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CAS No. : | 1279866-58-8 | MDL No. : | MFCD22209368 |
Formula : | C14H27ClN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LPRFEBCQOPCLMH-UHFFFAOYSA-N |
M.W : | 290.83 | Pubchem ID : | 71464197 |
Synonyms : |
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.93 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 87.13 |
TPSA : | 41.57 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.25 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.57 |
Log Po/w (WLOGP) : | 2.43 |
Log Po/w (MLOGP) : | 2.23 |
Log Po/w (SILICOS-IT) : | 1.82 |
Consensus Log Po/w : | 1.81 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.06 |
Solubility : | 0.251 mg/ml ; 0.000862 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.09 |
Solubility : | 0.236 mg/ml ; 0.000811 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.66 |
Solubility : | 0.639 mg/ml ; 0.0022 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.99 |
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 |
---|---|---|
Multi-step reaction with 2 steps 1.1: caesium carbonate / acetonitrile / 0.17 h / 20 °C 1.2: 18 h / Reflux 2.1: triethylamine; {(π-C5H5)2ZrCl} / dichloromethane / 3.5 h / 65 °C | ||
Multi-step reaction with 2 steps 1: caesium carbonate / acetonitrile / 60 °C 2: triethylamine; Schwartz's reagent / 48 h / 20 - 65 °C | ||
Multi-step reaction with 2 steps 1: caesium carbonate / acetonitrile / Reflux 2: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride With caesium carbonate In acetonitrile at 20℃; for 0.166667h; Stage #2: 4-bromobut-1-yne In acetonitrile for 18h; Reflux; | 17 Synthesis of tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate Scheme 3, step A: Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). 1H NMR (300.11 MHz, CDCl3): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.44 (s, 17H). |
98% | With caesium carbonate In acetonitrile for 18h; Reflux; | 14.3.A tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgS04, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). lH NMR (300.11 MHz, CDC13): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J= 2.6 Hz, 1H), 1.44 (s, 17H). |
72% | With caesium carbonate In acetonitrile at 60℃; | 7.A tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate Scheme 2, step A: A mixture of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (170.00 g, 584.53 mmoles), cesium carbonate (476.13 g, 1.46 moles), and 4-bromobutyne (93.28 g, 701.43 mmoles) in acetonitrile (1.70 L) is heated to 60° C. and stirred at this temperature overnight. Further 4-bromobutyne (46.64 g, 350.72 mmoles) is added and the mixture is stirred at 60° C. overnight. The mixture is cooled and filtered. The filtrate is concentrated under reduced pressure and the residue dissolved in ethyl acetate (500 mL), washed with water (1 L), and saturated aqueous sodium chloride (1 L), then dried over MgSO4, and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica column chromatography eluting with 20 to 70% ethyl acetate in dichloromethane to provide the title compound (129 g, 72% yield). Mass spectrum (m/z): 307.25 (M+1). |
13.6 g | With caesium carbonate In acetonitrile Reflux; | 9 Alternative Preparation of Final Title Compound Alternative Preparation of Final Title Compound Add tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (46.07 mmol) and cesium carbonate (115.2 mmol) to a solution of acetonitrile (200 mL). After stirring at room temperature for 20 minutes, add 4-bromobutyne (69.1 mmol) and heat the mixture to reflux with stirring overnight. Cool to room temperature and dilute with ethyl acetate (200 mL). Filter the reaction through a glass frit rinsing with ethyl acetate (2*100 mL). Concentrate the crude mixture under reduced pressure, then add ethyl acetate (200 mL) and wash the organics with water (200 mL) and brine (200 mL). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure to yield crude tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (13.6 g, 44.4 mmol): MS (m/z): 307.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
275 mg | With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 0.5h; | 7 Synthesis of tert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate Scheme 1, step G: Add sodium triacetoxyborohydride (98 mg, 0.46 mmol) to a solution of 4-{4-[(1E)-4-oxybut-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (270 mg, 0.31 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (179 mg, 0.62 mmol) in 1,2-dichloroethane (5 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL), dry organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (275 mg, 0.25 mmol). MS (m/z): 1115.6 (M+1). |
275 mg | With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 0.5h; | 7.1.G tert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-benzoyl-beta-D- glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl}-2,9- diazaspiro[5.5]undecane-9-carboxylate Add sodium triacetoxyborohydride (98 mg, 0.46 mmol) to a solution of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol- 3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (270 mg, 0.31 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (179 mg, 0.62 mmol) in 1,2- dichloroethane (5 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL), dry organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (275 mg, 0.25 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: caesium carbonate / acetonitrile / 0.17 h / 20 °C 1.2: 18 h / Reflux 2.1: triethylamine; {(π-C5H5)2ZrCl} / dichloromethane / 3.5 h / 65 °C 3.1: potassium carbonate; palladium diacetate; 2-(dicyclohexylphosphino)-2',4',6'-tri-1-propyl-1,1'-biphenyl / tetrahydrofuran; water / 16 h / Inert atmosphere; Reflux 4.1: trifluoroacetic acid / dichloromethane; water / 0.5 h / 20 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: caesium carbonate / acetonitrile / 0.17 h / 20 °C 1.2: 18 h / Reflux 2.1: triethylamine; {(π-C5H5)2ZrCl} / dichloromethane / 3.5 h / 65 °C 3.1: potassium carbonate; palladium diacetate; 2-(dicyclohexylphosphino)-2',4',6'-tri-1-propyl-1,1'-biphenyl / tetrahydrofuran; water / 16 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
