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CAS No. : | 862574-88-7 | MDL No. : | MFCD13190001 |
Formula : | C11H8F2O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IELWGOUPQRHXLS-UHFFFAOYSA-N |
M.W : | 242.18 | Pubchem ID : | 44206103 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 51.57 |
TPSA : | 55.76 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.14 cm/s |
Log Po/w (iLOGP) : | 1.96 |
Log Po/w (XLOGP3) : | 2.31 |
Log Po/w (WLOGP) : | 2.9 |
Log Po/w (MLOGP) : | 1.68 |
Log Po/w (SILICOS-IT) : | 2.57 |
Consensus Log Po/w : | 2.28 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.93 |
Solubility : | 0.287 mg/ml ; 0.00119 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.12 |
Solubility : | 0.184 mg/ml ; 0.00076 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.9 |
Solubility : | 0.308 mg/ml ; 0.00127 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.26 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
88% | Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In ethanol at 100℃; for 3h; Inert atmosphere; Stage #2: With hydrogenchloride In ethanol; water Cooling; Inert atmosphere; | 1.6 Step 6 Step 6[00162] l-(2.2-difluoro-2H-1.3-benzodioxol-5-yl)cvclopropane-l-carboxylic acid: To a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed l-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carbonitrile (10.12 g, 45.38 mmol, 1.00 equiv), 6 N NaOH (61 mL) and EtOH (60 mL). The resulting solution was stirred for 3 h at 100 °C. The reaction mixture was cooled and the pH value of the solution was adjusted to 2 with hydrogen chloride (1 mol/L) until LCMS indicated the completion of the reaction. The solids were collected by filtration to afford 9.68 g (88%) of l-(2,2-difluoro- 2H-l,3-benzodioxol-5-yl)cyclopropane-l-carboxylic acid as a light yellow solid. |
79% | Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In ethanol at 77 - 80℃; for 16h; Stage #2: With hydrogenchloride In ethanol; dichloromethane at 10 - 25℃; | Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid. The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in ethanol from the previous step was charged with 6 N NaOH (277 mL) over 20 min and heated to an internal temperature of 77 - 78 °C over 45 min. The reaction progress was monitored by HPLC after 16 h. Note: the consumption of both (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile and the primary amide resulting from partial hydrolysis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile were monitored. When a % conversion > 99 % was observed (typically 100% conversion after 16 h), the reaction mixture was cooled to 25 °C and charged with ethanol (41 mL) and DCM (164 mL). The solution was cooled to 10 °C and charged with 6 N HCl (290 mL) at such a rate as to maintain a temperature < 25 °C. After warming to 20 - 25 °C, the phases were allowed to separate. The bottom organic phase was collected and the top aqueous phase was back extracted with DCM (164 mL). Note: the aqueous phase was somewhat cloudy before and after the extraction due to a high concentration of inorganic salts. The organics were combined and concentrated under vacuum to 164 mL. Toluene (328 mL) was charged and the mixture condensed to 164 mL at 70 - 75 °C. The mixture was cooled to 45 °C, charged with MTBE (364 mL) and stirred at 60 °C for 20 min. The solution was cooled to 25 °C and polish filtered to remove residual inorganic salts. MTBE (123 mL) was used to rinse the reactor and the collected solids. The combined organics were transferred to a clean reactor in preparation for the next step. Isolation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid. The solution of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid from the previous step is concentrated under vacuum to 164 mL, charged with toluene (328 mL) and concentrated to 164 mL at 70 - 75 °C. The mixture was then heated to 100 - 105 °C to give a homogeneous solution. After stirring at that temperature for 30 min, the solution was cooled to 5 °C over 2 hours and maintained at 5 °C for 3 hours. The mixture was then filtered and the reactor and collected solid washed with cold 1 :1 toluene/n-heptane (2 X 123 mL). The material was dried under vacuum at 55 °C for 17 hours to provide 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid as an off-white crystalline solid. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid was isolated in 79% yield from (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (3 steps including isolation) and with an HPLC purity of 99.0% AUC. ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 7.40 (d, J= 1.6 Hz, 1H), 7.30 (d, J= 8.3 Hz, 1H), 7.17 (dd, J= 8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H). |
69% | Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In ethanol at 80℃; Stage #2: With hydrogenchloride In tert-butyl methyl ether | (2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarbonitrile is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 0C overnight. The mixture is cooled to room temperature and ethanol is evaporated under vacuum. The residue is taken into water and MTBE, 1 M HCl was added and the layers are separated. The MTBE layer was then treated with dicyclohexylamine (0.97 equiv). The slurry is cooled to 0 0C, filtered and washed with heptane to give the corresponding DCHA salt. The salt is taken into MTBE and 10% citric acid and stirred until all solids dissolve. The layers are separated and the MTBE layer was washed with water and brine. Solvent swap to heptane followed by filtration gives l-(2,2-difluoro-l,3- benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying in a vacuum oven at 50 0C overnight. |
69% | Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With water; sodium hydroxide In ethanol at 80℃; Stage #2: With hydrogenchloride In tert-butyl methyl ether; water Stage #3: With N-cyclohexyl-cyclohexanamine In tert-butyl methyl ether | 00205] Synthesis of l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid.) aq c tr c ac vo69% yield[00206] (2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarbonitrile is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 °C overnight. The mixture is cooled to room temperature and ethanol is evaporated under vacuum. The residue is taken into water and MTBE, 1 M HC1 was added and the layers are separated. The MTBE layer was then treated with dicyclohexylamine (0.97 equiv). The slurry is cooled to 0 °C, filtered and washed with heptane to give the corresponding DCHA salt. The salt is taken into MTBE and 10% citric acid and stirred until all solids dissolve. The layers are separated and the MTBE layer was washed with water and brine. Solvent swap to heptane followed by filtration gives l-(2,2-difluoro-l,3- benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying in a vacuum oven at 50 °C overnight. ESI-MS m/z calc. 242.04, found 241.58 (M+l)+; 1H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 7.40 (d, J= 1.6 Hz, 1H), 7.30 (d, J= 8.3 Hz, 1H), 7.17 (dd, J= 8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H). |
69% | With water; sodium hydroxide In ethanol at 80℃; | Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile was hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80° C. overnight. The mixture was cooled to room temperature and the ethanol was evaporated under vacuum. The residue was taken up in water and MTBE, 1 M HCl was added, and the layers were separated. The MTBE layer was then treated with dicyclohexylamine (DCHA) (0.97 equiv). The slurry was cooled to 0° C., filtered and washed with heptane to give the corresponding DCHA salt. The salt was taken into MTBE and 10% citric acid and stirred until all the solids had dissolved. The layers were separated and the MTBE layer was washed with water and brine. A solvent swap to heptane followed by filtration gave 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying in a vacuum oven at 50° C. overnight. |
2% | With sodium hydroxide; water for 2.5h; Heating / reflux; | f 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 2% over four steps). ESI-MS m/z calc. 242.0, found 241.6 (M+1)+; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). |
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide; water for 2.5h; Heating / reflux; Stage #2: With hydrogenchloride In water | 2 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In water for 2.5h; Heating / reflux; Stage #2: With hydrogenchloride In water | 2.f Step f: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-9) To 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was added 10% aqueous sodium hydroxide (50 mL) and the mixture was heated at reflux for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 2% over four steps). ESI-MS m/z calc. 242.2, found 243.3; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With water; sodium hydroxide for 2.5h; Reflux; Stage #2: With hydrogenchloride In water | f Step f: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With water; sodium hydroxide for 2.5h; Reflux; Stage #2: With hydrogenchloride; water | 2.f Step f: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With water; sodium hydroxide for 2.5h; Reflux; Stage #2: With hydrogenchloride In water | f 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.04, found 241.58 (M+1)-; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
With sodium hydroxide; water for 2.5h; Heating / reflux; | 17 1- (2, 2-Difluoro-benzo [1, 3] dioxol-5-yl) -cyclopropanecarboxylic acid; The 1- (2, 2- difluoro-benzo [1, 3] dioxol-5-yl) -cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1- (2, 2-Difluoro-benzo [1, 3] dioxol-5-yl)- cyclopropanecarboxylic acid as a white solid (0.15 g, 0.62 mmol, 1.6 % over four steps). ESI- MS m/z calc. 242.04, found 241. 58 (M-l)''H NMR (CDC13) : 5 7.14-7. 04 (m, 2 H), 6. 98-6. 96 (m, 1 H), 1. 74-1. 64 (m, 2 H), 1. 26-1. 08 (m, 2H) | |
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With water; sodium hydroxide for 2.5h; Reflux; Stage #2: With hydrogenchloride In water | 2 l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give l-(2,2-difluoro- benzo[l,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.04, found 241.58 (M+l)+; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, IH), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
With sodium hydroxide | 2.f Step f: Step f: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-9) To 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was added 10% aqueous sodium hydroxide (50 mL) and the mixture was heated at reflux for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 2% over four steps). ESI-MS m/z calc. 242.2, found 243.3; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
In sodium hydroxide | 2 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
In sodium hydroxide | II.1.f Step f: Step f: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-2) 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid. ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
With water; sodium hydroxide In ethanol at 80℃; | Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80° C. overnight. The mixture is cooled to room temperature and ethanol is evaporated under vacuum. The residue is taken into water and MTBE, 1 M HCl was added and the layers are separated. The MTBE layer was then treated With dicyclohexylamine (0.97 equiv). The slurry is cooled to 0° C., filtered and washed with heptane to give the corresponding DCHA salt. The salt is taken into MTBE and 10% citric acid and stirred until all solids dissolve. The layers are separated and the MTBE layer was washed with water and brine. Solvent swap to heptane followed by filtration gives 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying in a vacuum oven at 50° C. overnight. ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H). | |
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In ethanol at 77 - 78℃; for 16h; Stage #2: With hydrogenchloride In ethanol; dichloromethane; water at 10 - 25℃; | Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in ethanol from the previous step was charged with 6 N NaOH (277 mL) over 20 min and heated to an internal temperature of 77-78° C. over 45 min. The reaction progress was monitored by HPLC after 16 h. Note: the consumption of both (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile and the primary amide resulting from partial hydrolysis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile were monitored. When a % conversion >99% was observed (typically 100% conversion after 16 h), the reaction mixture was cooled to 25° C. and charged with ethanol (41 mL) and DCM (164 mL) The solution was cooled to 10° C. and charged with 6 N HCl (290 mL) at such a rate as to maintain a temperature <25° C. After warming to 20-25° C., the phases were allowed to separate. The bottom organic phase was collected and the top aqueous phase was back extracted with DCM (164 mL) Note: | |
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide In ethanol at 80℃; Stage #2: With hydrogenchloride; water; N-cyclohexyl-cyclohexanamine In tert-butyl methyl ether Stage #3: With citric acid In tert-butyl methyl ether | Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile was hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80° C. overnight. The mixture was cooled to room temperature and the ethanol was evaporated under vacuum. The residue was taken up in water and MTBE, 1 M HCl was added, and the layers were separated. The MTBE layer was then treated with dicyclohexylamine (DCHA) (0.97 equiv). The slurry was cooled to 0° C., filtered and washed with heptane to give the corresponding DCHA salt. The salt was taken into MTBE and 10% citric acid and stirred until all the solids had dissolved. The layers were separated and the MTBE layer was washed with water and brine. A solvent swap to heptane followed by filtration gave 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying in a vacuum oven at 50° C. overnight. | |
With sodium hydroxide In ethanol at 80℃; | 2g Example 2g: 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid. (2,2-Difluoro-1 ,3-benzodioxol-5-yl)-cyclopropanecarbonitrile wa.<> hydrolyzed using6 M NaOH (8 equiv) in ethanol (5 vol) at 80 oc overnight The mixture was cooled to roomtemperature and the ethanol was evaporated under vacuum. The residue was taken up in waterand MT.BE, 1 M HCl was added, and the layers were separated. The IVIT.BE layer was thentreated with dicyclohexylamine (DCHA) (0.97 equiv). The slurry was cooled to 0 °C, filteredand washed with heptane to give the corresponding DCHA salt The salt was taken into MTBEand 10% citric acid and stirred until all the solids had dissolved. The layers were separated andthe MT.BE layer was washed with water and brine. A solvent swap to heptane followed byfiltration gave 1-(2,2-dit1uoro-1 ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying ina vacuum oven at 50 oc overnight ESI-MS m/z calc. 242.04, found 241.58 (M+lf; tH NMR(500 MHz, DMSO) o 12.40 (s, lH), 7.40 (d, J= L6 Flz, lH), 7.30 (d, J= 8.3 Hz, lH), 7.17 (dd,J ''' 8.3, l. 7Hz, lH), 1.46 (m, 2H), L 17 (m, 2H). | |
With water; sodium hydroxide In ethanol at 80℃; | 1 [00294] Preparation of 1-(2,2-difluoro-1 ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid. [00295] (2,2-difluoro-1 ,3-benzodioxol-5-yl)-cyclopropanecarbonitrile was hydrolyzed using 6M NaOH (8 equiv) in ethanol (5 vol) at 80 oc overnight. The mixture was cooled to roomtemperature and the ethanol was evaporated under vacuum. The residue was taken up in waterand MTBE, 1 M HCl was added, and the layers were separated. The MTBE layer was thentreated with dicyclohexylamine (DCHA) (0.97 equiv). The slurry was cooled to 0 °C, filteredand washed with heptane to give the corresponding DCHA salt. The salt was taken into MTBEand 10% citric acid and stirred until all the solids had dissolved. The layers were separated andthe MTBE layer was washed with water and brine. A solvent swap to heptane followed byfiltration gave 1-(2,2-difluoro-1 ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying ina vacuum oven at 50 oc overnight. | |
With sodium hydroxide In ethanol at 80℃; | Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxylic acid [00310] (2,2-difluoro-l ,3-benzodioxol-5-yl)-cyclopropanecarbonitrile was hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 °C overnight. The mixture was cooled to room temperature and the ethanol was evaporated under vacuum. The residue was taken up in water and MTBE, 1 M HC1 was added, and the layers were separated. The MTBE layer was then treated with dicyclohexylamine (DCHA) (0.97 equiv). The slurry was cooled to 0 °C, filtered and washed with heptane to give the corresponding DCHA salt. The salt was taken into MTBE and 10% citric acid and stirred until all the solids had dissolved. The layers were separated and the MTBE layer was washed with water and brine. A solvent swap to heptane followed by filtration gave l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying in a vacuum oven at 50 °C overnight. | |
With sodium hydroxide In water for 2.5h; Reflux; | 2.f; II.II-1.f 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-9) To 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was added 10% aqueous sodium hydroxide (50 mL) and the mixture was heated at reflux for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 2% over four steps). ESI-MS m/z calc. 242.2. found 243.3; 1H NMR (CDCl3), δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
With sodium hydroxide | ||
Stage #1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile With sodium hydroxide; water for 2.5h; Heating / reflux; Stage #2: With hydrogenchloride In water | A.f Stepf: l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarboxylic acid; l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude from the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours. The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give l-(2,2-difluoro- benzo[l,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.2, found 243.3 (M+l)+; 1H NMR (CDCl3) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, IH), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H). | |
With sodium hydroxide | ||
With sodium hydroxide In ethanol at 80℃; | Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid. Hydrolysis of (2,2-difluoro-1,3-benzodioxole-5-yl)-cycle overnight at 80 ° C using 6 M NaOH (8 equivalents) in ethanol (5 vol) Propane carbonitrile. The mixture was allowed to cool to room temperature and the ethanol was evaporated under vacuum. The residue was taken up with water and MTBE, 1 M HCl was added and the layers were separated. The MTBE layer was then treated with dicyclohexylamine (DCHA) (0.97 equivalents). The slurry was cooled to 0 ° C, filtered and washed with heptane to give a corresponding DCHA salt. The salt was taken up with MTBE and 10% citric acid and stirred until all solids dissolved. The layers were separated and the MTBE layer was washed with water and brine. The solvent was changed to heptane, followed by filtration, and dried in a vacuum oven at 50 ° C overnight to give 1-(2,2-difluoro-1,3-benzodioxol-5-yl) - cyclopropanecarboxylic acid. | |
