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[ CAS No. 118725-00-1 ] {[proInfo.proName]}

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Chemical Structure| 118725-00-1
Chemical Structure| 118725-00-1
Structure of 118725-00-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 118725-00-1 ]

CAS No. :118725-00-1 MDL No. :MFCD07368325
Formula : C6H14ClNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :HVPPPARGXDTDEY-FYZOBXCZSA-N
M.W : 167.63 Pubchem ID :13018906
Synonyms :

Calculated chemistry of [ 118725-00-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 41.95
TPSA : 52.32 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.13
Log Po/w (WLOGP) : 1.09
Log Po/w (MLOGP) : 0.75
Log Po/w (SILICOS-IT) : 0.01
Consensus Log Po/w : 0.6

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.39
Solubility : 6.78 mg/ml ; 0.0404 mol/l
Class : Very soluble
Log S (Ali) : -1.82
Solubility : 2.52 mg/ml ; 0.015 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.79
Solubility : 27.2 mg/ml ; 0.163 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.57

Safety of [ 118725-00-1 ]

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:

Application In Synthesis of [ 118725-00-1 ]

* 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.

  • Downstream synthetic route of [ 118725-00-1 ]

[ 118725-00-1 ] Synthesis Path-Downstream   1~28

  • 1
  • [ 4512-51-0 ]
  • [ 118725-00-1 ]
  • Trifluoracetyl-><L-α-aethyl-alanyl>-> <L-α-aethyl-alanin-methylester> [ No CAS ]
YieldReaction ConditionsOperation in experiment
(i) DCC, CH2Cl2, (ii) /BRN= 4151222/, Et3N; Multistep reaction;
  • 2
  • [ 118724-99-5 ]
  • [ 118725-00-1 ]
  • [ 121141-85-3 ]
  • [ 118724-96-2 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 50℃; for 48h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
  • 3
  • [ 118725-00-1 ]
  • C13H23NO6 [ No CAS ]
  • [ 118995-20-3 ]
YieldReaction ConditionsOperation in experiment
With 4-methyl-morpholine 1.) DMF, 3 min. 2.) DMF, THF, -15 to RT; Yield given. Multistep reaction;
  • 4
  • [ 4530-20-5 ]
  • [ 118725-00-1 ]
  • [ 171416-03-8 ]
YieldReaction ConditionsOperation in experiment
82% With benzotriazol-1-ol; dicyclohexyl-carbodiimide
  • 5
  • [ 118725-00-1 ]
  • Dnp-Gly-D-Iva-L-Pro-Gly-p-NA [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 82 percent / DCC, HOBt 2: 88 percent / NaOH / methanol / 2 h / Ambient temperature 3: 1.) TFA, 2.) DCC, HOBt / 1.) room temperature, 30 min, 2.) CH2Cl2, room temperature, overnight 4: TFA / 0.33 h / Ambient temperature 5: Et3N / acetone / Ambient temperature
  • 6
  • [ 118725-00-1 ]
  • Dnp-Gly-D-Iva-L-Pro-Gca-pNA [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 82 percent / DCC, HOBt 2: 88 percent / NaOH / methanol / 2 h / Ambient temperature 3: 69 percent / DCC, HOBt / CHCl3 4: 100 percent / H2 / Pd-black / methanol 5: 49 percent / DCC, 4-DMAP / tetrahydrofuran / 48 h / Ambient temperature 6: 1.) TFA, 2.) Et3N / 1.) room temperature, 20 min, 2.) Me2CO, room temperature, overnight
  • 7
  • [ 118725-00-1 ]
  • [ 171416-04-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 82 percent / DCC, HOBt 2: 88 percent / NaOH / methanol / 2 h / Ambient temperature
