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CAS No. : | 49608-01-7 | MDL No. : | MFCD00082739 |
Formula : | C8H8ClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ILDJJTQWIZLGPO-UHFFFAOYSA-N |
M.W : | 185.61 | Pubchem ID : | 2799611 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.33 |
TPSA : | 39.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.81 cm/s |
Log Po/w (iLOGP) : | 2.18 |
Log Po/w (XLOGP3) : | 2.28 |
Log Po/w (WLOGP) : | 1.91 |
Log Po/w (MLOGP) : | 1.25 |
Log Po/w (SILICOS-IT) : | 2.16 |
Consensus Log Po/w : | 1.96 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.6 |
Solubility : | 0.467 mg/ml ; 0.00252 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.74 |
Solubility : | 0.338 mg/ml ; 0.00182 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.12 |
Solubility : | 0.14 mg/ml ; 0.000753 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.72 |
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 |
---|---|---|
69% | With tetrakis(triphenylphosphine) palladium(0); water; sodium carbonate In 1,4-dioxane at 110℃; for 18 h; | To a stirred solution of compound A (3 g, 16.16 mmol, 1 eq) in a mixture of dioxane and water (150 mL, 4: 1) mixture were added compound B (3 g, 24.2 mmol, 1.5 eq) and sodium carbonate (8.6 g, 80.8 mmol, 5 eq) and the mixture was degassed with argon for 30 minutes. Pd(Ph3P)4 (1.9 g, 1.62 mmol, 0.1 eq) was added to it and the resulting mixture was further degassed with argon for another 10 minutes and stirred at 110 °C for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with water (30 mL) and washed with ethyl acetate (20 mL). The aq. part was acidified with saturated aq. citric acid solution to pH 5. The organic components were extracted with 10percent MeOHZ CH2CI2 (100 mL) and the organic layer was concentrated in vacuo to obtain the compound C (2.2 g, 69percent) as white solid which was used in the next step without further purification. (0315) [0305] FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-cfe) δ 13.4(br s, 1 H), 9.14 (d, / = 2 Hz, 1 H), 8.33- 8.31 (m, 1 H), 8.17-8.15 (m, 2 H), 8.10 (d, / = 8 Hz, 1H), 7.55-7.48 (m, 3 H); (0316) [0306] LCMS: m/z = 200.1 [M+H], RT = 3.21 minutes; (Program Rl, Column Y). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium tetrahydroborate In methanol at 0 - 20℃; for 16 h; | To a solution of 19-2B (500 mg, 2.693 mmol) in MeOH (5 mL) was added sodium borohydride (153 mg, 4.04 mmol) portion wise at 0 °C and stirred at RT for 16 hr. The reaction was quenched with saturated ammonium chloride and diluted with EtOAc (50 mL) washed with water (50 mL), brine (20 mL) and dried over Na2S04, and the organic phase was concentrated under reduced pressure to get crude compound. Obtained crude was purified using silica gel chromatography (30percent EtOAc in hexanes) to afford 19-3B (230 mg, 1.60 mmol, 59percent yield) as a pale yellow solid. MS (ESI): m/z 144.0 (M+l)+. |
58% | With sodium tetrahydroborate In ethanol at 20℃; for 41 h; | To a solution of ethyl 6-chloronicotinate (25.8 g, 0.139 mol) in ethanol was added sodium borohydride (10.5 g, 0.278 mol), followed by stirring under an atmosphere of nitrogen gas at room temperature. After 41 hours, the reaction mixture was concentrated and then the residue was diluted with a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=4:1, 2:1, and 3:2), to give the title compound (11.7 g, 58percent) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm; 4.54 (2H, d, J=5.6Hz), 5.43 (1H, t, J = 5.6 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.80 (1H, dd, J = 2.4, 8.4 Hz), 8.35 (1H, d, J = 2.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: With potassium carbonate; triphenylphosphine In toluene at 45 - 50℃; Stage #2: at 45 - 115℃; |
Charged ethyl 6-chloronicotinate (10.0 gm) in a R.B. Flask arranged with reflux condenser on oil bath, containing toluene (100 ml). Stirred and charged potassium carbonate (30.0 gm), triphenylphosphine (4.0 gm) and 5percent Pd/C (4.0 gm) to the reaction solution. Gradually raised the temperature to 45-50 C and maintained under stirring at 45 - 50°C for 2 hours. Charged 6-ethynyl-4,4-dimethylthiochromane (8 gm) and Copper iodide (0.05 gm) at 45-50°C. After charging, the reaction temperature was raised to 105- 115°C and maintained under stirring at 105-1150C temperature for 10 hours. After completion, the reaction mass was cooled to 25-300C and filtered the catalyst Pd/C. To the filtrate charged water (300 ml) and stirred for 30 min. Separated the organic layer and the aqueous layer was extracted with toluene (100 ml). Separated the organic layer and combined all organic layers. Concentrated the solvent under reduced pressure to get residual mass. Charged hexane (25 ml) to the residual mass and stirred at 25-300C for 1.0 hour. Cooled the reaction to -10 to 5°C and maintained for 1.0 hour. Filtered the solid Tazarotene and dried in oven till constant weight. Weight of Tazarotene = 8.3 gm percent Yield = 60.0 percent. |
9 g | Stage #1: With palladium on activated charcoal; potassium carbonate; sodium sulfate; triphenylphosphine In toluene at 50 - 55℃; for 2 h; Inert atmosphere Stage #2: With copper(l) iodide In toluene at 105 - 115℃; |
To 188 ml of toluene was added palladium on carbon (10 g) under N2 atmosphere. The mixture was heated to 105-115 °C to remove water by azeotropic distillation. Thereaction mass was cooled to 50-55 °C. To the above mixture, anhydrous sodium sulphate(12.5 g), anhydrous potassium carbonate (37.5 g), triphenylphosphine (5 g), ethyl 6-chioronicotinoate (12.5 g) and toluene (12.5 ml) were added at 50-55 °C and stirred for 2hours. To the above mixture, 4,4-dimethyl-6-ethynylthiochroman (10 g), cuprous iodide(0.06 g) and toluene (12.5 ml) were added and the reaction mixture was heated to 105-115 °C for 10-12 hours. The reaction mixture was cooled to 25-30 °C and water (125 ml)was added. The biphasi reaction mixture was filtered and from the filtrate, product enriched organic layer was separated. The organic layer was washed with water (2 X 65. ml) and brine solution (2 X 65 ml), dried over anhydrous sodium sulphate (5 g) and all the solvent was distilled off to get residual mass. The residual mass was dissolved in n20 heptane (50 ml) at 75-80 °C, which was treated with activated charcoal, neutral aluminaand filtered. The filtrate was stirred at 25-30 °C for 20 hours. The resulted solid was filtered off, washed with n-heptane (12.5 ml) and dried to yield 9 g of tazarotene. (HPLC purity of tazarotene— 97.64percent; Content of dimer impurity - 1.31percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sulfuric acid Heating / reflux; | |
81% | With thionyl chloride at 0℃; Reflux; | 2.2.1 Ethyl 2-bromoisonicotinate (2a) General procedure: To a suspension of 2-bromoisonicotinic acid (1a, 1.00 mmol) in ethanol (10 mL), thionyl chloride (1.20 mmol) was added dropwise at 0. The mixture was heated to reflux and stirred overnight. Then remove the solvent in vacuo. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution followed by brine, dried over sodium sulfate, filtered and concentrated to afford 2a as a colorless oil (67% yield). |
46% | With sulfuric acid for 2h; Heating; |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran Ambient temperature; | ||
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 2h; Heating / reflux; | Ethyl 6-chloronicotinate (Compound 20) A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol) ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 g dimethylaminopyridine in 200 ml methylene chloride was heated at reflux for 2 hours. The mixture was allowed to cool, solvent removed in vacuo and residue subjected to flash chromatography to give the title compound as a low-melting white solid. PMR (CDCl3): δ 1.44 (3H, t, J-6.2 Hz) 4.44 (2H, q, J-4.4 Hz), 7.44 (1H, d, J-8.1 Hz), 8.27 (1H, dd, J-8.1 Hz, 3 Hz), 9.02 (1H, d, J-3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; at 60℃; for 3h; | [1165] To a sealed tube containing ethyl 6-chloronicotinate (2.0 g, 10.8 mmol), CuI (0.3 g, 1.6 mmol, 15 mol %), Pd(PPh3)2Cl2 (0.4 g, 0.5 mmol, 5 mol %), anhydrous Et3N (60 ml) is added prop-1-yne (7.0 ml, 129 mmol). The mixture is allowed to stir at 60 C. for 3 h. The mixture is filtered through a pad of celite and solvent is removed in vacuum. The resulting solid is purified by silica gel chromatography (30% EtOAc/Hexanes) to give a yellow solid (1.3 g, 6.8 mmol, 63%) for ethyl 6-prop-1-ynylnicotinate: HRMS (EI) calcd for C11H11O2 189.0790, found 189.0787. |
0.81 g | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃;Sealed tube; | To a sealed tube containing ethyl 6-chloronicotinate 28 (1.0 g, 5.39 mmol), Cul (0.154 g, 0.81 mmol), Pd(PPh )2Cl (0.189 g, 0.27 mmol) and anhydrous TEA (1.5 mL, 10.78 mmol) was added prop-1 -yne (16.16 mL, 16.16 mmol) (1 mol/L in DMF). The mixture was stirred at 60 C for 3 h. After cooling, the reaction mixture was poured into water and extracted with three 30 mL portions of EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The crude compound was purified by silica gel column chromatography eluting with a gradient of Petroleum Ethenethyl acetate, from 50:1 to 20:1 to give ethyl 6-prop-1 -ynylnicotinate 29 (0.81 g, 4.3 mmol). LCMS: (M+H)+ = 190; Purity 96% (UV 254 nm); Retention time =1 .1.64min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 20.25 - 23.3333h; | Example 108; (4-Cyclobutyl-[1,4]diazepan-1-yl)-[6-(4-fluoro-phenoxy)-pyridin-3-yl]-methanone hydrochloride monohydrate (Alternate Method) Step A: Ethyl 6-(4-fluorophenoxy)nicotinate. To a 2-L, 3-necked, round-bottomed flask equipped with a mechanical stirrer, a thermo couple, and a condenser was added DMF (194 mL), ethyl 6-chloronicotinate (100.00 g, 0.522 mol), and 4-fluorophenol (65.09 g, 0.575 mol). A brown solution formed after stirring for 5-10 min. To the solution was then added Cs2CO3 (189.19 g, 0.575 mol) in one portion. The reaction temperature increased from 20 C. to 30 C. over 10 min without external heating and then started cooling down. The resulting suspension was stirred at rt for 2-3 h and the internal reaction temperature cooled back to 23-25 C. The reaction mixture was then heated to 60 C. and stirred for 18-20 h. HPLC analysis indicated that the reaction was complete. The heating mantle was removed and the reaction mixture was allowed to cool to 25-30 C. To the mixture was added deionized water (145.5 mL) in a steady stream over 5 min and a slight exotherm was observed. The resulting suspension was stirred at rt for 15-20 min. Two additional portions of deionized water (145.5 mL each) were added and the suspension was stirred at rt for 15-30 min. The pH of the suspension was around 9-10. The solid product was collected by vacuum filtration, rinsed thoroughly with deionized water in portions. The filter cake as dried in a filter funnel by pulling through air for 24 h. The product was isolated as a white solid (133.6 g). mp: 68.0 C. (by DSC). 1H NMR (CDCl3): delta 8.81 (d, J=2.6 Hz, 1H), 8.22 (dd, J=8.5, 2.6 Hz, 1H), 7.12 (br s, 2H), 7.10 (d, J=1.0 Hz, 2H), 6.94 (d, J=8.5 Hz,1H), 4.38 (q, J=7.1 Hz, 2H), 4.38 (t, J=7.1 Hz, 3H). MS (ESI): M+H+=262.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.0 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.0 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 6-chloro-nicotinic acid ethyl ester (46.4 mg, 0.25 mmol, 1.67 equiv; commercially available) was added and the mixture heated by microwave irradiation to 220 C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.9 mg (18%) of the title compound. MS (ISP): 414.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.6% | With potassium carbonate; In acetonitrile; at 100℃; for 12h;Inert atmosphere; | Ethyl 6-chloronicotinate (12 g, 0.06 mol, 1.00 equiv), piperazine (8.35 g, 0.10 mol, 1.50 equiv) were dissolved in acetonitrile (100 ml).Potassium carbonate (17.87 g, 0.13 mol, 2.00 equiv) was added and the mixture was refluxed under nitrogen at 100 C. for 12 h.The reaction was monitored by TLC, suction filtered and the filtrate evaporated. Add ethyl acetate, water solution, wash a small amount of water twice,The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and allowed to stand. The filtrate was spin-dry,That is, the product 11.63g(Milky white solid) Yield: 86.6%. |