With methanol; sodium hydroxide In ethanol at 80℃; | 5.5 Step 5: l-(2,2-Difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (2,2-Difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarbonitrile was hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 °C overnight. The mixture was cooled to room temperature and the ethanol was evaporated under vacuum. The residue was taken up in water and MTBE, 1 M HC1 was added, and the layers were separated. The MTBE layer was then treated with dicyclohexylamine (DCHA) (0.97 equiv). The slurry was cooled to 0 °C, filtered and washed with heptane to give the corresponding DCHA salt. The salt was taken into MTBE and 10% citric acid and stirred until all the solids had dissolved. The layers were separated and the MTBE layer was washed with water and brine. A solvent swap to heptane followed by filtration gave l-(2,2-difluoro-l,3- benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying in a vacuum oven at 50 °C overnight. ESI-MS m/z calc. 242.04, found 241.58 (M+l)+; 1H NMR (500 MHz, DMSO) d 12.40 (s, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.17 (dd, J = 8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H). | |
With sodium hydroxide In ethanol; water at 77 - 78℃; for 16.75h; | 1 Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic Acid The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in ethanol from the previous step was charged with 6 N NaOH (277 mL) over 20 min and heated to an internal temperature of 77-78° C. over 45 min. The reaction progress was monitored by HPLC after 16 h. Note: the consumption of both (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile and the primary amide resulting from partial hydrolysis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile were monitored. When a percent conversion of >99% was observed (typically 100% conversion after 16 h), the reaction mixture was cooled to 25° C. and charged with ethanol (41 mL) and DCM (164 mL). The solution was cooled to 10° C. and charged with 6 N HCl (290 mL) at such a rate as to maintain a temperature phase was back extracted with DCM (164 mL). Note: the aqueous phase was somewhat cloudy before and after the extraction due to a high concentration of inorganic salts. The organics were combined and concentrated under vacuum to 164 mL. Toluene (328 mL) was charged and the mixture condensed to 164 mL at 70-75° C. The mixture was cooled to 45° C., charged with MTBE (364 mL) and stirred at 60° C. for 20 min. The solution was cooled to 25° C. and polish filtered to remove residual inorganic salts. MTBE (123 mL) was used to rinse the reactor and the collected solids. The combined organics were transferred to a clean reactor in preparation for the next step. The solution of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid from the previous step is concentrated under vacuum to 164 mL, charged with toluene (328 mL) and concentrated to 164 mL at 70-75° C. The mixture was then heated to 100-105° C. to give a homogeneous solution. After stirring at that temperature for 30 min, the solution was cooled to 5° C. over 2 hours and maintained at 5° C. for 3 hours. The mixture was then filtered and the reactor and collected solid washed with cold 1:1 toluene/n-heptane (2×123 mL). The material was dried under vacuum at 55° C. for 17 hours to provide 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid as an off-white crystalline solid. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid was isolated in 79% yield from (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (3 steps including isolation) and with an HPLC purity of 99.0% AUC. ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; N,N-dimethyl-formamide for 1h; | 2.4 Step 4: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HCl solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product (3 g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+1)+. Retention time 2.05 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.40 (m, 2H), 7.34-7.30 (m, 3H), 6.24 (s, 1H), 4.51-4.48 (m, 1H), 4.39-4.34 (m, 2H), 4.08 (dd, J=6.0, 8.3 Hz, 1H), 3.69 (t, J=7.6 Hz, 1H), 3.58-3.51 (m, 2H), 1.48-1.45 (m, 2H), 1.39 (s, 3H), 1.34-1.33 (m, 6H), 1.18 (s, 3H) and 1.14-1.12 (m, 2H) ppm |
99% | With thionyl chloride In toluene at 65℃; for 3h; | 1.7 Step 7 Step 7[00163] l-(2.2-difluoro-2H-1.3-benzodioxol-5-yl)cvclopropane-l-carbonyl chloride; To a solution of l-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)cyclopropane-l-carboxylic acid (687 mg, 2.84 mmol, 1.00 equiv.) in toluene (5 mL) was added thionyl chloride (1.67 g, 5.00 equiv.). The resulting solution was stirred for 3h at 65 °C. The reaction mixture was cooled and concentrated under vacuum to afford 738 mg (99%) of l-(2,2-difluoro-2H-l,3- benzodioxol-5-yl)cyclopropane-l-carbonyl chloride as a yellow solid. |
83% | With thionyl chloride In N,N-dimethyl-formamide at 20℃; for 2h; | a To 1-(2,2-difluorobenzo[ ][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (25.0 g, 103 mmol) in thionyl chloride (22.5 mL, 309 mmol) was added N,N-dimethylformamide (200 μL). The reaction mixture was stirred at room temperature for 2 h. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (26.3 g, 83%) |
With thionyl chloride In toluene at 60℃; for 0.5h; | Synthesis of l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride (compound 7).SOCl2, [00248] Compound 22 (1.2 eq) is slurried in toluene (2.5 vol) and the mixture heated to 60 0C. SOCI2 (1.4 eq) is added via addition funnel. The toluene and SOCI2 are distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) is added and distilled again. | |
With thionyl chloride In toluene at 60℃; for 0.5h; Reflux; | l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture heated to 60 0C. SOCI2 (1.4 eq) is added via addition funnel. The toluene and SOCI2 are distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) is added and distilled again. | |
With thionyl chloride at 20℃; for 2h; | To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (18.8 g, 78 mmol) in thionyl chloride (17 mL, 233 mmol) was added N,N-dimethylformamide (0.2 mL, 2.6 mmol). The reaction mixture was stirred at room temperature for two hours. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo and the resulting acid chloride was used directly in next step. | |
With thionyl chloride In toluene at 60℃; for 0.5h; | 1 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture heated to 60 0C. SOCI2 (1.4 eq) is added via addition funnel. The toluene and SOCI2 are distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) is added and distilled again. | |
With thionyl chloride at 20℃; for 0.5h; | 8.a To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (90.14 mg, 0.3722 mmol) in thionyl chloride (81.28 μL, 1.117 mmol) was added N1N -dimethyl formamide (8.204 μL, 0.1064 mmol). The reaction mixture was stirred at room temperature for 30 minutes before excess thionyl chloride and N,N -dimethyl formamide were removed in vacuo to yield the acid chloride. The acid chloride was then dissolved in dichloromethane (1.5 mL) and added slowly to a solution of tert-butyl 2-(5-amino-2-?ert-butyl-6-fluoro-l H-indol- l-yl)ethylcarbamate (156.1 mg, 0.4467 mmol) and triethylamine (155.6 μL, 1.117 mmol) in dichloromethane (1.5 mL). The resulting reaction mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with IN aqueous HCl (5 mL) and a saturated aqueous NaHCO3 solution (5 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield tørt-butyl 2-(2-tert-butyl- 5-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-lH-indol-l- yl)ethylcarbamate as a white solid (140 mg, 66%). ESI-MS m/z calc. 573.2, found 574.7 (M+l)+. Retention time 2.41 minutes. IH NMR (400.0 MHz, DMSO) d 8.35 (s, IH), 7.53 (s, IH), 7.44 - 7.41 (m, 2H), 7.34 - 7.29 (m, 2H), 7.13 - 7.10 (m, IH), 6.17 (s, IH), 4.24 - 4.20 (m, 2H), 3.20 - 3.17 (m, 2H), 1.48-1.45 (m, 2H), 1.41 (s, 18H) and 1.15-1.12 (m, 2H) ppm. | |
With thionyl chloride In toluene at 60℃; | 00234] Synthesis of benzyl protected Compound 1.[00235] l-(2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was slurried in toluene (2.5 vol, based on l-(2,2-difluoro-l,3-benzodioxol-5-yl)- cyclopropanecarboxylic acid) and the mixture was heated to 60 °C. SOCl2 (1.7 equiv) was added via addition funnel. The resulting mixture was stirred for 2 hr. The toluene and the excess SOCl2 were distilled off using rotavop. Additional toluene (2.5 vol, based on l-(2,2- difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added and distilled again. The crude acid chloride was dissolved in dichloromethane (2 vol) and added via addition funnel to a mixture of N-benzylglycolated-5-amino-2-(2-benzyloxy-l,l-dimethylethyl)-6-fluoroindole (1.0 equiv), and triethylamine (2.0 equiv) in dichloromethane (7 vol) while maintaining 0-3 °C (internal temperature). The resulting mixture was stirred at 0 °C for 4 hrs and then warmed to room temperature overnight. Distilled water (5 vol) was added to the reaction mixture and stirred for NLT 30 min and the layers were separated. The organic phase was washed with 20 wt% K2CO3 (4 vol x 2) followed by a brine wash (4 vol) and concentrated to afford crude benzyl protected Compound 1 as a thick brown oil, which was purified further using silica pad filtration. | |
With thionyl chloride In toluene | 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60° C. SOCl2 (1.4 eq) was added via addition funnel. The toluene and SOCl2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification. | |
With thionyl chloride In toluene at 60℃; | Synthesis of benzyl protected Compound 1 Synthesis of benzyl protected Compound 1 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was slurried in toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) and the mixture was heated to 60° C. SOCl2 (1.7 equiv) was added via addition funnel. The resulting mixture was stirred for 2 hr. The toluene and the excess SOCl2 were distilled off using rotavop. Additional toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added and distilled again. The crude acid chloride was dissolved in dichloromethane (2 vol) and added via addition funnel to a mixture of N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole (1.0 equiv), and triethylamine (2.0 equiv) in dichloromethane (7 vol) while maintaining 0-3° C. (internal temperature). The resulting mixture was stirred at 0° C. for 4 hrs and then warmed to room temperature overnight. Distilled water (5 vol) was added to the reaction mixture and stirred for NLT 30 min and the layers were separated. The organic phase was washed with 20 wt % K2CO3 (4 vol*2) followed by a brine wash (4 vol) and concentrated to afford crude benzyl protected Compound 1 as a thick brown oil, which was purified further using silica pad filtration. | |
With thionyl chloride In toluene at 60℃; for 2h; | 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was slurried in toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) and the mixture was heated to 60° C. SOCl2 (1.7 equiv) was added via addition funnel. The resulting mixture was stirred for 2 hr. The toluene and the excess SOCl2 were distilled off using rotavop. Additional toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added and distilled again. The crude acid chloride was dissolved in dichloromethane (2 vol) and added via addition funnel to a mixture of N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole (1.0 equiv), and triethylamine (2.0 equiv) in dichloromethane (7 vol) while maintaining 0-3° C. (internal temperature). The resulting mixture was stirred at 0° C. for 4 hrs and then warmed to room temperature overnight. Distilled water (5 vol) was added to the reaction mixture and stirred for NLT 30 min and the layers were separated. The organic phase was washed with 20 wt % K2CO3 (4 vol×2) followed by a brine wash (4 vol) and concentrated to afford crude benzyl protected (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-ypcyclopropanecarboxamide as a thick brown oil, which was purified further using silica pad filtration. | |
With thionyl chloride In toluene at 60℃; for 0.5h; | Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60° C. SOCl2 (1.4 eq) was added via addition funnel. The toluene and SOCl2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification. | |
With thionyl chloride In toluene at 60℃; for 0.5h; | 2h Example 21:1: 1-(2,2-Difluoro-1,3-benzodioxol~5~yl)~cydop:ropanecarbonyl chloride 1-(2,2-Difluoro-1 ,3-benzodiox.ol-5-yl)-cydopropanecarboxylic acid (1 ,2 eq) isslurried in toluene (2.5 vol) and the mixture was heated to 60 °C. SOCh (1.4 eq) was added viaaddition funneL The toluene and SOCh were distilled from the reaction mixture after 30minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again,leaving the product acid chloride as an oil, which was used without further purification | |
With thionyl chloride In toluene at 60℃; for 2h; | [00359] 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was slurried in toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) and the mixture was heated to 60 °C. SOCl2 (1.7 equiv) was added via addition runnel. The resulting mixture was stirred for 2 hr. The toluene and the excess SOCl2 were distilled off using rotavop. Additional toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added and distilled again. The crude acid chloride was dissolved in dichloromethane (2 vol) and added via addition funnel to a mixture of N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole (1.0 equiv), and triethylamine (2.0 equiv) in dichloromethane (7 vol) while maintaining 0-3 °C (internal temperature). The resulting mixture was stirred at 0 °C for 4 hrs and then warmed to room temperature overnight. Distilled water (5 vol) was added to the reaction mixture and stirred for NLT 30 min and the layers were separated. The organic phase was washed with 20 wt% K2CO3 (4 vol x 2) followed by a brine wash (4 vol) and concentrated to afford crude benzyl protected Compound 1 as a thick brown oil, which was purified further using silica pad filtration. [00360] Silica gel pad filtration: Crude benzyl protected Compound 1 was dissolved in ethyl acetate (3 vol) in the presence of activated carbon Darco-G (10 wt%, based on theoretical yield of benzyl protected Compound 1) and stirred at room temperature overnight. To this mixture was added heptane (3 vol) and filtered through a pad of silica gel (2x weight of crude benzyl protected Compound 1). The silica pad was washed with ethyl acetate/heptane (1:1, 6 vol) or until little color was detected in the filtrate. The filtrate was concentrated in vacuo to afford benzyl protected Compound 1 as viscous reddish brown oil, and used directly in the next step. | |
With thionyl chloride In toluene at 60℃; for 0.5h; | 1 [00296] Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonylchloride. [00297] 1-(2,2-difluoro-1 ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurriedin toluene (2.5 vol) and the mixture was heated to 60 °C. SOCb (1.4 eq) was added via additionfunnel. The toluene and SOCb were distilled from the reaction mixture after 30 minutes.Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving theproduct acid chloride as an oil, which was used without further purification. | |
With thionyl chloride In toluene at 60℃; for 0.5h; | Preparation of 1-(2,2-difluoro-1,3-benzodioxoI-5-yl)cyclopropanecarbonyl chloride [00312] l-(2,2-difluoro-l ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60 °C. SOCl2 (1.4 eq) was added via addition funnel. The toluene and SOCl2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification. | |
With thionyl chloride In toluene at 60℃; for 0.5h; | 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60° C. SOCl2 (1.4 eq) was added via addition funnel. The toluene and SOCl2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification. | |
With thionyl chloride In toluene | Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60° C. SOCl2 (1.4 eq) was added via addition funnel. The toluene and SOCl2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification. | |
With thionyl chloride In toluene at 60℃; | Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60° C. SOCl2 (1.4 eq) was added via addition funnel. The toluene and SOCl2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification. | |
With thionyl chloride; N,N-dimethyl-formamide at 20℃; for 2h; | 6 EXAMPLE 6 Preparation of 1-(2,2-difluoro- 1 ,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride To a mixture of 1 -(2,2-difluoro- 1,3 -benzodioxol-5-yl)cyclopropanecarboxylic acid(50mg) in thionyl chloride (lmL) was added dimethyl formamide (0. l2SmL). Thereaction mixture was stirred at about room temperature for about 2h. Excess of thionyl chloride and dimethyl formamide were removed in vacuum after co-distilling with toluene and the resulting product was used directly without further purification. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; | 10.10E 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carbonyl chloride A solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.78 g, 3.22 mmol) in CH2Cl2 (7 mL) at 0° C. was treated with oxalyl chloride (1.410 mL, 16.10 mmol), treated with a small amount of N,N-dimethylformamide (about 1 drop), stirred at room temperature for 2 hours, and concentrated to provide the title compound. 1H NMR (501 MHz, CDCl3) δ 7.10-7.07 (m, 2H), 7.04-7.01 (m, 1H), 2.03-1.92 (m, 2H), 1.52-1.43 (m, 2H). | |
With thionyl chloride; N,N-dimethyl-formamide for 1h; | 2.4 Step 4: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of 1 -(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-l- ((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-iluoro-lH-indol-2-yl)-2-methylpropan-l-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with IN HC1 solution, saturated NaHCCh solution and brine, dried over MgS04 and concentrated to yield the product (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+l)+. Retention time 2.05 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, IH), 7.53 (s, IH), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, IH), 4.51 - 4.48 (m, IH), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, IH), 3.69 (t, J = 7.6 Hz, IH), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm | |
With thionyl chloride In N,N-dimethyl-formamide; toluene for 1.16667h; | 4 Step 4: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl- 1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5- yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of 1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-1- ((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HCl solution, saturated NaHCO3solution and brine, dried over MgSO4and concentrated to yield the product (3g, 100%). | |
With thionyl chloride In N,N-dimethyl-formamide for 1h; | 1.D Step D: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxiolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol); After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3 -dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HCl solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product as a black foamy solid (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M*1)+. Retention time 2.05 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 s, 1H), 7.42-7.40 (m, 2H), 7.34-7.30 (m, 3H), 6.24 (s, 1H), 4.51-4.48 (m, 1H), 4.39-4.34 (in,2H), 4.08 (dd, J=6.0, 8.3 Hz, 1H), 3.69 (t, J=7.6 Hz, 1H), 3.58-3.51 (m, 2H), 1.48-1.45 (m, 2H), 1.39 (s, 3H), 1.34-1.33 (m, 6H), 1.18 (s, 3H) and 1.14-1.12(m, 2H) ppm. | |
With thionyl chloride at 20℃; for 2h; | L.a L. iV-f6-αiloro-5-methylpyridin-2-vn-l-f2.2-difluorobenzordiri.31dioxol-5- vDcyclopropanecarboxamide; Step a: l-(2,2-Difluorobenzo[d] [1 ,3] dioxolS-ytycyclopropanecarbonyl chloride; To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (18.8 g,78.0 mmol) in thionyl chloride (17.0 mL, 233 mmol) was added N,N-dimethylformamide (200 μL, 2.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. Excess thionyl chloride and N,N-dimethylformamide were removed in vacuo and the resulting acid chloride was used directly in next step. | |