  • 8
  • [ 118725-00-1 ]
  • [ 171416-13-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 82 percent / DCC, HOBt 2: 88 percent / NaOH / methanol / 2 h / Ambient temperature 3: 69 percent / DCC, HOBt / CHCl3 4: 100 percent / H2 / Pd-black / methanol
  • 9
  • [ 118725-00-1 ]
  • [ 171416-12-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 82 percent / DCC, HOBt 2: 88 percent / NaOH / methanol / 2 h / Ambient temperature 3: 69 percent / DCC, HOBt / CHCl3
  • 10
  • [ 118725-00-1 ]
  • [ 1026446-76-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 82 percent / DCC, HOBt 2: 88 percent / NaOH / methanol / 2 h / Ambient temperature 3: 1.) TFA, 2.) DCC, HOBt / 1.) room temperature, 30 min, 2.) CH2Cl2, room temperature, overnight 4: TFA / 0.33 h / Ambient temperature
  • 11
  • [ 118725-00-1 ]
  • [ 171416-05-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 82 percent / DCC, HOBt 2: 88 percent / NaOH / methanol / 2 h / Ambient temperature 3: 1.) TFA, 2.) DCC, HOBt / 1.) room temperature, 30 min, 2.) CH2Cl2, room temperature, overnight
  • 12
  • [ 118725-00-1 ]
  • [ 171416-14-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 82 percent / DCC, HOBt 2: 88 percent / NaOH / methanol / 2 h / Ambient temperature 3: 69 percent / DCC, HOBt / CHCl3 4: 100 percent / H2 / Pd-black / methanol 5: 49 percent / DCC, 4-DMAP / tetrahydrofuran / 48 h / Ambient temperature
  • 13
  • [ 118725-00-1 ]
  • [ 118995-19-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1.) N-methyl-1,4-morpholine 2.) N-methyl-1,4-morpholine / 1.) DMF, 3 min. 2.) DMF, THF, -15 to RT 2: 2M NaOH / methanol / 1.5 h / 40 °C
  • 14
  • [ 118725-00-1 ]
  • Benzyloxycarbonyl-(L-α-ethyl-alanyl)-(L-α-ethyl-alanin) [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (i) DCC, CH2Cl2, (ii) /BRN= 4151222/, Et3N 2: (i) aq. NaOH, (ii) /BRN= 509751/, acetone
  • 15
  • [ 67-56-1 ]
  • [ 32315-10-9 ]
  • [ 1311139-11-3 ]
  • [ 124-41-4 ]
  • [ 118725-00-1 ]
  • [ 1311137-37-7 ]
YieldReaction ConditionsOperation in experiment
Stage #1: bis(trichloromethyl) carbonate; 4-[(5-amino-2-pyridinyl)oxy]-2-[(1-methylethyl)oxy]benzonitrile With triethylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: methyl (R)-2-amino-2-methyl-butyrate hydrochloride In dichloromethane for 0.416667h; Stage #3: methanol; sodium methylate at 60℃; for 1.75h; 60 Example 604-((5-r(4R)-4-ethyl-4-methyl-2,5-dioxo-1 -imidazolidinyll-2-pyridinyl oxy)-2-r(1 -In a 2-necked round bottomed flask, bis(trichloromethyl) carbonate (174.5 mg, 0.59 mmol) was dissolved in DCM (10 mL). N,N-diethylethanamine (0.651 mL, 3.74 mmol) was added therein. The obtained solution was cooled to 0°C. In a separate vial, 4-[(5-amino-2-pyridinyl)oxy]-2-[(1- methylethyl)oxy]benzonitrile (Intermediate 156, 145.4 mg) was dissolved in DCM (10 mL). The obtained solution was added dropwise in 5 min to the chilled bis(trichloromethyl) carbonate solution. At the end of addition, at 0°C, having checked that 4-[(5-amino-2-pyridinyl)oxy]-2-[(1- methylethyl)oxy]benzonitrile completely disappeared, a solution in DCM (5 mL) of N,N- diethylethanamine (0.280 mL, 1.60 mmol) and (2R)-2-methyl-1-(methyloxy)-1-oxo-2-butanaminium chloride (Tetrahedron 1988, 44(15), 4793-6, 179.2 mg, 1.07 mmol) was added to the reaction mixture and it was stirred for 25 min. The reaction mixture was quenched with 10 mL of water, diluted with 50 mL of DCM, and acidified to pH -5-6 using an aqueous pH 3 buffer solution. Phases were separated. The organic layer was washed with 15 mL of brine, dried over dry sodium sulphate, filtered and evaporated in vacuo to obtain a white foam. This foam was dissolved in 8 mL of methanol and Sodium methoxide (17.3 mg, 0.32 mmol) was added to the reaction mixture. The vial was sealed and shaken on PLS at 60°C. After 15 min, futher sodium methoxide (17.3 mg, 0.32 mmol) was added portionwise to the reaction mixture and it was shaken up to 1.5 hr. The reaction mixture was then evaporated in vacuo using a biotage V10 apparatus to obtain a pale yellow solid. This crude was purified by Biotage SP1 (Silica; from 100:0 to 50:50 Cyclohexane/EtOAc in 10 CV) to give the title compound (1 16.5 mg).H NMR (400 MHz, CDCI3) δ ppm 8.30 (1 H, d), 7.84 (1 H, dd), 7.56 (1 H, d), 7.08 (1 H, d), 6.78 (1 H, d), 6.75 (1 H, dd), 6.10 (1 H, br. s.), 4.49 - 4.69 (1 H, m), 1.91 - 2.04 (1 H, m), 1.71 - 1.83 (1 H, m), 1.55 (3H, s), 1.41 (3H, s), 1.40 (3H, s), 0.98 (3H, t); UPLCjpqc: 1.03 min, 395 [M+H]+.
  • 16
  • [ 32315-10-9 ]
  • [ 1311139-09-9 ]
  • [ 118725-00-1 ]
  • [ 1311139-73-7 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.75h; Intermediate 2074-(^5-r(4 ?)-4-ethyl-4-methyl-2,5-dioxo-1-imidazolidinyl1-2-pyridinyl oxy)-2-(1- methylethenvDbenzonitrileTo a solution of triphosgene (1 18 mg, 0.40 mmol) in dry DCM (3 mL) at 0°C DIPEA (0.695 ml, 4.0 mmol) was added followed by a solution of 4-[(5-amino-2-pyridinyl)oxy]-2-(1- methylethenyl)benzonitrile (Intermediate 154, 100 mg) in dry DCM (6 mL) slowly added (5 minutes). After that (2R)-2-methyl-1-(methyloxy)-1-oxo-2-butanaminium chloride (268 mg, 1.6 mmol) dissolved in dry DCM (3 mL) was added at the same temperature and the reaction mixture was stirred for 45 minutes at 0°C. The reaction was quenched with water and aqueous buffer (pH 3) was added while the pH was allowed to reach -5-6. Ethyl acetate (40 ml) was added and two phases were separated. The organic layer was washed with brine (2x10ml), dried (Na2S04), filtered and evaporated affording the urea intermediate as yellow foam. This urea was dissolved in MeOH (10 mL), NaOMe (10 mg) was added and the reaction mixture was refluxed for 45 minutes under stirring. After cooling the mixture was quenched with an aqueous saturated solution of ammonium chloride (10 mL) and diluted with ethyl acetate (20 mL). Two phases were separated and the organic layer was dried (Na2S04), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 10g) eluting from 75:25 to 50:50 cyclohexane/ethyl acetate affording the title compound as a white solid (100 mg).H NMR (400 MHz, CDCI3) δ ppm 8.31 (1 H, d), 7.87 (1 H, dd), 7.71 (1 H, d), 7.14 - 7.20 (2H, m), 7.12 (1 H, d), 5.94 (1 H, br. s.), 5.42 (1 H, s), 5.34 (1 H, s), 2.20 (3H, s), 1.95 - 2.05 (1 H, m), 1.79 (1 H, dd), 1.56 (3H, s), 1.00 (3H, t); UPLCjpqc: 1 .04 min, 377 [M+H]+.
