procedure for preparing 4-(tert-butoxycarbonylamino)phenyl phenylsulfide (3n), 4-methoxycarbonylphenyl 4-tolyl sulfide (3a) (60.0 mg, 92.0%), 3-methoxyphenyl 4-tolyl sulfide (3b) (49.8 mg, 86.7%), phenyl 4-tolyl sulfide (3c) (40.1 mg,80.7%), 4-methoxyphenyl 4-tolyl sulfide (3d) (42.1 mg, 73.1%), 4-(dimethylamino)phenyl 4-tolyl sulfide (3e) (41.4 mg, 67.7%), 4-hydroxyphenyl 4-tolyl sulfide (3f) (36.0 mg, 66.5%), 4-bromophenyl 4-tolyl sulfide (3g) (62.8 mg, 91.0%), 2-bromophenyl 4-tolyl sulfide (3h) (62.8mg, 89.8%), 3-thienyl 4-tolyl sulfide (3i) (38.6 mg, 74.2%), (E)-2-(4-tolylthio)styrene (3j)(38.7 mg, 68.3%), diphenyl sulfide (3k) (34.0 mg, 72.8%), 4-methoxyphenyl phenyl sulfide(3l) (45.3 mg, 84.1%), 4-aminophenyl phenyl sulfide (3m) (5.0 mg, 50%), 4-chlorophenylphenyl sulfide (3o) (40.5 mg, 73.3%), 2-(benzamido)phenyl phenyl 4-toluenethiosulfonate(3p) (54.5 mg, 71.1%), 2-fluorophenyl phenyl 4-toluenethiosulfonate (3q) (40.9 mg, 80.6%),phenyl 3-thienyl sulfide (3r) (16.5 mg, 67.8%), and phenethyl phenyl sulfide (3s) (46.6 mg,86.5%) were prepared from the corresponding organoboronic acid pinacol esters 1 andthiosulfonates 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88 % ee | With dipotassium hydrogenphosphate; (S)-N-(1-([1,1':3,1“-terphenyl]-2-yl)-3-(dimethylamino)propan-2-yl)acetamide; water; palladium diacetate; silver carbonate; p-benzoquinone In <i>tert</i>-butyl alcohol at 60℃; for 12h; Sealed tube; Overall yield = 53 %; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: phosphoric acid 5,6-dihydro-4H-pyran-2-yl ester diphenyl ester With tetrakis(triphenylphosphine) palladium(0); triethylamine In tetrahydrofuran at 22℃; Inert atmosphere; Stage #2: methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate With sodium carbonate In tetrahydrofuran; water at 65℃; for 18h; | A. Synthesis of Dihydropyrans 6a-6o. General procedure: Representative Procedure (dihydropyran 6b is used as an example). To a solution of ketene acetal phosphate 1 (0.283 g, 0.854 mmol, 2.0 equiv) in anhydrous THF (3.0 mL) at room temperature was added Et3N (0.180 mL, 1.28 mmol, 3.0 equiv) followed by (Ph3P)4Pd (0.050 g, 0.042 mmol, 0.10 equiv) turning the reaction a bright yellow. Sodium carbonate (0.640 mL of a 2.0 M solution in water, 1.28 mmol, 3.0 equiv) was then added followed by 2-methoxyphenylboronic acid pinacol ester (5b) (0.100 g, 0.427 mmol, 1.0 equiv) and the reaction was heated to 65 C for 18 hrs. The reaction was cooled to room temperature and poured into H2O (10 mL). The aqueous layer was extracted with EtOAc (3 X 10 mL) and the combined organic layers were washed with saturated sodium chloride (10 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (50:1 hexanes:EtOAc + 2% Et3N) to afford 0.069 g (85%) of dihydropyran 6b as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 20 - 105℃; for 3h; Inert atmosphere; | 21.1 Step 1: Example 119c At room temperature, to compound 119a (209 mg, 1 mmol), which is 4-chloro-N- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-amine,Compound 119b (314.4 mg, 1.2 mmol) is methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate,To a mixture of [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (73.1 mg, 0.1 mmol) and cesium carbonate (651.6 mg, 2 mmol) was added 1,4-dioxane (20 mL) and water (3 mL).The mixture was then degassed under vacuum, and under nitrogen,The mixture was heated to 105 ° C and stirred for 3 hours.After the reaction was completed, the mixture was concentrated under reduced pressure. It was purified through a silica gel column (petroleum ether: ethyl acetate = 30: 70) to obtain a yellow solid compound 119c (381 mg, yield 71.6%), that is 