With thionyl chloride; N,N-dimethyl-formamide for 1h; | 2.4 j00320J Step 4: (R)-1-(2,2-difluorobenzo jdj 11 ,3J dioxol-5-yl)-N-(1-((2,2-dimethyl-1 ,3- dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)- 1H-indol-5- yl)cyclopropanecarboxamide 1003211 DMF (3 drops) was added to a stirring mixture of 1-(2,2- difluorobenzo[d] [1,3 ]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of(R)-2-(5-amino-1-((2,2-dimethyl-1,3- dioxolan-4-yl)methyl)-6-fluoro- 1 H-indol-2-yl)-2-methylpropan- 1 -ol (1 .8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with iN HC1 solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product as a black foamy solid (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+1)t Retention time 2.05 minutes. ‘H NIVIR (400 MHz, DMSO-d6) 8.31 (s, 1H), 7.53 (s, 1H), 7.42 -7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H),4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m,2H), 1.39 (s, 3H), 1.34-1.33 (m, 6H), 1.18 (s, 3H) and 1.14- 1.12 (m, 2H) ppm | |
With thionyl chloride; N,N-dimethyl-formamide for 1h; | 2.D Step D: (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-((2,2-dimethyl-l,3-dioxolan- 4-yl)methyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-l-((2,2-dimethyl- l,3- dioxolan-4-yl)methyl)-6-fluoro- lH-indol-2-yl)-2-methylpropan- l-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with IN HC1 solution, saturated NaHC03 solution and brine, dried over MgS04 and concentrated to yield the product as a black foamy solid (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+l)+. Retention time 2.05 minutes. lH NMR (400 MHz, DMSO- 6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm | |
With thionyl chloride; N,N-dimethyl-formamide for 1h; | 2.D; 5 Step D: (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-((2,2-dimethyl-l,3- dioxolan-4-yl)methyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-l-((2,2-dimethyl- l,3-dioxolan-4-yl)methyl)-6-fluoro-lH-indol-2-yl)-2-methylpropan-l-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with IN HCl solution, saturated NaHC03 solution and brine, dried over MgS04 and concentrated to yield the product as a black foamy solid (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+l)+. Retention time 2.05 minutes. lH NMR (400 MHz, DMSO- 6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm | |
With thionyl chloride In toluene at 60℃; for 0.5h; | Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonylhydrazine chloride. Slurry 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq.) in toluene (2.5 vol) and heat the mixture to 60 °C. SOCl2 (1.4 equivalents) was added via an addition funnel. Toluene and SOCl2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the mixture was distilled again to leave the chloroform product as an oil which was used without further purification. | |
With thionyl chloride; N,N-dimethyl-formamide for 1h; | 2.4 (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-((2,2-dimethyl-l,3- dioxolan-4-yl)methyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-l-((2,2-dimethyl- l,3- dioxolan-4-yl)methyl)-6-fluoro- lH-indol-2-yl)-2-methylpropan- l-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with IN HC1 solution, saturated NaHC03 solution and brine, dried over MgS04 and concentrated to yield the product as a black foamy solid (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+l)+. Retention time 2.05 minutes. lH NMR (400 MHz, DMSO- 6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm | |
With thionyl chloride; N,N-dimethyl-formamide for 1h; | 2.4 Step 4: (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-((2,2-dimethyl-l,3- dioxolan-4-yl)methyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino- 1 -((2, 2-dimethyl - l,3-dioxolan-4-yl)methyl)-6-fluoro-lH-indol-2-yl)-2-methylpropan-l-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HC1 solution, saturated NaHC03 solution and brine, dried over MgS04 and concentrated to yield the product (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+l)+. Retention time 2.05 minutes. 1H NMR (400 MHz, DMSO- 6) d 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm | |
With thionyl chloride In N,N-dimethyl-formamide for 1h; | 3.4 Step 4: (R)- 1 -(2,2-difluorobenzo[d] [1 ,3]dioxol-5- yl)-N-(1-((2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl)- 6-fluoro-2-(1 -hydroxy-2-methylpropan-2-yl)- 1 Hindol-5-yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HCl solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product (3 g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+1)+. Retention time 2.05 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.40 (m, 2H), 7.34-7.30 (m, 3H), 6.24 (s, 1H), 4.51-4.48 (m, 1H), 4.39-4.34 (m, 2H), 4.08 (dd, J=6.0, 8.3 Hz, 1H), 3.69 (t, J=7.6 Hz, 1H), 3.58-3.51 (m, 2H), 1.48-1.45 (m, 2H), 1.39 (s, 3H), 1.34-1.33 (m, 6H), 1.18 (s, 3H) and 1.14-1.12 (m, 2H) ppm | |
With oxalyl dichloride; N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide In N,N-dimethyl-formamide for 1h; | 3.4 Step 4: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide [DMF (3 drops) was added to a stirring mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HC1 solution, saturated NaHC03 solution and brine, dried over MgS04 and concentrated to yield the product (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+l)+. Retention time 2.05 minutes. 1H NMR (400 MHz, DMSO- 6) d 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm | |
With thionyl chloride In toluene at 60℃; for 0.5h; | 5.6 Step 6: l-(2,2-Difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride l-(2,2-Difluoro-l,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60 °C. SOCh (1.4 eq) was added via addition funnel. The toluene and SOCh were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification. | |
With thionyl chloride In N,N-dimethyl-formamide for 1h; | 2.4 Step 4: (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-((2,2-dimethyl-l,3- dioxolan-4-yl)methyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide DMF (3 drops) was added to a stirring mixture of l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-l- ((2, 2-dimethyl- l,3-dioxolan-4-yl)methyl)-6-fluoro-lH-indol -2 -yl)-2-methylpropan-l-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with IN HC1 solution, saturated NaHCCh solution and brine, dried over MgSCri and concentrated to yield the product (3g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+l)+. Retention time 2.05 minutes. NMR (400 MHz, DMSO-^6) d 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30 (m, 3H), 6.24 (s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz, 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm | |
With thionyl chloride In toluene at 60℃; for 2h; | 1 Synthesis of Benzyl Protected Compound 1 1-(2,2-Difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was slurried in toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid). Thionyl chloride (SOCl2, 1.7 equiv) was added via addition funnel and the mixture was heated to 60° C. The resulting mixture was stirred for 2 h. The toluene and the excess SOCl2 were distilled off using rotavop. Additional toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added and the mixture was distilled down to 1 vol of toluene. A solution of (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol (1 eq) and triethylamine (3 eq) in DCM (4 vol) is cooled to 0° C. The acid chloride solution in toluene (1 vol) is added while maintaining the batch temperature below 10° C. The reaction progress is monitored by HPLC, and the reaction is usually complete within minutes. After warming to 25° C., the reaction mixture is washed with 5% NaHCO3(3.5 vol), 1 M NaOH (3.5 vol) and 1 M HCl (5 vol). A solvent swap to into methanol (2 vol) is performed and the resulting solution of (R)-N-(1-(3-(benzyloxy)-2-hydroxypropyl)-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide in methanol is used without further manipulation in the next step (hydrogenolysis). | |
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 36 - 40℃; for 3h; | 22 Thionyl chloride (24 mL) was added to a mixture of compound of Formula IX (56.4g), dimethyl formamide (4 mL) in methylene chloride (400 mL) and temperature of the reaction mass was raised to reflux at 36-40°C, aged at the same temperature for 3h. The reaction mass was distilled till 1.5 volumes are left behind at atmospheric pressure, co distilled with toluene (200 mL) under vacuum till 1 volume is left behind and methylene chloride (200 mL) was added to get the acid chloride solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.7% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With thionyl chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: (5-methyl-pyridin-2-yl)amine With triethylamine In dichloromethane at 20℃; | 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (2.32 g, 9.58 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (3 mL) and N,N-dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 30 minutes at room temperature. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in anhydrous dichloromethane (10 mL). This solution was then slowly added to a solution 5-methylpyridin-2-amine (0.798 g, 7.38 mmol) in anhydrous dichloromethane (10 mL) containing triethylamine (4.11 mL, 29.5 mmol). The resulting mixture was allowed to stir for 15 hours at room temperature. The crude product was then washed two times with a 1M aqueous solution of hydrochloric acid, two times with a saturated aqueous solution of sodium bicarbonate, and finally two times with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, evaporated to near dryness, and then purified on 120 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield the pure product (1.20 g, 3.60 mmol, 48.7%). ESI-MS m/z calc. 332.1, found 333.1 (M+1)+. Retention time 1.48 minutes. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With thionyl chloride at 20℃; for 0.5h; Inert atmosphere; Stage #2: tert-butyl 3-(2-amino-5-methylpyridin-4-yl)benzoate With triethylamine In dichloromethane at 20℃; | 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (144 mg, 0.593 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (1 mL) and N,N-dimethylformamide (0.1 mL) were added and the solution was allowed to stir for 30 minutes at room temperature. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in 2 mL of anhydrous dichloromethane. This solution was then slowly added to a solution of tert-butyl 3-(2-amino-5-methylpyridin-4-yl)benzoate (129 mg, 0.454 mmol) in 5 mL of anhydrous dichloromethane containing triethylamine (0.165 mL, 1.19 mmol). The resulting mixture was allowed to stir for 15 hours at room temperature. The crude product was evaporated to dryness and then purified on 12 g of silica gel utilizing a gradient of 0-40% ethyl acetate in hexanes to yield the pure product as a yellow solid (162 mg, 0.319 mmol, 70.3%). ESI-MS m/z calc. 508.2, found; 509.1 (M+1)+Retention time 2.22 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.18 (s, 1H), 7.98-7.96 (m, 1H), 7.89 (s, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.64-7.62 (m, 2H), 7.57 (d, J=1.6 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.7, 8.3 Hz, 1H), 2.14 (s, 3H), 1.55 (s, 9H), 1.51-1.49 (m, 2H) 1.19-1.15 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; HATU In N,N-dimethyl-formamide at 60℃; for 18h; | 12 12. Preparation of N-(2-tert-butyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide HATU (31 mg, 0.083 mmol) was added to a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (18 mg, 0.075 mmol), 2-tert-butyl-1H-pyrrolo[3,2-b]pyridin-5-amine (16 mg, 0.083 mmol) and triethylamine (21 μL, 0.15 mmol) in DMF (1 mL). The reaction was stirred at 60° C. for 18 h. The mixture was filtered and purified by reverse-phase HPLC (10-99% CH3CN-H2O with 0.035% TFA) to yield N-(2-tert-butyl-1H-pyrrolo[3,2-b]pyridin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as the TFA salt. ESI-MS m/z calc. 413.2, found 414.1 (M+1)+. Retention time 2.86 minutes. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In N,N-dimethyl-formamide at 60℃; for 18h; | 13 13. Preparation of N-(2-tert-butyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide HATU (31 mg, 0.083 mmol) was added to a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (18 mg, 0.075 mmol), 2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-5-amine (16 mg, 0.083 mmol) and triethylamine (21 μL, 0.15 mmol) in DMF (1 mL). The reaction was stirred at 60° C. for 18 h. The mixture was filtered and purified by reverse-phase HPLC (10-99% CH3CN-H2O with 0.035% TFA) to yield N-(2-tert-butyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as the TFA salt. ESI-MS m/z calc. 413.2, found 414.3 (M+1)+. Retention time 3.25 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; | 11 HATU (38 mg, 0.10 mmol) was added to a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (24 mg, 0.10 mmol), 2-(5-amino-2-tert-butyl-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (23 mg, 0.10 mmol) and triethylamine (42 μL, 0.30 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was filtered and purified by reverse-phase HPLC (10-99% CH3CN-H2O with 0.035% TFA) to yield N-(2-tert-butyl-1-(2-hydroxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 457.2, found 458.5 (M+1)+. Retention time 1.77 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (br s, 1H), 8.84 (s, 1H), 7.83 (s, 1H), 7.58 (d, J=1.7 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 6.67 (s, 1H), 4.58 (t, J=5.7 Hz, 2H), 3.76 (t, J=5.7 Hz, 2H), 1.58 (m, 2H), 1.46 (s, 9H), 1.28 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; | 14.b To a mixture of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (183 mg, 0.75 mmol), (R)-3-(5-amino-l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-lH- indol-2-yl)-3-methylbutan-l-ol containing some 3-(5-amino-6-fluoro-lH-indol-2-yl)-3- methylbutan-1-ol (220 mg, 0.63 mmol) and HATU (287 mg, 0.75 mmol) in DMF (3.0 mL) was added triethylamine (0.21 mL, 1.5 mmol). The reaction was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20- 40% ethyl acetate - hexanes) to afford (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-((2,2- dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-lH-indol-5- yOcyclopropanecarboxamide (315 mg, 87 %, contains some l-(2,2-difluorobenzo[d][l,3]dioxol- 5-yl)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-lH-indol-5-yl)cyclopropanecarboxaniide). ESI-MS mJz calc. 574.2 found 575.7 (M+l)+. Retention time 2.08 minutes |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid was isolated in 79% yield from <strong>[68119-31-3](2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile</strong> (3 steps including isolation) and with an HPLC purity of 99.0% AUC. ESI-MS m/z calc. 242.04. found 241.58 (M+1)+; 1H NMR (500 MHz, DMSO) delta 12.40 (s, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H). | |
79% | 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid was isolated in 79% yield from <strong>[68119-31-3](2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile</strong> (3 steps including isolation) and with an HPLC purity of 99.0% AUC. ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; 1H NMR (500 MHz, DMSO) delta 12.40 (s, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.3, 1.7 Hz, 1H), 1.46 (m, 2H), 1.17 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; triethylamine; In dichloromethane; water; toluene; | Synthesis of Benzyl Protected Compound 1. 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.3 equiv) was slurried in toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) and the mixture was heated to 60 C. SOCl2 (1.7 equiv) was added via addition funnel. The resulting mixture was stirred for 2 hr. The toluene and the excess SOCl2 were distilled off using rotavop. Additional toluene (2.5 vol, based on 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added and distilled again. The crude acid chloride was dissolved in dichloromethane (2 vol) and added via addition funnel to a mixture of N-benzylglycolated-5-amino-2-(2-benzyloxy-1,1-dimethylethyl)-6-fluoroindole (1.0 equiv), and triethylamine (2.0 equiv) in dichloromethane (7 vol) while maintaining 0-3 C. (internal temperature). The resulting mixture was stirred at 0 C. for 4 hrs and then warmed to room temperature overnight. Distilled water (5 vol) was added to the reaction mixture and stirred for NLT 30 min and the layers were separated. The organic phase was washed with 20 wt % K2CO3 (4 vol*2) followed by a brine wash (4 vol) and concentrated to afford crude benzyl protected Compound 1 as a thick brown oil, which was purified further using silica pad filtration. Silica gel pad filtration: Crude benzyl protected Compound 1 was dissolved in ethyl acetate (3 vol) in the presence of activated carbon Darco-G (10 wt %, based on theoretical yield of benzyl protected Compound 1) and stirred at room temperature overnight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With thionyl chloride In toluene at 60℃; for 2h; Stage #2: (2R)-1-{5-amino-2-[1-(benzyloxy)-2-methylpropan-2-yl]-6-fluoro-1H-indol-1-yl}-3-(benzyloxy)propan-2-ol With triethylamine In dichloromethane; toluene | 3h Example 3h: Synthesis of (R)-N-(1-(3-(benzyloxy)-2-b.yd:roxyp:ropyl)-2-(1-(be:nzyloxy )-2-methylpropa:n-2-yl)-6-f1uoro-1H-indol-5-yl)-1-(2,2-difluorohenzo[d] [l ,3] dioxol-5-yl)cyclopropa:necarhoxamide. 1-(2,2-Difluoro-1 ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid ( 1.3 equiv) wasslurried in toluene (2.5 voi, based on 1-(2,2-ditluoro-1,3-benzodioxol-5-yl)cyclopropanecarboxylicacid). Thionyl chloride (SOCh, 1.7 equiv) was added via additionfunnel and the mixture was heated to 60 oc. The resulting mixture was stirred for 2 h. Thetoluene and the excess SOCh were distilled off using a rotovap. Additional toluene (2.5 vol,based on 1-(2,2-difluoro-1 ,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid) was added and themixture was distilled down to 1 vol of toluene. A solution of (R)-l-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-:t1uoro-1H-i:ndol-1-yl)-3-(benzyloxy)propan-2-ol ( 1 eq) andtriethylamine (3 eq) in DCM (4 vol) was cooled to 0 °C. The acid chloride solution in toluene (1vol) was added while maintaining the batch temperature below 10 "C. The reaction progresswas monitored by HPLC, and the reaction was usually complete within minutes. After warmingto 25 "C, the reaction mixture was washed with 5% NaHC03 (3.5 vol), 1 M NaOH (3.5 vol) and1 M HCl (5 vol). A solvent swap to into methanol (2 vol) was performed and the resultingsolution of (R)-N-( 1-(3-(benzyloxy)-2-hydroxypropyl)-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fl.uoro-lH-indol-5-yl)-1-(2,2-ditluorobenzo( dJ( 1,3 ]dioxol-5-yl)cyclopropanecarboxamide inmethanol was used without further purification in the next step (hydrogenolysis). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16h; | 32.6 Step 6: To l-(2,2-difluorobenzo[6) δ ppm 7.91 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.24 (dd, J = 8.3, 1.8 Hz, 1H), 6.75 (d, J = 6.1 Hz, 1H), 4.73 (dd, J = 11.2, 3.1 Hz, 1H), 3.98 (dd, J = 10.7, 4.8 Hz, 1H), 3.82 (s, 3H), 1.83 (dt, J = 13.7, 3.6 Hz, 1H), 1.73 (dd, J = 13.9, 4.9 Hz, 1H), 1.58 (ddd, J = 13.7, 11.2, 5.4 Hz, 1H), 1.50 (dd, J = 14.0, 4.7 Hz, 1H), 1.34 (pt, J = 4.7, 2.4 Hz, 2H), 1.12 (s, 3H), 1.10 - 1.02 (m, 2H), 1.02 (s, 3H); MS (ESI+) m/z 488 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