  • 17
  • [ 1311139-09-9 ]
  • [ 118725-00-1 ]
  • [ 1311137-67-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.75 h / 0 °C 2: hydrogen / palladium 10% on activated carbon / methanol / 1 h / 760.05 Torr
  • 18
  • [ 10320-42-0 ]
  • [ 32315-10-9 ]
  • [ 118725-00-1 ]
  • [ 1380699-24-0 ]
YieldReaction ConditionsOperation in experiment
Intermediate 165(5R)-3-(2-chloropyrimidin-5-yl)-5-ethyl-5-methyl-imidazolidine-2,4-dioneTo a solution of triphosgene (1.38 g, 4.65mmol) in Ethyl acetate (20 ml) at 0°C a solution of 2-chloro-5- aminopyrimidine (1 g, 7.75 mmol)/DIPEA (8 ml, 4.65 mmol) in ethyl acetate (40 ml) was slowly added (20 minutes) and the reaction mixture was stirred for 15 minutes at the same temperature. Maintaining the reaction mixture at 0°C, vacuum was applied (10 minutes) for removingthe excess of phosgene. A solution of DMAP (0.945g, 7.75mmol) in ethyl acetate/dichloromethane 1:1 (8 ml) was added and the reaction mixture was stirred for 5 minutes at the same temperature. A solution of methyl (R)-2-amino-2- methyl-butyrate hydrochloride (2.59 g, 15.5 mmol) in ethyl acetate (30 ml) was slowly added (15 minutes) at 0°C and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with aqueous buffer (pH3) while the pH was allowed to reach ~5-6 and two phases were separated. The organic layer was washed with aqueous buffer (pH3) (2x20 ml) and then brine (20 ml), dried (Na2S04), filtered and evaporated affording the urea intermediate as orange foam.The urea was dissolved in MeOH (20 ml), NaOMe (0.41 g, 7.75 mmol) was added and the reaction mixture was stirred for 15 minutes at r.t.. The mixture was quenched with an aqueous saturated solution of ammonium chloride (25 ml) and diluted with ethyl acetate (50 ml). Two phases were separated and the organic layer was washed with brine (2x20 ml), dried (Na2S04), filtered and evaporated. The residue was triturated with Et20 (10 ml) and the solid collected affording the title compound (1.22 g) as a beige solid. LC/MS: QC_3_MIN: Rt = 1.341 min; 255 [M+H]+.
  • 19
  • [ 32315-10-9 ]
  • [ 1380698-56-5 ]
  • [ 118725-00-1 ]
  • C23H27N3O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: bis(trichloromethyl) carbonate; 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: methyl (R)-2-amino-2-methyl-butyrate hydrochloride In dichloromethane at 0℃; for 0.5h; 65 Example 65 (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,l'-cyclopropanel-4-yl)oxy-3-Pyridyllimidazolidine-2,4-dioneTo a solution of triphosgene (30 mg, O.lmmol) in dry DCM (1ml) at 0°C, under nitrogen atmosphere, DIPEA (0.175 ml, 1.0 mmol) was added followed by the addition (slowly added) of a solution of 6-(7- methylspiro[2H-benzofuran-3,l'-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 158, 27 mg, 0.1 mmol) in dry DCM (2ml) and the reaction mixture was stirred for 15 minutes at the same temperature. After that a solution of Methyl (R)-2-amino-2-methyl-butyrate hydrochloride (33mg, 0.2mmol) in dry DCM (2ml) was added and the reaction mixture was stirred for 30 minutes at 0°C. The reaction was quenched with a 1M aqueous solution of HCI (5ml), diluted with DCM (10ml) and two phases were separated. The organic layer was washed with brine (10ml), dried (IS^SC^), filtered and evaporated affording the urea intermediate as yellow foam.The urea was dissolved in MeOH (5ml), NaOMe (lOmg) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (20ml) and diluted with ethyl acetate (40ml). Two phases were separated and the organic layer was dried (Na2S04), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a lOg SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (29mg) as a white solid. XH-NMR (400 MHz, DMSO-d6) δ ppm: 8.60 (1H, s), 8.15 (1H, d), 7.85 (1H, dd), 7.06 (1H, d), 6.94 (1H, d), 6.44 (1H, d), 4.46 (2H, s), 2.15 (3H, s), 1.73-1.83 (1H, m), 1.62-1.72 (1H, m), 1.40 (3H, s), 1.10-1.14 (2H, m), 0.84-0.92 (5H, m). LC/MS: QC_3_MIN: Rt = 2.076 min; 394 [M+H]+.
