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CAS No. : | 137682-89-4 | MDL No. : | MFCD01863257 |
Formula : | C6H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DPMGQZGXWRHYPE-UHFFFAOYSA-N |
M.W : | 130.14 | Pubchem ID : | 2733706 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 31.33 |
TPSA : | 46.53 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.97 cm/s |
Log Po/w (iLOGP) : | 1.4 |
Log Po/w (XLOGP3) : | 0.17 |
Log Po/w (WLOGP) : | 0.01 |
Log Po/w (MLOGP) : | 0.0 |
Log Po/w (SILICOS-IT) : | 0.74 |
Consensus Log Po/w : | 0.47 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.56 |
Solubility : | 36.2 mg/ml ; 0.278 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.7 |
Solubility : | 25.7 mg/ml ; 0.197 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.57 |
Solubility : | 35.2 mg/ml ; 0.27 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.5 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362 | UN#: | |
Hazard Statements: | H315-H319 | Packing Group: | |
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 |
---|---|---|
71% | With 15-crown-5; sodium hydride In tetrahydrofuran at 20℃; for 17h; | |
Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With sodium hydride In tetrahydrofuran; mineral oil for 0.166667h; Inert atmosphere; Stage #2: 4-Bromo-1-fluoro-2-nitrobenzene With 15-crown-5 In tetrahydrofuran; mineral oil at 20℃; | 48-49.I To a stirred solution of ethyl-1 -hydroxycyclopropane carboxylate (2.93 g, 20.5 mmol) in THF (50 mL) was added sodium hydride (60% in mineral oil, 981 mg, 24.5 mmol) under argon atmosphere. After 10 min, 15-crown-5 (0.2 mL) followed by 4- bromo-2-nitro-fluorphenol (4.5 g, 20.5 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched by the addition of methanol (1.5 mL) and diluted with ethyl acetate. The mixture was washed with brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give 1 -(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester (3.51 g).1H NMR (400 MHz, CDCI3): δ 1.20 (t, J = 6.8 Hz, 3H), 1.95-1.42 (m, 2H), 1.65-1.69 (m, 2H), 4.19 (q, J = 6.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 1 H), 7.58 (dd, J = 8.8, 2.8 Hz, 1 H), 7.96 (d, J = 2.4 Hz, 1 H). | |
750 mg | Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 4-Bromo-1-fluoro-2-nitrobenzene With 15-crown-5 In tetrahydrofuran at 20℃; for 24h; | 7.20 Example 7.20 Preparation of ethyl 1-(4-bromo-2-nitrophenoxy)cyclopropanecarboxylate Sodium hydride (60%, 166 mg, 4.15 mmol) was added to a solution of ethyl 1-hydroxycyclopropanecarboxylate (0.41 mL, 3.59 mmol) in THF (10 mL) at room temperature. After 15 min, 3 drops of 15-crown-5 were added followed by 4-bromo-1-fluoro-2-nitrobenzene (0.42 mL, 3.41 mmol). Mixture was stirred at room temperature for 24 hours. After diluting with 50 mL of ethyl acetate, mixture was quenched by addition of brine (25 mL) and layers were separated. Aqueous phase was extracted with ethyl acetate and combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure. Resulting residue was purified via silica gel column chromatography (0-30% ethyl acetate/hexanes) to yield ethyl 1-(4-bromo-2-nitrophenoxy)cyclopropanecarboxylate 7.20 (750 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,6-dimethylpyridine In dichloromethane at 0 - 20℃; for 0.75h; | A.12.1; B.1.8.I; B.1.13.I To a solution of 1-HYDROXY-CYCLOPROPANECARBOXYLIC acid ethyl ester (3. 