4- (2-((1-methyl-1H-pyrazole) -4-yl) amino) pyrimidin-4-yl) methyl benzoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Dioxaborolane lviii (5.3 g, 20.1 mmol) and dibromopyridine lix (4 g, 16.9 mmol) are dissolved in toluene (200 mL) and methanol (120 mL) in a pressure tube. The mixture is degassed under nitrogen atmosphere for 10 minutes, then sodium carbonate (5.3 g, 50.0 mmol) and tetrakis(triphenylphosphine)palladium (1.9 g, 1.7 mmol) are added. The tube is sealed, and the mixture is heated to 110 C for 12 hours before it is concentrated under reduced pressure. (0280) The residue is purified by flash column chromatography (10%-15% ethyl acetate in petroleum ether) to give bromide lx (2.1 g, 7.2 mmol) in 43% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); cesium fluoride In water; N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; | 11.1 Methyl 4-(4-amino-6-(4-methacrylamidophenyl)-7H-cyclopenta[d]pyrimidin-5- yl)benzoate Step 1: A round bottomed flask was charged with N-(4-{4-amino-5-bromo-7H- cyclopenta[d]pyrimidin-6-yl}phenyl)-2-methylprop-2-enamide (800 mg, 2.15 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (731 mg, 2.79 mmol), Pd(dtbpf)Cl2 (139 mg, 215 µmol), CsF (980 mg, 6.45 mmol), DMF:H2O=16:1 (8 mL) and a stirbar. The solution was stirred for 2h at 90 °C under N2. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography. Concentration in vacuo resulted in methyl 4-{4-amino-6-[4-(2-methylprop-2-enamido)phenyl]-7H- cyclopenta[d]pyrimidin-5-yl}benzoate (600 mg, 56%) as an off-white amorphous solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane at 90℃; for 1.16667h; Inert atmosphere; Microwave irradiation; | 1 Step 1. Synthesis of methyl 4-[1-(benzenesulfonyl)-5-(3,4-difluorophenyl)-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazol-7-yl]benzoate (C29) A mixture of 1-(benzenesulfonyl)-5-(3,4-difluorophenyl)-7-iodo-6-tetrahydropyran-4-yl-pyrrolo[2,3-f]indazole S1 (5000 mg, 7.6 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4 g, 15.3 mmol) and PdCl2(dppf)2 (300 mg, 0.37 mmol) was placed in a vial and purged with nitrogen. 1,4-dioxane (30 mL) and sodium carbonate (11 mL of 2 M, 22.0 mmol) were added and the mixture purged with nitrogen for 10 min. The mixture was then heated at 90° C. under microwave conditioned for 60 min. Water and CH2Cl2 were added and the aqueous and organic layers separated. The organic layer was concentrated in vacuo and the crude product mixture was purified by silica gel chromatography (Eluent: Ethyl acetate/CH2Cl2) to afford the product as a beige solid (4 g, 83%). 1H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 8.22 (d, J=7.7 Hz, 2H), 7.91 (d, J=10.3 Hz, 2H), 7.71 (qt, J=15.0, 8.4 Hz, 6H), 7.53 (t, J=8.1 Hz, 3H), 7.33 (s, 1H), 3.94 (s, 3H), 3.73 (d, J=10.7 Hz, 2H), 3.14 (d, J=12.1 Hz, 2H), 3.01 (dt, J=10.9, 6.6 Hz, 1H), 1.73-1.53 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane at 90℃; for 1h; Inert atmosphere; | 1 Step 1. Synthesis of methyl 4-[1-(2,2-dimethylpropanoyl)-5-(3-fluorophenyl)-6-methyl-pyrrolo[2,3-f]indazol-7-yl]benzoate (C31) A mixture of 1-[5-(3-fluorophenyl)-7-iodo-6-methyl-pyrrolo[2,3-f]indazol-1-yl]-2,2-dimethyl-propan-1-one S2 (38 mg, 0.08 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (41 mg, 0.16 mmol) and Pd(dppf)Cl2 (3 mg, 0.004 mmol) in a reaction vial were placed under a nitrogen atmosphere. 1,4-Dioxane (500 μL) and sodium carbonate (25 mg, 0.24 mmol) were added and the mixture purged with nitrogen. The reaction was heated at 90° C. for 60 min. Water and CH2Cl2 were added. The organic layer was passed through a phase separator and concentrated in vacuo to afford the crude product which was used in the subsequent step without further purification (37.4 mg, 100%). LCMS m/z 484.