With triethylamine; In ethanol; water; at 170℃; for 0.333333h;Microwave irradiation; | Ethyl 6-chloronicotinate (117 mg, 1.0 mmol) was transferred to a microwave vial. Piperazine (103 mg, 1.2 mmol), TEA (0.17 mL, 1.2 mmol) and EtOH/H2O 1:3 (1.0 mL) were added. The slurry was heated in a microwave oven, single node heating, at 170 C for 20 minutes. The material was extracted with EtOAc (2 x 8 mL) from Na2CO3 (8 mL, 10%, aq.). Combined organic phases were dried with sodium sulphate and evaporated. This gave 117 mg crude material that was used without further purification in the next step. Ethyl 6-(piperazin-1-yl)nicotinate (117 mg, 0.30 mmol), as a crude material, was dissolved in DCM (4 mL) and isocyanatobenzene (43 mg, 0.36 mmol) was added. The reaction mixture was stirred at r.t. under nitrogen for 16 h. PS-TRIS (ca. 100 mg, loading 4.08 mmol/g) was added and the mixture was stirred gently at r.t. for 2 h and then filtered while rinsing with DCM. The crude material was purified by flash chromatography on Si-gel (pentane/EtOAc 2:1). Yield: 72 mg (20%, two steps). 1H NMR (400 MHz) delta 1.36 (3H, t, J = 7.2 Hz), 3.57 - 3.71 (4H, m), 3.71 - 3.87 (4H, m), 4.33 (2H, q, J = 7.2 Hz), 6.52 - 6.62 (2H, m), 7.01 - 7.07 (1H, m), 7.25 - 7.31 (2H, m), 7.34 - 7.39 (2H, m), 8.04 - 8.08 (1H, m), 8.81 (1H, br s). MS m/z: 355 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 16h; | To a solution of 19-2B (500 mg, 2.693 mmol) in MeOH (5 mL) was added sodium borohydride (153 mg, 4.04 mmol) portion wise at 0 C and stirred at RT for 16 hr. The reaction was quenched with saturated ammonium chloride and diluted with EtOAc (50 mL) washed with water (50 mL), brine (20 mL) and dried over Na2S04, and the organic phase was concentrated under reduced pressure to get crude compound. Obtained crude was purified using silica gel chromatography (30% EtOAc in hexanes) to afford 19-3B (230 mg, 1.60 mmol, 59% yield) as a pale yellow solid. MS (ESI): m/z 144.0 (M+l)+. |
58% | With sodium tetrahydroborate; In ethanol; at 20℃; for 41h; | To a solution of ethyl 6-chloronicotinate (25.8 g, 0.139 mol) in ethanol was added sodium borohydride (10.5 g, 0.278 mol), followed by stirring under an atmosphere of nitrogen gas at room temperature. After 41 hours, the reaction mixture was concentrated and then the residue was diluted with a saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=4:1, 2:1, and 3:2), to give the title compound (11.7 g, 58%) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) delta ppm; 4.54 (2H, d, J=5.6Hz), 5.43 (1H, t, J = 5.6 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.80 (1H, dd, J = 2.4, 8.4 Hz), 8.35 (1H, d, J = 2.4 Hz). |
With lithium aluminium tetrahydride; In tetrahydrofuran; toluene; at -78 - 0℃; for 1h; | EXAMPLE 2; Synthesis of N2- [ (lS)-I- (4-15- [l- (aminocarbonyl) cyclopropyl] pyridin-2-yl} phenyl)-2, 2,2-trifluoroethyl]- Nl- (1-cyanocyclopropyl)-4-fluoro-L-leucinamide; Step 1 : Preparation of (6-chloropyridin-3-yl) methanol; To a-78 C solution of ethyl 6-chloronicotinate (10 g) in 250 mL of THF was slowly added 126 mL of lithium aluminium hydride (1.5 M in toluene). The mixture was stirred at 0 C for 1 hour. Poured into saturated aqueous tartaric acid (200 mL) and extracted with ethyl acetate (2 X 200 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on Si02 using ethyl acetate and hexanes (1: 2 to 1: 1) to yield the title compound. 'H NMR (CD3COCD3) 8 8.35 (1H, s), 7.80 (1H, d), 7.40 (1H, d), 4. 68 (2H, d), 4.55 (1H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; In dimethyl sulfoxide; at 160℃; for 16h; | A mixture of 3,5-dimethyl-4-phenyl-1H-pyrazole (2.50 g, 14.5 mmol), ethyl 6-chloronicotinate (5.39 g, 29.0 mmol), potassium carbonate (8.02 g, 58.1 mmol) and dimethyl sulfoxide (100 mL) was stirred at 160 C. for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and toluene (2:1) and washed with water. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with hexane/ethyl acetate (8:1) to afford 2.43 g (52%) of the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In DMF (N,N-dimethyl-formamide); at 100℃; for 2h; | To a solution of 6-chloronicotinic acid ethyl ester (1.92 g) in N,N-dimethylformamide (1 ml), trimethylsilylacetylene (2.0 g), bistriphenylphosphine palladium dichloride (210 mg), cuprous iodide (60 mg) and triethylamine (1.2 g) were added successively and the mixture was stirred in a sealed tube at 100 C. for 2 hours.. After cooling, the reaction solution was poured into a saturated aqueous sodium hydrogencabonate solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.38 g of the desired product as a brown oil. 1H-NMR (CDCl3) delta: 0.29 (9H, s), 1.41 (3H, t, J=7.3 Hz), 4.42 (2H, q, J=7.3 Hz), 7.52 (1H, d, J=7.9 Hz), 8.25 (1H, dd, J=2.0, 7.9 Hz), 9.15 (1H, d, J=1.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; at 60℃; | Step 1: Ethyl 6-{4-[(1-[(1, 1-DIMETHYLETHYL) oxy] CARBONYL}-4-PIPERIDINYL) OXY]-1- PIPERIDINYL}-3-PYRIDINECARBOXYLATE tert-Butyl 4- (4-piperidinyloxy)-1-piperidinecarboxylate (D4) (1. 7G), potassium carbonate (1.5g) and ethyl 6-chloro-3-pyridinecarboxylate (1.0 G) were heated at 60C under argon overnight. The reaction mixture was evaporated and redissolved in DCM (100 ML) and washed with saturated sodium hydrogen carbonate (3 x 50ml), dried (MgSO4) and evaporated to give a crude product which was chromatographed [silica gel, eluting with (10% NH3 in MeOH/DCM, 0-10%] to give the subtitle compound (1.43 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | EXAMPLE 2; Step I: Preparation of tazarotene hydrochloride salt; [0029] Into a 2L 4-neck round bottom flask, dimethyl sulfoxide (700 ml), palladium chloride (3.83 g), and triphenyl phosphine (14.06 g) were added under stirring under a nitrogen atmosphere at room temperature and the temperature was slowly raised to about 145C. The solution became clear at a temperature of about 145C after about 10 minutes. Then the solution was slowly cooled to room temperature over about 45 minutes. In a separate 2L 4-neck round bottom flask, ethyl-6-chloro-3-nicotinate (96.40 g), 4,4- dimethy-6-ethynylthiochroman (100 g) obtained in Example 1, cuprous iodide (6.5 g), and triethanolamine (TEA) (165 g) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for about 2 to about 5 minutes and the contents from the other round bottom flask (now containing bis(triphenylphosphine) palladium (II) chloride formed in situ) were added to the reaction mixture. The temperature was slowly raised to a temperature of about 98C and maintained for about three hours. After the reaction was completed as determined by TLC, the reaction mixture was cooled to a temperature of about 20C to form tazarotene. The reaction mixture was then filtered, and the resulting cake was washed with DMSO (20 ml). All the filtrate was combined, and ethyl acetate (1 L) was added to the filtrate. The solution was washed with water (3 x 400 ml). The organic layer was separated, and the ethyl acetate was distilled out completely (KFR < 0.2%) under vacuum. An ethyl acetate HCI solution (1000 ml) was added to the residue within 15 minutes. The reaction mixture was maintained for 2 hours at room temperature to form tazarotene hydrochloride salt. The tazarotene hydrochloride solid was filtered and washed with ethyl acetate (2x150 ml). The solid was dried at room temperature for about 6 hours (to remove excess HCl gas). Tazarotene hydrochloride salt appears as a yellow solid after drying. The solid weighed about 140 g. Yield = 81 %, m. p. 112-114 C, purity 99.6 % (by HPLC). [0030] The IR (KBr) spectrum showed stretching at 2204 cm-1 and 1720 cm-1. The ¹H NMR (CDCl3) showed signals at No. 9.2(s,lH), 8.6(lH,d), 7.8 (d,2H), 7.4(d,lH), 4.4 (q,2H), 3.1(dd,2H), 2.0 (dd,2H), 1.5-1.6 (t,3H), 1.2-1.4 (s,6H). The CI Mass showed M+. m/z 352. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 95℃; for 3h; | Ethyl-6-chloronicotinate (1.86 g, 10 mmol) and piperidine-4-carboxamide (1.54 g, 12mmol) are dissolved in DMSO (7 ml). N,N-Diisopropylethylamine (2.1 ml, 12 mmol) is added and the reaction mixture is heated at 95 0C for 3 hours. Methanol (8 ml) is added as the reaction mixture cools to give a precipitate. The solid is collected, washed with water followed by diethyl ether, and dried in vacuo at 45 0C to yield the title compound as a white solid. MS (ES+) mle 278 (MH+) | |
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃; for 2h; | A stirred suspension comprising 6-chloro-nicotinic acid ethyl ester (1.86 g, 10.0 mmol), piperidine-4-carboxamide (1.54 g, 12.0 mmol) and DIPEA (2.1 mL, 12 mmol) in DMSO (7 mL) is heated to 90C for 2 hours. MeOH (8 mL) is then added as the reaction mixture cools and the resulting precipitate is filtered, washed with water followed by ether and dried in vacuo (45C) to yield the titled compound as a white powder. | |
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 95℃; for 3h; | Ethyl-6-chloronicotinate (1.86 g, 10 mmol) and piperidine-4-carboxamide (1.54 g, 12mmol) are dissolved in DMSO (7 ml). N,N-Diisopropylethylamine (2.1 ml, 12 mmol) is added and the <n="89"/>reaction mixture is heated at 95 0C for 3 hours. Methanol (8 ml) is added as the reaction mixture cools to give a precipitate. The solid is collected, washed with water followed by diethyl ether, and dried in vacuo at 45 0C to yield the title compound as a white solid. MS (ES+) m/e 278 (MH*) |