684 mg | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16.3h; | 34.4 Step 4: To l-(2,2-difluorobenzo[6) δ ppm 7.89 (d, J = 8.3 Hz, 2H), 7.46 - 7.38 (m, 2H), 7.34 - 7.25 (m, 2H), 7.11 (dd, J = 8.3, 1.8 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 4.79 - 4.63 (m, 1H), 4.18 (dtt, J = 12.3, 8.2, 4.3 Hz, 1H), 3.82 (s, 3H), 1.85 - 1.74 (m, 1H), 1.65 - 1.54 (m, 1H), 1.31 (dt, J = 6.8, 2.9 Hz, 2H), 1.26-1.15 (m, 2H), 1.23 (s, 3H), 1.20 (s, 3H), 0.95 (q, J = 4.0 Hz, 2H); MS (ESI+) m/z 488 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.7% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16h; | 36.4 Step 4: To l-(2,2-difluorobenzo[6) δ ppm 7.73 (dd, J = 8.1, 1.8 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.11 (dd, J = 8.3, 1.7 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 4.53 (dd, J = 11.4, 2.0 Hz, 1H), 4.06 - 3.92 (m, 2H), 3.79 (s, 3H), 3.53 (td, J = 12.2, 2.2 Hz, 1H), 2.29 (s, 3H), 1.77 - 1.69 (m, 1H), 1.65 - 1.57 (m, 1H), 1.48 (qd, J = 12.4, 4.7 Hz, 1H), 1.37 - 1.24 (m, 3H), 1.00 - 0.89 (m, 2H); MS (ESI+) m/z 474 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 35℃; for 2h; | 38.6 Step 6: A mixture of l-(2,2-difluorobenzo[3) δ ppm 7.19 - 7.12 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.86 (dd, J = 8.5, 1.0 Hz, 1H), 6.44 (dd, J = 8.6, 2.6 Hz, 1H), 6.32 (d, J = 2.6 Hz, 1H), 5.32 (d, J = 8.8 Hz, 1H), 5.26 - 5.17 (m, 1H), 4.07 (dd, J = 11.9, 1.6 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 2.21 (ddd, J = 13.0, 6.2, 1.8 Hz, 1H), 2.08 - 1.99 (m, 6H), 1.97 - 1.84 (m, 1H), 1.74 (ddd, J = 9.0, 5.4, 2.2 Hz, 1H), 1.69 - 1.63 (m, 1H), 1.08 (tdd, J = 9.6, 6.2, 3.0 Hz, 2H); MS (ESI-) m/z 498 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 68% 2: 4.5% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 35℃; for 2h; | 39.5 Step 5: To l-(2,2-difluorobenzo[,,6i?)-4-([l-(2,2-dif uoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-methyltetrahydro-2H-pyran-2-yl]benzoate (225 mg, 68%). 1H NMR (400 MHz, CDC13) δ ppm 8.04 - 7.92 (m, 2H), 7.43 - 7.32 (m, 2H), 7.18 - 6.96 (m, 3H), 5.08 (d, J = 8.0 Hz, 1H), 4.48 (dd, J = 11.3, 2.1 Hz, 1H), 4.14 (tdt, J = 11.9, 8.1, 4.3 Hz, 1H), 3.90 (s, 3H), 3.68 (dtd, J = 12.3, 6.0, 1.8 Hz, 1H), 2.17 - 2.00 (m, 1H), 1.91 (ddt, J = 12.7, 4.1, 2.0 Hz, 1H), 1.63 - 1.59 (m, 2H), 1.26 (d, J = 6.2 Hz, 3H), 1.14 - 1.05 (m, 1H), 1.03 - 0.99 (m, 2H), 0.86 (ddt, J = 9.9, 6.3, 3.5 Hz, 1H); MS (ESI-) m/z 472 (M-H)~. The second eluting compound was not pure and was subjected to a second chromatography to give methyl rac-4-[(2i?,4i?,6i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-methyltetrahydro-2H-pyran-2-yl]benzoate (15 mg, 4.5%, Example 46). 1H NMR (400 MHz, CDC13) δ ppm 8.09 - 7.92 (m, 2H), 7.34 (dd, J = 25.0, 8.3 Hz, 2H), 7.25 - 6.99 (m, 3H), 5.64 (d, J = 7.1 Hz, 1H), 4.27 (dq, J = 6.6, 3.2 Hz, 1H), 4.18 (dd, J = 12.1, 2.2 Hz, 1H), 3.90 (d, J = 2.7 Hz, 3H), 3.39 (ddt, J = 12.6, 6.5, 3.2 Hz, 1H), 1.87 (dq, J = 13.8, 2.2 Hz, 1H), 1.67 - 1.63 (m, 2H), 1.58 (s, 3H), 1.10 - 1.04 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 47.5 Step 5: To l-(2,2-difluorobenzo[3) δ ppm 8.05 - 7.94 (m, 2H), 7.42 - 7.27 (m, 9H), 7.25 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 5.77 (d, J = 7.0 Hz, 1H), 4.38 (ddd, J = 8.5, 6.6, 2.9 Hz, 2H), 4.30 (dd, J = 9.9, 4.4 Hz, 1H), 3.91 (s, 3H), 2.03 (m, 1H), 1.91 - 1.75 (m, 3H), 1.69 (q, J = 3.7 Hz, 2H), 1.26 (s, 1H), 1.12 (q, J = 3.5 Hz, 2H); MS (ESI-) m/z 534 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 48 Example 48 me l rac^-[(2R,45,6S)^-([l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoate Example 48 me l rac^-[(2R,45,6S)^-([l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoate To l-(2,2-difluorobenzo[(i][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (145 mg, 0.601 mmol) in DMF (2 mL) was added l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-]pyridinium 3-oxid hexafluorophosphate (HATU, 311 mg, 0.819 mmol), and the mixture was stirred for 5 min. Then methyl rac-4-[(2i?,45',65)-4-amino-6-phenyltetrahydro-2H-pyran-2-yl]benzoate from Step 4 of Example 47 (170 mg, 0.546 mmol) was added following by N-ethyl-N- isopropylpropan-2-amine (0.380 mL, 2.184 mmol). The mixture was stirred at room temperature for 2 h when LC/MS indicated the reaction was complete. The reaction mixture was loaded on a 24 g silica gel cartridge directly without workup and purified by chromatography eluted with EtOAc in heptane at 5-40% gradient give the titled compound (230 mg, 79%). 1H NMR (400 MHz, CDC13) δ ppm 8.04 - 7.94 (m, 2H), 7.49 - 7.41 (m, 2H), 7.40 - 7.30 (m, 4H), 7.29 - 7.23 (m, 2H), 7.11 - 6.96 (m, 3H), 5.11 (d, J = 8.1 Hz, 1H), 4.66 (ddd, J = 20.7, 11.4, 2.2 Hz, 2H), 4.34 (tdt, J = 12.0, 8.2, 4.2 Hz, 1H), 3.90 (s, 3H), 2.20 (dddt, J = 19.3, 12.8, 4.2, 2.0 Hz, 2H), 1.62 (q, J = 3.2 Hz, 2H), 1.28 (dq, J = 17.6, 11.9 Hz, 2H), 1.02 (q, J = 3.3 Hz, 2H); MS (ESI-) m/z 534 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 22.6% 2: 39.2% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 55.2 Step 2: A mixture of l-(2,2-difluorobenzo[3) δ ppm 8.01 - 7.96 (m, 2H), 7.40 - 7.33 (m, 2H), 7.28 (dd, J = 8.1, 1.7 Hz, 1H), 7.26 - 7.20 (m, 3H), 7.16 (d, J = 8.1 Hz, 1H), 6.90 - 6.85 (m, 2H), 5.76 (d, J = 7.0 Hz, 1H), 4.37 (ddd, J = 10.3, 5.3, 2.0 Hz, 2H), 4.24 (dd, J = 9.8, 4.5 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 2.02 - 1.94 (m, 1H), 1.87 (d, J = 3.6 Hz, 1H), 1.78 (ddd, J = 14.1, 12.1, 3.8 Hz, 1H), 1.69 (q, J = 3.7 Hz, 2H), 1.26 (s, 1H), 1.14 - 1.10 (m, 2H); MS (ESI-) m/z 564 (M-H)~. The second eluting diastereomer was the titled compound, methyl rac-4-[(2R,4R,6S)-4-([l-(2,2- difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6-(4-methoxyphenyl)tetrahydro- 2H-pyran-2-yl]benzoate (104 mg, 39.2%). 1H NMR (400 MHz, CDC13) δ ppm 8.05 - 7.90 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.13 - 7.04 (m, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.91 - 6.81 (m, 2H), 5.11 (d, J = 8.1 Hz, 1H), 4.67 (dd, J = 11.2, 2.2 Hz, 1H), 4.58 (dd, J = 11.4, 2.2 Hz, 1H), 4.32 (dtd, J = 11.9, 7.9, 4.2 Hz, 1H), 3.90 (d, J = 1.2 Hz, 3H), 3.79 (d, J = 1.3 Hz, 3H), 2.26 - 2.05 (m, 2H), 1.62 (q, J = 3.4 Hz, 2H),1.31 - 1.23 (m, 2H), 1.02 (q, J = 3.4 Hz, 2H); MS (ESI-) m/z 564 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 26.2% 2: 59.2% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 62.2 Step 2: A mixture of l-(2,2-difluorobenzo[~. The titled compound, methyl rac-4-[(2i?,45',65)-4-([l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]-3-methylbenzoate was obtained as the second eluting diastereomer (290 mg, 0.528 mmol, 59.2%> yield). 1H NMR (400 MHz, CDCI3) δ ppm 7.86 (dd, J = 8.2, 1.7 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.41 - 7.29 (m, 4H), 7.29 - 7.23 (m, 2H), 7.11 - 7.04 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 5.12 (d, J = 8.1 Hz, 1H), 4.81 (dd, J = 11.2, 2.0 Hz, 1H), 4.65 (dd, J = 11.3, 2.1 Hz, 1H), 4.34 (tdt, J = 12.1, 8.3, 4.2 Hz, 1H), 3.89 (d, J = 0.7 Hz, 3H), 2.37 (s, 3H), 2.18 (dddt, J = 26.5, 12.9, 4.0, 1.9 Hz, 2H), 1.61 (t, J = 3.3 Hz, 2H), 1.30 - 1.17 (m, 2H), 1.02 (q, J = 3.6 Hz, 2H); MS (ESI-) m/z 548 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 24.3% 2: 18.93% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 63.2 Step 2: To l-(2,2-difluorobenzo[+. The first eluting diastereomer was methyl rac-4-[(2i?,4i?,65)-4-([l-(2,2-difluoro-l,3- benzodioxol-5 -yl)cyclopropyl] carbonyl} amino)-6-phenyltetrahydro-2H-pyran-2-yl] -3 - fluorobenzoate (70 mg, 18.93%). 1H NMR (400 MHz, CDC13) δ ppm 7.83 (dd, J = 8.1, 1.5 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.38 - 7.27 (m, 6H), 7.25 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 5.78 (d, J = 6.9 Hz, 1H), 4.68 - 4.58 (m, 1H), 4.41 - 4.29 (m, 2H), 3.91 (s, 3H), 2.04 (dq, J = 14.3, 2.4 Hz, 1H), 1.96 - 1.64 (m, 5H), 1.19 - 1.05 (m, 2H); MS (ESI+) m/z 554 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.7% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 68.4 Step 4: A mixture of l-(2,2-difluorobenzo[3) δ ppm 8.04 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.24 (s, 1H), 7.11 - 7.04 (m, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.83 - 6.74 (m, 1H), 5.12 (d, J = 8.2 Hz, 1H), 4.63 (ddt, J = 19.6, 10.5, 5.2 Hz, 2H), 4.41 - 4.35 (m, 2H), 4.35 - 4.25 (m, 1H), 3.80 (d, J = 2.8 Hz, 3H), 2.27 - 2.13 (m, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.1.62 (m, 2H), 1.35 - 1.25 (m, 2H); MS (ESI-) m/z 578 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide Stage #2: methyl rac-3-[(2R,4R)-4-aminotetrahydro-2H-pyran-2-yl]benzoate With triethylamine In dichloromethane for 0.25h; | 4.4 Step 4: To l-(2,2-difluorobenzo[6) δ ppm 7.90 (t, J = 1.7 Hz, 1H), 7.85 (dt, J = 7.6, 1.5 Hz, 1H), 7.56 (dt, J = 7.8, 1.5 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 1.5 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.27 (dd, J = 8.3, 1.7 Hz, 1H), 7.05 (d, J = 6.0 Hz, 1H), 4.56 (dd, J = 10.3, 2.6 Hz, 1H), 3.98 (q, J = 4.6 Hz, 1H), 3.85 (s, 3H), 3.75 (dt, J = 11.7, 3.9 Hz, 1H), 3.60 (td, J = 11.4, 2.9 Hz, 1H), 1.90 (dt, J = 14.0, 3.3 Hz, 1H), 1.77 - 1.60 (m, 3H), 1.39 (dt, J = 5.7, 2.7 Hz, 2H), 1.11 - 1.04 (m, 2H); MS (ESI+) m/z 460 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 3h; | 11.5 Step 5: To l-(2,2-difluorobenzo[6) δ ppm 7.75 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 4.2 Hz, 2H), 7.42 - 7.36 (m, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.14 (dd, J = 8.3, 1.7 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 4.94 (dd, J = 11.0, 1.9 Hz, 1H), 4.05 - 3.93 (m, 2H), 3.83 (s, 3H), 3.50 (td, J = 12.1, 2.3 Hz, 1H), 1.95 - 1.86 (m, 1H), 1.67 - 1.59 (m, 1H), 1.51 (qd, J = 12.2, 4.6 Hz, 1H), 1.39 - 1.30 (m, 3H), 0.97 (qt, J = 7.7, 3.8 Hz, 2H); MS (ESI+) m/z 460 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50 mg | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: 2-(1,3-benzodioxol-5-yl)tetrahydro-2H-pyran-4-amine With triethylamine In dichloromethane at 20℃; for 1.5h; | 15.4 Step 4: To a suspension of l-(2,2-difluorobenzo[2 over 10 minutes at a flow rate of 70 mL/minute with a retention time of 6.8 minutes to give N-[(25',4i?)-2-(l,3- benzodioxol-5-yl)tetrahydro-2H-pyran-4-yl]-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (50 mg, 0.112 mmol). 1H NMR (400 MHz, CDC13) δ ppm 0.95 - 1.07 (m, 2 H) 1.11 - 1.44 (m, 3 H) 1.85 (dd, J=12.51, 1.83 Hz, 1 H) 2.03 (dd, J=12.51, 1.83 Hz, 1 H) 3.09 (s, 1 H) 3.49 - 3.66 (m, 1 H) 4.02 - 4.15 (m, 2 H) 4.27 (dd, J=l 1.14, 1.68 Hz, 1 H) 5.09 (d, J=7.93 Hz, 1 H) 5.91 (s, 2 H) 6.73 (s, 2 H) 6.80 (s, 1 H) 7.00 - 7.06 (m, 1 H) 7.07 - 7.16 (m, 2 H); MS (ESI+) m/z 446 (M+H)+. Absolute stereochemistry was assigned using X-ray diffraction analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.2% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 22.6 Step 6: A mixture of l-(2,2-difluorobenzo[3OH:C02, 10 minutes 3 mL/minute, 150 bar, column: Chiralcel OJ-H). 1H NMR (400 MHz, CDC13) δ ppm 7.99 - 7.89 (m, 2H), 7.55 (dt, J = 7.9, 1.5 Hz, 1H), 7.41 (td, J = 7.6, 0.8 Hz, 1H), 7.34 - 7.24 (m, 7H), 7.17 (d, J = 8.2 Hz, 1H), 5.79 (d, J = 7.0 Hz, 1H), 4.43 - 4.35 (m, 2H), 4.30 (dd, J = 9.2, 5.2 Hz, 1H), 3.92 (s, 3H), 2.02 - 1.83 (m, 4H), 1.70 (d, J = 3.3 Hz, 2H), 1.15 - 1.10 (m, 2H); MS (ESI-) m/z 534.2 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 23 Example 23 me l rac-3-[(2R,45,6S)^-([l-(2,2-difluoro ,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoate To l-(2,2-difluorobenzo[(i][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (156 mg, 0.642 mmol) in N,N-dimethylformamide (2 mL) was added (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-]pyridinium 3-oxid hexafluorophosphate (HATU, 366 mg, 0.963 mmol). The mixture was stirred for 5 minutes, and then methyl rac-3-[(2R,4S,6S)-4-ammo-6- phenyltetrahydro-2H-pyran-2-yl]benzoate from Step 5 of Example 22 (200 mg, 0.642 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.448 mL, 2.57 mmol) were sequentially added. The mixture was stirred at room temperature for 2 hours. The crude material was loaded on 25 g silica gel cartridge without work up and eluted with 5-40% ethyl acetate in heptane to give the titled compound. Analytical chiral supercritical fluid chromatography spectrum showed two peaks with ratio 1 :1, retention time = 3.268 minutes and 3.940 minutes (method: 5-50% CH3OH:C02, 10 minutes 3 mL/minute, 150 bar, column: Chiralcel OJ-H). 1H NMR (400 MHz, CDCl3) 5 ppm 8.04 (t, J = 1.8 Hz, 1H), 7.93 (dt, J = 7.7, 1.6 Hz, 1H), 7.59 (dt, J = 8.1, 1.6 Hz, 1H), 7.43 - 7.29 (m, 5H), 7.28 - 7.21 (m, 1H), 7.11 - 7.04 (m, 2H), 7.01 (d, J = 8.1 Hz, 1H), 5.12 (d, J = 8.0 Hz, 1H), 4.72 - 4.56 (m, 2H), 4.34 (tdt, J = 12.1, 8.2, 4.3 Hz, 1H), 3.91 (d, J = 1.4 Hz, 3H), 2.20 (ddd, J = 14.8, 9.0, 3.4 Hz, 2H), 1.62 (q, J = 3.5 Hz, 2H), 1.27 (d, J = 11.3 Hz, 3H), 1.02 (q, J = 3.5 Hz, 2H); MS (ESI-) m/z 534.2 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.2% | With triethylamine; HATU In N,N-dimethyl-formamide for 0.75h; | 1.2 Step 2: To l-(2,2-difluorobenzo[+. Relative stereochemistry was assigned by 1H, H-H COSY, H-H ROESY, H-C HSQC and H-C HMBC NMR experiments. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU In tetrahydrofuran at 20℃; for 1h; | 24I Example 241 ethyl re/-3-[(25,,45)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate Example 241 ethyl re/-3-[(25,,45)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate A mixture of the product from Example 24H (14 mg, 0.042 mmol), l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxylic acid (10.13 mg, 0.042 mmol) and 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (17.49 mg, 0.046 mmol) in tetrahydrofuran (1 mL) was treated with triethylamine (17.49 μ, 0.125 mmol). The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate (30 mL), washed with 1 M HC1 (10 mL), washed with saturated NaHC03 solution (10 mL), washed with brine, dried (MgS04), filtered, and concentrated. The residue was chromatographed on silica gel, eluting with a gradient of 50 % - 100 % [1 : 1 CH2Cl2:ethyl acetate] in heptanes to provide the title compound. 1H NMR (400 MHz, CDC13) δ ppm 8.25 (s, 1H), 8.17 (d, J= 5.1 Hz, 1H), 8.06 (s, 1H), 8.03 (d, J= 8.1 Hz, 1H), 7.59 (d, J= 8.1 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.17 - 7.02 (m, 4H), 5.57 - 5.45 (m, 2H), 5.34 - 5.26 (m, 1H), 4.39 (q, J= 7.1 Hz, 2H), 2.49 (ddd, J= 13.5, 5.9, 1.9 Hz, 1H), 1.92 (q, J= 11.8 Hz, 1H), 1.81 - 1.62 (m, 2H), 1.40 (t, J= 7.1 Hz, 3H), 1.19 - 1.08 (m, 2H); MS (ESI) m/z 523 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU In tetrahydrofuran at 20℃; for 1h; | 25C Example 25 C ethyl rel-3-[(2R,4R)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate Example 25 C ethyl rel-3-[(2R,4R)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 3,4-dihydro-2H-pyrano[2,3-c]pyridin-2-yl]benzoate A mixture of the product from Example 25B (7.7 mg, 0.023 mmol), 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.62 mg, 0.025 mmol) and 1 -(2,2-difluoro- l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (5.57 mg, 0.023 mmol) in tetrahydrofuran (1 mL) was treated with triethylamine (9.62 μΕ, 0.069 mmol). The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate (30 mL), washed with 1 M HC1 (10 mL), washed with saturated NaHC03 solution (10 mL), washed with brine, dried (MgS04), filtered, and concentrated. The crude product was chromatographed on silica gel eluting with a gradient of 50 % - 100 % [1 : 1 CH2Cl2:ethyl acetate] in heptanes to provide the title compound. 1H NMR (400 MHz, CDC13) δ ppm 8.26 (s, 1H), 8.17 (d, J= 5.0 Hz, 1H), 8.06 (s, 1H), 8.03 (d, J= 7.8 Hz, 1H), 7.58 (d, J= 7.8 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.15 (dd, J= 8.2, 1.6 Hz, 1H), 7.10 (d, J= 1.5 Hz, 1H), 7.06 - 7.02 (m, 2H), 5.52 (td, J= 10.8, 10.1, 6.0 Hz, 1H), 5.43 (d, J= 8.9 Hz, 1H), 5.28 (dd, J= 11.7, 1.9 Hz, 1H), 4.39 (q, J= 7.1 Hz, 2H), 2.50 (ddd, J = 13.5, 6.0, 2.0 Hz, 1H), 1.89 (dt, J= 13.3, 11.4 Hz, 1H), 1.80 - 1.63 (m, 2H), 1.40 (t, J= 7.1 Hz, 3H), 1.17 - 1.08 (m, 2H); MS (ESI) m/z 523 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 43.7% 2: 9.04% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: methyl 3-((2R,4R)-4-amino-7-(difluoromethoxy)chroman-2-yl)benzoate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 27E; 26A Example 27E methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- (difluoromethoxy)chroman-2-yl)benzoate Example 27E methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- (difluoromethoxy)chroman-2-yl)benzoate A mixture of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (41.6 mg, 0.172 mmol) and HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate) (98 mg, 0.258 mmol) in DMF (1 mL) was stirred for 5 minutes, and Example 27D (60 mg, 0.172 mmol) was added, followed by addition of N-ethyl- N-isopropylpropan-2-amine (0.120 mL, 0.687 mmol). The mixture was stirred at ambient temperature for 2 hours and LC/MS showed the reaction was complete. The crude product was purified by preparative LC method TFA2 to provide the title compound (43 mg, 43.7 % yield) as the first eluting compound and Example 26A as the second eluenting compound. Example 26A methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- (difluoromethoxy)chroman-2-yl)cyclohexanecarboxylate The title compound (9.0 mg, 0.016 mmol, 9.04 % yield) was isolated as a second eluting compound from the purification of the crude product as described in Example 27E. LC/MS m/z 580 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide at 100℃; Flow reactor; | |