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere; | synthesis of dimethyl 5-(azidomethyl)-[1,1'-biphenyl]-3,4'-dicarboxylate (15) Methyl 3-(azidomethyl)-5-bromobenzoate (9) (39 mg, 0.145 mmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (12), (29 mg, 0.112 mmol) were dissolved in anhydrous dimethylformamide and purged under argon. Tetrakis(triphenylphosphine)-palladium(0) (Pd(PPh3)4) (3.35 mg, 2.23 μmol) and potassium carbonate (80.4 mg, 0.446 mmol) were added under argon. The reaction mixture was heated to 80oC for 2 h. The reaction was then cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water (3 × 15 mL) and brine (2 × 15 mL), dried with anhydrous MgSO4 and filtered. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate : hexane = 1 : 20 to 1 : 10 to 1 : 5) to give 15 (83%). 1H NMR (600 MHz, CDCl3) δ 8.25 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.00 (s, 1H), 7.75 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 4.48 (s, 2H), 3.96 (s, 3H), 3.94 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 166.85, 166.46, 143.97, 141.14, 136.88, 131.61, 131.17, 130.36, 129.77, 128.74, 128.35, 127.25, 54.38, 52.52, 52.31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 2,5-di-tert-butyl-p-benzoquinone; oxygen; potassium carbonate; potassium hydrogencarbonate In tert-Amyl alcohol at 90℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With (2S,3S)-N-acetyl-2-amino-3-methylpentanoic acid; 2,5-di-tert-butyl-p-benzoquinone; oxygen; potassium hydrogencarbonate In tert-Amyl alcohol at 90℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With SIPr-PdCl<SUB>2</SUB>-Py; cesium fluoride In tetrahydrofuran at 80℃; for 8h; Schlenk technique; Inert atmosphere; | 3.1.3. General procedure for the Suzuki reaction General procedure: THF (2.5 mL) was injected into the mixture of ammonium salts (1 mmol), boronic acid (0.5 mmol), SIPr-PdCl2-Py (0.05 mmol) and CsF (1 mmol) in a Schleck tube under N2 atmosphere. After stirring for 8 h at 80 °C, the mixture was concentrated via reduced pressure. Finally, the residue was purified by flash chromatography on silica gel with an eluent to afford the target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; cesium fluoride In 1,2-dimethoxyethane at 85℃; | 1.B.5 Step 5. tert-butyl 4-[4-benzyloxy-l-(4-fluorophenyl)-3-(4-methoxycarbonylphenyl)indol-2- yl ] piperidine- 1 -carboxylate ( C257) A mixture of tert-butyl 4-[4-benzyloxy-l-(4-fluorophenyl)-3-iodo-indol-2- yl]piperidine-l -carboxylate C256 (1 g, 1.6 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (1.26 g, 4.8 mmol), CsF (970 mg, 6.4 mmol), and PdCh(dppf) (130 mg, 0.16 mmol) in DME (8 mL) was stirred overnight at 85 °C. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was concentrated to dryness and purified via silica gel chromatography (Gradient: 0-45% EtOAc in heptane) tert-butyl 4-[4-benzyloxy-l-(4-fluorophenyl)-3-(4-methoxycarbonylphenyl)indol-2- yl]piperidine-l-carboxylate (480 mg, 47%). NMR (400 MHz, Chloroform-r/) d 7.54 - 7.49 (m, 2H), 7.42 - 7.37 (m, 2H), 7.28 (d, J = 2.4 Hz, 2H), 7.21 - 7.12 (m, 3H), 7.10 - 7.04 (m, 1H), 6.91 - 6.86 (m, 1H), 6.84 - 6.79 (m, 2H), 6.61 (dd, J = 7.8, 0.7 Hz, 1H), 6.54 (dd, J = 8.3, 0.7 Hz, 1H), 4.94 (s, 2H), 3.95 (d, J = 35.8 Hz, 6H), 2.73 (tt, J = 12.4, 3.3 Hz, 1H), 2.43 (s, 2H), 1.67 - 1.42 (m, 2H), 1.38 (s, 10H). LCMS m/z 635.0 [M+H]+. |
47% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; cesium fluoride In 1,2-dimethoxyethane at 85℃; | 1.B.5 Step 5. tert-butyl 4-[4-benzyloxy-l-(4-fluorophenyl)-3-(4-methoxycarbonylphenyl)indol-2- yl ] piperidine- 1 -carboxylate ( C257) A mixture of tert-butyl 4-[4-benzyloxy-l-(4-fluorophenyl)-3-iodo-indol-2- yl]piperidine-l -carboxylate C256 (1 g, 1.6 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (1.26 g, 4.8 mmol), CsF (970 mg, 6.4 mmol), and PdCh(dppf) (130 mg, 0.16 mmol) in DME (8 mL) was stirred overnight at 85 °C. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was concentrated to dryness and purified via silica gel chromatography (Gradient: 0-45% EtOAc in heptane) tert-butyl 4-[4-benzyloxy-l-(4-fluorophenyl)-3-(4-methoxycarbonylphenyl)indol-2- yl]piperidine-l-carboxylate (480 mg, 47%). NMR (400 MHz, Chloroform-r/) d 7.54 - 7.49 (m, 2H), 7.42 - 7.37 (m, 2H), 7.28 (d, J = 2.4 Hz, 2H), 7.21 - 7.12 (m, 3H), 7.10 - 7.04 (m, 1H), 6.91 - 6.86 (m, 1H), 6.84 - 6.79 (m, 2H), 6.61 (dd, J = 7.8, 0.7 Hz, 1H), 6.54 (dd, J = 8.3, 0.7 Hz, 1H), 4.94 (s, 2H), 3.95 (d, J = 35.8 Hz, 6H), 2.73 (tt, J = 12.4, 3.3 Hz, 1H), 2.43 (s, 2H), 1.67 - 1.42 (m, 2H), 1.38 (s, 10H). LCMS m/z 635.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1 ‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II) methanesulfonate; sodium carbonate In 1,4-dioxane at 80℃; for 2h; Sealed tube; Inert atmosphere; | 1.B.1 Step 1. Synthesis of methyl 4-[l-(4-fluorophenyl)-2-isopropyl-4-(methoxymethoxy)-pyrrolo[2,3- c]pyridin-3-yl]benzoate (C399) To a vial was added 3-bromo-5-fluoro-l-(4-fluorophenyl)-2-isopropyl-4- (methoxymethoxy)pyrrolo[2,3-c]pyridine S23 (0.050 g, 0.109 mmol), methyl 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (0.046 g, 0.175 mmol), [2-(2- aminophenyl)phenyl]-sulfooxy-palladium;dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl] phosphane (0.009 g, 0.011 mmol). The vial was sealed and flushed by nitrogen. To the vial was added dioxane (1 mL) and Na2CCb (0.218 mL of 2 M, 0.436 mmol). The reaction was stirred at 80 °C for 2 hours. The reaction was quenched with aqueous saturated NH4CI solution and extracted with EtOAc. The organic solution was dried with Na2SC>4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (24 g silica gel column, 20% to 50% EtOAc/ heptanes gradient) to afford 34 mg of product. Methyl 4-[l-(4-fluorophenyl)-2- isopropyl-4-(methoxymethoxy)pyrrolo[2,3-c]pyridin-3-yl]benzoate (62%). ESI-MS m/z calc. 448.18, found 448.77 (M+l)+. |
62% | With (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1 ‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl)]palladium(II) methanesulfonate; sodium carbonate In 1,4-dioxane at 80℃; for 2h; Sealed tube; Inert atmosphere; | 1.B.1 Step 1. Synthesis of methyl 4-[l-(4-fluorophenyl)-2-isopropyl-4-(methoxymethoxy)-pyrrolo[2,3- c]pyridin-3-yl]benzoate (C399) To a vial was added 3-bromo-5-fluoro-l-(4-fluorophenyl)-2-isopropyl-4- (methoxymethoxy)pyrrolo[2,3-c]pyridine S23 (0.050 g, 0.109 mmol), methyl 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (0.046 g, 0.175 mmol), [2-(2- aminophenyl)phenyl]-sulfooxy-palladium;dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl] phosphane (0.009 g, 0.011 mmol). The vial was sealed and flushed by nitrogen. To the vial was added dioxane (1 mL) and Na2CCb (0.218 mL of 2 M, 0.436 mmol). The reaction was stirred at 80 °C for 2 hours. The reaction was quenched with aqueous saturated NH4CI solution and extracted with EtOAc. The organic solution was dried with Na2SC>4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (24 g silica gel column, 20% to 50% EtOAc/ heptanes gradient) to afford 34 mg of product. Methyl 4-[l-(4-fluorophenyl)-2- isopropyl-4-(methoxymethoxy)pyrrolo[2,3-c]pyridin-3-yl]benzoate (62%). ESI-MS m/z calc. 448.18, found 448.77 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 90℃; for 0.333333h; Microwave irradiation; | 1.B.4 Step 4. Synthesis of 4-[5-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3- yl] benzoic acid (Bl) A suspension of M3 (120 mg, 0.2647 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (83 mg, 0.3167 mmol), PdCh(dppf) (22 mg, 0.02694 mmol) and NaHCCb (45 mg, 0.5357 mmol) in DMF (750 pL) and water (250 pL) was microwaved at 90 °C for 20 minutes. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated to dryness and purified via silica gel chromatography, eluting with 0- 30% EtOAc in heptane. Methyl 4-[5-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4- yl-indol-3-yl]benzoate Bl (90 mg, 74%) NMR (300 MHz, CDCb) d 8.23 - 8.15 (m, 2H), 7.58 - 7.51 (m, 2H), 7.28 - 7.18 (m, 3H), 7.04 (ddd, J = 9.5, 2.5, 0.5 Hz, 1H), 6.95 - 6.85 (m, 1H), 6.79 (ddd, J = 8.9, 4.5, 0.6 Hz, 1H), 4.00 (s, 3H), 3.86 (ddt, J = 11.3, 4.0, 1.7 Hz, 2H), 3.23 (td, J = 11.8, 2.1 Hz, 2H), 3.01 (tt, J = 12.3, 3.5 Hz, 1H), 2.45 - 2.37 (m, 3H), 1.91 - 1.76 (m, 2H), 1.69 - 1.55 (m, 2H). ESI-MS m/z 462.0 (M+l)+. |
74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 90℃; for 0.333333h; Microwave irradiation; | 1.B.4 Step 4. Synthesis of 4-[5-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3- yl] benzoic acid (Bl) A suspension of M3 (120 mg, 0.2647 mmol), methyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (83 mg, 0.3167 mmol), PdCh(dppf) (22 mg, 0.02694 mmol) and NaHCCb (45 mg, 0.5357 mmol) in DMF (750 pL) and water (250 pL) was microwaved at 90 °C for 20 minutes. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated to dryness and purified via silica gel chromatography, eluting with 0- 30% EtOAc in heptane. Methyl 4-[5-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4- yl-indol-3-yl]benzoate Bl (90 mg, 74%) NMR (300 MHz, CDCb) d 8.23 - 8.15 (m, 2H), 7.58 - 7.51 (m, 2H), 7.28 - 7.18 (m, 3H), 7.04 (ddd, J = 9.5, 2.5, 0.5 Hz, 1H), 6.95 - 6.85 (m, 1H), 6.79 (ddd, J = 8.9, 4.5, 0.6 Hz, 1H), 4.00 (s, 3H), 3.86 (ddt, J = 11.3, 4.0, 1.7 Hz, 2H), 3.23 (td, J = 11.8, 2.1 Hz, 2H), 3.01 (tt, J = 12.3, 3.5 Hz, 1H), 2.45 - 2.37 (m, 3H), 1.91 - 1.76 (m, 2H), 1.69 - 1.55 (m, 2H). ESI-MS m/z 462.0 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In 1,4-dioxane; water monomer at 80℃; for 6.08333h; Inert atmosphere; | 14.10 Step 10. tert-Butyl 2-(tert-butyl)-9-(4-(methoxycarbonyl)phenyl)-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido[3,4-d]pyrimidine-7-carboxylate A vial containing dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3.33 mg, 4.08 µmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.014 g, 0.054 mmol) was charged with a solution of tert-butyl 2-(tert-butyl)-9-iodo-4-methyl-8-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-oxo-1,2,3,4-tetrahydro-7H-pyrrolo[3',2':5,6]pyrido[3,4-d]pyrimidine-7-carboxylate (0.020 g, 0.027 mmol) in 1,4-dioxane (0.544 mL), followed by 1.0 M potassium carbonate in water (0.082 mL, 0.082 mmol). The mixture was bubbled with nitrogen for 5 min and the sealed vial was heated at 80 °C for 6 h. The reaction mixture was diluted with ethyl acetate and filtered through a 0.45 micron filter cartridge. The solids were rinsed with ethyl acetate and the filtrate was concentrated to a brown oil. Purification by flash column chromatography using ethyl acetate (containing 5% methanol) in hexanes (0% to 100%) afforded the desired product (15 mg, 74.3%) as a brown oil. LCMS for C40H50N5O7S (M+H)+: m/z = 744.3; Found: 744.