0g) and 2,6-lutidine (2.72g) in dichloromethane (20mL) at 0 °C was added tert butyldimethyl SILYLTRIFLUOROMETHANESULFONATE (6.09g). After 15 minutes at 0 °C, the reaction mixture was warmed to room temperature. After 30 minutes, the reaction mixture was concentrated to afford crude 1- (tert-Butyl-dimethyl- silanyloxy) -cyclopropanecarboxylic acid ethyl ester, which was used immediately without purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,6-dimethylpyridine In dichloromethane at 0 - 20℃; for 0.75h; | 12.1 To a solution of 1-HYDROXY-CYCLOPROPANECARBOXYLIC acid ethyl ester (3. 0G) and 2, 6-LUTIDINE (2.72g) in dichloromethane (20ML) at 0 °C was added tert BUTYLDIMETHYL silyltrifluoromethanesulfonate (6.09g). After 15 minutes at 0 °C, the reaction mixture was warmed to room temperature. After 30 minutes, the reaction mixture was concentrated to afford crude 1- (TERT-BUTYL-DIMETHYL- silanyloxy) -cyclopropanecarboxylic acid ethyl ester, which was used immediately without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine In tetrahydrofuran; toluene at 0℃; | B.81.a A TM solution (50 mL) of 1-hydroxy-cyclopropanecarboxylic acid ethyl ester (5 g, 38.4 mmol) and pyridine (3.3 mL, 41 mmol) was added dropwise a phosgen/toleune solution (25 mL, 47.5 mmol) at 0° C. in 5-10 min. the reaction mixture was allowed slowly warm up overnite. The solid was filtered off and the filtration was concentrated in vacuo. The residue was dissolved in hexane, refiltered, and concentrated in vacuo to afford.7.4 g (100%) the product. The product was dissolved in CH2Cl2 (100 mL) as a stack solution: 1H NMR (300 MHz, CHLOROFORM-D) ppm 1.25 (t, J=7.14 Hz, 3H), 1.37 (m, 2H), 1.57 (m, 2H), 4.21 (q, J=6.95 Hz, 2H); (ppm) 13.97, 15.75, 62.07, 62.13, 150.54, 168.71. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In 1-methyl-pyrrolidin-2-one | 17 1-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]cyclopropanecarboxylic acid trifluoroacetate Example 17 1-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]cyclopropanecarboxylic acid trifluoroacetate 20 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 20 mg of ethyl 1-hydroxycyclopropanecarboxylate were dissolved in 0.2 ml of N-methylpyrrolidone, and 10 mg of sodium hydride was added thereto. The mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated to give 63 mg of t-butyl 4-[7-(2-butynyl)-2-(1-ethoxycarbonylcyclopropyloxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With 15-crown-5; sodium hydride In tetrahydrofuran; mineral oil for 0.166667h; Inert atmosphere; Stage #2: 4-bromo-3-fluoro-2-nitrophenol In tetrahydrofuran; mineral oil at 20℃; | 48.I; 49.I Step I. To a stirred solution of ethyl-1-hydroxycyclopropane carboxylate (2.93 g, 20.5 mmol) in THF (50 mL) was added sodium hydride (60% in mineral oil, 981 mg, 24.5 mmol) under argon atmosphere. After 10 min, 15-crown-5 (0.2 mL) followed by 4-bromo-2-nitro-fluorphenol (4.5 g, 20.5 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched by the addition of methanol (1.5 mL) and diluted with ethyl acetate. The mixture was washed with brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give 1-(4-bromo-2-nitro-phenoxy)-cyclopropanecarboxylic acid ethyl ester (3.51 g). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=6.8 Hz, 3H), 1.95-1.42 (m, 2H), 1.65-1.69 (m, 2H), 4.19 (q, J=6.8 Hz, 2H), 7.05 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.8:2.8 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H). MS (ES) m/z 329.9 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; for 20h; | 20.1 Step 1 - ethyl l-(tetrahydro-2H-pyran-2-yloxy)cyclopropanecarboxylate To a solution of ethyl 1-hydroxycyclopropanecarboxylate (1040 mg, 8.000 mmol) and PTSA (137 mg, 0.800 mmol) in DCM (20 mL) was added a solution of DHP (1344 mg, 16.00 mmol) in DCM (10 mL) dropwise at 0 °C. The mixture was stirred for 20 h at room temperature. After concentration, the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (10/1) to afford the title compound (1500 mg, 85%) as oil. LC-MS (ESI): m/z = 215 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: methyl iodide at 0 - 20℃; | 115.A Step A: Ethyl 1 -methoxycyclopropane- 1 -carboxylate Step A: Ethyl 1 -methoxycyclopropane- 1 -carboxylateTo a stirred solution of ethyl 1 -hydroxycyclopropanecarboxylate (1.2 g, 8.30 mmol) in THF(41.5 ml) was added NaH (0.23 1 g, 9.13 mmol) at 0°C. After 30mm at 0°C, iodomethane (0.571 10 ml, 9.13 mmol) was added dropwise. The reaction mixture was slowly warmed to RT and stirredovernight. The reaction mixture was quenched by adding sat. aq. NH4C1 and dissolved in EtOAc. The organic layer was washed with brine and dried over Mg504, filtered and concentrated. The crude product was purified by flash silica gel column chromatography (100% Hex to 50/5 0 = Hex/EtOAc) to provide ethyl 1-methoxycyclopropane-1-carboxylate. LCMS [M+1] 145 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 60℃; for 16h; | 115.A Step A: A42-((iH-indazol5-yl)amino)6-(trifluorornethyl)pyridin-3-yl)hydroxycyciopropanecarboxamide. AT2_( I I-Iindazol-5-yl)-6-(trif1uoroniethvi)pyridine-2,3-diarnine(Intermediate 47, 70 irig. 0239 mmol) was dissolved in DMF (0.6 mL) in a dry vial. Sodium hydride (60% in mineral oil, 9,5 mg, 0.24 mmol) was added followed by the dropwise addition of ethyl 1 -hydroxycyclopropanecarboxylate (28.8 tL, 0.24 rnmol). This reaction was stirred at 60 °Cfor 16 Ii. The reaction was diluted with EtOAc and water and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were combined, dried (Na2SO4), filtered, and concentrated in vaeuo. The crude material was purified by reverse phase I-{PLC (595% ACN in 20 riM NK4OH in water, 254 nm) to provide the title compound (19 mg, 21%). MS ESi): mass calcd. for C17H14F3N502 377.3, rn/z found 378.0 [M-f-HJ. 1H NMR (400 MHz, CD3OD) 8.11 8.06 (m,IH), 7.96 (s, IH), 7.84 (ci, J= 7.9 Hz, 1H), 7.56 7.45 (m, 21-1). 719 (d, J == 7.9 Hz, IFI), 1.381.32 (m, 21-1), 115 1.09 (rn, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: 2,4-Difluoronitrobenzene With 15-crown-5 In tetrahydrofuran at 20℃; for 18h; | Intermediate 1: Ethyl 1-(5-fluoro-2-nitrophenoxy)cyclopropane-1-carboxylate Ethyl-1-hydroxycyclopropanecarboxylate (0.491 g, 3.77 mmol) was dissolved in THF (5 mL) and cooled to 0 °C. Sodium hydride (0.181 g, 4.53 mmol) was added and the reaction was stirred for 20mins. 2,4-Difluoronitrobenzene (0.414 mL, 3.77 mmol) was then added followed by 15-crown- 5 (0.015 mL, 0.075 mmol) and the reaction was stirred at room temperature for 18h. The reaction was treated with aqueous NH4CI and extracted with DCM. The organics were dried over MgS04 and concentrated in vacuo. The crude product was purified by chromatography (S1O2, 0-50% EtOAc in PE) and the title compound was isolated as a yellow solid (622 mg, 61 %). 