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃; for 2h; | Step BC1: 4-Carbamoyl-3,4,5,6-tetrahydro-2H-[1,2I]bipyridinyl-5I-carboxylic acid ethyl esterA stirred suspension comprising 6-chloro-nicotinic acid ethyl ester (1.86 g, 10.0 mmol), piperidine-4-carboxamide (1.54 g, 12.0 mmol) and DIPEA (2.1 mL, 12 mmol) in DMSO (7 mL) is heated to 900C for 2 hours. MeOH (8 mL) is then added as the reaction mixture cools and the resulting precipitate is filtered, washed with water followed by ether and dried in vacuo (45C) to yield the titled compound as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 50℃; for 3h; | EXAMPLE 5 Preparation of ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate S-oxide (4) from (8) and (3) Compound (3) (21.24 g, 114.5 mmols), triethylamine (60 ml) and (8) (21.7 g, 99.54 mmol) are dissolved in N,N-dimethylformamide (400 ml) and added with copper(I) iodide (2.37 g, 12.44 mmol) and bis(triphenylphosphine) palladium (II) dichloride (5.93 g, 8.46 mmol), under nitrogen. The reaction mixture is heated at 50 C. under stirring for 3 hours, then left to cool and the reaction crude is diluted with ethyl acetate (600 ml) and washed with water. The aqueous phases are re-extracted with ethyl acetate (2*200 ml). The combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting reaction crude is subjected to column chromatography (eluent:hexane:ethyl acetate=5:2), then crystallized from hexane (90 ml) and ethyl acetate (10 ml) thereby obtaining 29.0 g of the desired product (yield=79%; m.p.=144-146 C.). 1H NMR delta 1.34 (3H, s), 1.43 (3H, t, J=7.1 Hz), 1.48 (3H, s), 1.91 (1H, ddd, J=2.4, 8.9, 15.1 Hz), 2.45 (1H, ddd, J=2.4, 10.1, 15.1 Hz), 3.16 (2H, m), 4.45 (2H, q, J=7.1 Hz), 7.58 (1H, dd, J=1.6, 8.1 Hz), 7.62 (1H, m), 7.71 (1H, d, J=1.6 Hz), 7.78 (1H, d, J=8.1 Hz), 8.31 (1H, dd, J=2.1, 8.1 Hz), 9.23 (1H, m). |
79% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 50℃; for 3h; | Compound (3) (21.24 g, 114.5 mmols), triethylamine (60 ml) and (8) (21.7 g, 99.54 mmol) are dissolved in N,N-dimethylformamide (400 ml) and added with copper(I) iodide (2.37 g, 12.44 mmol) and bis(trxphenylphosphi.ne) palladium (II) dichloride (5.93 g, 8.46 mmol), under nitrogen. The reaction mixture is heated at 50C under stirring for 3 hours, then left to cool and the reaction crude is diluted with ethyl acetate (600 ml) and washed with water. The aqueous phases are re-extracted with ethyl acetate (2 x 200 ml). The combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting reaction crude is subjected to column chromatography (eluent:hexane: ethyl acetate = 5:2), then crystallized from hexane (90 ml) and ethyl acetate (10 ml) thereby obtaining 29.0 g of the desired product (yield = 79%; m.p. = 144-146C). 1H NMR delta 1.34 (3H, s), 1.43 (3H, t, J = 7,1 Hz), 1.48 (3H, s), 1.91 (1H, ddd, J = 2.4, 8.9, 15.1 Hz), 2.45 (1H, ddd, J = 2.4, 10.1, 15.1 Hz), 3,16 (2H, m), 4.45 (2H, q, J = 7.1 Hz), 7.58 (1H, dd, J = 1.6, 8.1 Hz), 7.62 (1H, m), 7.71 (1H, d, J = 1.6 Hz), 7.78 (1H, d, J = 8.1 Hz), 8.31 (1H, dd, J = 2.1, 8.1 Hz), 9.23 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; lithium;Zinc chloride; tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; ethyl acetate; | EXAMPLE 18 Ethyl 6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinate Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0 C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-buryl lithium in hexane. Stirring was commenced at 0 C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0 C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0 C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with (MgSO4). Solvent was removed in vacuo and the residue further 3*75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid. PMR (CDCl3): delta 1.36 (6H, s), 1.44 (3H, t, J~7.1 Hz), 1.83-1.87 (2H, m), 4.22-4.26 (2H, m), 4.44 (2H, q, J~7.1 Hz), 6.80 (1H, d, J~7.6 Hz), 7.35 (1H, d, J~8.9 Hz), 7.58 (1H, d, J~7.6 Hz), 7.60 (1H, M), 8.28 (1H, d, J~8.9 Hz), 9.21 (1H, s). | |
With hydrogenchloride; n-butyllithium;Zinc chloride; tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; hexane; ethyl acetate; | EXAMPLE 18 Ethyl 6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinate Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0 C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium in hexane. Stirring was commenced at 0 C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0 C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0 C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with 3*75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid. PMR (CDCl3): delta1.36 (6H, s), 1.44 (3H, t, J~7.1 Hz), 1.83-1.87 (2H, m), 4.22-4.26 (2H, m), 4.44 (2H, q, J~7.1 Hz), 6.80 (1H, d, J~7.6 Hz), 7.35 (1H, d, J~8.9 Hz), 7.58 (1H, d, J~7.6 Hz), 7.60 (1H, M), 8.28 (1H, d, J~8.9 Hz), 9.21 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; | 2-Amino-4-(l-isopropyl-2-methyl-lH-imidazol-5-yl)pyrimidine (Method 39 of WO 03/076436, 477.4mg, 2.2mmol), ethyl 6-chloronicotinate (373mg, 2mmol), tris(dibenzylideneacetone)dipalladium(0) (9.2mg, 0.5mol%), BINAP (12.5mg, lmol%) and caesium carbonate (912.3mg, 2.8mmol) in anhydrous 1,4-dioxane (6ml) were evacuated and refilled with nitrogen (3 times). The reaction was heated under nitrogen at 1000C overnight. The residue obtained after evaporation of solvent under reduced pressure was partitioned between DCM and water and the aqueous layer was extracted with DCM twice. The organics were combined, washed with brine, dried and the solvent was evaporated to give a solid which was purified by chromatography eluting with MeOH:DCM:EtOAc (1:49.5:49.5 to 10:45:45). After trituration with ether and evaporation of the solvent, the title compound was obtained as a solid (1 :2 mixture ethykmethyl ester) which was dried in vac oven overnight at 50C (293.5mg, 40%). NMR for ethyl compound (400MHz): 1.34 (t, 3H), 1.48 (d, 6H), 2.58 (s, 3H under DMSO signal), 4.33 (q, 2H), 5.93 (septet, IH), 7.29 (d, IH), 7.57 (s, IH), 8.23 (dd, IH), 8.31 (d, IH), 8.52 (d, IH), 8.84 (d, IH), 10.43 (s, IH); m/z 367 & m/z 353. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate; In N,N-dimethyl-formamide; | (a) 4-Chloro-1-(5-ethoxycarbonylpyrid-2-yl)-2-methylimidazo[4,5-c]pyridine 4-Chloro-2-methylimidazo[4,5-c]pyridine described in C.A. 79, 105515f but made by the method of Chem. Pharm. Bull, 12 (8) 866-872 (1964) (3.34 g, 20 mmol), and ethyl 6-chloronicotinate (3.71 g, 26.2 mmol) were dissolved in N,N-dimethylformamide (42 ml). Potassium carbonate (2.76 g, 20 mmol) was added and the reaction was refluxed overnight. The reaction mixture was cooled, the solvent removed under reduced pressure and the crude product purified by flash chromatography eluding with ethyl acetate. Fractions containing product were evaporated and the resulting foam triturated with ether. The solid was filtered and dried under reduced pressure yielding the title compound as a yellow solid (3.2 g, 51%). 1 H NMR (3000 MHz, CHCL3) 1.47 (3H, t, J 6 Hz), 2.84 (3H, s), 4.56 (2H, q, J 6 Hz), 7.38 (1H, d, J 4 Hz), 7.59 (1H, d, J 6 Hz), 8.25 (1H, d, J 4 Hz), 8.63 (1H, d, J 6 Hz), 9.36 (1H, s). |
51% | With potassium carbonate; In N,N-dimethyl-formamide; | (a) 4-Chloro-1-(5-ethoxycarbonylpyrid-2-yl)-2-methylimidazo[4,5-c]pyridine 4-Chloro-2-methylimidazo[4,5-c]pyridine described in C.A. 79 , 105515f but made by the method of Chem. Pharm. Bull, 12 (8) 866-872 (1964) (3.34 g, 20 mmol), and ethyl 6-chloronicotinate (3.71 g, 26.2 mmol) were dissolved in N,N-dimethylformamide (42 ml). Potassium carbonate (2.76 g, 20 mmol) was added and the reaction was refluxed overnight. The reaction mixture was cooled, the solvent removed under reduced pressure and the crude product purified by flash chromatography eluding with ethyl acetate. Fractions containing product were evaporated and the resulting foam triturated with ether. The solid was filtered and dried under reduced pressure yielding the title compound as a yellow solid (3.2 g, 51%). 1H NMR (300 MHz, CDCl3) 1.47 (3H, t, J 6Hz), 2.84 (3H, s), 4.56 (2H, q, J 6Hz), 7.38 (1H, d, J 4Hz), 7.59 (1H, d, J 6Hz), 8.25 (1H, d, J 4Hz), 8.63 (1H, d, J 6Hz), 9.36 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 75℃; for 72h; | To a solution of tert-butyl hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylate (1.11g, 5.23mmol) in dioxane were added ethyl 6-chloronicotinate (1.28g, 6.9mmol) and DIPEA (2ml, 11.6mmol). The mixture was heated at 75C for 3 days. The mixture was then poured into EtOAc (100ml) and washed with saturated ammonium chloride (50ml), water (50ml) and brine (50ml). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (5% MeOH-DCM) to yield the title compound (1.429g, 75%). m/z 362.25 [M+H]+; 1H NMR (300 MHz, CDCI3) delta: 8.32 (1 H, dd, J = 0.6, 2.1 Hz), 8.03 (1 H, dd, J = 2.4, 9.0 Hz), 6.32 (1 H, d, J = 8.7 Hz), 4.34 (2H, q, J = 6.9 Hz), 3.24-3.85 (8H, m), 3.03 (2H, m), 1.47 (9H, s), 1.38 (3H, t, J = 7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; triethylamine; | Alternative synthesis: The title compound of Example 6, ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, was also prepared as follows. A solution of 15.4 g (76.2 mmol) of <strong>[118292-06-1]4,4-dimethyl-6-ethynylthiochroman</strong> and 14.0 g (75.5 mmol) of ethyl-6-chloronicotinate in 35 ml of freshly distilled triethylamine was degassed and then treated under nitrogen with a finely powdered mixture of 1 g (5.25 mmol) of high purity cuprous iodide and 2 g (2.85 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was heated under nitrogen at 55 C. for 20 hours and then cooled to room temperature. The triethylamine was then removed under vacuum and the residue was diluted with 200 ml of a 1:4 mixture of ethyl acetate and hexanes. This mixture was filtered through silica and the filtrate concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel; 15% ethyl acetate in hexanes) and recrystallized from a mixture of ethyl acetate and hexanes to give the title compound as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Example 36; Ethyl 6-(2-hydroxe-5-cyano-lH-indol-3-yl) nicotinate; To a solution of 5-cyanooxindole (360 mg, 2.27 mmol) in N, N-dimethylformamide (5 mL) was added sodium hydride (106 mg, 4.41 mmol). The greenish reaction mixture was stirred for 50 min whereafter 6-chloronicotinic acid ethyl ester (350 mg, 1.89 mmol) dissolved in N, N-dimethylformamide (5 mL) was added. The reaction mixture was heated at 110 C for 30 min and water (50 mL) and saturated NH4Cl (aq) (20 mL) was added, followed by extraction with ethyl acetate. The phases were separated and the organic phase contained the title compound as a precipitation that was filtered off. The solvent was concentrated in vacuo and additional product precipitated that was filtered to give 200 mg (34% yield) of the title compound in total :'H NMR (DMSO-d6,300 MHz) 8 14.50 (br s, 1 H), 11.00 (s, 1 H), 8.73 (s, 1 H), 7.95 (s, 2 H), 7.80 (s, 1 H), 7.48 (s, 1 H), 6.95 (d, J = 7 Hz, 1 H), 4.50- 4.15 (m, 2 H), 1.32 (t, J = 7 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 80℃; for 12h;Sealed tube; | A mixture of ethyl-6-chloro-nicotinate (10 g, 53.9 mmol) in cyclopropyl amine (10 mL) was heated in a sealed tube at 800C for 12 hours. The reaction was cooled and the mixture purified by chromatography (silica gel; ethyl acetate : hexane gradient <n="132"/>elution) to provide 6-cyclopropylamino-nicotinic acid ethyl ester (6.9 g, 32.2 mmol) as an oil. | |