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane at 80℃; for 2h; Inert atmosphere; | 47 Synthesis of 47.2 To a stirred mixture of 47.1 (314.4 mg, 1.2 mmol, 1.2 eq) and 5- bromo-3-ethyl-lH-pyrrolo[2,3-b]pyridine (225 mg, 1 mmol, 1 eq) in dioxane (20 mL) and water (5 mL) were added potassium carbonate (1.58 g, 11.45 mmol, 3 eq) and Pd(dppf)C12 (277.8 mg, 0.38 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and compound was eluted with 10% ethyl acetate in petroleum ether to obtain methyl 4-[3-ethyl-lH-pyrrolo[2,3-b]pyridin-6-yl]benzoate (47.2) as a white solid. (220 mg, 79%), MS (ES): m/z 281 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 80℃; for 3h; | 2 Synthesis of 51.2. To a solution of 51.1 (1.45 g, 8.4 mmol, 1 eq) and methyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (2.64 g, 10.07 mmol, 1.2 eq) in 1, 4-di oxane (25 mL) and water (5 mL) were added potassium carbonate (3.48 g, 25.2 mmol, 3 eq) and Pd(dppf)C12 (610 mg, 0.83 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 80°C under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and compound was eluted in 30% ethyl acetate in petroleum ether to obtain methyl 4-(6-isopropoxypyrazin-2-yl)benzoate (51.2) as a yellow solid. (1.8 g, 79%), MS (ES): m/z 273 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; | 73 Synthesis of compound 73.3. (General Procedure F) To a stirred solution of 73.1 (700mg, 2.67mmol, leq) and 73.2 (539mg, 2.67mmol, leq) in dioxane (8mL) and H2O (2mL) (4:1) was added potassium carbonate (738mg, 5.34mmol, 2eq). The reaction mixture was degassed for lOmin under argon atmosphere. Then PdChdppf (195mg, 0.26mmol, O.leq) was added to the reaction mixture and degassed for another lOmin. The reaction mixture was heated at 90°C for 16h. After completion of the reaction, the reaction mixture was filtered through a celite bed and concentrated under reduced pressure to obtain crude product. This was purified by combi-flash column chromatography (RediSepRf 12g flash column) and eluted in 40% ethylacetate in hexane to provide pure 73.3 (380mg, 55%) as white solid. MS(ES): m/z 258.8 [M+H]+, LCMS purity 99.82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 80℃; for 2h; | 16 Synthesis of 16.1. To a solution of 2-chl oro-6- ethoxypyrazine (3.16 g, 20 mmol, 1 eq) and methyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl) benzoate (6.28 g, 24 mmol, 1.2 eq) in 1,4-di oxane (80 mL) and water (20 mL) was added potassium carbonate (8.28 g, 60 mmol, 3 eq) and Pd(dppf)C12CH2C12(l .63 g, 2 mmol, 0.1 eq). The resulting solution was stirred for 2 h at 80°C. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and compound was eluted in 20% ethyl acetate in petroleum ether to obtain methyl 4-(6-ethoxypyrazin- 2-yl) benzoate (16.1) as an off-white solid. (4.18 g, 78%), MS (ES): m/z 259 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 80℃; for 2h; | 83 Synthesis of 83.2 To a solution of 2-chloro-6-(trifluoromethyl)pyrazine (546.0 mg, 3.00 mmol, 1.0 eq) and methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (943.2 mg, 3.60 mmol, 1.2 eq) in 1,4-di oxane (20 mL) and water (4 mL) was added potassium carbonate (1.24 g, 9.00 mmol, 3.0 eq) and Pd(dppf)C12 (244.8 mg, 0.30 mmol, 0.1 eq). The resulting solution was stirred for 2 h at 80°C. The mixture was cooled to r.t, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and compound was eluted in 30% ethyl acetate in petroleum ether to obtain methyl 4-(6-(trifluoromethyl)pyrazin-2-yl)benzoate (83.2) as an off-white solid. (0.72 g, 85%), MS (ES): m/z 283 [M+H]+. |
Tags: 171364-80-0 synthesis path| 171364-80-0 SDS| 171364-80-0 COA| 171364-80-0 purity| 171364-80-0 application| 171364-80-0 NMR| 171364-80-0 COA| 171364-80-0 structure
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P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
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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