1 H NMR 5H (500 MHz, CDC ) δ 7.94 (dd, J = 9.1 , 5.9 Hz, 1 H), 6.86 (dd, J = 10.1 , 2.5 Hz, 1 H), 6.78 (ddd, J = 9.1 , 7.3, 2.5 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2H), 1.74 - 1.64 (m, 2H), 1.49 - 1.38 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.0833333h; Inert atmosphere; Stage #2: hex-5-enyl 4-methylbenzenesulfonate In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; | Intermediate 118a: Ethyl 1-(hex-5-en-1-yloxy)cyclopropane-1-carboxylate Intermediate 118a: Ethyl 1-(hex-5-en-1-yloxy)cyclopropane-1-carboxylate Ethyl 1-hydroxycyclopropane-1-carboxylate (0.31 mL, 2.6 mmol) was added to 60% sodium hydride in mineral oil (102 mg, 2.56 mmol) in DMF (10 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 20° C. for 5 minutes. A solution of hex-5-en-1-yl 4-methylbenzenesulfonate (650 mg, 2.56 mmol) in DMF (2 mL) was added and the mixture was stirred at 20° C. for 3 days. The reaction mixture was quenched with saturated NH4Cl (3 mL), diluted with EtOAc (75 mL), and washed sequentially with 2M HCl (3*2 mL) and saturated brine (2 mL). The organic layer was dried with MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane to afford the title compound (73 mg, 13%) as a pale yellow oil; 1H NMR (400 MHz, CDCl3, 30° C.) 0.99-1.1 (2H, m), 1.21 (3H, t), 1.29-1.43 (2H, m), 1.44-1.56 (3H, m), 1.53-1.67 (1H, m), 1.93-2.05 (2H, m), 3.51 (2H, t), 4.12 (2H, q), 4.83-5.02 (2H, m), 5.73 (1H, ddt); m/z: ES+ [M+H]+ 213.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 25℃; for 48.83h; Inert atmosphere; | Intermediate 135a: Ethyl 1-(3-(3-(benzyloxy)propoxy)propoxy)cyclopropane-1-carboxylate Intermediate 135a: Ethyl 1-(3-(3-(benzyloxy)propoxy)propoxy)cyclopropane-1-carboxylate Trifluoromethanesulfonic anhydride (0.47 mL, 2.8 mmol) was added dropwise to a stirred solution of 3-(3-(benzyloxy)propoxy)propan-1-ol (575 mg, 2.56 mmol), and 2,6-dimethylpyridine (0.33 mL, 2.8 mmol) in DCM (6 mL) at -78° C., under nitrogen. The resulting solution was stirred at -78° C. for 1 hour. The reaction mixture was diluted with DCM (25 mL), and washed sequentially with saturated NH4Cl (20 mL) and water (25 mL). The organic layer was dried with a phase separating cartridge, filtered and evaporated to afford crude 3-(3-(benzyloxy)propoxy)propyl trifluoromethanesulfonate that was dissolved in THF (9.42 mL). Ethyl 1-hydroxycyclopropane-1-carboxylate (0.311 ml, 2.56 mmol) was added to the mixture and cooled to -78° C. under nitrogen. A solution of 1 N lithium bis(trimethylsilyl)amide THF (3.07 ml, 3.07 mmol) was added dropwise to the solution over 10 minutes. The resulting mixture was stirred at -78° C. for 40 minutes and warmed to 0° C. The reaction mixture was warmed to room temperature and stirred at 25° C. for 2 days. The reaction mixture was diluted with saturated NH4Cl (30 mL), ethyl acetate (50 mL) and 5 mL of 2N HCl. The layers were separated and the aqueous phase back extracted with ethyl acetate (3*30 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, filtered and concentrated to a crude oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane to afford ethyl 1-(3-(3-(benzyloxy)propoxy)propoxy)cyclopropane-1-carboxylate (213 mg, 25%) as a colourless oil; 1H NMR (400 MHz, CDCl3, 30° C.) 1.09-1.15 (2H, m), 1.24-1.32 (5H, m), 1.81 (2H, p), 1.88 (2H, q), 3.47 (2H, t), 3.51 (2H, t), 3.56 (2H, t), 3.66 (2H, t), 4.19 (2H, q), 4.50 (2H, s), 7.26-7.37 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene at 80℃; for 4h; Microwave irradiation; Sealed tube; | 33.A A. Preparation of ethyl 1-((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)cyclopropane-1- carboxylate (20) 5-bromo-2-chloro-4-methyl-3-nitropyridine (0.5 g, 1.98 mmol) was weighed into a microwave vial and dissolved in ethyl 