at 80℃; for 12h;Sealed tube; Neat (no solvent); | A mixture of ethyl-6-chloro-nicotinate (10 g, 53.9 mmol) in cyclopropyl amine (10 mL) was heated in a sealed tube at 800C for 12 hours. The reaction was cooled and the mixture purified by chromatography (silica gel; ethyl acetate : hexane gradient elution) to provide 6-cyclopropylamino-nicotinic acid ethyl ester (6.9 g, 32.2 mmol) as an oil. | |
at 80℃; for 12h; | A mixture of ethyl-6-chloro-nicotinate (10 g, 53.9 mmol) in cyclopropyl amine (10 mL) was heated in a sealed tube at 800C for 12 hours. The reaction was cooled and the mixture purified by chromatography (silica gel; ethyl acetate : hexane gradient elution) to provide 6-cyclopropylamino-nicotinic acid ethyl ester (6.9 g, 32.2 mmol) as an oil. |
at 80℃; for 12h; | Part I: Preparation of 6-cyclopropylamino-nicotinic acid ethyl esterA mixture of ethyl-6-chloro-nicotinate (10 g, 53.9 mmol) in cyclopropyl amine (10 mL) was heated in a sealed tube at 800C for 12 hours. The reaction was cooled and the mixture purified by chromatography (silica gel; ethyl acetate : hexane gradient elution) to provide 6-cyclopropylamino-nicotinic acid ethyl ester (6.9 g, 32.2 mmol) as an oil. | |
Intermediate 1.6 To a solution of 6-chloronicotinic acid ethyl ester (1 g, 5.4 mmol) in NMP (10 mL) are added cyclopropylamine (4.12 g, 72.2 mmol) and K2CO3 (2.2 g, 16 mmol) at room temperature, then the mixture is stirred at 70 C. After stirring for 12 h, the reaction mixture is cooled down to room temperature and quenched with H2O (100 mL). The reaction mixture is extracted with EtOAc (200 mL). The organic phase is washed with H2O and brine, then dried over Na2SO4. The organic phase is concentrated in vacuo to give the crude residue, which is recrystallized from n-hexane/Et2O to give Intermediate 1.6 as a white amorphous material; ES-MS: M+H=207; HPLC: ctRet=1.98 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 0.5h;Microwave irradiation; | Triethylamine (3.7 mL, 27 mmol, 5.0 eq) is added to a solution of 6-chloronicotinic acid ethyl ester (1.0 g, 5.4 mmol, leq), (<S)-2-methyl- piperazine (540 mg, 5.4 mmol, leq) in NMP (6 mL) in a microwave vial. The vial is sealed and irradiated in the microwave at 15O0C (high absorption setting) for 30 min. Water (15 mL) and EtOAc (100 mL) are added, the organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The desired compound is isolated by silica gel chromatography (5 -60% EtO Ac/Heptane, then 10% MeOH/Heptane), (700 mg, 52 % yield).IH NMR (400 MHz, CHLOROFORM-^) delta ppm 8.81 (d, J=2.27 Hz, 1 H) 8.02 (dd, J=9.03, 2.34 Hz, 1 H) 6.59 (d, J=8.97 Hz, 1 H) 4.34 (q, J=7.24 Hz, 2 H) 3.12 (d, J=9.09 Hz, 1 H) 2.89 - 3.00 (m, 2 H) 2.81 - 2.90 (m, 2 H) 2.60 (d, J=10.48 Hz, 1 H) 2.56 (d, J=I 0.36 Hz, 1 H) 1.37 (t, J=7.07 Hz, 3 H) 1.15 (d, J=6.32 Hz, 3 H) MS (m/z, MH+): meas. 250.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With urea hydrogen peroxide adduct; trifluoroacetic anhydride; In acetonitrile; at 0 - 20℃; for 2.16667h; | Urea hydroperoxid complex (1.19 g, 12.6 mmol) was added to a stirred solution of ethyl 6- chloronicotinate (1.10 g, 6.0 mmol) in acetonitrile (15 mL) at room temperature. This mixture was stirred for 10 min at 0 C followed by slow addition of an acetonitrile solution (5 ML) of trifluoroacetic anhydride (2.52 g, 12.0 mmol). After the addition the mixture was stirred for 2 h at room temperature. Thereafter, the reaction mixture was diluted with a saturated aqueous NAHCO3 solution and extracted with dichloromethane. The organic phase was dried (NA2SO4) and concentrated to afford 0. 98 g (81% yield) of the title compound as a white solid : LH NMR (DMSO-d6, 400 MHz) 8 8.94 (s, 1 H), 7. 81 (dd, J = 8.4, 1. 6 HZ, 1 H), 7.60 (d, J=8. 4HZ, 1 H), 4.43 (q, J = 7. 2 HZ, 2 H), 1.40 (t, J = 7. 2 Hz, 3 H); MS (EI) NILZ 202 and 204 (M++L). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Intermediate Example, 1-11Acid 30: 6-(3,3,3-Trifluoropropoxy)nicotinic acidTo a solution of potassium tert-butoxide (0.864 g, 7.7 mmol) in tetrahydrofuran (10 mL) 3,3,3-trifluoropropan-l-ol (0.878 g, 7.7 mmol) was added at 0 0C. After 5 min ethyl 6- chloronicotinate (1.3 g, 7.0 mmol) was added to the stirred solution. The mixture was allowed to reach ambient temperature and stirred for an additional 2 h. Brine was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue (1.26 g, 4.8 mmol) was dissolved in a mixture of tetrahydrofuran (4 mL) and water (1 mL) and treated with lithium hydroxide (0.126 g, 3.0 mmol). The mixture was stirred at ambient temperature for 16 h and the tetrahydrofuran was removed in vacuo. Water (5 mL) was added and the pH adjusted to 2 with hydrochloric acid (4 M). The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 0.913 g (81% yield) of the title compound: 1H NMR (DMSO-J6) delta 8.72 (d, 1 H), 8.16 (dd, 1 H), 6.91 (d, 1 H), 4.56 (t, 2 H), 2.81 (dd, 2 H); MS (ESI) m/z 236 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In 1,2-dimethoxyethane; at 130℃;Autoclave; | Step 1: A solution of compound 220-1 (5 g, 36.9 mmol), compound 220-2 (5.34 g, 28.8 mmol) and DIPEA (7mL, 40 mmol) in DME (30 mL) was heated to 130C overnight in an autoclave. The mixture was diluted with EtOAc (200 mL), washed with 10% NaOH aqueous solution twice, citric acid and brines once respectively. The organic phase was dried over sodium sulfate and concentrated, the crude product was purified by silica gel column chromatography to deliver compound 220-3 (7.7 g, yield 85%) as yellow solid. 1H NMR (400MHz, CDCl3) delta 8.81 (s, 1H) 8.04 (d, J =12.0 Hz, 1H) 6.59 (d, J =8.0 Hz, 1H) 4.37-4.31 (m, 2H) 3.70-3.67 (m, 4H) 3.56-3.54 (m, 4H) 1.49 (s, 9H) 1.39-1.36 (m, 3 H). MS ESI calcd for C17H25N3O4 [M+H]+ 336, found 336. |
With N-ethyl-N,N-diisopropylamine; In 1,2-dimethoxyethane; at 120℃; for 12h; | STEP 1 : A mixture of ethyl 6-chloronicotinate (2.67 g, 14.4 mmol), tert- butyl piperazine-1 -carboxylate (2.5 g, 13.4 mmol) and N,N-diisopropylethylamine (3.5 mL, 20 mmol) in DME (15 mL) was heated at 12O0C for 12 hours. The mixture was then cooled to room temperature and partitioned with ethyl acetate and 10% aqueous citric acid. The organic layer was washed twice with 10% aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using 3:1 hexanes:ethyl acetate to 100% ethyl acetate afforded tert-butyl 4-(5-(ethoxycarbonyl)pyridin-2- yl)piperazine-l -carboxylate (3.65 g). 1H NMR (400 MHz, CDCl3): 8.81 (s, IH), 8.04 (d, IH), 6.58 (d, IH), 4.33 (q, 2H), 3.70-3.67 (m, 4H), 3.56-3.53 (m, 4H), 1.49 (s, 9H), 1.37 (tr, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Charged ethyl 6-chloronicotinate (10.0 gm) in a R.B. Flask arranged with reflux condenser on oil bath, containing toluene (100 ml). Stirred and charged potassium carbonate (30.0 gm), triphenylphosphine (4.0 gm) and 5% Pd/C (4.0 gm) to the reaction solution. Gradually raised the temperature to 45-50 C and maintained under stirring at 45 - 50C for 2 hours. Charged <strong>[118292-06-1]<strong>[118292-06-1]6-ethynyl-4,4-dimethylthiochroman</strong>e</strong> (8 gm) and Copper iodide (0.05 gm) at 45-50C. After charging, the reaction temperature was raised to 105- 115C and maintained under stirring at 105-1150C temperature for 10 hours. After completion, the reaction mass was cooled to 25-300C and filtered the catalyst Pd/C. To the filtrate charged water (300 ml) and stirred for 30 min. Separated the organic layer and the aqueous layer was extracted with toluene (100 ml). Separated the organic layer and combined all organic layers. Concentrated the solvent under reduced pressure to get residual mass. Charged hexane (25 ml) to the residual mass and stirred at 25-300C for 1.0 hour. Cooled the reaction to -10 to 5C and maintained for 1.0 hour. Filtered the solid Tazarotene and dried in oven till constant weight. Weight of Tazarotene = 8.3 gm % Yield = 60.0 %. | |
9 g | To 188 ml of toluene was added palladium on carbon (10 g) under N2 atmosphere. The mixture was heated to 105-115 C to remove water by azeotropic distillation. Thereaction mass was cooled to 50-55 C. To the above mixture, anhydrous sodium sulphate(12.5 g), anhydrous potassium carbonate (37.5 g), triphenylphosphine (5 g), ethyl 6-chioronicotinoate (12.5 g) and toluene (12.5 ml) were added at 50-55 C and stirred for 2hours. To the above mixture, <strong>[118292-06-1]4,4-dimethyl-6-ethynylthiochroman</strong> (10 g), cuprous iodide(0.06 g) and toluene (12.5 ml) were added and the reaction mixture was heated to 105-115 C for 10-12 hours. The reaction mixture was cooled to 25-30 C and water (125 ml)was added. The biphasi reaction mixture was filtered and from the filtrate, product enriched organic layer was separated. The organic layer was washed with water (2 X 65. ml) and brine solution (2 X 65 ml), dried over anhydrous sodium sulphate (5 g) and all the solvent was distilled off to get residual mass. The residual mass was dissolved in n20 heptane (50 ml) at 75-80 C, which was treated with activated charcoal, neutral aluminaand filtered. The filtrate was stirred at 25-30 C for 20 hours. The resulted solid was filtered off, washed with n-heptane (12.5 ml) and dried to yield 9 g of tazarotene. (HPLC purity of tazarotene- 97.64%; Content of dimer impurity - 1.31%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With lithium hydride; In 1-methyl-pyrrolidin-2-one; at 50 - 75℃;Inert atmosphere; Cooling; | (a) Ethyl 6-(5-cyano-2-hydroxy-1H-indol-3-yl)pyridine-3-carboxylate Lithium hydride (51 mg, 6.10 mmol, 95%) was added to 2-oxo-1,3-dihydroindole-5-carbonitrile (0.48 g, 3.05 mmol) in NMP (5.0 mL) under argon atmosphere. The mixture was flushed with argon and ethyl 6-chloropyridine-3-carboxylate (0.85 g, 4.58 mmol) was added dropwise. The mixture was heated at 50 C. for 1 h and additional ethyl 6-chloropyridine-3-carboxylate (0.28 g, 1.53 mmol) was added. The mixture was heated at 75 C. for 3 h and allowed to cool over night, and was poured into a mixture of NH4Cl (sat.) and EtOAc. The aqeous phase was extracted with EtOAc and was filtered. The yellow/orange solids (0.14 mg, 0.46 mmol, 15%) were dried in a 40 C. vacuum oven over night. 1H NMR (400 MHz, DMSO-d6) delta 8.73 (s, 1 H) 7.96 (br. s., 2 H) 7.79 (d, 1 H) 7.37 (d, 1 H) 7.02 (d, 1 H) 4.30 (q, 2 H) 1.30 (t, 3 H); MS (ESI) m/z 308 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; | Step 1 Synthesis of 6-Pyrrolidin-1-yl-nicotinic acid ethyl ester Potassium carbonate (3.89 g, 28 mmol) was added to a stirred solution of pyrrolidine (1.0 g, 14 mmol) and 6-chloronicotinic acid ethyl ester (2.87 g, 15.5 mmol) in DMF (10 mL) and the resulting mixture was stirred with heating at 60 C. overnight. Cold water was then added to and the resulting precipitate was dried to afford 498 mg (80%) of 6-pyrrolidin-1-yl-nicotinic acid ethyl ester. LCMS-purity: 97%. |