189 mg | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 2-(3,4-dimethoxyphenyl)-7-methoxychroman-4-ylamine With triethylamine In N,N-dimethyl-formamide for 0.75h; | 3 Example 3 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3,4-dimethoxyphenyl)-7-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide Example 3 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-2-(3,4-dimethoxyphenyl)-7-methoxy-3,4- dihydro-2H-chromen-4-yl]cyclopropanecarboxamide To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (CAS 68015- 98-5) (120 mg, 0.496 mmol) in DMF (1239 μ,) was added HATU (1- [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate) (245 mg, 0.644 mmol). The mixture was stirred for 5 minutes at room temperature, and then 2-(3,4-dimethoxyphenyl)-7-methoxychroman-4-amine (156 mg, 0.496 mmol) was added, followed by dropwise addition of triethylamine (276 μ,, 1.982 mmol). After 45 minutes, the mixture was quenched with saturated aqueous sodium bicarbonate, and the aqueous layer removed. The resulting oil was triturated with water and filtered to give 283 mg of a white solid. The solid was dissolved in dichloromethane and purified using a 24 g silica gel cartridge with a gradient of 5-50% ethyl acetate/heptanes to give 189 mg of a mixture of the two diastereomers. The mixture was subjected to preparative supercritical fluid chromatography set to maintain a backpressure at 100 bar using a CHIRALPAK IA, 21 x 250 mm, 5 micron, with the sample at a concentration of 20 mg/mL in methanol using 16 % methanol in C02 at a flow rate of 70 mL/minute with a retention time of 7.2 minutes to give the title compound (111 mg, 0.206 mmol, 41.5 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 6.98 - 6.91 (m, 4H), 6.50 (dd, J = 8.5, 2.6 Hz, 1H), 6.36 (d, J = 2.5 Hz, 1H), 5.36 - 5.24 (m, 1H), 5.15 (dd, J = 11.5, 1.9 Hz, 1H), 3.75 (d, J = 1.4 Hz, 6H), 3.68 (s, 3H), 2.10 (q, J = 11.8 Hz, 1H), 1.99 (ddd, J = 12.9, 6.2, 2.1 Hz, 1H), 1.53 - 1.46 (m, 1H), 1.37 (ddd, J = 8.4, 5.8, 2.8 Hz, 1H), 1.05 (dtdd, J = 12.7, 9.6, 6.4, 3.3 Hz, 2H); MS (ESI+) m/z 402 (M+H)+. Absolute stereochemistry was assigned by X-ray diffraction analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 8% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: methyl 3-((2R,4R)-4-amino-7-fluorochroman-2-yl)benzoate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 39E; 36A Example 39E methyl 3-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- fluoro-3,4-dihydro-2H-chromen-2-yl]benzoate Example 39E methyl 3-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- fluoro-3,4-dihydro-2H-chromen-2-yl]benzoate A mixture of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (108 mg, 0.444 mmol) and HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate) (220 mg, 0.577 mmol) in DMF (3 mL) was stirred for 5 minutes, followed by addition of Example 39D (150 mg, 0.48 mmol), followed by addition of N-ethyl-N-isopropylpropan-2-amine (0.31 mL, 1.78 mmol). The mixture was stirred at ambient temperature for 2 hours; LC/MS indicated the reaction was complete. Ethyl acetate (20 mL) and water (10 mL) were added. The mixture was partitioned. The organic layer was washed with saturated NaHC03 aqueous solution and brine sequentially, dried over MgS04, filtered, and concentrated. The residue was purified by chromatography on a 40 g silica gel cartridge, eluting with ethyl acetate in heptane at 0-30 % gradient to provide the title compound as the first eluting compound (140 mg, 60.0 % yield) and Example 36A as the second eluting compound. 1H NMR (400 MHz, CDC13) δ 8.13 - 7.91 (m, 2H), 7.57 (dt, J= 7.8, 1.5 Hz, 1H), 7.45 (t, J= 7.7 Hz, 1H), 7.14 - 6.99 (m, 4H), 6.69 - 6.58 (m, 2H), 5.44 (td, J= 10.1, 6.4 Hz, 1H), 5.33 (d, J= 8.9 Hz, 1H), 5.23 (dd, J= 11.5, 1.9 Hz, 1H), 3.93 (s, 3H), 3.48 (q, J= 7.0 Hz, 1H), 2.50 (ddd, J= 13.4, 6.0, 2.0 Hz, 1H), 1.77 - 1.60 (m, 2H), 1.10 - 1.06 (m, 2H); MS (ESI+) m/z 525.9 (M+H)+; The 1HNMR and Analytical Chiral SFC (5-30 % methanol:C02, 10 minutes at 3mL/minutes 150 bar, Column ChiralCel OJ-H) indicated the isolated product was a cis-stereoeisomer with 94% ee purity. Example 36A methyl 3-((2i?,4i?)-4-amino-7-fluorochroman-2-yl)cyclohexanecarboxylate The title compound was isolated as the second eluting compound from the purification of Example 39E (19 mg, 8.0 % yield). LC/MS m/z 532 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 9.23% 2: 8.07% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; Stage #2: 2-cyclopropyl-7-methoxychroman-4-amine hydrochloride With triethylamine In dichloromethane at 20℃; for 0.333333h; | 40E; 41 Example 40E rac-N-[(2i?,4i?)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide Example 40E rac-N-[(2i?,4i?)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (142 mg, 0.587 mmol) in dichloromethane (1.5 mL) was added half of a solution of oxalyl dichloride (0.205 mL, 2.346 mmol) in dichloromethane (1 mL), followed by 1 drop of DMF. The reaction bubbled vigorously, then the remainder of the oxalyl chloride solution was added dropwise. The reaction was stirred for 30 minutes at room temperature, then the solvent removed under a stream of nitrogen, then chased with 2 x 1 mL of dichloromethane, drying under a stream of nitrogen. The intermediate was taken up in dichloromethane (1.5 mL) and added to a mixture of the product from Example 40D (150 mg, 0.587 mmol) and triethylamine (0.327 mL, 2.346 mmol) in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 20 minutes. The mixture was quenched with saturated aqueous bicarbonate, and the aqueous layer removed. The organic phase was concentrated and the resulting oil dissolved in dichloromethane and purified on a 24 g silica gel cartridge, eluting with a gradient of 5-60 % ethyl acetate/heptanes in 20 minutes to provide 110 mg of a mixture of diastereomers. The mixture was further purified via preparative supercritical fluid chromatography set to maintain a backpressure at 100 bar using a Lux Cellulose (21 x 250 mm, 5 micron), with the sample at a concentration of 25 mg/mL in methanol using 16 % methanol in C02 at a flow rate of 70 mL/minute to provide the title compound (retention time = 4.4 minutes, 24 mg, 0.054 mmol, 9.23 % yield) and Example 41 (retention time = 3.7 minutes). 1H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.32 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 8.4, 1.7 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.43 (dd, J = 8.5, 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 4.93 (dt, J = 8.3, 4.4 Hz, 1H), 3.67 (s, 3H), 3.37 (td, J = 9.2, 2.6 Hz, 1H), 1.89 (dt, J = 14.0, 3.3 Hz, 1H), 1.81 (ddd, J = 14.0, 9.6, 5.0 Hz, 1H), 1.41 - 1.31 (m, 2H), 1.08 - 0.97 (m, 3H), 0.60 - 0.46 (m, 2H), 0.36 - 0.28 (m, 1H), 0.14 (dt, J = 9.5, 4.6 Hz, 1H); MS (ESI+) m/z 444 (M+H)+. Example 41 rac-N-[(2i?,45)-2-cyclopropyl-7-methoxy-3,4-dihydro-2H-chromen-4-yl]-l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarboxamide The title compound (retention time = 3.7 minutes, 21 mg, 0.047 mmol, 8.07 % yield) was isolated from the preparative supercritical fluid chromatography as described in Example 40E. 1H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.32 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 8.4, 1.7 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.43 (dd, J = 8.5, 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 4.93 (dt, J = 8.3, 4.4 Hz, 1H), 3.67 (s, 3H), 3.37 (td, J = 9.2, 2.6 Hz, 1H), 1.89 (dt, J = 14.0, 3.3 Hz, 1H), 1.81 (ddd, J = 14.0, 9.6, 5.0 Hz, 1H), 1.41 - 1.31 (m, 2H), 1.08 - 0.97 (m, 3H), 0.60 - 0.46 (m, 2H), 0.36 - 0.28 (m, 1H), 0.14 (dt, J = 9.5, 4.6 Hz, 1H); MS (ESI+) m/z 444 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.3% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: (2R,4R)-methyl 4-amino-2-(3-methoxyphenyl)chroman-6-carboxylate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 47E Example 47E methyl (2R,4R)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-2-(3- methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylate Example 47E methyl (2R,4R)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-2-(3- methoxyphenyl)-3,4-dihydro-2H-chromene-6-carboxylate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (34.8 mg, 0.144 mmol) in DMF (3 mL) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (82 mg, 0.215 mmol). The mixture was stirred for 5 minutes, and then Example 47D (45 mg, 0.144 mmol) was added, followed by addition of N-ethyl-N-isopropylpropan-2-amine (0.100 mL, 0.574 mmol). The mixture was stirred at ambient temperature for 2 hours. The reaction was purified on a 12 g silica gel cartridge and eluted with a gradient of 5-100 % ethyl acetate/heptanes over 20 minutes to prodide the title compound (45 mg, 0.084 mmol, 58.3 % yield). 1H NMR (400 MHz, CDC13) δ 7.91 - 7.75 (m, 2H), 7.29 (d, J= 7.8 Hz, 1H), 7.18 (dd, J= 8.1, 1.7 Hz, 1H), 7.13 (d, J= 1.7 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.97 - 6.83 (m, 4H), 5.46 (td, J= 10.1, 6.0 Hz, 1H), 5.36 (d, J= 8.9 Hz, 1H), 5.23 (dd, J= 11.5, 2.0 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 2.52 (ddd, J= 13.3, 5.9, 2.1 Hz, 1H), 1.89 - 1.75 (m, 2H), 1.67 - 1.59 (m, 1H), 1.10 (dtd, J= 9.5, 6.5, 3.2 Hz, 2H); MS (ESI+) m/z 537.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: 7-bromo-3,4-dihydro-2H-1-benzopyran-4-amine With triethylamine In N,N-dimethyl-formamide for 0.75h; | 56C Example 56C N-(7-bromo-3,4-dihydro-2H-chromen-4-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide Example 56C N-(7-bromo-3,4-dihydro-2H-chromen-4-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (80 mg, 0.330 mmol) in DMF (826 μ) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (163 mg, 0.429 mmol). The mixture was stirred for 5 minutes, and then the product from Example 56B (75 mg, 0.330 mmol) was added, followed by dropwise addition of triethylamine (184 μ^, 1.321 mmol). After 45 minutes the mixture was quenched with water, the aqueous layer removed, the resulting oil was dissolved in dichloromethane and purified on a 12 g silica gel cartridge, eluting with a gradient of 5-100 % ethyl acetate/heptanes to provide the title compound (120 mg, 0.265 mmol, 80 % yield) as a white solid. 1H NMR (501 MHz, DMSO-d6) δ 7.39 (d, J = 1.7 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.19 (dd, J = 8.3, 1.8 Hz, 1H), 7.01 (dd, J = 8.3, 2.0 Hz, 1H), 6.96 (dd, J = 8.2, 0.9 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 5.01 (td, J = 8.2, 6.0 Hz, 1H), 4.20 - 4.09 (m, 2H), 1.97 - 1.84 (m, 2H), 1.48 - 1.42 (m, 1H), 1.36 (ddd, J = 8.7, 5.9, 3.0 Hz, 1H), 1.04 (dtdd, J = 12.7, 9.4, 6.3, 3.2 Hz, 2H); MS (ESI-) m/z 450 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: 7-methoxychroman-4-amine sulfuric acid With triethylamine In N,N-dimethyl-formamide for 0.75h; | 59 Example 59 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-methoxy-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide Example 59 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-methoxy-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide To a solution of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.165 mmol) in DMF (413 μ) was added HATU (l-[bis(dimethylamino)methylene]-lH- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (82 mg, 0.215 mmol). The mixture was stirred for 5 minutes, and then 7-methoxychroman-4-amine, sulfuric acid salt (45.8 mg, 0.165 mmol) was added, followed by dropwise addition of triethylamine (92 μ,, 0.661 mmol). After 45 minutes the mixture was quenched with saturated aqueous bicarbonate, and the aqueous layer removed. The resulting oil was triturated with water to give a pink goo, which was dissolved in dichloromethane and purified on a 12 g silica gel cartridge, eluted with a gradient of 5-50 % ethyl acetate/heptanes to provide the title compound (61 mg, 0.151 mmol, 92 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.3, 1.8 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.44 (dd, J = 8.5, 2.6 Hz, 1H), 6.27 (d, J = 2.5 Hz, 1H), 4.98 (q, J = 7.2 Hz, 1H), 4.18 - 4.04 (m, 2H), 3.66 (s, 3H), 1.94 - 1.83 (m, 2H), 1.45 (ddd, J = 9.6, 5.8, 2.7 Hz, 1H), 1.36 (ddd, J = 8.6, 5.6, 2.8 Hz, 1H), 1.11 - 0.97 (m, 2H); MS (ESI+) m/z 404 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide at 50℃; | 60 Example 60 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-methoxy-2-phenyl-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide Example 60 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-methoxy-2-phenyl-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide In a 4 mL vial, 300 of a stock solution containing l-(2,2-difluorobenzo[d][l,3]dioxol- 5-yl)cyclopropanecarboxylic acid (0.25 M, 0.073 mmol, 1.0 equivalent) and diispropylethylamine (0.74 M, 0.22 mmol, 3.0 equivalents) in dimethyl acetamide was added to a stock solution containing 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, 1,3,3- tetramethylisouronium hexafluorophosphate(V) (0.30 M in dimethyl acetamide, 300 μ^, 0.089 mmol, 1.2 equivalents). A stock solution of 7-methoxy-2-phenyl-chroman-4-ylamine hydrochloride (0.40 M in dimethyl acetamide, 278 μ,, 0.111 mmol, 1.5 equivalents) was added and the reaction was stirred at 50 °C until complete as determined by LC. The material was loaded directly into a Gilson GX-271 autosampler and purified using preparative LC method TFA4 to provide the title compound (27. lmg, 76% yield). 1H NMR (400 MHz, DMSO-d6 :D20 = 9: 1 (v/v)) δ 7.44 - 7.25 (m, 7H), 7.25 - 7.12 (m, 2H), 6.95 (dd, J= 8.6, 1.1 Hz, 1H), 6.52 (dd, J= 8.5, 2.6 Hz, 1H), 6.36 (d, J= 2.5 Hz, 1H), 5.38 - 5.27 (m, 1H), 5.22 (dd, J= 11.3, 2.5 Hz, 1H), 3.69 (s, 3H), 2.19 - 1.93 (m, 2H), 1.50 (dt, J= 8.5, 3.0 Hz, 1H), 1.44 - 1.32 (m, 1H), 1.12 - 1.00 (m, 2H); MS (APCI+) m/z 480.4 (M+H)+. |
76% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide at 100℃; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide at 100℃; | 72 Example 72 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-6-methoxy-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide Example 72 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-6-methoxy-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide A stock solution of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid and N,N-diisopropylethylamine (0.218 M and 0.654 M in dimethylacetamide, respectively, 284 μ, 0.061 mmol l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.0 equivalent) and 0.18 mmol N,N-diisopropylethylamine (3.0 equivalents)), 2-(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-l , 1 ,3,3-tetramethylisouronium hexafluorophosphate(V) (0.26 M in dimethylacetamide, 284 μΕ, 0.074 mmol, 1.2 equivalents), and 3-(3,4-dimethoxy-benzyl)- 6-methoxy-chroman-4-ylamine (Von P. Pfeiffer et al., Justus Liebigs Annalen der Chemie (1949), 564, 208-19) (0.40 M in dimethylacetamide, 232 pL, 0.093 mmol, 1.5 equivalents) were aspirated from their respective source vials, mixed through a PFA (perfluoroalkoxy) mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100 °C, and passed through the reactor at 180 min"1 (10 minute residence time). Upon exiting the reactor, the reaction was loaded directly into an injection loop and purified using preparative LC method TFA1 to yield the title compound (10.69 mg, 49% yield). 1H NMR (400 MHz, DMSO- d6 :D20 = 9: l (v/v)) δ 7.42 (d, J= 8.9 Hz, 1H), 7.36 (d, J= 1.6 Hz, 1H), 7.31 (d, J= 8.3 Hz, 1H), 7.20 (dd, J= 8.3, 1.8 Hz, 1H), 6.86 (d, J= 8.1 Hz, 1H), 6.77 - 6.61 (m, 4H), 6.50 (d, J= 2.9 Hz, 1H), 4.91 - 4.79 (m, 1H), 4.02 - 3.93 (m, 1H), 3.75 (s, 6H), 3.64 (s, 3H), 3.46 (s, OH), 2.70 - 2.60 (m, 1H), 2.36 - 2.21 (m, 2H), 1.51 - 1.32 (m, 2H), 1.15 - 0.97 (m, 2H); MS (APCI+) m/z 554.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide at 20℃; | 91 Example 91 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-7-methoxy-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide Example 91 l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[3-(3,4-dimethoxybenzyl)-7-methoxy-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide A stock solution of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid and N,N-diisopropylethylamine (0.218 M and 0.654 M in dimethylacetamide, respectively, 284 μ, 0.061 mmol l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.0 equivalent) and 0.18 mmol N,N-diisopropylethylamine (3.0 equivalents)), 2-(3H- [1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-l , 1 ,3,3-tetramethylisouronium hexafluorophosphate(V) (0.26 M in dimethylacetamide, 284 μ,, 0.074 mmol, 1.2 equivalents), and 3-(3,4-dimethoxy-benzyl)- 7-methoxy-chroman-4-ylamine (Von P. Pfeiffer et al., Justus Liebigs Annalen der Chemie (1949), 564, 208-19) (0.40 M in dimethylacetamide, 232 pL, 0.093 mmol, 1.5 equivalents) were mixed in a 4 mL vial at room temperature. The reaction was deemed complete by LC and the reaction mixture was loaded directly into an injection loop and purified using preparative LC method TFA1 to provide the title compound (9.9 mg, 29% yield). 1H NMR (400 MHz, DMSO- d6 :D20 = 9: 1 (v/v)) δ 7.38 - 7.24 (m, 3H), 7.19 (dd, J= 8.3, 1.7 Hz, 1H), 6.90 (d, J= 8.7 Hz, 1H), 6.86 (d, J= 8.2 Hz, 1H), 6.73 (d, J= 2.0 Hz, 1H), 6.65 (dd, J= 8.1, 2.0 Hz, 1H), 6.48 (dd, J = 8.6, 2.6 Hz, 1H), 6.27 (d, J= 2.5 Hz, 1H), 4.80 (t, J= 8.5 Hz, 1H), 4.00 (dd, J= 11.3, 2.7 Hz, 1H), 3.74 (s, 5H), 3.67 (s, 3H), 2.68 - 2.56 (m, 1H), 2.35 - 2.19 (m, 2H), 1.48 - 1.36 (m, 2H), 1.14 - 1.07 (m, 1H), 1.03 - 0.97 (m, 1H); MS (APCI+) m/z 554.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; HATU In tetrahydrofuran at 20℃; for 3h; | 92D Example 92D tert-butyl 4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4- dihydro- 1 'H-spiro[chromene-2,4'-piperidine]- 1 '-carboxylate Example 92D tert-butyl 4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4- dihydro- 1 'H-spiro[chromene-2,4'-piperidine]- 1 '-carboxylate A mixture of the product from Example 92C (0.15 g, 0.446 mmol), 0-(7-azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.186 g, 0.490 mmol) and l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (0.108 g, 0.446 mmol) in tetrahydrofuran (2 mL) was treated with triethylamine (0.124 ml, 0.892 mmol) and stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate (30 mL), washed with 5 % aqueous citric acid (20 mL), washed with saturated NaHC03 solution (10 mL), washed with brine, dried (MgS04), filtered, concentrated, and chromatographed on silica gel eluted with a gradient of 50 % - 100 % [9:1 CH2Cl2:ethyl acetate] in heptanes, then eluted with a gradient of 0 % - 100 % ethyl acetate in [9: 1 CH2Cl2:ethyl acetate] to provide the title compound (220 mg, 0.392 mmol, 88 % yield). 1H NMR (400 MHz, CDC13) δ ppm 7.15 (dd, J= 8.2, 1.8 Hz, 1H), 7.11 (d, J= 1.7 Hz, 1H), 7.05 - 6.98 (m, 2H), 6.59 (td, J= 8.3, 2.6 Hz, 1H), 6.52 (dd, J= 10.1, 2.6 Hz, 1H), 5.33 (d, J= 8.9 Hz, 1H), 5.27 - 5.15 (m, 1H), 3.84 (s, 2H), 3.26 (t, J= 12.3 Hz, 1H), 3.12 - 2.98 (m, 1H), 2.11 (dd, J= 13.4, 6.3 Hz, 1H), 1.82 (d, J= 12.6 Hz, 1H), 1.77 - 1.48 (m, 6H), 1.46 (s, 9H), 1.16 - 1.04 (m, 2H); MS (ESI) m/z 559 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.2% | With triethylamine; HATU In tetrahydrofuran at 20℃; for 1h; | 100F Example 100F benzyl 4'-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7'-fluoro-3',4'- dihydro- 1 H-spiro [azetidine-3 ,2'-chromene] - 1 -carboxylate Example 100F benzyl 4'-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7'-fluoro-3',4'- dihydro- 1 H-spiro [azetidine-3 ,2'-chromene] - 1 -carboxylate A mixture of the product from Example 100E (86 mg, 0.251 mmol), 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (201 mg, 0.528 mmol) and l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (122 mg, 0.502 mmol) in tetrahydrofuran (2 mL) was treated with triethylamine (140 μ, 1.005 mmol), and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (30 mL), washed with 10 % aqueous citric acid (10 mL), washed with saturated NaHC03 solution (10 mL), washed with brine, dried (MgS04), filtered, concentrated and chromatographed on silica gel eluting with a gradient of 50 % - 100 % [9: 1 CH2CI2: ethyl acetate] in heptanes to provide the title compound (90 mg, 0.159 mmol, 63.2 % yield). 1H NMR (400 MHz, CDC13) δ ppm 7.40 - 7.29 (m, 5H), 7.16 - 7.07 (m, 2H), 6.97 (dd, J= 8.6, 6.2 Hz, 2H), 6.63 (td, J= 8.4, 2.6 Hz, 1H), 6.55 (dd, J= 9.8, 2.6 Hz, 1H), 5.33 - 5.27 (m, 1H), 5.20 - 5.09 (m, 3H), 4.09 - 3.95 (m, 4H), 2.41 (dd, J= 13.5, 5.7 Hz, 1H), 1.97 (dd, J= 13.5, 9.1 Hz, 1H), 1.76 - 1.65 (m, 2H), 1.15 - 1.06 (m, 2H); MS (ESI) m/z 565 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.3% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 1-(4-amino-7-methoxyspiro[chroman-2,4'-piperidin]-1'-yl)-3-hydroxy-2,2-dimethylpropan-1-one With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 107D Example 107D 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-N-[ 1 '-(3-hydroxy-2,2-dimethylpropanoyl)-7-methoxy-3,4- dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanecarboxamide Example 107D 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-N-[ 1 '-(3-hydroxy-2,2-dimethylpropanoyl)-7-methoxy-3,4- dihydrospiro[chromene-2,4'-piperidin]-4-yl]cyclopropanecarboxamide To l-(2,2-difluorobenzo[d][l ,3]dioxol-5-yl)cyclopropanecarboxylic acid (57.6 mg, 0.238 mmol) in DMF (4 mL) was added HATU (l-[bis(dimethylamino)methylene]-lH-l ,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (123 mg, 0.324 mmol). The mixture was stirred for 5 minutes at room temperature, followed by the sequential addition of Example 107C (100 mg, 0.216 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.151 ml, 0.865 mmol). The mixture was stirred at room temperature for 2 hours. LC/MS showed the reaction was complete. Purification of the reaction mixture by chromatography on 24 g silica gel cartridge, eluting with 5-50% ethyl acetate in heptane provided the title compound (35 mg, 28.3 % yield). 1H NMR (500 MHz, CDCl3) 5 7.14 (dd, J= 8.2, 1.7 Hz, 1H), 7.11 (d, J= 1.7 Hz, 1H), 7.02 (d, J= 8.2 Hz, 1H), 6.94 (d, J= 8.7 Hz, 1H), 6.49 (dd, J= 8.6, 2.6 Hz, 1H), 6.36 (d, J= 2.5 Hz, 1H), 5.35 (d, J= 8.5 Hz, 1H), 5.23 - 5.11 (m, 1H), 4.15 (d, J= 60.1 Hz, 2H), 3.75 (s, 3H), 3.50 (dd, J= 9.9, 5.6 Hz, 2H), 3.27 (d, J= 69.6 Hz, 2H), 2.56 (s, 1H), 2.12 (dd, J= 13.4, 6.3 Hz, 1H), 1.93 (dq, J= 14.2, 2.6 Hz, 1H), 1.81 - 1.49 (m, 6H), 1.26 (d, J= 1.9 Hz, 6H), 1.10 (td, J= 3.3, 1.8 Hz, 2H); MS (ESI+) m/z 573 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.5% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: methyl 3-((2R,4R)-4-amino-7-(trifluoromethyl)chroman-2-yl)benzoate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 108E Example 108E methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- (trifluoromethyl)chroman-2-yl)benzoate Example 108E methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- (trifluoromethyl)chroman-2-yl)benzoate A mixture of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (76 mg, 0.313 mmol) and HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate) (162 mg, 0.427 mmol) in DMF (4 mL) was stirred for 5 minutes at room temperature, followed by the sequential addition of Example 108D (150 mg, 0.48 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.198 mL, 1.14 mmol). The mixture was stirred at ambient temperature for 2 hours. LC/MS indicated the reaction was complete. Purification by chromatography on 12 g silica gel cartridge, eluting with 5-40 % ethyl acetate in heptane to provide the title compound (45 mg, 27.5 % yield). 1H NMR (400 MHz, CDC13) δ 8.07 (t, J= 1.9 Hz, 1H), 8.05 - 7.99 (m, 1H), 7.59 (dt, J= 7.7, 1.6 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.21 - 7.15 (m, 3H), 7.14 - 7.08 (m, 2H), 7.03 (d, J= 8.2 Hz, 1H), 5.60 - 5.48 (m, 1H), 5.40 (d, J= 9.0 Hz, 1H), 5.28 (dd, J= 11.5, 2.0 Hz, 1H), 3.94 (s, 3H), 3.69 - 3.63 (m, 1H), 2.53 (ddd, J = 13.5, 6.2, 2.1 Hz, 1H), 1.89 - 1.79 (m, 2H), 1.12 (td, J= 6.6, 3.2 Hz, 2H); MS (ESI-) m/z 574 (M-H)~ |