500 mg | With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 0.5h; | 12 Synthesis of tert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate Scheme 2, Step D: Add sodium triacetoxyborohydride (303 mg, 1.4 mmol) to a solution of 4-{4-[(1E)-4-oxybut-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (600 mg, 0.95 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (333 mg, 1.2 mmol) in 1,2-dichloroethane (30 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (15 mL). Extract with dichloromethane (60 mL). Wash extract with water (30 mL) and brine (60 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (500 mg, 0.58 mmol). MS (m/z): 866.8, 867.8 (M+1), 864.8, 865.8 (M-1). |
500 mg | With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 0.5h; | 12a.2.D tert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D- glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl} -2,9-diazaspiro[5.5]undecane-9-carboxylate Add sodium triacetoxyborohydride (303 mg, 1.4 mmol) to a solution of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol- 3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (600 mg, 0.95 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (333 mg, 1.2 mmol) in 1,2- dichloroethane (30 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (15 mL). Extract with dichloromethane (60 mL). Wash extract with water (30 mL) and brine (60 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (500 mg, 0.58 mmol). MS (m/z): 866.8, 867.8 (M+l), 864.8, 865.8 (M-l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
630 mg | With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; | 9.A tert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate Scheme 3, step A: Heat a mixture of (3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl methanesulfonate (1.0 g, 1.41 mmol), tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (451 mg, 1.55 mmol), and diisopropylethylamine (730 mg, 5.64 mmol) in acetonitrile (4 mL) at 80° C. overnight. Remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography (silica gel, gradient ethyl acetate/dichloromethane from 25-85% over 15 min, then with methanol/dichloromethane from 1-3% over 10 min, 40 g column) to provide the title compound (630 mg, 0.73 mmol). MS (m/z): 867.2, 868.4 (M+1), 865.2, 866.4 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / acetonitrile / 60 °C 2: triethylamine; Schwartz's reagent / 48 h / 20 - 65 °C 3: potassium carbonate; palladium diacetate; 2-(dicyclohexylphosphino)-2',4',6'-tri-1-propyl-1,1'-biphenyl / tetrahydrofuran; water / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / acetonitrile / 60 °C 2: triethylamine; Schwartz's reagent / 48 h / 20 - 65 °C 3: potassium carbonate; palladium diacetate; 2-(dicyclohexylphosphino)-2',4',6'-tri-1-propyl-1,1'-biphenyl / tetrahydrofuran; water / Reflux 4: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / acetonitrile / 60 °C 2: triethylamine; Schwartz's reagent / 48 h / 20 - 65 °C 3: potassium carbonate; palladium diacetate; 2-(dicyclohexylphosphino)-2',4',6'-tri-1-propyl-1,1'-biphenyl / tetrahydrofuran; water / Reflux 4: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 20 °C 5: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / acetonitrile / 60 °C 2: triethylamine; Schwartz's reagent / 48 h / 20 - 65 °C 3: potassium carbonate; palladium diacetate; 2-(dicyclohexylphosphino)-2',4',6'-tri-1-propyl-1,1'-biphenyl / tetrahydrofuran; water / Reflux 4: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 20 °C 5: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 2 h / 20 °C 6: hydrogenchloride / dichloromethane; 1,4-dioxane / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: caesium carbonate / acetonitrile / 60 °C 2.1: triethylamine; Schwartz's reagent / 48 h / 20 - 65 °C 3.1: potassium carbonate; palladium diacetate; 2-(dicyclohexylphosphino)-2',4',6'-tri-1-propyl-1,1'-biphenyl / tetrahydrofuran; water / Reflux 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 2 h / 20 °C 5.1: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 2 h / 20 °C 6.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 4 h / 20 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.17 h 7.2: 0.33 h / 5 °C 7.3: 20 - 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.38 g | 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; | 7 Preparation of Final Title Compound Preparation of Final Title Compound To a round bottom flask add tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (1.38 mmol), 2-(isobutylcarbamoylamino)acetic acid (1.15 mmol), dimethylformamide (3.8 mL), triethylamine (1.72 mmol), and HATU (1.26 mmol Stir at room temperature for 16 hours, then dilute with water (50 mL) and ethyl acetate (50 mL). Wash the organic phase with concentrated ammonium chloride (50 mL) and brine (50 mL). Dry the organics over sodium sulfate, filter, and concentrate under reduced pressure. Purify the intermediate by flash chromatography (40 g silica gel cartridge) eluting with 0-10% methanol in ethyl acetate to yield tert-butyl 9-12-(isobutylcarbamoylamino)acetyl[-4,9-diazaspiro[5.5]undecane-4-carboxylate (0.38 g, 0.93 mmol): MS (m/z): 411.