  • 20
  • [ 118725-00-1 ]
  • [ 1380698-63-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / ethyl acetate / 0.58 h / 0 °C 1.2: 0.08 h / 0 °C 1.3: 0.5 h / 0 °C 2.1: sodium methylate / methanol / 0.25 h / 20 °C
  • 21
  • [ 118725-00-1 ]
  • [ 1380696-57-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / ethyl acetate / 0.58 h / 0 °C 1.2: 0.08 h / 0 °C 1.3: 0.5 h / 0 °C 2.1: sodium methylate / methanol / 0.25 h / 20 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / ethyl acetate / 0.58 h / 0 °C 1.2: 0.75 h / 0 °C 1.3: 0.25 h / 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / ethyl acetate / 0.25 h / 0 °C 1.2: 0.75 h / 0 °C 1.3: 0.25 h / 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / ethyl acetate / 0.58 h / 0 °C 1.2: 0.83 h / 0 °C 1.3: 0.25 h / 20 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C

  • 22
  • [ 32315-10-9 ]
  • [ 1380698-56-5 ]
  • [ 118725-00-1 ]
  • [ 1380696-79-6 ]
YieldReaction ConditionsOperation in experiment
29 mg Stage #1: bis(trichloromethyl) carbonate; 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: methyl (R)-2-amino-2-methyl-butyrate hydrochloride In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #3: With sodium methylate In methanol at 20℃; for 0.25h; 9 Example 9 (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,l'-cyclopropane1-4-yl)oxy-3- PVridyllimidazolidine-2,4-dione To a solution of triphosgene (30 mg, O.lmmol) in dry DCM (1ml) at 0°C, under nitrogen atmosphere, DIPEA (0.175 ml, 1.0 mmol) was added followed by the addition (slowly added) of a solution of 6-(7- methylspiro[2H-benzofuran-3,l'-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 15, 27 mg, 0.1 mmol) in dry DCM (2ml) and the reaction mixture was stirred for 15 minutes at the same temperature. After that a solution of Methyl (R)-2-amino-2-methyl-butyrate hydrochloride (33mg, 0.2mmol) in dry DCM (2ml) was added and the reaction mixture was stirred for 30 minutes at CPC. The reaction was quenched with a 1M aqueous solution of HCI (5ml), diluted with DCM (10ml) and two phases were separated. The organic layer was washed with brine (10ml), dried (IN^SC ), filtered and evaporated affording the urea intermediate as yellow foam. The urea was dissolved in MeOH (5ml), NaOMe (lOmg) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (20ml) and diluted with ethyl acetate (40ml). Two phases were separated and the organic layer was dried (Na2S04), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a lOg SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (29mg) as a white solid. 1H-NM (400 M Hz, DMSO-d6) δ ppm: 8.60 (1H, s), 8.15 (1H, d), 7.85 (1H, dd), 7.06 (1H, d), 6.94 (1H, d), 6.44 (1H, d), 4.46 (2H, s), 2.15 (3H, s), 1.73-1.83 (1H, m), 1.62-1.72 (1H, m), 1.40 (3H, s), 1.10-1.14 (2H, m), 0.84-0.92 (5H, m). LC/MS: QC_3_M IN: Rt = 2.076 min; 394 [M+H]+.