27.5% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: methyl 3-((2R,4R)-4-amino-7-(trifluoromethyl)chroman-2-yl)benzoate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.1% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: methyl 3-((2R,4R)-4-amino-7-(trifluoromethyl)chroman-2-yl)cyclohexanecarboxylate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 109A Example 109A methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- (trifluoromethyl)chroman-2-yl)cyclohexanecarboxylate Example 109A methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- (trifluoromethyl)chroman-2-yl)cyclohexanecarboxylate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (52.2 mg, 0.215 mmol) in DMF (1 mL) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (112 mg, 0.294 mmol). The mixture was stirred for 5 minutes at room temperature, followed by sequential addition of methyl 3-((2R,4R)- 4-amino-7-(trifluoromethyl)chroman-2-yl)cyclohexanecarboxylate (70 mg, 0.196 mmol) and N- ethyl-N-isopropylpropan-2-amine (0.136 ml, 0.784 mmol). The mixture was stirred at ambient temperature for 2 hours. LC/MS showed the reaction was complete. Purification by chromatography on 12g silica gel cartridge, eluting with 5-40 % ethyl acetate in heptane provided the title compound (40 mg, 0.069 mmol, 35.1 % yield). MS (ESI+) m/z 581.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: methyl 4-((2R,4R)-4-amino-7-methoxychroman-2-yl)benzoate With triethylamine In N,N-dimethyl-formamide at 20℃; for 5h; | 110D Example HOD methyl 4-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate Example HOD methyl 4-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]benzoate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (83 mg, 0.345 mmol) in DMF (1 mL) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (183 mg, 0.483 mmol). The solution was stirred for 15 minutes at room temperature, followed by sequential addition of Example 1 IOC (108 mg, 0.345 mmol) and triethylamine (0.144 mL, 1.034 mmol). The mixture was stirred at ambient temperature for 5 hours and water (10 mL) was added. The resulted white precipitate was filtered and purified by flash chromatography on a 12 g cartridge, eluted with 5-60 % ethyl acetate/heptane over 20 minutes to provide the title compound (126 mg, 0.234 mmol, 68.0 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.94 (m, 2H), 7.58 - 7.52 (m, 2H), 7.37 (d, J = 1.7 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.18 (dd, J = 8.4, 1.7 Hz, 1H), 7.15 (d, J = 8.9 Hz, 1H), 6.93 (dd, J = 8.5, 1.1 Hz, 1H), 6.51 (dd, J = 8.6, 2.6 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 5.33 (q, J = 9.5, 8.4 Hz, 2H), 3.84 (s, 3H), 3.67 (s, 3H), 2.11 - 1.99 (m, 2H), 1.54 - 1.41 (m, 1H), 1.41 - 1.29 (m, 1H), 1.07 - 0.96 (m, 2H); MS (ESI-) m/z 536 (M-H)". |
68% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: methyl 4-((2R,4R)-4-amino-7-methoxychroman-2-yl)benzoate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: methyl 4-[(2R,4R)-4-amino-3,4-dihydro-2H-1-benzopyran-2-yl]benzoate hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 120D Example 120D Methyl 4-((2i?,4i?)-4-(l-(2,2-difiuorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarboxamido)chroman-2-yl)benzoate Example 120D Methyl 4-((2i?,4i?)-4-(l-(2,2-difiuorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarboxamido)chroman-2-yl)benzoate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (300 mg, 1.239 mmol) in DMF (2 mL) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 642 mg, 1.689 mmol). The mixture was stirred for 5 minutes at room temperature, followed by the addition of Example 120C (319 mg, 1.0 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.785 mL, 4.50 mmol). The mixture was stirred at room temperature for 2 hours, LC/MS showed the conversion was complete. The reaction mixture was directly loaded on a 50 g silica gel cartridge, eluting with 5-50%, ethyl acetate in heptane to provide the title compound (320 mg, 56.0 % yield). 1H NMR (400 MHz, CDC13) δ 8.07 - 8.02 (m, 2H), 7.50 - 7.44 (m, 2H), 7.21 - 7.15 (m, 1H), 7.14 - 7.05 (m, 3H), 7.00 (d, J = 8.2 Hz, 1H), 6.96 - 6.87 (m, 2H), 5.53 - 5.44 (m, 1H), 5.38 (d, J = 8.8 Hz, 1H), 5.24 (dd, J = 11.3, 1.9 Hz, 1H), 3.93 (s, 3H), 2.52 (ddd, J = 13.3, 6.1, 2.1 Hz, 1H), 1.84 - 1.72 (m, 2H), 1.26 (s, 1H), 1.08 (td, J = 3.5, 2.1 Hz, 2H); MS (ESI-) m/z = 506.1(M-H) · |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.3% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate trifluororoacetic acid salt With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 123D Example 123D methyl 4-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- hydroxychroman-2-yl)benzoate Example 123D methyl 4-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- hydroxychroman-2-yl)benzoate A mixture of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (162 mg, 0.668 mmol) and HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 380 mg, 1.0 mmol) in DMF (2 mL) was stirred for 5 minutes at room temperature, followed by the addition of Example 123C (200 mg, 0.334 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.466 ml, 2.67 mmol). The mixture was stirred at room temperature for 2 hours, LC/MS showed reaction complete. The mixture was loaded on to a 25 g silica gel cartridge eluting with 5-50% ethyl acetate in heptane provide the title compound (204 mg, 58.3 % yield). 1H NMR (400 MHz, CDC13) 5 8.11 - 7.90 (m, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.16 - 7.02 (m, 2H), 6.94 (dd, J = 37.7, 8.3 Hz, 2H), 6.49 - 6.32 (m, 2H), 5.67 (s, 1H), 5.36 (dt, J = 15.3, 8.7 Hz, 2H), 5.18 (d, J = 10.7 Hz, 1H), 3.93 (s, 3H), 2.56 - 2.36 (m, 1H), 1.80 - 1.70 (m, 2H), 1.26 (d, J = 2.2 Hz, 1H), 1.10 - 1.04 (m, 2H); MS (ESI-) m/z = 521.9 (M-H)". |
58.3% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate trifluororoacetic acid salt With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.4% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 4-amino-2,2-dimethylchroman-7-ol hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 124C Example 124C l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide Example 124C l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-(7-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-4- yl)cyclopropanecarboxamide To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (CAS 68015- 98-5) (485 mg, 2.0 mmol) in N,N-dimethylformamide (4 mL) was added HATU (1- [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate) (1142 mg, 3.00 mmol). The mixture was stirred at room temperature for 5 minutes, and Example 124B was added, followed by addition of N-ethyl-N-isopropylpropan-2- amine (1.395 mL, 8.01 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was purification by chromatography, eluting with a gradient of 0-50 % ethyl acetate in heptane, to yield the title compound (505 mg, 1.210 mmol, 60.4 % yield). 1H NMR (400 MHz, CDC13) δ 7.20 - 7.07 (m, 2H), 7.01 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.5, 1.0 Hz, 1H), 6.36 (dd, J = 8.4, 2.5 Hz, 1H), 6.23 (d, J = 2.6 Hz, 1H), 5.41 - 5.25 (m, 2H), 5.23 - 5.08 (m, 1H), 2.11 (dd, J = 13.2, 6.2 Hz, 1H), 1.76 - 1.63 (m, 2H), 1.50 (dd, J = 13.2, 10.5 Hz, 1H), 1.32 (s, 3H), 1.26 (s, 3H), 1.09 (td, J = 3.2, 1.5 Hz, 2H); MS (ESI+) m/z 417.7 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; HATU In tetrahydrofuran at 20℃; Inert atmosphere; | 126G Example 126G l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[7-methoxy-2-(tetrahydrofuran-2-yl)-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide Example 126G l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[7-methoxy-2-(tetrahydrofuran-2-yl)-3,4-dihydro-2H- chromen-4-yl]cyclopropanecarboxamide A mixture of the product from Example 126F (50.7 mg, 0.177 mmol), l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (55.9 mg, 0.231 mmol) and HATU ( 1 - [bis(dimethylamino)methy lene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate) (101 mg, 0.266 mmol) in tetrahydrofuran (2 mL) under N2 was treated with triethylamine (99 μ, 0.710 mmol) and stirred overnight at room temperature. The mixture was partitioned between methyl tert-butyl ether (30 mL) and 10 % citric acid (15 mL). The layers were separated and the methyl tert-butyl ether layer was washed with saturated NaHC03 solution (about 15 mL), washed with brine, dried (MgS04), filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with a gradient of 50-100 % [9: 1 CH2Cl2:ethyl acetate] in heptane to provide the title compound (67.9 mg, 0.143 mmol, 81 % yield). 1H NMR (400 MHz, CDC13) δ 7.18 - 7.07 (m, 2H), 7.05 - 6.98 (m, 1.5H), 6.93 (d, J= 8.7 Hz, 0.5H), 6.50 - 6.43 (m, 1.5H), 6.40 (d, J= 2.4 Hz, 0.5H), 5.70 (d, J= 8.9 Hz, 0.5H), 5.46 (d, J= 6.8 Hz, 0.5H), 5.31 - 5.22 (m, 0.5H), 5.03 - 4.95 (m, 0.5H), 4.10 - 3.83 (m, 2H), 3.82 - 3.65 (m, 4H), 2.29 (ddd, J= 13.2, 6.2, 2.3 Hz, 0.5H), 2.10 - 1.83 (m, 4.5H), 1.77 - 1.57 (m, 3H), 1.15 - 1.00 (m, 2H); MS (ESI-) m/z 472 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: methyl 4-amino-7-methoxyspiro[chroman-2,1'-cyclobutane]-3'-carboxylate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 129D Example 129D methyl 4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- methoxyspiro[chroman-2, 1 '-cyclobutane]-3'-carboxylate Example 129D methyl 4-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-7- methoxyspiro[chroman-2, 1 '-cyclobutane]-3'-carboxylate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (34.9 mg, 0.144 mmol) in N,N-dimethylformamide (4 mL) was added HATU (1- [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate) (82 mg, 0.216 mmol). The mixture was stirred for 5 minutes, and then Example 129C (40 mg, 0.144 mmol) was added, following by addition of N-ethyl-N- isopropylpropan-2-amine (0.100 mL, 0.577 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was purified by chromatography, eluting with 0-50% ethyl acetate in heptane to provide the title compound (60 mg, 83 % yield). 1H NMR (400 MHz, CDC13) δ 7.18 - 7.07 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.94 (dd, J = 8.6, 0.9 Hz, 1H), 6.46 (dd, J = 8.6, 2.6 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 5.32 (d, J = 8.5 Hz, 1H), 5.17 - 5.05 (m, 1H), 3.73 (d, J = 9.6 Hz, 6H), 3.29 (tt, J = 9.3, 7.7 Hz, 1H), 2.47 - 2.32 (m, 4H), 2.26 (dd, J = 13.3, 5.8 Hz, 1H), 1.79 (dd, J = 13.4, 8.4 Hz, 1H), 1.69 (t, J = 3.6 Hz, 2H), 1.12 - 1.05 (m, 2H); MS(ESI-) m/z 500.2 (M-H)~. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 7-methoxy-4-(methoxyimino)chroman-2-carboxylate With hydrogen In methanol; water at 20℃; for 4h; Stage #2: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere; | 130E; 131 Example 130E ethyl rac-(2R,4S)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-chromene-2-carboxylate Example 130E ethyl rac-(2R,4S)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methoxy-3,4-dihydro-2H-chromene-2-carboxylate A mixture of the product from Example 130D (650 mg, 2.59 mmol), l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (689 mg, 2.85 mmol) and HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (1475 mg, 3.88 mmol) in N,N-dimethylformamide (20 mL) under N2 was treated with triethylamine (1082 μ^, 7.76 mmol) and stirred at room temperature for 90 minutes. The mixture was partitioned between methyl tert-butyl ether (30 mL) and 1 M HC1 (15 mL). The layers were separated and the ethyl acetate layer was washed sequentially with saturated NaHC03 solution (10 mL) and brine, dried (MgS04), filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with a gradient of 10 to 100 % ethyl acetate in heptane to provide the title compound as the first eluting product. This product was further purified by chromatography on silica gel eluting with a gradient of 25-100 % [9: 1 CH2Cl2:ethyl acetate] in heptanes. 1H NMR (400 MHz, CDC13) δ 7.13 (dd, J= 8.2, 1.7 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.00 (d, J= 8.1 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.50 (dd, J= 8.4, 2.5 Hz, 1H), 6.48 (d, J= 2.5 Hz, 1H), 5.42 (d, J= 6.9 Hz, 1H), 5.02 - 4.96 (m, 1H), 4.44 (dd, J= 9.2, 3.5 Hz, 1H), 4.29 (q, J= 7.1 Hz, 2H), 3.75 (s, 3H), 2.31 - 2.18 (m, 2H), 1.74 - 1.65 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H), 1.12 - 1.04 (m, 2H); MS (ESI-) m/z 474 (M-H)~. Example 131 methyl rac-(2i?,45)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-chromene-2-carboxylate The title compound was isolated as the second eluting isomer from the first chromatography as described in Example 130E. This product was further purified by chromatography on silica gel eluting with a gradient of 25-100 % [9: 1 CH2C12: ethyl acetate] in heptanes.1H NMR (400 MHz, CDC13) δ 7.15 (dd, J= 8.2, 1.6 Hz, 1H), 7.12 (d, J= 1.6 Hz, 1H), 7.02 (d, J= 8.2 Hz, 1H), 6.98 (d, J= 8.5 Hz, 1H), 6.52 (dd, J= 8.5, 2.5 Hz, 1H), 6.49 (d, J= 2.5 Hz, 1H), 5.44 (d, J= 6.8 Hz, 1H), 5.02 - 4.96 (m, 1H), 4.48 (dd, J = 9.7, 3.1 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.36 - 2.29 (m, 1H), 2.22 (ddd, J= 14.2, 9.7, 4.8 Hz, 1H), 1.71 (tq, J= 7.3, 4.2 Hz, 2H), 1.09 (p, J = 6.1, 5.6 Hz, 2H); MS (ESI-) m/z 460 (M-H)". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.2% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: methyl 4-((2R,4R)-4-amino-7-methoxychroman-2-yl)-2-fluorobenzoate hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 137D Example 137D methyl 4-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoate Example 137D methyl 4-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methoxy-3,4-dihydro-2H-chromen-2-yl]-2-fluorobenzoate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (87 mg, 0.359 mmol) in N,N-dimethylformamide (4 mL) was added HATU (1- [bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate) (186 mg, 0.489 mmol). The mixture was stirred for 5 minutes, and then Example 137C (120 mg, 0.326 mmol) was added, followed by the addition of N-ethyl-N- isopropylpropan-2-amine (0.227 mL, 1.305 mmol). The mixture was stirred at room temperature for 2 hours. Purification by chromatography on silica gel and eluting with a gradient of 5-40% ethyl acetate in heptane provided the title compound (120 mg, 66.2 % yield). 1H NMR (400 MHz, CDCls) δ 7.94 (t, J = 7.7 Hz, 1H), 7.24 - 7.17 (m, 2H), 7.12 - 7.03 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.52 (dd, J = 8.7, 2.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 5.38 (td, J = 10.0, 9.5, 5.8 Hz, 1H), 5.30 (d, J = 8.6 Hz, 1H), 5.19 (dd, J = 11.1, 2.0 Hz, 1H), 3.94 (s, 3H), 3.76 (s, 3H), 2.51 (ddd, J = 13.4, 6.1, 2.2 Hz, 1H), 1.79 - 1.70 (m, 2H), 1.29 - 1.23 (m, 1H), 1.07 (d, J = 3.8 Hz, 2H); MS(ESI-) m/z 554 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.8% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: methyl rac-3-((2R,4R)-4-amino-7-methoxychroman-2-yl)bicyclo[1.1.1]pentane-1-carboxylate hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 147D Example 147D methyl rac-3-[(2R,4R)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 7-methoxy-3 ,4-dihydro-2H-chromen-2-yl]bicyclo [1.1.1 Jpentane- 1 -carboxylate Example 147D methyl rac-3-[(2R,4R)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)- 7-methoxy-3 ,4-dihydro-2H-chromen-2-yl]bicyclo [1.1.1 Jpentane- 1 -carboxylate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (78 mg, 0.324 mmol) in N,N-dimethylformamide (2 mL) was added HATU (l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (168 mg, 0.441 mmol). The mixture was stirred at room temperature for 5 minutes, followed by addition of Example 147C (100 mg, 0.294 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.177 mmol). The mixture was stirred at room temperature for 2 hours. Purification by chromatography, eluting with 0-40% ethyl acetate in heptane to provide the title compound (68 mg, 43.8 %). 1H NMR (500 MHz, CDCls) δ 7.19 - 7.12 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.86 (dd, J = 8.5, 1.0 Hz, 1H), 6.44 (dd, J = 8.6, 2.6 Hz, 1H), 6.32 (d, J = 2.6 Hz, 1H), 5.32 (d, J = 8.8 Hz, 1H), 5.26 - 5.17 (m, 1H), 4.07 (dd, J = 11.9, 1.6 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 2.21 (ddd, J = 13.0, 6.2, 1.8 Hz, 1H), 2.08 - 1.99 (m, 6H), 1.97 - 1.84 (m, 1H), 1.74 (ddd, J = 9.0, 5.4, 2.2 Hz, 1H), 1.69 - 1.63 (m, 1H), 1.08 (tdd, J = 9.6, 6.2, 3.0 Hz, 2H); MS(ESI-) m/z 526 (M-H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 22.3% 2: 16.27% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; Stage #2: methyl 3-((2R)-4-amino-6-methylchroman-2-yl)benzoate hydrochloride With pyridine In dichloromethane at 20℃; for 2h; | 11D; 12 Example 11D methyl 3-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate Example 11D methyl 3-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (332 mg, 1.372 mmol) in CH2C12 (6 mL) was added a few drops of DMF, followed by the drop wise addition of oxalyl dichloride (0.290 ml, 3.43 mmol). The mixture was stirred at room temperature for 30 minutes. LC/MS with methanol as solvent showed a completed methyl ester's peak. Solvent was removed in vacuo, excess oxalyl chloride removed via azeotrope with dichloroethane, and the crude material in CH2C12 (4 mL) was added to the product from Example 11C (340 mg, 1.143 mmol) and pyridine (543 mg, 6.86 mmol) in CH2C12 (6 mL). The mixture was stirred at room temperature for 2 hours and saturated NaHC03 aqueous solution and CH2C12 was added. The phases were separated and the aqueous layer was extracted with CH2C12. The combined organics were dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the residue by chromatography using a 40 g silica gel cartridge, and eluting with 0-30 % ethyl acetate in hexane provide Example 12 as the first eluting isomer, and the title compound as the second eluting isomer (133 mg, 0.255 mmol, 22.30 % yield). 