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / acetonitrile / Reflux 2: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C 3: palladium diacetate; potassium carbonate; XPhos / tetrahydrofuran; water / 16 h / 65 °C / Inert atmosphere 4: hydrogenchloride / dichloromethane; 1,4-dioxane / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: caesium carbonate / acetonitrile / Reflux 2.1: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C 3.1: palladium diacetate; potassium carbonate; XPhos / tetrahydrofuran; water / 16 h / 65 °C / Inert atmosphere 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 3 h / 20 °C 5.1: triethylamine / dichloromethane 5.2: 1.75 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: caesium carbonate / acetonitrile / Reflux 2.1: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C 3.1: palladium diacetate; potassium carbonate; XPhos / tetrahydrofuran; water / 16 h / 65 °C / Inert atmosphere 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 3 h / 20 °C 5.1: triethylamine / dichloromethane 5.2: 1.75 h 6.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 4.5 h / 20 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: caesium carbonate / acetonitrile / Reflux 2.1: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C 3.1: palladium diacetate; potassium carbonate; XPhos / tetrahydrofuran; water / 16 h / 65 °C / Inert atmosphere 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 3 h / 20 °C 5.1: triethylamine / dichloromethane 5.2: 1.75 h 6.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 4.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 80 °C | ||
Multi-step reaction with 5 steps 1: caesium carbonate / acetonitrile / Reflux 2: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C 3: palladium diacetate; potassium carbonate; XPhos / tetrahydrofuran; water / 16 h / 65 °C / Inert atmosphere 4: hydrogenchloride / dichloromethane; 1,4-dioxane / 3 h / 20 °C 5: triethylamine / dichloromethane / 0.17 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C | ||
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 5 - 20 °C 3.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 20 °C 3.2: 3 h / 20 °C 4.1: 5%-palladium/activated carbon; cyclohexene / ethanol / 0.75 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 80 °C 4: sodium methylate / methanol / 0.67 h | ||
Multi-step reaction with 6 steps 1: caesium carbonate / acetonitrile / Reflux 2: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C 3: palladium diacetate; potassium carbonate; XPhos / tetrahydrofuran; water / 16 h / 65 °C / Inert atmosphere 4: hydrogenchloride / dichloromethane; 1,4-dioxane / 3 h / 20 °C 5: triethylamine / dichloromethane / 0.17 h 6: sodium methylate / methanol / 0.67 h | ||
Multi-step reaction with 8 steps 1.1: caesium carbonate / acetonitrile / Reflux 2.1: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C 3.1: palladium diacetate; potassium carbonate; XPhos / tetrahydrofuran; water / 16 h / 65 °C / Inert atmosphere 4.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 3 h / 20 °C 5.1: triethylamine / dichloromethane 5.2: 1.75 h 6.1: hydrogenchloride / dichloromethane; 1,4-dioxane / 4.5 h / 20 °C 7.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C 8.1: sodium hydrogencarbonate / water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / acetonitrile / Reflux 2: triethylamine; zirconocene dichloride / 2-methyltetrahydrofuran / 60 °C 3: palladium diacetate; potassium carbonate; XPhos / tetrahydrofuran; water / 16 h / 65 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In dichloromethane at 0 - 20℃; | 10c Preparation of O4-benzyl O9-tert-butyl 4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate Preparation of O4-benzyl O9-tert-butyl 4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate To a 20 L temperature controlled reactor charge tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (2.06 moles; 600.00 g) followed by dichloromethane (6.00 L), then triethylamine (4.33 moles; 604 mL) is added. Set the jacket of the reactor to 0° C. When the temperature of the reaction mixture reaches 5° C., add benzyl chloroformate (2.10 moles; 311 mL) over about 20 minutes keeping the internal temperature below 20° C. When the addition is complete, warm the jacket to room temperature and stir the mixture overnight. Pour the reaction mixture into water (4 L) and separate the mixture. Concentrate the organics under reduced pressure to give the title compound (838 g; assumed 95.65% purity and 100% yield for the purposes of calculation in the next reaction) mass spectrum (m/z): 411.2 (M+23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 5 - 20 °C 3.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 20 °C 3.2: 3 h / 20 °C 4.1: 5%-palladium/activated carbon; cyclohexene / ethanol / 0.75 h / Reflux 5.1: potassium carbonate; potassium iodide / acetonitrile / Reflux; Inert atmosphere 5.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: hydrogenchloride / 1,4-dioxane / 5 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 5 - 20 °C 3.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 20 °C 3.2: 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 5 - 20 °C 3.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 20 °C 3.2: 3 h / 20 °C 4.1: 5%-palladium/activated carbon; cyclohexene / ethanol / 0.75 h / Reflux 5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 16 h / 80 °C 5.2: 1 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: hydrogenchloride / 1,4-dioxane / 5 - 20 °C 3.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 20 °C 3.2: 3 h / 20 °C 4.1: 5%-palladium/activated carbon; cyclohexene / ethanol / 0.75 h / Reflux 5.1: potassium carbonate; potassium iodide / acetonitrile / Reflux; Inert atmosphere 5.2: 1 h / 20 °C 6.1: sodium methylate; methanol / 0.17 h / Cooling with ice |
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