Yield | Reaction Conditions | Operation in experiment |
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53% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 170℃; for 2h;Microwave irradiation; | Example 101 6-{4-[4-(Indan-5-ylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid To a solution of N-indan-5-yl-4-piperazin-1-yl-benzamide (80 mg) and 2-chloropyridine-5-carboxylic acid ethyl ester (220 mg) in THF (4 mL) was added diisopropylethylamine (0.1 mL). The solution was heated in a microwave at 170 C for 2 hrs. The crystalline precipitate was filtered and washed with THF to give 6-{4-[4-(indan-5-ylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid ethyl ester (62 mg, Yied:53%). LCMS calc for C28H30N4O3 (m/e) 470, obsd 471 (M+H). The above ethyl ester (47 mg, 0.10 mmol) was suspended in THF (6 mL) and methanol (6 mL). Then lithium hydroxide solution (0.5N, 1 mL) was added. The mixture was refluxed for 8 hrs and then evaporated. The residue was dissolved in hot methanol (35 mL) and the solution was cooled to room temperature before aqueous hydrochloric acid (1N, 0.55 mL) was added. The white crystalline material was filtered and washed with methanol to give 6-{4-[4-(indan-5-ylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid (38 mg, Yield:85%). LCMS calc for C26H26N4O3 (m/e) 442, obsd 443 (M+H). |
53% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 170℃; for 2h;Microwave irradiation; | To a solution of N-indan-5-yl-4-piperazin-1-yl-benzamide (80 mg) and 2-chloropyridine-5-carboxylic acid ethyl ester (220 mg) in THF (4 mL) was added diisopropylethylamine (0.1 mL). The solution was heated in a microwave at 170 C. for 2 hrs. The crystalline precipitate was filtered and washed with THF to give 6-{4-[4-(indan-5-ylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid ethyl ester (62 mg, Yield:53%). LCMS calc for C28H30N4O3 (m/e) 470, obsd 471 (M+H).The above ethyl ester (47 mg, 0.10 mmol) was suspended in THF (6 mL) and methanol (6 mL), Then lithium hydroxide solution. (0.5 N, 1 mL) was added. The mixture was refluxed for 8 hrs and then evaporated. The residue was dissolved in hot methanol (35 mL) and the solution was cooled to room temperature before aqueous hydrochloric acid (1 N, 0.55 mL) was added. The white crystalline material was filtered and washed with methanol to give 6-{4-[4-(indan-5-ylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid (38 mg, Yield: 85%). LCMS calc for C26H26N4O3 (m/e) 442, obsd 443 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate; In N,N-dimethyl-formamide; at 100 - 120℃; for 16h; | Ethyl 6-chloronicotinate (567 mg, 3.05 mmol), tert-butyl 3,4,5,6-tetrahydro-1H-pyrrolo-[3,4-c]pyrrole-2-carboxylate (565.9 mg, 2.7 mmol) and cesium carbonate (878 mg, 2.7 mmol) were stirred in 20 ml of DMF at 100 C. for 8 h and at 120 C. for 8 h. The residue was filtered off, washed with water and ethyl acetate, and dried. The first filtrate was concentrated and stirred with ethyl acetate, and the product was filtered off. Yield: 72%, M+H+: 360.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[1196473-37-6]3H-benzo[c][1,2]oxaborole-1,6-diol</strong> (1.2 g, 8.0 mmol) in anhydrous dioxane (100 mL) was slowly added KHMDS (48 mL, 0.5 M solution in toluene, 24.0 mmol) at 0° C. After stirring for 15 min at room temperature, 6-chloro-nicotinic acid ethyl ester (2.97 g, 16.0 mmol) was added slowly to the reaction mixture at 0° C. The resulting mixture was stirred at 80° C. for 22 h. The reaction quenched by adding cold brine at 0° C. and the mixture was acidified to pH 3 using diluted hydrochloric acid. The resulting mixture was extract with EtOAc. The extract was washed with brine, dried and concentrated to dryness. The residue was purified by chromatography on silica gel (DCM/methanol=40:1) to give 0.521 g of material. This material was purified by prep-TLC (silica gel, THF/hexanes/AcOH=2:4:trace) to give 0.261 g of purer material which was purified again by chromatography on silica gel (DCM/methanol=40:1) to give 0.109 g of pure product as a pale-yellow solid. Mp 84-85° C. 1H NMR (400 MHz, DMSO-d6) delta 9.23 (s, 1H), 8.68 (d, J=2.34 Hz, 1H), 8.31 (dd, J=8.50, 2.34 Hz, 1H), 7.41-7.54 (m, 2H), 7.30 (dd, J=8.20, 2.34 Hz, 1H), 7.15 (d, J=8.50 Hz, 1H), 5.02 (s, 2H), 4.32 (q, J=7.03 Hz, 2H), 1.31 (t, J=7.03 Hz, 3H). MS (ESI) m/z=300 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | EXAMPLE 7 Preparation of ethyl 6-[(3-methyl-3-hydroxy)butyn-1-yl]nicotinate (9) from ethyl 6-chloronicotinate (3) Compound (3) (7.0 g, 37.72 mmol) is dissolved in dimethoxyethane (200 ml) and added in succession with water (90 ml), potassium carbonate (20.85 g, 150.88 mmol), copper(I) iodide (0.29 g, 1.5 mmols), triphenylphosphine (0.79 g, 3.01 mmol) and 10% (w/w) palladium on carbon (0.80 g, 0.75 mmol). The reaction mixture is stirred for 30 minutes at room temperature, then added with 2-methyl-3-butyn-2-ol (14.7 ml, 150.88 mmol), heated at 80 C. for 2 hours 30 minutes, then cooled, filtered through Celite, diluted with water (400 ml) and extracted with ethyl acetate (2*300 ml). The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting reaction crude is subjected to column chromatography (eluent:hexane:ethyl acetate=9:1) thereby obtaining 6.1 g of compound (9) (yield =69%; oil). 1H NMR delta 1.40 (3H, t, J=7.1 Hz), 1.65 (6H, s), 4.40 (2H, q, J=7.1 Hz), 7.50 (1H, dd, J=0.7, 8.0 Hz), 8.20 (1H, dd, J=2.1, 8.0 Hz), 9.10 (1H, dd, J=0.7, 2.1 Hz). | |
69% | Compound (3) (7.0 g, 37.72 mmol) is dissolved in dimethoxyethane (200 ml) and added in succession with water (90 ml), potassium carbonate (20.85 g, 150.88 mmol), copper(I) iodide (0.29 g, 1.5 mmols), triphenylphosphine (0.79 g, 3.01 mmol) and 10% (w/w) palladium on carbon (0,80 g, 0.75 mmol). The reaction mixture is stirred for 30 minutes at room temperature, then added with 2-methyl-3-butyn-2-ol (14.7 ml, 150.88 mmol), heated at 80C for 2 hours 30 minutes, then cooled, filtered through Celite, diluted with water (400 ml) and extracted with ethyl acetate (2 x 300 ml). The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting reaction crude is subjected to column chromatography (eluent:hexane: ethyl acetate = 9:1) thereby obtaining 6.1 g of compound (9) (yield = 69%; oil). 1H NMR delta 1.40 (3H, t, J = 7.1 Hz), 1.65 (6H, s), 4.40 (2H, q, J = 7.1 Hz), 7.50 (1H, dd, J = 0.7, 8.0 Hz), 8.20 (1H, dd, J = 2.1, 8.0 Hz), 9.10 (1H, dd, J = 0.7, 2.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole With potassium carbonate In dimethyl sulfoxide at 80℃; for 0.5h; Inert atmosphere; Stage #2: 6-chloro-3-pyridinecarboxylic acid ethyl ester In dimethyl sulfoxide at 80℃; for 4h; | [225] Intermediate 49: Ethyl 6-[5-cyclopropyl-3-(trifluoromethyI)-lH-pyrazol- l-yl] nicotinate:A solution of intermediate 5 (0.84 g, 4.7 mmol) and K2C03 (1.9 g, 14.1 mmol) in DMSO (10 mL) was heated at 80 °C under nitrogen for 0.5 h. To the mixture, ethyl-6- chloronicotinate (3.8 g, 20.3 mmol) was added and stirred at 80 °C for 4 h. Work-up (H20/AcOEt) and purification afforded the title compound (0.26 g). -NMR (δ ppm, CDC13, 400 MHz): 9.11 (d, J 1, 1H), 8.44 (d, J 2.2, 8.6, 1H), 8.00 (d, J8.6, 1H), 6.25 (s, 1H), 4.45 (q, J 7.1, 2H), 2.91-2.80 (m, 1H), 1.43 (t, J 7.1, 3H), 1.11-1.01 (m, 2H), 0.79- 0.70 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 1.0h;Inert atmosphere; Microwave irradiation; | General procedure: To an oven-dried microwave vial was added <strong>[113853-16-0]ethyl 2-amino-1,3-oxazole-5-carboxylate</strong> (546 mg, 3.50 mmol), Cs2CO3 (2279 mg, 6.99 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. 2,4-Dichloropyridine (0.378 mL, 3.50 mmol) was added via syringe, followed by 1,4-dioxane (18 mL) (degassed) and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. CH2Cl2 (40 mL) was added to the crude reaction mixture together with silica (5 g). The solvents were removed under reduced pressure and the crude product was purified by flash silica chromatography with CH2Cl2 (containing 1% methanolic ammonia) as eluent.The resulting brown solid was triturated with Et2O to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (626 mg, 67%) as a pale yellow solid, which was collected by filtration and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In ethanol; acetonitrile; at 70 - 80℃;Inert atmosphere; | To a flask equipped with a short-path distillation head was added 6.2 g (ca. 22.06 ramol) of Amine B, 135 mL acetonitrile, 50mL absolute EtOH (200pf). The mixture was heated and ca. 10 mL of solvent was distilled-off to remove water. To the remaining solution under an argon atmosphere was added 4.29 g (23.17mraoi) of the ethyl 6-chloropyridine-3- carboxylate (Aldrich), followed by 4.6 mL (30.89 mmol) DBU, and the reaction mixture heated between 70-80oC until complete by TLC (2% MeOH/CH2C12, 20 % MeOH/CH2C12) with additional chloropyridine added if needed to drive reaction to completion. After completion, the reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in CH2C12 (150mL) (some precipitate remains), and the CH2C12 suspension was washed 3 x lOOmL with a 1 :1 solution of saturated ammonium chloride/H20 solution. The aqueous layers were combined and washed with CH2C12 (4x 50 mL), The CH2C12 layers were combined and dried with Na2S04, filtered, and concentrated to a white solid. To the solid was added CH2C12 (50mL), MeOH (ca. 5 mL) and 11 g Si02, and the resultant mixture concentrated. The solid was purified on a column of 220g Si02 packed in 2%MeOH/CH2C12 by eluting with a gradient of 2-9% MeOH/CH2C12 . The desired fractions were concentrated and dried under high- vacuum overnight to give 6.2 g (65%) of the amine-pyridylester adduct. 