29 mg Stage #1: bis(trichloromethyl) carbonate; 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: methyl (R)-2-amino-2-methyl-butyrate hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #3: With methanol; sodium methylate at 20℃; for 0.25h; 65 Example 65 (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione Example 65 (5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione To a solution of triphosgene (30 mg, 0.1 mmol) in dry DCM (1 ml) at 0° C., under nitrogen atmosphere, DIPEA (0.175 ml, 1.0 mmol) was added followed by the addition (slowly added) of a solution of 6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 158, 27 mg, 0.1 mmol) in dry DCM (2 ml) and the reaction mixture was stirred for 15 minutes at the same temperature. After that a solution of Methyl (R)-2-amino-2-methyl-butyrate hydrochloride (33 mg, 0.2 mmol) in dry DCM (2 ml) was added and the reaction mixture was stirred for 30 minutes at 0° C. The reaction was quenched with a 1M aqueous solution of HCl (5 ml), diluted with DCM (10 ml) and two phases were separated. The organic layer was washed with brine (10 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as yellow foam. The urea was dissolved in MeOH (5 ml), NaOMe (10 mg) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (20 ml) and diluted with ethyl acetate (40 ml). Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (29 mg) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.60 (1H, s), 8.15 (1H, d), 7.85 (1H, dd), 7.06 (1H, d), 6.94 (1H, d), 6.44 (1H, d), 4.46 (2H, s), 2.15 (3H, s), 1.73-1.83 (1H, m), 1.62-1.72 (1H, m), 1.40 (3H, s), 1.10-1.14 (2H, m), 0.84-0.92 (5H, m). LC/MS: QC-3_MIN: Rt=2.076 min; 394 [M+H]+.
29 mg Stage #1: bis(trichloromethyl) carbonate; 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: methyl (R)-2-amino-2-methyl-butyrate hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #3: With sodium methylate In methanol at 20℃; for 0.25h; 9 Example 9
(5R)-5-ethyl-5-methyl-3-[6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxy-3-pyridyl]imidazolidine-2,4-dione To a solution of triphosgene (30 mg, 0.1 mmol) in dry DCM (1 ml) at 0° C., under nitrogen atmosphere, DIPEA (0.175 ml, 1.0 mmol) was added followed by the addition (slowly added) of a solution of 6-(7-methylspiro[2H-benzofuran-3,1'-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 15, 27 mg, 0.1 mmol) in dry DCM (2 ml) and the reaction mixture was stirred for 15 minutes at the sane temperature. After that a solution of Methyl (R)-2-amino-2-methyl-butyrate hydrochloride (33 mg, 0.2 mmol) in dry DCM (2 ml) was added and the reaction mixture was stirred for 30 minutes at 0° C. The reaction was quenched with a 1M aqueous solution of HCl (5 ml), diluted with DCM (10 ml) and two phases were separated. The organic layer was washed with brine (10 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as yellow foam. The urea was dissolved in MeOH (5 ml), NaOMe (10 mg) was added and the reaction mixture was stirred for 15 minutes at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (20 ml) and diluted with ethyl acetate (40 ml). Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (29 mg) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.60 (1H, s), 8.15 (1H, d), 7.85 (1H, dd), 7.06 (1H, d), 6.94 (1H, d), 6.44 (1H, d), 4.46 (2H, s), 2.15 (3H, s), 1.73-1.83 (1H, m), 1.62-1.72 (1H, m), 1.40 (3H, s), 1.10-1.14 (2H, m), 0.84-0.92 (5H, m). LC/MS: QC-3_MIN: Rt=2.076 min; 394 [M+H]+.