1H NMR (400 MHz, CDC13) δ 8.07 (t, J= 1.7 Hz, 1H), 7.99 (dt, J= 8.0, 1.4 Hz, 1H), 7.58 (dt, J= 7.8, 1.4 Hz, 1H), 7.44 (t, J= 7.7 Hz, 1H), 7.18 - 7.06 (m, 2H), 7.05 - 6.92 (m, 2H), 6.88 - 6.72 (m, 2H), 5.53 - 5.29 (m, 2H), 5.19 (dd, J= 11.5, 1.9 Hz, 1H), 3.92 (s, 3H), 2.53 (ddd, J= 13.4, 5.9, 2.0 Hz, 1H), 2.26 (s, 3H), 1.86 - 1.67 (m, 2H), 1.61 (d, J= 16.1 Hz, 1H), 1.17 - 1.00 (m, 2H); MS (ESI+) m/z 522 (M+H)+. Example 12 methyl 3-[(2i?,45)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-6- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate The title compound was isolated as the first eluting isomer from the chromatography as described in Example 1 ID (97 mg, 16.27 % yield). 1H NMR (400 MHz, CDC13) δ 8.05 (t, J = 1.7 Hz, 1H), 8.00 (d, J= 7.7 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.05 - 6.99 (m, 2H), 6.93 (d, J= 2.2 Hz, 1H), 6.81 (d, J= 8.3 Hz, 1H), 5.62 (d, J= 6.9 Hz, 1H), 5.01 (ddd, J= 7.1, 4.6, 2.8 Hz, 1H), 4.80 (dd, J= 11.2, 2.3 Hz, 1H), 3.94 (s, 3H), 2.34 - 2.23 (m, 4H), 2.17 (ddd, J= 14.4, 11.1, 4.7 Hz, 1H), 1.74 - 1.64 (m, 2H), 1.13 - 1.04 (m, 2H); MS (ESI+) m/z 522 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.56 g | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With iron(III) chloride; N-Bromosuccinimide In acetonitrile at 20℃; for 16h; Stage #2: diazomethyl-trimethyl-silane In tetrahydrofuran; methanol; diethyl ether | 202C Example 202C methyl 1 -(6-bromo-2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl)cyclopropanecarboxylate Example 202C methyl 1 -(6-bromo-2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl)cyclopropanecarboxylate l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (2 g, 8.26 mmol) was suspended in acetonitrile (16.52 mL) and N-bromosuccinimide (1.911 g, 10.74 mmol) was added, followed by iron (III) chloride (0.670 g, 4.13 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water, saturated sodium thiosulfate, and brine then dried over sodium sulfate then concentrated to give a dark crude oil. The crude material was dissolved in a 2: 1 mixture of tetrahydrofuran and methanol (20 mL total) and TMS-diazomethane (2M in diethyl ether, 5.37 mL, 10.74 mmol) was added drop wise. After the addition was complete, TLC indicated that complete conversion to the methyl ester had occurred. The solvent was removed in vacuo and the resulting crude residue was purified by flash column chromatography, eluting with 0-10% ethyl acetate/heptanes over 20 minutes on a 40 g silica gel column to give 1.56 g of the title compound as a colorless oil. 1H NMR (400 MHz, CDC13) δ 7.29 (s, 1H), 7.04 (s, 1H), 3.64 (s, 3H), 1.78 (m, 2H), 1.21 - 1.09 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 36.6% 2: 26.5% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: methyl 3-((2R)-4-amino-7-methylchroman-2-yl)benzoate monohydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 18E; 17 Example 18E methyl 3-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate Example 18E methyl 3-[(2i?,4i?)-4-([l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (559 mg, 2.3 mmol) in DMF (5 ml) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate ,1196 mg, 3.15 mmol). The mixture was stirred for 10 minutes at room temperature, followed by addition of the product from Example 18D (700 mg, 2.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.461 ml, 8.39 mmol) sequentially. The mixture was stirred at room temperature for 2 hours. LC/MS indicated the reaction was complete. Dichloromethane (40 mL) was added and the solution was washed with brine (20 mL x 2). The organic layer was dried over MgSC^ and concentrated under reduced pressure. The resulting residue was purified by chromatography on a 40 g silica gel cartridge, eluting with a gradient of 0-25 % ethyl acetate in heptane to provide Example 17 as the first eluting isomer and the title compound as the second eluting isomer (400 mg, 36.6 % yield). 1H NMR (400 MHz, CDC13) δ 8.07 (d, J= 1.9 Hz, 1H), 7.99 (dt, J= 7.9, 1.4 Hz, 1H), 7.58 (dt, J = 7.8, 1.5 Hz, 1H), 7.44 (t, J= 7.7 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.97 (dd, J= 21.0, 8.0 Hz, 2H), 6.74 (d, J= 9.5 Hz, 2H), 5.49 - 5.39 (m, 1H), 5.36 (d, J= 8.7 Hz, 1H), 5.20 (dd, J= 11.3, 1.9 Hz, 1H), 3.92 (s, 3H), 2.51 (ddd, J= 13.2, 6.0, 2.0 Hz, 1H), 2.28 (s, 3H), 1.67 - 1.59 (m, 1H), 1.57 (d, J = 1.1 Hz, 2H), 1.07 (td, J= 3.6, 2.2 Hz, 2H); MS (ESI+) m/z 522(M+H)+. Example 17 methyl 3-[(2i?,45)-4-( [ 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)cyclopropyl]carbonyl} amino)-7- methyl-3,4-dihydro-2H-chromen-2-yl]benzoate The title compound (290 mg, 26.5 % yield) was isolated as the first eluting isomer from the separation of the isomers as described in Example 18E. 1H NMR (400 MHz, CDC13) δ 8.05 (t, J= 1.8 Hz, 1H), 8.01 (dt, J= 7.7, 1.5 Hz, 1H), 7.58 (dt, J= 7.5, 1.4 Hz, 1H), 7.47 (t, J= 7.7 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.03 (dd, J= 8.2, 1.7 Hz, 2H), 6.75 (dd, J= 6.2, 1.9 Hz, 2H), 5.61 (d, J= 6.8 Hz, 1H), 5.01 (dt, J= 7.1, 3.3 Hz, 1H), 4.81 (dd, J= 11.3, 2.3 Hz, 1H), 3.94 (s, 3H), 2.34 - 2.29 (m, 1H), 2.29 (s, 3H), 2.16 (ddd, J= 14.2, 11.3, 4.6 Hz, 1H), 1.73 - 1.65 (m, 2H), 1.11 - 1.03 (m, 2H). ); MS (ESI+) m/z 522 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.5% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide for 0.0833333h; Stage #2: (2R,4R)-4-amino-2-(3-methoxyphenyl)chroman-7-ol hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 20D Example 20D l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-hydroxy-2-(3-methoxyphenyl)-3,4-dihydro- 2H-chromen-4-yl]cyclopropanecarboxamide Example 20D l-(2,2-difluoro-l,3-benzodioxol-5-yl)-N-[(2i?,4i?)-7-hydroxy-2-(3-methoxyphenyl)-3,4-dihydro- 2H-chromen-4-yl]cyclopropanecarboxamide To l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.165 mmol) in DMF (1 mL) was added HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (82 mg, 0.215 mmol). The mixture was stirred for 5 minutes, and the product from Example 20C (50.8 mg, 0.165 mmol) was added, followed by addition of N-ethyl-N-isopropylpropan-2-amine (0.115 mL, 0.661 mmol). The mixture was stirred at ambient temperature for 2 hours, then purified by chromatography on a 25 g silica gel, eluting with a gradient of 5-50 % ethyl acetatein heptanes to provide the title compound (25 mg, 0.050 mmol, 30.5 % yield). 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.38 (d, J= 1.6 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.19 (dd, J= 8.3, 1.7 Hz, 1H), 7.07 (d, J= 8.9 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.88 (dd, J= 8.1, 2.6 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.34 (dd, J= 8.3, 2.4 Hz, 1H), 6.18 (d, J= 2.4 Hz, 1H), 5.27 (td, J= 9.9, 6.8 Hz, 1H), 5.16 (dd, J= 10.8, 2.7 Hz, 1H), 3.75 (s, 3H), 2.09 - 1.95 (m, 2H), 1.49 (ddd, J= 9.0, 5.4, 2.2 Hz, 1H), 1.41 - 1.30 (m, 1H), 1.10 - 0.98 (m, 2H); MS (ESI-) m/z 494 (M-H)". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.9% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: methyl 3-((2R,4R)-4-amino-6-methoxychroman-2-yl)benzoate monohydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; | 21D Example 2 ID methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d] [1,3] dioxol-5-yl)cyclopropanecarboxamido)-6- methoxychroman-2-yl)benzoate Example 2 ID methyl 3-((2i?,4i?)-4-(l-(2,2-difluorobenzo[d] [1,3] dioxol-5-yl)cyclopropanecarboxamido)-6- methoxychroman-2-yl)benzoate The mixture of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (779 mg, 3.22 mmol) and HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (1427 mg, 3.75 mmol) in DMF (4 mL) was stirred for 10 minutes at room temperature, and the product from Example 21B (840 mg, 2.68 mmol) was added, followed by the addition of N-ethyl-N-isopropylpropan-2-amine (1.868 mL, 10.72 mmol). The mixture was stirred at ambient temperature for 2 hours. LC/MS indicated the reaction was complete. Purification of the mixture by chromatography on 80 g silica gel cartridge, eluting with a gradient of 5-40 % ethyl acetate in heptane provided the title compound (835 mg, 57.9 % yield). 1H NMR (400 MHz, CDC13) δ 8.07 (t, J= 1.8 Hz, 1H), 7.99 (dt, J= 7.9, 1.5 Hz, 1H), 7.59 (d, J= 7.7 Hz, 1H), 7.44 (t, J= 7.8 Hz, 1H), 7.15 - 7.10 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.83 (d, J= 9.0 Hz, 1H), 6.75 (dd, J= 8.9, 3.0 Hz, 1H), 6.59 (d, J= 2.9 Hz, 1H), 5.49 - 5.33 (m, 2H), 5.20 - 5.13 (m, 1H), 3.92 (s, 3H), 3.74 (s, 3H), 2.52 (ddd, J= 13.4, 5.9, 1.9 Hz, 1H), 1.84 - 1.72 (m, 2H), 1.66 - 1.61 (m, 1H), 1.11 - 1.06 (m, 2H); MS (ESI+) m/z 537.9 (M+H)+. |
57.9% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: methyl 3-((2R,4R)-4-amino-6-methoxychroman-2-yl)benzoate monohydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.8% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; Stage #2: 7-methoxy-2-(pyridin-3-yl)chroman-4-amine hydrochloride With triethylamine In dichloromethane at 20℃; for 0.333333h; | 22E Example 22E rac-l-(2,2-difiuoro-l,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(pyridin-3-yl)-3,4-dihydro- 2H-chromen-4-yl]cyclopropanecarboxamide Example 22E rac-l-(2,2-difiuoro-l,3-benzodioxol-5-yl)-N-[(2i?,45)-7-methoxy-2-(pyridin-3-yl)-3,4-dihydro- 2H-chromen-4-yl]cyclopropanecarboxamide To a solution of l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid (45.5 mg, 0.188 mmol) in dichloromethane (1 mL) was added half of a solution of oxalyl dichloride (0.060 mL, 0.683 mmol) in 1 mL of dichloromethane followed by 1 drop of DMF. The reaction bubbled vigorously, then the remainder of the oxalyl chloride solution was added dropwise. The reaction was stirred for 30 minutes at room temperature. The solvent was removed under a stream of nitrogen, then chased with 2 x 1 mL of dichloromethane, drying under a stream of nitrogen. This reagent was taken up in dichloromethane (1 mL) and added to a mixture of the product from Example 22D (50 mg, 0.171 mmol) and triethylamine (0.095 mL, 0.683 mmol) in dichloromethane (1 mL). After 20 minutes of stirring at room temperature, the mixture was quenched with saturated aqueous sodium bicarbonate. The aqueous layer was removed and the organic phase concentrated. The resulting oil was dissolved in dichloromethane and purified on a 12 g silica gel cartridge, eluting with a gradient of 5-100 % ethyl acetate/heptanes in 16 minutes to provide the crude product (71 mg) as an oil. The crude product was loaded onto a 2 X 0.25 mm plates and eluted with 100% ethyl acetate. The desired fractions were collected and concentrated to give l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(7-methoxy- 2- (pyridin-3-yl)chroman-4-yl)cyclopropanecarboxamide (45 mg, 0.094 mmol, 54.8 % yield) as a pale foam. This material was further purified via preparative supercritical fluid chromatography set to maintain a back pressure at 100 bar using a CHIRALPAK OD-H, 21 x 250 mm, 5 micron, with the sample at a concentration of 10 mg/rnL in methanol using 16 % methanol in C02 at a flow rate of 70 mL/minute to provide the title compound (retention time = 3.8 minutes 18 mg, 0.037 mmol, 21.94 % yield) and Example 57 (retention time = 5.1 minutes). 1H NMR (400 MHz, DMSO-de) δ 8.57 (d, J = 2.2 Hz, 1H), 8.55 (dd, J = 4.7, 1.5 Hz, 1H), 7.77 (dt, J = 8.0, 1.9 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.43 (dd, J = 5.5, 3.1 Hz, 2H), 7.32 (d, J = 8.3 Hz, 1H), 7.21 (dd, J = 8.4, 1.7 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.52 (dd, J = 8.5, 2.5 Hz, 1H), 6.46 (d, J = 2.5 Hz, 1H), 5.30 (dd, J = 9.5, 2.7 Hz, 1H), 4.88 (dt, J = 8.6, 4.7 Hz, 1H), 3.70 (s, 3H), 2.20 (ddd, J = 14.4, 9.7, 4.9 Hz, 1H), 2.10 (dt, J = 14.1, 3.6 Hz, 1H), 1.40 (td, J = 12.8, 9.4 Hz, 2H), 1.04 (d, J = 2.9 Hz, 2H); MS (ESI+) m/z 481 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.3% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With N,N-dimethyl-formamide In toluene for 0.25h; Stage #2: With thionyl chloride In toluene at 60 - 65℃; Stage #3: With ammonia In water; toluene at 10 - 30℃; for 2h; | 1 Example 1:Preparation of 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acidamide A mixture of 10 g of 1 -(2-2-difluoro-benzo[ 1,3] dioxol-5-yl)-cyclopropanecarboxylic acid50 ml toluene, and 0.1 ml dimethylformamide (DMF) was stined for 15 mm. To thereaction mixture was added 6.4 g of thionyl chloride, then the reaction mixture washeated to 60-65 °C and maintained for 2-3 hours. After completion of reaction, thesolvent was completely distilled off under vacuum. Toluene (15 ml) was added and distilled out completely under vacuum. To the residue, 25 ml toluene was added at room temperature. To the reaction mass, aqueous ammonia solution (40 mL) was slowly added at 10-15 °C and maintained for 2 hours at 25-30 °C. After completion of reaction, 20 mlof water was added to the reaction mixture, and the reaction mixture was then stined for 15 mm. The layers were separated, the aqueous layer was extracted with 40 ml toluene. The combined toluene layer was washed with water. The remaining solvent was completely removed under vacuum at 50-5 5 °C. The resulting residue was triturated with acetone and hexane mixture (10 mL) for 1 hour. The obtained solid was filtered andwashed with hexane (5 ml). The wet material was dried under vacuum to afford 1-(2-2- difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid amide (6.0 g , 60.3 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.94% | Example 30A N-(3,6-dichloropyridazin-4-yl)-1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carboxamide To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (2.0453 g, 8.45 mmol) in N,N-dimethylformamide (10.56 mL) was added N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU, 3.700 g, 9.73 mmol). The mixture was stirred for 5 minutes, and then Example 24A (1.429 g, 8.71 mmol) was added, followed by dropwise addition of triethylamine (4.71 mL, 33.8 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) and diluted with 400 mL of tert-butyl methyl ether. The aqueous layer was removed, and the organic fraction was washed with water (50 mL) and brine (50 mL), and dried over sodium sulfate. The reaction solution was adsorbed onto silica gel (5 g) and purified using a 150 g silica gel cartridge eluted with a gradient of 5-100% ethyl acetate/heptanes to give the title compound (0.752 g, 1.937 mmol, 22.94% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.34 (s, 1H), 8.29 (s, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.4, 1.8 Hz, 1H), 1.60 (q, J=4.1 Hz, 2H), 1.36 (q, J=4.1 Hz, 2H); MS (ESI+) m/z 389 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | To a solution of 1 -(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (5g) in toluene (5OmL) and dimethylformamide (1 .25mL) was slowly added thionyl chloride(3.63mL) and the reaction mixture was stirred for about 3h at about 80C. The reaction mixture was concentrated under reduced pressure at about 50C. To the obtained residue in dichloromethane (lOmL) were added <strong>[89466-17-1]6-amino-2-bromo-3-methylpyridine</strong> (3.86g) in dichloromethane (SOmL) and pyridine (SmL) at about room temperature. The reaction mixture was maintained for about 3h at about room temperature and water was added toit. The two layers were separated and the organic layer was treated with 10% hydrochloric acid solution and then with sodium bicarbonate solution. The organic layer was washed with water and brine solution, treated with charcoal, filtered, concentrated under reduced pressure at about 50C and was co-distilled with hexane. Hexane was added to the obtained residue and the mixture was stirred for about 6h. The solid obtainedwas filtered and dried at about 60C for about 8h. Yield: 65.3g (76%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | With sodium hydroxide at 85℃; for 2h; | 7 Example 7: Synthesis of Compound 1 Compound 2a (3.3 g, 0.013 mol) was added to a 100 ml three-necked bottle,20ml 5% NaOH solution,Heat to 85°C and react for 2h. After the reaction is complete, adjust the pH = 7, add 30ml of ethyl acetate,It was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give 3.0 g of compound 1 in a yield of 95.2%. |
87.3% | With methanol; sodium hydroxide at 20℃; for 20h; | 4 Example 4: Compound 2a (3.00 g, 1 eq) was added to the reaction kettle,Methanol (25 ml) was added and NaOH was added with stirring at room temperature(1.76 g, 4 equiv), stirred for 20 hours,Evaporated to dryness, diluted with water (50 ml)Dichloromethane (50 ml * 2) was added,The aqueous phase was added to concentrated hydrochloric acid to a pH of about 5,Precipitation of solid filtration,The cake was dried to give 2.47 g of a white solid (yield 87.3%). |
Yield | Reaction Conditions | Operation in experiment |