1HNMR (300MHz, CDC13) = 8.80 (br s, 1H), 8.77 (br s, 1H), 8.58 (d, J=4.8, IH), 8.00 (d, J=2Hz, 1H), 7.97 (br s, 1H), 7.87 (m, 1H), 7.7 (m, 2H), 7.51 (t, J=8 Hz, IH), 7.34 (m, IH), 6.60 (d, J-9Hz5 IH), 6.36 (d, J=8Hz, IH), 4.45 (d, J= 13 Hz, 2H), 4.31 (q, J=7 Hz, 3H), 3.1 1 (t, J=12 Hz, 2H), 2.15 (d, J=10 Hz, 2H), 1.54 (m, 2H), 1.35 (t, J= 7Hz, 3H). MS(ESI+) m z = 431 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 100℃; for 4h; | Example 13(1) 6-(4-aminopiperidin-1-yl)nicotinic acid ethyl ester 6-chloronicotinic acid ethyl ester (4.27 g, 23 mmol) was dissolved in DMF (30 ml), and potassium carbonate (4.77 g, 35 mmol) and 4-aminopiperidine (2.76 g, 28 mmol) were added thereto, followed by stirring at 80C for 3 hours and at 100C for 1 hour. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure, thereby obtaining 6-(4-aminopiperidin-1-yl)nicotinic acid ethyl ester (4.17 g, 73%) as a pale brown oil. 1H-NMR (CDCl3): delta (ppm) 1.20-1.65 (m, 4H), 1.36 (t, J = 7.1 Hz, 3H), 1.83-2.00 (m, 2H), 2.84-3.15 (m, 3H), 4.33 (q, J = 7.1 Hz, 2H), 4.23-4.47 (m, 2H), 6.60 (dd, J = 9.1, 0.6 Hz, 1H), 7.99 (dd, J = 9.1, 2.4 Hz, 1H), 8.79 (dd, J = 2.4, 0.6 Hz, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | In DMSO (5 mL) was dissolved 2-methyl-1H-imidazole (575 mg, 7.00 mmol). To the solution 60% sodium hydride (in oil) (323 mg, 8.08 mmol) was added at 0 C. and the mixture was stirred at room temperature for 30 minutes. Ethyl 6-chloronicotinate (1.00 g, 5.39 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=97/3) to give ethyl 6-(2-methyl-1H-imidazol-1-yl)nicotinate (455 mg, 37% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 16h; | Step-I: Ethyl 6-pyrazol-l-ylpyridine-3-carboxylateA stirred suspension of ethyl 6-chloropyridine-3-carboxylate (500 mg, 2.7 mmol), 1H- pyrazole (270 mg, 4.0 mmol) and cesium carbonate(1.32 g, 4.0 mmol) in DMSO (5 mL) was heated at 100 C for 16 h. Reaction mixture was cooled to room temperature and quenched with water (20 mL). This was extracted with ethyl acetate (2 X 25 mL), combined organic layer washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 500 mg (85%) of ethyl 6-pyrazol- 1 -ylpyridine-3 -carboxylate.? NMR (400 MHz, CDC13): delta 1.42 (t, J= 7.1 Hz, 3H), 4.42 (q, J = 7.1 Hz, 2H), 6.50 (t, J = 1.8 Hz, 1H), 7.78 (s, 1H), 8.04 (d, J= 8.6 Hz, 1H), 8.40 (dd, J= 8.5, 2.1 Hz, 1H), 8.62 (d, J = 2.5 Hz, 1H), 9.03 (d, J= 2.0 Hz, 1H). MS (ES) m/z 218.0 (M+l). |
85% | With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 16h; | Step-I: Ethyl 6-pyrazol-1-ylpyridine-3-carboxylate A stirred suspension of ethyl 6-chloropyridine-3-carboxylate (500 mg, 2.7 mmol), 1H-pyrazole (270 mg, 4.0 mmol) and cesium carbonate (1.32 g, 4.0 mmol) in DMSO (5 mL) was heated at 100 C. for 16 h. Reaction mixture was cooled to room temperature and quenched with water (20 mL). This was extracted with ethyl acetate (2*25 mL), combined organic layer washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 500 mg (85%) of ethyl 6-pyrazol-1-ylpyridine-3-carboxylate. 1H NMR (400 MHz, CDCl3): delta 1.42 (t, J=7.1 Hz, 3H), 4.42 (q, J=7.1 Hz, 2H), 6.50 (t, J=1.8 Hz, 1H), 7.78 (s, 1H), 8.04 (d, J=8.6 Hz, 1H), 8.40 (dd, J=8.5, 2.1 Hz, 1H), 8.62 (d, J=2.5 Hz, 1H), 9.03 (d, J=2.0 Hz, 1H). MS (ES) m/z 218.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; sodium carbonate; In ethanol; water; toluene; for 19h;Inert atmosphere; Reflux; | Step-I: Ethyl 6-(lH-pyrazol-4-yI)pyridine-3-carboxyIateA mixture of ethyl 6-chloropyridine-3-carboxylate (450 mg, 2.4 mmol), lH-pyrazole-4- ylboronic acid (540 mg, 4.8 mmol), tetra-w-butyl ammonium bromide (30 mg), 2M sodium carbonate solution in water (1.5 mL), toluene (18 mL) and ethanol (18 mL) was degassed for 30 min using argon. To this was added tertakis-(triphenylphosphine) palladium (0) (70 mg) and refluxed for 19 h. Reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), filtered through celite bed. Fitrate was washed with water (2 X 20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to furnish 270 mg (51%) of ethyl 6-(lH-pyrazol-4-yl)pyridine-3- carboxylate.? NMR (400 MHz, CDC13): delta 1.41 (t, J = 7.0 Hz, 3H), 4.41 (q, J = 7.1 Hz, 2H), 6.36 (s, 1H), 7.56 (d, J= 8.3 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 8.19 (s, 1H), 8.27 (dd, J = 8.3, 2.2 Hz, lH), 9.17 (d, J= 1.9 Hz, 1H). MS (ES) m/z 218.1 (M+l). |
51% | With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; sodium carbonate; In ethanol; water; toluene; for 19h;Inert atmosphere; Reflux; | A mixture of ethyl 6-chloropyridine-3-carboxylate (450 mg, 2.4 mmol), 1H-pyrazole-4-ylboronic acid (540 mg, 4.8 mmol), tetra-n-butyl ammonium bromide (30 mg), 2M sodium carbonate solution in water (1.5 mL), toluene (18 mL) and ethanol (18 mL) was degassed for 30 min using argon. To this was added tertakis-(triphenylphosphine) palladium (0) (70 mg) and refluxed for 19 h. Reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), filtered through celite bed. Fitrate was washed with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to furnish 270 mg (51%) of ethyl 6-(1H-pyrazol-4-yl)pyridine-3-carboxylate. [0308] 1H NMR (400 MHz, CDCl3): delta 1.41 (t, J=7.0 Hz, 3H), 4.41 (q, J=7.1 Hz, 2H), 6.36 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 8.19 (s, 1H), 8.27 (dd, J=8.3, 2.2 Hz, 1H), 9.17 (d, J=1.9 Hz, 1H). MS (ES) m/z 218.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Example 1Step 1 To a solution of Intermediate 2 (8g, 27.8 mmol) in dry THF (200 mL) under nitrogen at -78 degC was added n-BuLi (2.5M in hexanes, 24.5 mL, 61.2 mmol, 2.2 eq.) dropwise and the solution stirred at -78 degC for 1 h. Ethyl 6-chloronicotinate (4.3 mL, 30.6 mmol, 1.1 eq.) was added quickly and the reaction stirred for a further 30 min before it was quenched with NH4CI (aq.). Once warmed to room temperature, the mixture was partitioned between EtOAc (200 mL) and water (200 mL). The organic phase was washed with water (200 mL) and brine (100 mL) before it was dried (MgS04), filtered and concentrated. The material was triturated with Et20 twice to give 2 crops of {(R)-1-[4-chloro-3-(6-chloro-pyridine-3- carbonyl)-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester, totalling (6.4g, 15 mmol, 54 %) between them. [MH]+ 371 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 95℃; for 10h; | Example 9 6-(2-Methoxy-ethylamino)-nicotinic acid ethyl ester 500 ml 3-necked round bottom flask is charged with pyridine chloride (27.69 g, 150 mmol), DMF (200 ml), K2CO3 (31.05 g, 225 mmol, 1.5 eq), methoxy ethylene amine (16.9 ml, 195 mmol, 1.3 eq) and heated while stirring at 90-95 C. Monitor by HPLC for every 2 hours. Reaction completed after 10 hours. Solid was filtered, washed with toluene (70 ml). The filtrate was extracted with water and back extracted with toluene. The combined organic layers were washed with brine, dried, and concentrated under reduce pressure. Heptane was added to the crude product and stirred for 30 min at 0 C. before filtered and dried to give 22.71 g (67.6%) of clean product: 1H NMR (400 MHz, DMSO-d6) delta 8.55 (1H), 7.78 (1H), 7.48 (1H), 6.55 (1H), 4.2 (2H), 3.48 (4H), 3.25 (3H), 1.25 (3H); m/z (ES+) 224.26 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.9% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 140℃; for 0.666667h;Microwave irradiation; | To 4- [3 - [(4,4- difluorocyclohexyl)methyl]-lH-pyrrolo[2,3-b]pyridin-5-yl]-3,5-dimethyl-isoxazole (P-0034, 0.35 g, 1.01 mmol) in NMP (3 ml) was added ethyl 6-chloropyridine-3-carboxylate (0.23 g, 1.22 mmol) followed by cesium carbonate (0.6 g, 1.84 mmol). The reaction was heated at 140 C in a microwave reactor for 40 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 silica gel flash chromatography eluting with 20- 100% ethyl acetate in hexane to give product (P-0429, 0.27 g, 53.9%) MS (ESI) [M+H+]+ = 495.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.3% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; | A mixture of benzyl (2-hydroxypyridin-3-yl)carbamate (A29 step 1, 1.20 g, 4.91 mmol), ethyl 6-chloronicotinate (1.459 g, 7.86 mmol), N1,N2-dimethylethane-1,2- diamine (0.209 mL, 1.965 mmol), copper(I) iodide (0.28 1 g, 1.474 mmol), and potassium carbonate (1.698 g, 12.28 mmol) in 1,4-Dioxane (25 mL) in a pressure tube was heated at 110 oC for 60 h (weekend). Upon cooling to rt, the mixture was diluted with ethyl acetate(50 mL) and filtered through Celite. The filtrate was further diluted with ethyl acetate (150 mL), washed with water (2 x 35 mL) and brine (35 mL). The organic solution was dried over anhydrous Mg504.The desired product, ethyl 3-(((benzyloxy)carbonyl)amino)-2-oxo-2H-[1,2?-bipyridine]-S?-carboxylate (0.857 g, 2.178 mmol, 44.3 % yield), was isolated as a white solid by ISCO (120 g silica gel, solid loading, 15-50% ethylacetate/hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 80 - 180℃; for 0.333333h;Microwave irradiation; | Step 4-Preparation of 6-[7-[(4,4-difluorocyclohexyl)methyl]-2-(3,5-dimethylisoxazol-4-yl)pyrrolo[2,3-b]pyrazin-5-yl]pyridine-3-carboxylic acid (P-2078): To 4-[7-[(4,4-difluorocyclohexyl)methyl]-5H-pyrrolo[2,3-b]pyrazin-2-yl]-3,5-dimethyl-isoxazole (P-2077, 0.1 g, 0.29 mmol) in N-methyl-2-pyrrolidone ("NMP") (20 ml) was added ethyl 6-chloropyridine-3-carboxylate (0.125 g, 0.67 mmol) and cesium carbonate (1 g, 3.07 mmol). The reaction was allowed to stir at 80 C. overnight. LCMS showed that the reaction was not complete. The reaction was heated at 180 C. in a microwave for 20 min LCMS showed that the reaction was complete. 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, purified by silica gel column chromatography eluting with 0% to 60% ethyl acetate in hexane and further purified via prep RP-HPLC to give product P-2078 (34 mg, 25%) MS (ESI) MH(+)=468.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.1% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; | To a solution of 4-hydroxy-6-nitro-quinoline (5.5 g, 28.9 mmol, 1 eq.) in DMF (50 mL) was added potassium carbonate (7.9 g, 57.8 mmol, 2 eq.). Ethyl 6-chloropyridine-3-carboxylate (8.0 g, 43.3 mmol, 1.2 eq.) was added and the reaction mixture was heated at 100 C for 2 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get crude mass that was purified by washing with DCM and pentane to get pure ethyl 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxylate (5.5 g, 59.1%) light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.6% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere; | General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.5% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere; | General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere; | General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.5% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere; | General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.7% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere; | General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere; | General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.3% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1.0h;Sealed tube; Microwave irradiation; Inert atmosphere; | General procedure: 6-chloronicotinate (2 mmol) and amine 5a-5g (3 mmol) were added to amicrowave vial (10 ml) equipped with a stir bar. NMP (3 mL) was then addedfollowed by triethylamine (6 mmol). The vial was sealed and irradiated in themicrowave at 180 C (high absorption) for 60 min. The mixture was then dilutedwith H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The combinedorganic layers were dried over MgSO4 and concentrated. The residuewas purified by flash chromatography on silica gel using ethylacetate-petroleum ether gradient elution (1:4 - 1:2, v/v) to afford the titlecompound 7a-7g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In acetonitrile; at 60℃; for 18h; | 15 g (81 mmol) of ethyl 6-chloronicotinate were dissolved in 150 ml of acetonitrile, and 39mg of potassium carbonate (283 mmol) were added. 