1-hydroxycyclopropane-1-carboxylate (6.0 eq). DBU (3.0 eq) was added, the vial was sealed, and the reaction was heated to 80 °C for 4 hours. The reaction was diluted with water (20 mL) and EtOAc (10 mL) and extracted multiple times with EtOAc (5 x 10 mL). Combined organic fractions were concentrated under reduced pressure and the crude material was purified by silica gel chromatography (MeOH/CH2Cl2) to give ethyl 1- ((5-bromo-4-methyl-3-nitropyridin-2-yl)oxy)cyclopropane-1-carboxylate (20). LCMS-ESI+ (m/z): [M+H]+ calcd for C12H13BrN2O5: 345.0; found: 345.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
583 mg | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 19 Example 19 Preparation of compound 19 of the present invention 500mg (1.0mmol, 1.0eq) 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1, 2-a][1,4]diaza-4-yl)propionic acid was dissolved in 10mL DCM, and 182.20mg (1.4mmol, 1.4eq) ethyl 1-hydroxycyclopropane-1-carboxylate, 290mg ( 1.4mmol, 1.4eq) DCC and 14mg (0.11mmol, 0.1eq) DMAP, react overnight at room temperature.Click the board, and the raw materials have basically reacted completely.After filtering the reaction solution, it was concentrated under reduced pressure, and 583 mg of pale yellow oily substance (Compound 19) was obtained by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
563 mg | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 26 500mg (1.32mmol, 1.0eq) 3-((4S)-8-fluoro-1,9-dimethyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1, 2-a][1,4]diaza-4-yl)propionic acid was dissolved in 10mL DCM, and 180mg (1.41mmol, 1.07eq) ethyl 1-hydroxycyclopropane-1-carboxylate, 290mg (1.41 mmol, 1.07eq) DCC and 20mg (0.16mmol, 0.12eq) DMAP, react overnight at room temperature.Click the board, and the raw materials have basically reacted completely.After filtering the reaction solution, it was concentrated under reduced pressure, and 563 mg of light buttery substance (Compound 26) was obtained by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: tert-butyl 4-[(trifluoromethanesulfonyl)oxy]methyl}piperidine-1-carboxylate In tetrahydrofuran at 20℃; for 16h; Inert atmosphere; | 2 Step 2: Preparation of 1-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]cyclopropanecarboxylic acid To a solution of ethyl 1-hydroxycyclopropanecarboxylate (100 mg, 0.768 mmol, 1 eq) in THF (5 mL) at -78 °C was added LiHMDS (1 M, 0.922 mL, 1.2 eq), and the reaction mixture was stirred at -78 °C under N2 for 1 hour. A solution of tert-butyl 4-(trifluoromethylsulfonyloxymethyl)piperidine-1-carboxylate (320 mg, 0.922 mmol, 1.2 eq) in THF (5 mL) was then added at -78 °C, and the reaction mixture was warmed to 20 °C and stirred at 20 °C for 16 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (20 mL), and the resulting aqueous mixture was extracted with EtOAc (3 x 20 mL). The combined organic extract was washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. To the resulting residue in CH3OH (2 mL), THF (2 mL), and water (2 mL) was added LiOH·H2O (98 mg, 2.3 mmol, 3 eq), and the reaction mixture was stirred at 50 °C under N2 for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Water (20 mL) was then added, and the resulting mixture was extracted with EtOAc (3 x 10 mL). The organic extract was discarded, and the aqueous layer was adjusted to pH=5 with 2 N aqueous HCl and lyophilized to give 1-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]cyclopropanecarboxylic acid (94 mg, crude) as a red oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 2 h / 25 °C 2.1: potassium osmate(VI) dihydrate; sodium periodate / tetrahydrofuran; water / 4 h / 15 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 2 h / 25 °C 2.1: potassium osmate(VI) dihydrate; sodium periodate / tetrahydrofuran; water / 4 h / 15 °C 3.1: acetic acid; sodium tris(acetoxy)borohydride / 36 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 2-methyl-3-bromo-1-propene In N,N-dimethyl-formamide at 25℃; for 2h; | 30.1 Step 1: Preparation of ethyl l-((2-methylallyl)oxy)cyclopropane-l-carboxylate (INT-32) To a solution of ethyl 1-hydroxycyclopropane-l-carboxylate (INT-31) in DMF is added NaH and the reaction mixture is stirred at 0°C for 0.5 hours. l-bromo-2-methyl-2-propene is added and the reaction mixture is stirred at 25 °C for 2 hours, quenched with brine, and extracted with EtOAc. The combined organic layers are washed with brine, dried over NaiSCri, filtered, and concentrated to provide ethyl l-((2-methylallyl)oxy)cyclopropane-l-carboxylate (INT-32). The crude product is used directly in the next step without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3 g | With 4-dimethylaminopyridine In dichloromethane at 20℃; for 1h; Inert atmosphere; Cooling with ice; | 27.1 Step 1: Preparation of compound 161 Add 0.5 g of ethyl 1-hydroxy-1-cyclopropanecarboxylate, 0.64 g of DMAP, and 30 g of dichloromethane into the reaction flask, cool down and stir in an ice bath,Nitrogen was bubbled, and 10 mL of a dichloromethane solution of the intermediate 1-8 (1.35 g) described in Example 1 was added dropwise, and the reaction was carried out at room temperature for 1 h after the completion of the dropping. After the reaction was completed, column chromatography was used to obtain 1.3 g of compound 161. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 25℃; for 0.25h; Inert atmosphere; Stage #2: 4-bromo-2-fluoro-1-nitro-benzene With benzo-15-crown-5 In tetrahydrofuran; mineral oil at 25℃; for 16h; Inert atmosphere; | Step 1. Synthesis of compound AG-1 Under the protection of nitrogen, compound ethyl 1-hydroxycyclopropanecarboxylate (683 mg, 5.25 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (240 mg, 6.00 mmol, 60%) was slowly added, the mixture was stirred at 25 °C for 15 min, and 15-crown -5 (0.1 mL) and compound AE (1.10 g, 5.00 mmol) were added sequentially, and the reaction was stirred at 25 °C for 16 hours. The reaction mixture was poured into ice water (10 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 25 : 75) to obtain compound AG-1.MS (ESI) m/z (M+H)+ = 330.2. | |
Stage #1: ethyl 1-hydroxycyclopropane-1-carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 25℃; for 0.25h; Inert atmosphere; Stage #2: 4-bromo-2-fluoro-1-nitro-benzene With benzo-15-crown-5 In tetrahydrofuran; mineral oil at 25℃; for 16h; Inert atmosphere; | Step 1. Synthesis of compound AG-1 Under the protection of nitrogen, compound ethyl 1-hydroxycyclopropanecarboxylate (683 mg, 5.25 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (240 mg, 6.00 mmol, 60%) was slowly added, the mixture was stirred at 25 °C for 15 min, and 15-crown -5 (0.1 mL) and compound AE (1.10 g, 5.00 mmol) were added sequentially, and the reaction was stirred at 25 °C for 16 hours. The reaction mixture was poured into ice water (10 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 25 : 75) to obtain compound AG-1.MS (ESI) m/z (M+H)+ = 330.2. |
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