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69.4 g | To a mixture of 1 -(2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)cyclopropane carboxylic acid (50 g) in toluene (500 mL) at 26C, Thionyl chloride (31 .9 g) and dimethyl formamide (0.5 mL) was added. The reaction mixture was heated to 59.6C and stirred for 2 hours at the same temperature. The solvent was removed from the reaction mixture through evaporation at 52C under reduced pressure and the crude product was dissolved in toluene (300 mL). A mixture of 6-chloro-5- methylpyridin-2-amine (29.4 g) in toluene (400 mL) was added to the reaction mixture at 30C in 35 minutes and stirred for 10 minutes at the same temperature. Triethylamine (20.89 g) was added in 10 minutes at 27.3C and stirred for 2 hours at the same temperature. Quenched the reaction mixture with water (250 mL) and separated the organic layer. The organic layer was washed with 5% HCI (2 x 50 mL), then with 3% sodium carbonate (2 x 100 mL) and then with water (50 mL). The solvent was removed completely from the organic layer through evaporation under reduced pressure at 55C. Hexane (2 x 100 mL) was added to the crude product and removed by evaporation at 55C. Again hexane (130 mL) was added and stirred the mixture at 26C for 1 hour and the solid was filtered. Washed the wet compound with hexane (50 mL) and dried under reduced pressure at 53C for 1 .5 hours to obtain the title compound. Yield: 69.4 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 12% 2: 8% | With N-ethyl-N,N-diisopropylamine; HATU In ethyl acetate at 0℃; | 14D-14E methyl cis-4-[(2R,4R)-4-[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate; methyl trans-4-[(2R,4R)-4-[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate Example 14C (0.50 g, 1.407 mmol) was mixed with 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.59 g, 1.548 mmol) and 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (0.36 g, 1.477 mmol) in ethyl acetate (5 mL) and cooled to 0° C. N-ethyl-N-isopropylpropan-2-amine (0.86 mL, 4.92 mmol) was added and the mixture was stirred overnight at 0° C. The reaction mixture was filtered and then washed with 5% sodium bicarbonate solution (2.5 mL), and concentrated. The residue was purified by preparative HPLC on a Chiralpak IC SFC column (30×25 mm, 5 um), and eluted with an isocratic mixture of 93% hexane:7% ethanol at a flow rate of 30 mL/min to provide the title compound (100 mg, 0.172 mmol, 12% yield) as the first eluted isomer. 1H NMR (700 MHz, DMSO-d6) δ 7.44 (d, J=1.7 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.28-7.22 (m, 2H), 7.18 (t, J=74.3, 1H), 7.02 (dd, J=8.5, 1.1 Hz, 1H), 6.67 (dd, J=8.5, 2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 5.20-5.12 (m, 1H), 4.03 (ddd, J=11.8, 5.9, 1.6 Hz, 1H), 3.64 (s, 3H), 2.67 (p, J=4.4 Hz, 1H), 2.02 (ddd, J=13.8, 9.1, 4.3 Hz, 2H), 1.86 (ddd, J=12.9, 6.0, 1.7 Hz, 1H), 1.78-1.66 (m, 2H), 1.64-1.49 (m, 6H), 1.39 (ddd, J=9.9, 6.7, 3.6 Hz, 1H), 1.35-1.28 (m, 2H), 1.14-1.00 (m, 2H); The title compound (65 mg, 0.112 mmol, 8% yield) was obtained as the second eluting isomer from the chromatography separation as described in Example 14D. 1H NMR (700 MHz, DMSO-d6) δ 7.44 (d, J=1.7 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.28-7.22 (m, 2H), 7.18 (t, J=74.2 Hz, 1H), 7.02 (dd, J=8.5, 1.1 Hz, 1H), 6.68 (dd, J=8.5, 2.5 Hz, 1H), 6.55 (d, J=2.5 Hz, 1H), 5.21-5.13 (m, 1H), 4.06-3.96 (m, 1H), 2.29 (tt, J=12.1, 3.6 Hz, 1H), 1.94 (dd, J=30.1, 12.3 Hz, 3H), 1.90-1.84 (m, 1H), 1.81 (t, J=12.0 Hz, 1H), 1.79-1.72 (m, 1H), 1.53 (dtd, J=19.7, 7.2, 6.6, 3.5 Hz, 2H), 1.42-1.32 (m, 3H), 1.24-1.12 (m, 3H), 1.10 (ddd, J=9.9, 6.6, 3.2 Hz, 1H), 1.05 (ddd, J=10.8, 7.1, 3.9 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h; | 8 Preparation of S-(((R)-3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxamido)-4-(((R)-2,3-dihydroxypropyl)amino)-2-methyl-4-oxobutan-2-yl)thio)-N-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyl)-L-cysteine (I-14) 10300] In a typical run, (R)-2-amino-3-mercapto-3-meth- ylbutanoic acid (0.25 g, 1.68 mmol, 1 eq) and 1-(2,2- difluorobenzo[d] [1 ,3]dioxol-5-yl)cyclopropane-1 -carboxylic acid (0.45 g, 1.85 mmol, 1.1 eq) were taken up in DMF (10 mE) and HATU (0.83 g, 2.18 mmol, 1.3 eq) was added, followed by Et3N (0.508 g, 5.03 mmol, 3 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. The following morning, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by preparative HPEC afford (R)-2-(1 -(2,2- difluorobenzo[d] [1 ,3]dioxol-5-yl)cyclopropane-1 -carboxamido)-3-mercapto-3-methylbutanoic acid (0.368 g, 59%yield) as a white solid. This material (0.368 g, 0.987 mmol, 1 eq) and (R)-(2,2-dimethyl-1 ,3-dioxolan-4-yl)methan- amine (0.155 g, 1.2 mmol, 1.1 eq) were taken up in DMF (5 mE) and HATU (0.487 g, 1.28 mmol, 1.3 eq) was added, followed by Et3N (0.299 g, 2.96 mmol, 3 eq). The resulting reaction mixture was stirred at room temperature for 16 hours. The following morning, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated and concentrated under reduced pressure. The resulting residue was purified by preparative HPEC to afford 1 -(2,2-difluorobenzo[d] [1 ,3]dioxol-5-yl)-N-((R)- 1 -((((R)2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl)amino)-3-mercapto-3-methyl-i -oxobutan-2-yl)cyclopropane-1 -carboxamide(0.27 g, 56% yield) as a colorless oil. This material (0.27 g, 0.556 mmol, 1 eq) was taken up in DMF (2 mE) along with tert-butyl N-((4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)-docosa-4,7, 10,13, 16,1 9-hexaenoyl)-S-(pyridin-2-ylthio)-E-cysteinate (0.365 g, 0.611 mmol, 1.1 eq) and methanol (2 mE) was added. tert-butyl N-((4Z,7Z, 1 OZ, 13Z, 1 6Z, 1 9Z)-Docosa-4,7, 10,13, 16,1 9-hexaenoyl)-S-(pyridin-2-ylthio)-E-cysteinate, in turn, was prepared according to the procedures outlined in example 3. The resulting reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The resulting residue was purified by preparative HPEC to afford tert-butyl S-(((R)-3-(i-(2,2- difluorobenzo[d] [1 ,3]dioxol-5-yl)cyclopropane-i -carboxamido)-4-((((R)-2,2-dimethyl-i ,3-dioxolan-4-yl)methyl) amino)-2-methyl-4-oxobutan-2-yl)thio)-N-((4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)-docosa-4,7, 10,13,16,1 9-hexaenoyl)-E-cysteinate (0.22 g, 40.8% yield) as a colorless oil. This material (0.22 g, 0.467 mmol, 1 eq) was taken up in CH2C12 (5 mE) and TFA (1 mE) was added. The resulting reaction mixture was stirred at room temperature for 4 hour and then concentrated under reduced pressure. The resulting residue was purified by preparative HPEC to afford S-(()-3-(i -(2,2-difluorobenzo[d] [1 ,3]dioxol-5-yl)cyclopropane- 1-car- boxamido)-4-(((R)-2,3-dihydroxypropyl)amino)-2-methyl- 4-oxobutan-2-yl)thio)-N-((4Z,7Z, 1 OZ, 13Z, 1 6Z, 1 9Z)- docosa-4,7, 10,13,16,1 9-hexaenoyl)-E-cysteine (0.02 g, 10% yield) as a colorless oil. MS, calculated for CH59F2N3O9S2: 875.37; found 876 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 24h; | General procedure: The benzo [1, 3] dioxol-5-yl-cyclopropanecarboxylic acid (1 eq) was resuspended in anhydrous DMF (1ml), HBTU (1 eq) and DIPEA (1 eq) were added. The reaction was vigorously stirred for 5min and the appropriate thiazole or aminic derivative (1 eq) in anhydrous DMF (500muL) was added, and the reaction was kept at T=40C until completeness (from 14h to 24h) depending from reactants. The mixture was concentrated under vacuum and after extraction with organic solvent (3×3ml), washed with H2O (3×2ml). The organic phases were dried over Na2SO4 and concentrated under reduced pressure and concentrated under vacuum. The crude product was then purified by preparative HPLC; the peak of interest was concentrated in vacuum and finally lyophilized to obtain the final compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 18h; | 2 4.1.5. General procedure C: conjugation of cyclopropanecarboxylic acid derivative with aminothiazole or amine General procedure: The benzo [1, 3] dioxol-5-yl-cyclopropanecarboxylic acid (1 eq) was resuspended in anhydrous DMF (1ml), HBTU (1 eq) and DIPEA (1 eq) were added. The reaction was vigorously stirred for 5min and the appropriate thiazole or aminic derivative (1 eq) in anhydrous DMF (500μL) was added, and the reaction was kept at T=40°C until completeness (from 14h to 24h) depending from reactants. The mixture was concentrated under vacuum and after extraction with organic solvent (3×3ml), washed with H2O (3×2ml). The organic phases were dried over Na2SO4 and concentrated under reduced pressure and concentrated under vacuum. The crude product was then purified by preparative HPLC; the peak of interest was concentrated in vacuum and finally lyophilized to obtain the final compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 24h; | General procedure: The benzo [1, 3] dioxol-5-yl-cyclopropanecarboxylic acid (1 eq) was resuspended in anhydrous DMF (1ml), HBTU (1 eq) and DIPEA (1 eq) were added. The reaction was vigorously stirred for 5min and the appropriate thiazole or aminic derivative (1 eq) in anhydrous DMF (500muL) was added, and the reaction was kept at T=40C until completeness (from 14h to 24h) depending from reactants. The mixture was concentrated under vacuum and after extraction with organic solvent (3×3ml), washed with H2O (3×2ml). The organic phases were dried over Na2SO4 and concentrated under reduced pressure and concentrated under vacuum. The crude product was then purified by preparative HPLC; the peak of interest was concentrated in vacuum and finally lyophilized to obtain the final compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 22h; | 2 4.1.5. General procedure C: conjugation of cyclopropanecarboxylic acid derivative with aminothiazole or amine General procedure: The benzo [1, 3] dioxol-5-yl-cyclopropanecarboxylic acid (1 eq) was resuspended in anhydrous DMF (1ml), HBTU (1 eq) and DIPEA (1 eq) were added. The reaction was vigorously stirred for 5min and the appropriate thiazole or aminic derivative (1 eq) in anhydrous DMF (500μL) was added, and the reaction was kept at T=40°C until completeness (from 14h to 24h) depending from reactants. The mixture was concentrated under vacuum and after extraction with organic solvent (3×3ml), washed with H2O (3×2ml). The organic phases were dried over Na2SO4 and concentrated under reduced pressure and concentrated under vacuum. The crude product was then purified by preparative HPLC; the peak of interest was concentrated in vacuum and finally lyophilized to obtain the final compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide; In water; at 75℃; for 24h; | To a solution of 2, 2-difluorobenzo [1, 3] dioxol-5-yl-methanol (930 mg, 5 mmol) in anhydrous THF (5 ml) was added NaBH4 (208 mg, 5.5 mmol) in portions at T = 0 C in ten minutes. The mixture was then stirred at the same temperature for about 2 h (controlled with HPLC). H2O (1.5 ml) was added and the mixture was stirred for about 15 min. The mixture was then extracted with diethyl ether (3 * 3 ml) and washed with water (2 * 1 ml). The organic phase was completely dried and lyophilized to obtain 2,2-difluorobenzo [1, 3] dioxol-5-yl-methanol as colorless oil and used without further purification (865 mg, 85%). A solution of 2,2-difluorobenzo [1, 3] dioxol-5-yl-methanol (865mg, 4.6mmol) in thionyl chloride (2ml) was stirred at room temperature upon completeness. When the reaction was complete (about 1h), the solution was concentrated under vacuum to remove the excess of thionyl chloride. Then, the residue was resuspended in a solution of dichloromethane and saturated NaHCO3 1:1 (2ml). The aqueous layer was then back-extracted with dichloromethane (2×1ml) and the combined organic layers were dried over Na2SO4 and finally concentrated to vacuum to give 5(chloromethyl)-2,2-difluorobenzo [1, 3] dioxole (823mg, 87%) which was used directly in the next step. A mixture of 5(chloromethyl)-2,2-difluorobenzo [1, 3] dioxole (823 mg, 3.99 mmol) and KCN (519 mg, 7.98 mmol) was stirred in dimethyl sulfoxide (DMSO) (3 ml) for 3 h at room temperature. H2O (1.5 ml) was added and the mixture extracted with ethyl acetate (EtOAc) (3 * 3 ml) and the organic phases were dried over Na2SO4 and concentrated under reduced pressure. The product was purified by preparative HPLC to afford 2(2, 2-difluorbenzo [1, 3] dioxol-5-yl)-acetonitrile (432 mg, 55%). A mixture of 2(2, 2-difluorbenzo [1, 3] dioxol-5-yl)-acetonitrile (432 mg, 2.2 mmol), 1-bromo-2-chloro-ethane (615 muL, 7.5 mmol) and benzyltriethylammonium chloride (5 mg, 0.02 mmol) was heated to T = 75 C and then 50% (wt./wt.) aqueous sodium hydroxide (5 ml) was slowly added. The reaction was stirred at T = 75 C for 24 h. After this time 1-bromo-2-chloro-ethane (310 muL, 3.8 mmol) and 50% (wt./wt.) aqueous sodium hydroxide (1 mL) were added to insure the complete formation of the cyclopropyl moiety (about 12-14 h). The reaction was then heated to T = 150 C for about 60 h to insure complete conversion from the nitrile to the carboxylic acid. When the hydrolysis was complete (controlled with HPLC-MS) the dark brown mixture was diluted with water (10 mL) and extracted three times with equal volumes of dichloromethane to remove all the sub-products. The basic aqueous solution was acidified with concentrated hydrochloric acid to pH = 1. The reaction mixture was centrifuged at 4000g for 5 min and the pellet was washed with 1 M hydrochloric acid (3 * 1 ml). The solid material was dissolved in dichloromethane (5 mL) and extracted twice with equal volumes of 1 M hydrochloric acid. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by preparative HPLC to afford the title compound (276 mg, 52%). 1H NMR (200 MHz, CDCl3) 7.17-6.96 (m, 3H), 1.82-1.65 (m, 2H), 1.39-1.22 (m, 2H). 13C NMR (50 MHz, CDCl3) delta, 179.4, 142.4, 141.9, 135.7, 133.7, 130.6, 124.6, 111.0, 107.9, 27.6 16.6. HRMS (ESI) calculated for C11H9N2O4F2: 243.0469 [M + H] + found 243.0464. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | With sodium hydroxide In methanol at 10 - 30℃; for 2h; | 8 Example 8: Preparation of 1-(2,2-Difluorobenzo[D][1,3]dioxol-5-yl)cyclopropanecarboxylic acid 300ml of water was added to a 500ml three-necked flask,Add 8.9 g of sodium hydroxide and dissolve by stirring.Cool down to below 30°C,A solution of 30 g of ethyl 1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)cyclopropanecarboxylate and 50 ml of methanol was added slowly.Then react at 10-30°C for 2 hours.The system was extracted twice with toluene,150ml each time;Then the aqueous phase is adjusted to pH 4-5 with reagent hydrochloric acid.Then cool to 0-10 ° C and stir 1h;Solid filtration,A small amount of filter cake washed,21.8 grams of white solids were dried.The yield is 81.1%.98.5% purity |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In ethyl acetate at 0℃; for 5h; | 1E Example 1E methyl 4- [(2R,4R)-4-({ [1 -(2,2-difluoro- 1,3 -benzodioxol-5 -yl)cyclopropyljcarbonyl} amino)-7-methoxy(3 ,3 ,4,5 ,6-H5)-3 ,4-dihydro-2H-chromen-2-ylj(2,3 ,5 -H)benzoate Methyl 4- [(2R,4R)-4-amino-7-methoxy(3 ,3 ,4,5 ,6-H5)-3 ,4-dihydro-2H-chromen-2-ylj(2,3 ,5 - 2H3)benzoate (1.28 g, 3.66 mmol), 1 -(2,2-difluorobenzo [dj [1 ,3jdioxol-5 -yl)cyclopropane- 1 -carboxylic acid (0.916 g, 3.76 mmol), and O-(7-azabenzotriazol- 1 -yl)-N,N,N ‘,N ‘-tetramethyluronium hexafluorophosphate (HATU, 1.49 g, 3.93 mmol) were charged to a 50 mL round-bottom flask equipped with a magnetic stir bar, and the mixture was cooled to 0 °C. Ethyl acetate (15 mL) was added. N-EthylN-isopropylpropan-2-amine (DIPEA) (1.62 g, 12.5 mmol) was dissolved in ethyl acetate (3.8 mL) in a separate vial. The DIPEA solution in ethyl acetate was charged to the 50 mL round-bottom flask and stirred for 5 hours. The reaction mixture was filtered using a Buchner funnel and washed with ethyl acetate (10 mL). The organic layer was washed with 20 mL of 10 % aqueous NaHCO3 solution and brine (6 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Ethyl acetate (5.75 mL) was added to the oil obtained after concentration. Heptanes (35 mL) were added dropwise and the resulting solid was stirred overnight. The white solids were collected by filtration, washed with heptanes (2 x 17 mL), and dried in a vacuum oven at 45 °C to afford 1.51 g (2.76 mmol, 77%) of the title compound. The isolated solid showed incorporation of 7.6 D-atoms by APCI-LC/MS.Mass fragment data for native and labeled: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With dmap; diisopropyl-carbodiimide In dichloromethane | |
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; | ||
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With thionyl chloride; N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: tert-butyl (4-amino-2-bromo-5-fluorophenyl)carbamate With triethylamine In dichloromethane at 20℃; for 16h; | 3 Example 3: Preparation of tert-butyl (2-bromo-4-[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-5-fluorophenyl)carbamate (Compound of Formula (8-A)) N,N-dimethylformamide (2 drops) was added to a slurry of the compound of Formula (9-A) (11.81 g, 48.77 mmol) in thionyl chloride (10.6 mL, 146.32 mmol) at room temperature. Following stirring at room temperature for about 1.5 hours, the excess thionyl chloride was removed in vacuo from the clear solution, and the resulting material was dissolved in dichloromethane (50 mL) to provide a solution of the corresponding acid chloride. The acid chloride solution was added to a solution of the compound of Formula (10-A) (13.53 g, 44.34 mmol) and triethylamine (20.4 mL, 146.32 mmol) in dichloromethane (50 mL) at room temperature, whereupon a slight exotherm occurred. The resulting mixture was stirred at room temperature for 16 hours, following which, the reaction mixture was quenched with water (100 mL) and the resulting layers were separated. The organic layer was dried over sodium sulfate, filtered and diluted with heptanes (100 mL). The solvent from this solution was reduced in vacuo, resulting in formation of a precipitate, which was collected by filtration, washed with heptanes (50 mL) and dried in vacuo at 40° C. for 2 hours to afford the compound of Formula (8-A) as a brown solid (20.14 g, 38.05 mmol, 86% yield). (0165) 1H-NMR of the compound of Formula (8-A) (CDCl3, 400 MHz) δ: 8.46 (d, J=8.0 Hz, 1H), 7.98 (d, J=13.4 Hz, 1H), 7.24-7.19 (m, 2H), 7.18 (br s, 1H), 7.12 (d, 8.2 Hz, 1H), 6.95 (br s, 1H), 1.73 (dd, J=6.8, 3.9 Hz, 2H), 1.51 (s, 9H), 1.17 (dd, J=6.8, 3.9 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.9 g | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With thionyl chloride; N,N-dimethyl-formamide In cyclohexane at 25 - 65℃; Stage #2: (R)-2-(1-(benzyloxy)-2-methylpropan-2-yl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-5-amine With triethylamine In dichloromethane at 25 - 30℃; | 9 Example-9: Preparation (R)-N-(2-(1-(benzyloxy)-2-methylpropan-2-yl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide [Formula-11] Thionyl chloride (0.66 g) was added to the mixture 1 -(2,2-difluorobenznzo[d][1,3]dioxol-5-yl)cyclopropane carboxylic acid (0.45 g), cyclohexane (8 ml) and dimethyl formamide (0.1 ml) at 25-30°C. Heated the mixture to 60-65°C and stirred. Distilled off the solvent completely form the reaction mixture. Triethyl amine (0.76 g) was added to the solution of (R)-2-(1-(benzyloxy)-2-methylpropan-2-yl)- 1 -((2,2-dimethyl- 1 ,3-dioxolan-4-yl)methyl)-6-fluoro- 1 H-indol-5-amine (formula-9) (0.8 g) in dichloromethane at 25-30°C. To this mixture, above obtained acid chloride was added at 25-30°C and stirred. Aqueous sodium carbonatesolution was added to the resultant reaction mixture. Aqueous phase was extracted with dichloromethane. Distilled off the solvent from the organic phase to get the title compound.Yield: 0.9 g. |
28.5 g | Stage #1: 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 38 - 40℃; for 3h; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Stage #3: (R)-2-(1-(benzyloxy)-2-methylpropan-2-yl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-5-amine In dichloromethane at 38 - 40℃; for 3h; | 21 EXAMPLE-21: Preparation of compound of Formula Xb Dimethyl formamide (1 mL) and a solution of oxalyl chloride (8.6 mL) in methylene chloride (26 mL) were added to a compound of Formula IX (16.1 gms) in methylene chloride (104 mL) in a round bottom flask at 25°C. The temperature of the reaction mass was raised to mild reflux at 38-40°C, aged at the same temperature for 3h. The reaction mass was cooled to room temperature and a solution of N,N-diisopropylethylamine (28.6 mL) in methylene chloride (52 mL) was added over a period of lh. A solution of intermediate VUIb (26 gms) in methylene chloride (78 mL) was added to the resulting reaction mass. The temperature of the reaction mass was raised to mild reflux at 38-40°C and aged at the same temperature for 3 hrs. The reaction mass was cooled to ambient temperature, washed with aq 5% NaHC03 solution (50 mL) and 5% aq NaCl solution (50 mL) and the layers were separated. The organic layer was concentrated under reduced pressure at below 50°C. The resulting residue was purified by silica gel column chromatography using a gradient of 5-20% v/v ethyl acetate and n-hexane to afford title compound. Yield= 28.5 gms. Purity by HPLC: 98%. LC/MS m/z: 651.6(M+1). lH NMR (300 MHz, DMSO-d6) d 8.31 (s, 1H, NH), 7.53 (s,lH, Ar-H), 7.52-7.22 ( m, 9H, Ar-H), 6.26 (s , 1H, Ar-H), 4.47 (s, 2H, Ph-CH2), 4.41-4.29 (m, 2H, N-CH2), -4.03 (t, J=4.6 Hz, CH), 3.63-3.56 (m, 4H, BnO-CH2, 0-CH2), 1.46 (t, J=3.2 Hz, 2H, CH2), 1.41(s, 3H, CH3), 1.40 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.16-1.13 (m, 5H, CH3, cyclopropyl- C). |
Tags: 862574-88-7 synthesis path| 862574-88-7 SDS| 862574-88-7 COA| 862574-88-7 purity| 862574-88-7 application| 862574-88-7 NMR| 862574-88-7 COA| 862574-88-7 structure
[ 862574-87-6 ]
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile
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P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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