23 g (121 mmol) of 2-oxa-6-azaspiro [3 .3]heptane oxalate salt, prepared according to Angew. Chem. mt. Ed. 2008, 47, 4512-4515, were then added and the mixture was stirred at 60 C. for 18 h. The mixture was then stirred with water and extracted with ethyl acetate. The organic phase was washed with water, then dried over sodium sulphate, filtered oil and concentrated. This gave 18 g (92% of theory) of the desired compound which was reacted further directly without thrther purification. LC-MS [Method 1]: R=0.65 mm; MS (ESIpos):mlz=248 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 2-methyltetrahydrofuran; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; | A solution of intermediate (G30) (7.5 g, 14.81 mmol) and ethyl 6- chloronicotinate (5.50 g, 29.62 mmol) in K2C03(9.48 mL, 2 M, 18.96 mmol) and Me-THF (36 mL) was degased with nitrogen for 10 min. PdCl2(dppf)DCM (1.21 g, 1.48 mmol) was added and the mixture was heated at 120C using a singlemode microwave (Anton Paar Monowave 300) with a power output ranging from 0 to 850 W for 30min. The reaction mixture was filtered through a short pad of Celite, the cake was washed with EtOAc, the organic layer was separated, washed with brine, dried (MgSG*4) and evaporated till dryness. Purification of the residue was carried out by flash chromatography over silica gel (cartridge 180 g, 15-40muetaiota, Heptane/EtOAc 80/20). The pure fractions were collected and evaporated to dryness to afford 4.3 g (55%) of intermediate (G316). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,4-dioxane; water; at 100℃; for 18h;Sealed tube; Inert atmosphere; | General procedure: In a sealed tube, a solution of intermediate (G103) (765 mg; 1.04 mmol, purity 69%), ethyl 6-chloronicotinate (232 mg; 1.25 mmol) and Rho04 (662 mg; 3.12 mmol) in dioxane (10 mL) and H20 (2 mL) was purged with N2. Pdl 18 (54 mg; 83 muiotaetaomicron) was added, the mixture was purged again with N2 and heated at 100C for 18 hours. The reaction mixture were filtered over celite, celite was rinsed with EtOAc and water. Brine was added to the filtrate. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over MgS04, filtered and evaporated in vacuo. The residue was purified by preparative LC (irregular SiOH, 15-40 muetaiota, 40 g Grace Resolve , liquid loading (DCM), mobile phase: heptane/EtOAc 80/20) give 267 mg (48%) of intermediate (G104) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,4-dioxane; water; at 80℃; for 4h;Schlenk technique; Inert atmosphere; | General procedure: In a Schlenk tube, a solution of intermediate (G272) (1.79 g; 2.35 mmol; 75% purity), ethyl-6-chloronicotinate (522 mg; 2.81 mmol) and K3PO4 (1.49 g; 7.04 mmol) in dioxane (32 mL) and H20 (6 mL) was purged with N2. PdCl2dtbpf (153 mg; 0.234 mmol) was added, the mixture was purged again with N2 and heated at 80C for 4 h. EtOAc and water were added. The layers were separated and the organic layer was washed with brine (3 times), dried on MgSG*4, filtered, concentrated and purified by preparative LC (Regular SiOH, 30 muiotaeta, 80 g Grace Resolv, liquid loading (DCM), mobile phase gradient: from Heptane/EtOAc 90/10 to 60/40) to give 913 mg (65%) of intermediate (G286) as a yellowish solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 130℃; for 2h;Microwave irradiation; | A mixture of 9a (390 mg, 2 mmol), ethyl-6-chloronicotinate (389 mg, 2.1 mmol), Pd2(dba)3 (55 mg, 0.6 mmol), xantphos(69.3 mg, 0.12 mmol) and K3PO4 (636 mg, 3.0 mmol) in 1,4-dioxane(0.5 ml) was heated at 130 C for 2 h under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with water. The aqueous layer was separated and then extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated.The residue was purified by crystalization with EtOAc to afford 10a(530 mg, 77.0%) as a pale brown solid. MS-ESI (m/z) = 345 [M+H]+.To a solution of 10a (530 mg, 1.53 mmol) in ethanol (5 ml) wasadded 2N NaOH (1.53 ml, 3.06 mmol) solution at room temperature.The mixture was stirred at 70 C for 8 h. After concentration,the residue was neutralized with 2N HCl solution at 0 C to afford the brown precipitation. The resulting solid was collected by filtration to afford 11a (438 mg, 90.5%) as the brown solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; for 16h;Reflux; | General procedure: A mixture of 2a (5000 mg, 23.66 mmol), Ethyl-6-chloronicotinate (4392 mg, 23.66 mmol), Pd(dba)2 (1361 mg, 2.366 mmol), xantphos (2054 mg, 3.55 mmol) and Na2CO3 (3010 mg, 28.4 mmol)in 1,4-dioxane (50 ml) was refluxed for 16 h. After cooling to room temperature, the reaction mixture was diluted with water. The aqueous layer was separated and then extracted with EtOAc. The combined organic extracts were washed with water and brine,dried over MgSO4, filtered, and concentrated. The residue was purified by crystalization (EtOAc/diethyl ether = 1:1) to afford 3a (4010 mg, 47.0%) as a pale brown solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.7% | With sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; for 16h;Reflux; | General procedure: A mixture of 2a (5000 mg, 23.66 mmol), Ethyl-6-chloronicotinate (4392 mg, 23.66 mmol), Pd(dba)2 (1361 mg, 2.366 mmol), xantphos (2054 mg, 3.55 mmol) and Na2CO3 (3010 mg, 28.4 mmol)in 1,4-dioxane (50 ml) was refluxed for 16 h. After cooling to room temperature, the reaction mixture was diluted with water. The aqueous layer was separated and then extracted with EtOAc. The combined organic extracts were washed with water and brine,dried over MgSO4, filtered, and concentrated. The residue was purified by crystalization (EtOAc/diethyl ether = 1:1) to afford 3a (4010 mg, 47.0%) as a pale brown solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.4% | With sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; for 16h;Reflux; | General procedure: A mixture of 2a (5000 mg, 23.66 mmol), Ethyl-6-chloronicotinate (4392 mg, 23.66 mmol), Pd(dba)2 (1361 mg, 2.366 mmol), xantphos (2054 mg, 3.55 mmol) and Na2CO3 (3010 mg, 28.4 mmol)in 1,4-dioxane (50 ml) was refluxed for 16 h. After cooling to room temperature, the reaction mixture was diluted with water. The aqueous layer was separated and then extracted with EtOAc. The combined organic extracts were washed with water and brine,dried over MgSO4, filtered, and concentrated. The residue was purified by crystalization (EtOAc/diethyl ether = 1:1) to afford 3a (4010 mg, 47.0%) as a pale brown solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; In acetonitrile; at 80℃; for 24h; | General procedure: 4-hydroxy-3,5-dimethylbenzaldehyde(13a)(1.5 g, 10 mmol) and ethyl4-bromobutanoate (1.95g, 10mmol) were dissolved in acetonitrile (100 mL) andtreated with K2CO3 (5.52g, 40mmol). The reaction mixturewas stirred at 80 C for 24 h.Water was added to thereaction,and the aqueouslayer was extracted with EA (3 × 20 mL). The organic layers were combined,washed with water (3 × 25 mL),dried over anhydrous Na2SO4,and concentrated in vacuo to give compound 14aa(1.87g,71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: 6-bromo-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran With magnesium In diethyl ether; ethylene dibromide at 20℃; for 3h; Sealed tube; Inert atmosphere; Stage #2: [1.1.1]propellane In diethyl ether; ethylene dibromide at 100℃; for 6h; Inert atmosphere; Sealed tube; Stage #3: 6-chloro-3-pyridinecarboxylic acid ethyl ester Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 24h; | A solution of the respective phenol and the benzoate derivative or, respectively, the carboxylic acid derivative of an aromatic 6-membered heterocycle having 1 or 2 N-atoms, as defined in connection with formula (I), or their substituted derivatives in an appropriate solvent, preferably a polar aprotic solvent, most preferably DMSO, and preferably under addition of anhydrous K2C03 , was stirred at a temperature between 80C and 120C depending on the substrate until the limiting reactant was fully converted. The reaction was guenched by addition of water, extracted with organic solvent (preferably Et20, EtOAc and DCM depending on the substrate). The combined organic layers were washed with sat. agueous NaCI solution, dried over Na2S04 and evaporated to dryness under reduced pressure. The crude product was purified by flash column chromatography to give the desired biarylether. General procedure A: Ethyl 6-chloronicotinate (840 mg, 4.53 mmol, 1.00 equiv), 4-(tert- butyOphenol (875 mg, 5.82 mmol, 1.29 equiv) and K2C03 (958 mg, 6.93 mmol, 1.53 equiv) in DMSO (5 mL) were stirred at 100 C for 24 h. Purification by column chromatography (EtOAc/petroleum ether 1/15) gave the desired product as colourless solid (1.23 g, 4.10 mmol, 90%); HRMS (ESI) m/z calcd. for C18H22N03+ [M+H]+ 300.1594, found: 300.1589; NMR (400 MHz, Chloroform-ci) delta 8.88 - 8.79 (m, 1H), 8.26 (dd, J = 8.6, 2.4 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.13 - 7.04 (m, 2H), 6.91 (dd, J = 8.6, 0.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 96h; | General procedure: A solution of the respective phenol and the benzoate derivative or, respectively, the carboxylic acid derivative of an aromatic 6-membered heterocycle having 1 or 2 N-atoms, as defined in connection with formula (I), or their substituted derivatives in an appropriate solvent, preferably a polar aprotic solvent, most preferably DMSO, and preferably under addition of anhydrous K2C03 , was stirred at a temperature between 80C and 120C depending on the substrate until the limiting reactant was fully converted. The reaction was guenched by addition of water, extracted with organic solvent (preferably Et20, EtOAc and DCM depending on the substrate). The combined organic layers were washed with sat. agueous NaCI solution, dried over Na2S04 and evaporated to dryness under reduced pressure. The crude product was purified by flash column chromatography to give the desired biarylether. General procedure A: Ethyl 6-chloronicotinate (205 mg, 1.10 mmol, 1.00 equiv), 4-(tert- pentyOphenol (238 mg, 1.45 mmol, 1.31 equiv) and K2C03 (240 mg, 1.73 mmol, 1.57 equiv) in DMSO (2 mL) were stirred at 80 C for 4 days. Purification by column chromatography (EtOAc/petroleum ether 1:20) gave the desired product as colourless oil (332 mg, 1.06 mmol, 96%); HRMS (ESI) m/z calcd. for C19H24N03+ [M+H]+ 314.1751, found: 314.1753; NMR (400 MHz, Chloroform-d) delta 8.85 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 8.6, 2.4 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.6 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.65 (q, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.29 (s, 6H), 0.71 (t, J = 7.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 72h; | A solution of the respective phenol and the benzoate derivative or, respectively, the carboxylic acid derivative of an aromatic 6-membered heterocycle having 1 or 2 N-atoms, as defined in connection with formula (I), or their substituted derivatives in an appropriate solvent, preferably a polar aprotic solvent, most preferably DMSO, and preferably under addition of anhydrous K2C03 , was stirred at a temperature between 80C and 120C depending on the substrate until the limiting reactant was fully converted. The reaction was guenched by addition of water, extracted with organic solvent (preferably Et20, EtOAc and DCM depending on the substrate). The combined organic layers were washed with sat. agueous NaCI solution, dried over Na2S04 and evaporated to dryness under reduced pressure. The crude product was purified by flash column chromatography to give the desired biarylether. (V131) General procedure A: Ethyl 6-chloronicotinate (210 mg, 1.13 mmol, 1.00 eg.), 4-(tert-butyl)-2- methylphenol (245 mg, 1.49 mmol, 1.32 eguiv) and K2C03 (247 mg, 1.79 mmol, 1.58 eguiv) in DMSO (2 ml_) were stirred at 80 C for 3 days. Purification by column chromatography (EtOAc/petroleum ether 1:20) gave the desired product as colourless oil (259 mg, 0.83 mmol, 73%); HRMS (ESI) m/z calcd. for C19H24N03+ [M+H]+ 314.1751, found: 314.1759; NMR (400 MHz, Chloroform-d) delta 8.92 - 8.78 (m, 1H), 8.25 (dd, J = 8.7, 2.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.27 - 7.23 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 8.7, 0.6 Hz, 1H), 4.37 (g, J = 7.1 Hz, 2H), 2.15 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.1% | With iron(III)-acetylacetonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; diethyl ether; at -78℃; for 1h; | Toa stirring solution of ethyl 6-chloronicotinate (1 g, 5.4 mmol) in THF wasadded Fe(acac)3 (0.190 g, 0.54 mmol), followed by NMP (0.723 mL, 7.5mmol) at room temperature and then reaction mixture was cooled to -78 C.To the reaction mixture 3M solution of EtMgBr in Et2O (2.6 mL, 8.08mmol) was added drop wise and stirred at -78 C for 1 h. After the completionof reaction, crushed ice was added. The reaction mixture was extracted in to EtOAc,the organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated. The crude product was purified by Combiflash purifier using 14%EtOAc in Hexane to afford the title compound as colorless liquid (0.350 g,36.1%). 1H NMR (DMSO-d6,400 MHz) delta 1.21 (t, J= 8 Hz, 3H), 1.30 (t, J = 8 Hz, 3H),2.80 (q, J = 8 Hz, 2H), 4.31 (q, J = 8 Hz, 2H), 7.38 (d, J = 8 Hz, 1H), 8.15 (dd, J = 1.6 Hz, J = 2 Hz, 1H), 8.96 (s, 1H); MS(ESI) m/z 180.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;Inert atmosphere; | To a stirred solutionof ethyl 6-chloronicotinate (0.5 g, 2.702 mmol) in DMF (20.0 mL) was addedsodiumthiomethoxide (0.378 g, 5.400 mmol) portion wise, under nitrogenatmosphere at 0 C and the reaction was stirred for 3 h at room temperature.The reaction mixture was slowly quenched with ice and extracted with EtOAc. Theorganic layer was washed with water, brine and NaHCO3 solution,dried over anhydrous Na2SO4 and concentrated to the titlecompound as colorless liquid (0.5 g, 94%). 1H NMR (CDCl3, 400MHz) delta 1.38 (t, J= 6.8 Hz, 3H), 2.59 (s, 3H), 4.37 (q, J= 6.8 Hz, 2H), 7.22 (t, J = 13.2 Hz,1H), 8.02 (d, J = 13.6 Hz, 1H), 9.02(s, 1H); MS (ESI) m/z 198.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tetrakis(triphenylphosphine) palladium(0); water; sodium carbonate; In 1,4-dioxane; at 110℃; for 18h; | To a stirred solution of compound A (3 g, 16.16 mmol, 1 eq) in a mixture of dioxane and water (150 mL, 4: 1) mixture were added compound B (3 g, 24.2 mmol, 1.5 eq) and sodium carbonate (8.6 g, 80.8 mmol, 5 eq) and the mixture was degassed with argon for 30 minutes. Pd(Ph3P)4 (1.9 g, 1.62 mmol, 0.1 eq) was added to it and the resulting mixture was further degassed with argon for another 10 minutes and stirred at 110 °C for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with water (30 mL) and washed with ethyl acetate (20 mL). The aq. part was acidified with saturated aq. citric acid solution to pH 5. The organic components were extracted with 10percent MeOHZ CH2CI2 (100 mL) and the organic layer was concentrated in vacuo to obtain the compound C (2.2 g, 69percent) as white solid which was used in the next step without further purification. (0315) [0305] FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-cfe) delta 13.4(br s, 1 H), 9.14 (d, / = 2 Hz, 1 H), 8.33- 8.31 (m, 1 H), 8.17-8.15 (m, 2 H), 8.10 (d, / = 8 Hz, 1H), 7.55-7.48 (m, 3 H); (0316) [0306] LCMS: m/z = 200.1 [M+H], RT = 3.21 minutes; (Program Rl, Column Y). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 48h;Inert atmosphere; | Following general procedure A, to 4-ethylphenol (1.36 g, 11.1 mmol) and K2CO3 (1.89 g, 13.7 mmol) in DMSO (18 mL) was added ethyl 6- chloronicotinate (1.65 mL, 10.9 mmol) and the reaction was then stirred at 80 C for 48 hours in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed first with 1 M aqueous NaOH (1x) then washed with brine (1x), dried over Na2SO^ filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 90% to 60% PE-MeOH gradient to give the title compound as colorless oil (1.78 g, 60%).1H NMR (300 MHz, CDCI3) delta 8.83 (dd, / = 2.4, 0.7 Hz, 1H), 8.25 (dd,j = 8.6, 2.4 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.11 - 7.00 (m, 2H), 6.90 (dd,j = 8.7, 0.8 Hz, 1H), 4.37 (qj = 7.1 Hz, 2H), 2.68 (q,/ = 7.6 Hz, 2H), 1.38 (tj = 7.1 Hz, 3H), 1.26 (tj = 7.6 Hz, 3H)1. 3C NMR (75 MHz, CDCI3) delta 166.8, 165.2, 151.3, 150.5, 141.4, 140.6, 129.3, 121.4, 121.3, 110.7, 61.2, 28.4, 15.6, 14.4. HRMS (C16H18N03+): expected: 272.1281; found: 272.1271. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 72h;Inert atmosphere; | Following general procedure A, to 4-(l- (perfluoroethyl)cyclopropyl)phenol (330 mg, 1.3 mmol) and K2CO3 (305 mg, 2.2 mmol) in DMSO (2.7 mL) was added ethyl 6- chloronicotinate (0.2 mL, 1.3 mmol) and the reaction was then stirred at 80 C for 3 days in an argon atmosphere. The reaction was cooled to room temperature and quenched by the addition of water. The aqueous layer was extracted with EtOAc (3x). The combined organics were washed first with 1 M aqueous NaOH (1x) then washed with brine (1x), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 100% to 90% PE-EtOAc gradient to give the title compound as yellow oil (445 mg, 88%).1H NMR (300 MHz, CDCI3) delta 8.83 (dd,j = 2.4, 0.7 Hz, 1H), 8.28 (dd,j = 8.6, 2.4 Hz, 1H), 7.48 (d,j = 8.6 Hz, 2H), 7.14 - 7.07 (m, 2H), 6.93 (dd,j = 8.6, 0.7 Hz, 1H), 4.38 (q, ; = 7.1 Hz, 2H), 1.43 - 1.34 (m, 5H), 1.12 - 1.04 (m, 2H)1.3C NMR (75 MHz, CDC13) delta 166.14, 165.10, 153.39, 150.44, 140.84, 133.21, 133.12, 121.86, 121.20, 111.12, 61.31, 25.88 (tj = 23.9 Hz), 14.42, 10.02 (t, J = 4.0 Hz). The two multiplets of the CF2(tq) and the CF3(qt) are too weak to be resolved. HRMS (C19 H17FsN03+): expected: 402.1123; found: 402.1124. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.3% | With palladium on activated charcoal; potassium acetate; triphenylphosphine; In N,N-dimethyl-formamide; at 80℃; for 5h;Inert atmosphere; | To a clean 250 mL three-necked flask, 90 g of DMF was added, 0.81 g of palladium carbon and 0.40 g of triphenylphosphine were recovered, stirred, and replaced with nitrogen. Maintaining a slight nitrogen stream, stirring for 10 to 20 minutes. 15.0 g of 4,4-dimethylbenzothiopyran-6-yl-acetylene and 15.0 g of ethyl 6-chloronicotinate, 15.0 g of potassium acetate, and 1.62 g of purified water were added in that order. The temperature was raised to 80 C, and the reaction was carried out for 5 hours, and then sampled by TLC until the 4,4-dimethylbenzothiopyran-6-yl-acetylene spot disappeared (developing solvent methylene chloride: n-hexane = 1:6). The mixture was cooled to room temperature, suction-filtered, and 55 g of dichloromethane was added to the filtrate, and 470 g of drinking water was stirred, allowed to stand, and liquid was separated. The organic phases were combined and washed twice with saturated sodium bicarbonate (250 g). The layers were separated, and the organic phases were combined and washed twice with 250 g of saturated sodium chloride solution. The layers were separated, and the organic phases were combined, and dried over anhydrous magnesium sulfate (20 g). Filter and the filtrate was concentrated to dryness under reduced pressure. 15 g of ethyl acetate was added, and the mixture was heated under reflux for 10 to 20 minutes. After the material was dissolved, 15 g of n-hexane was added, and the mixture was cooled to -5 C, and crystallized for 1 hour. After suction filtration, it was dried under reduced pressure at 60 C for 3 hours to obtain 22.5 g of tazarotene in a yield of 86.3 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In N,N-dimethyl-formamide; for 3h; | General procedure: The intermediate 4a (0.3g, 1.24mmol) was dissolved in 12ml of DMF, then ethyl 2-chloropyrimidine-5-carboxylate (0.23g, 1.24mmol), K2CO3 (0.68g, 4mmol) were added. Refluxing for 3h at 100C, the reaction was completed via TLC detection. After the solution was cooled to room temperature, 5ml of water was added to precipitate a solid product, which was filtered and dried to give white product 22 (0.35g, 72.9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In N,N-dimethyl-formamide; for 3h; | General procedure: The intermediate 4a (0.3g, 1.24mmol) was dissolved in 12ml of DMF, then ethyl 2-chloropyrimidine-5-carboxylate (0.23g, 1.24mmol), K2CO3 (0.68g, 4mmol) were added. Refluxing for 3h at 100C, the reaction was completed via TLC detection. After the solution was cooled to room temperature, 5ml of water was added to precipitate a solid product, which was filtered and dried to give white product 22 (0.35g, 72.9). |
Tags: 49608-01-7 synthesis path| 49608-01-7 SDS| 49608-01-7 COA| 49608-01-7 purity| 49608-01-7 application| 49608-01-7 NMR| 49608-01-7 COA| 49608-01-7 structure
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