  • 23
  • [ 56621-90-0 ]
  • [ 32315-10-9 ]
  • [ 118725-00-1 ]
  • [ 1380698-63-4 ]
YieldReaction ConditionsOperation in experiment
1.22 g To a solution of triphosgene (1.38 g, 4.65mmol) in Ethyl acetate (20 ml) at 0C a solution of 2-chloro-5- aminopyrimidine (1 g, 7.75 mmol)/DIPEA (8 ml, 4.65 mmol) in ethyl acetate (40 ml) was slowly added (20 minutes) and the reaction mixture was stirred for 15 minutes at the same temperature. Maintaining the reaction mixture at 0C, vacuum was applied (10 minutes) for removing the excess of phosgene. A solution of DMAP (0.945g, 7.75mmol) in ethyl acetate/dichloromethane 1:1 (8 ml) was added and the reaction mixture was stirred for 5 minutes at the same temperature. A solution of methyl (R)-2-amino-2- methyl-butyrate hydrochloride (2.59 g, 15.5 mmol) in ethyl acetate (30 ml) was slowly added (15 minutes) at 0C and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with aqueous buffer (pH3) while the pH was allowed to reach ~5-6 and two phases were separated. The organic layer was washed with aqueous buffer (pH3) (2x20 ml) and then brine (20 ml), dried (Na2S04), filtered and evaporated affording the urea intermediate as orange foam. The urea was dissolved in MeOH (20 ml), NaOMe (0.41 g, 7.75 mmol) was added and the reaction mixture was stirred for 15 minutes at r.t.. The mixture was quenched with an aqueous saturated solution of ammonium chloride (25 ml) and diluted with ethyl acetate (50 ml). Two phases were separated and the organic layer was washed with brine (2x20 ml), dried (IN^SC ), filtered and evaporated. The residue was triturated with Et20 (10 ml) and the solid collected affording the title compound (1.22 g) as a beige solid. LC/MS: QC_3_M IN: Rt = 1.341 min; 255 [M+H]+.
1.22 g Intermediate 165 (5R)-3-(2-chloropyrimidin-5-yl)-5-ethyl-5-methyl-imidazolidine-2,4-dione [0981] [0982] To a solution of triphosgene (1.38 g, 4.65 mmol) in Ethyl acetate (20 ml) at 0 C. a solution of <strong>[56621-90-0]2-chloro-5-aminopyrimidine</strong> (1 g, 7.75 mmol)/DIPEA (8 ml, 4.65 mmol) in ethyl acetate (40 ml) was slowly added (20 minutes) and the reaction mixture was stirred for 15 minutes at the same temperature. Maintaining the reaction mixture at 0 C., vacuum was applied (10 minutes) for removing the excess of phosgene. A solution of DMAP (0.945 g, 7.75 mmol) in ethyl acetate/dichloromethane 1:1 (8 ml) was added and the reaction mixture was stirred for 5 minutes at the same temperature. A solution of methyl (R)-2-amino-2-methyl-butyrate hydrochloride (2.59 g, 15.5 mmol) in ethyl acetate (30 ml) was slowly added (15 minutes) at 0 C. and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with aqueous buffer (pH3) while the pH was allowed to reach 5-6 and two phases were separated. The organic layer was washed with aqueous buffer (pH3) (2×20 ml) and then brine (20 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as orange foam. [0983] The urea was dissolved in MeOH (20 ml), NaOMe (0.41 g, 7.75 mmol) was added and the reaction mixture was stirred for 15 minutes at r.t. The mixture was quenched with an aqueous saturated solution of ammonium chloride (25 ml) and diluted with ethyl acetate (50 ml). Two phases were separated and the organic layer was washed with brine (2×20 ml), dried (Na2SO4), filtered and evaporated. The residue was triturated with Et2O (10 ml) and the solid collected affording the title compound (1.22 g) as a beige solid. [0984] LC/MS: QC-3_MIN: Rt=1.341 min; 255 [M+H]+.
1.22 g To a solution of triphosgene (1.38 g, 4.65 mmol) in Ethyl acetate (20 ml) at 0 C. a solution of <strong>[56621-90-0]2-chloro-5-aminopyrimidine</strong> (1 g, 7.75 mmol)/DIPEA (8 ml, 4.65 mmol) in ethyl acetate (40 ml) was slowly added (20 minutes) and the reaction mixture was stirred for 15 minutes at the same temperature. Maintaining the reaction mixture at 0 C., vacuum was applied (10 minutes) for removing the excess of phosgene. A solution of DMAP (0.945 g, 7.75 mmol) in ethyl acetate/dichloromethane 1:1 (8 ml) was added and the reaction mixture was stirred for 5 minutes at the same temperature. A solution of methyl (R)-2-amino-2-methyl-butyrate hydrochloride (2.59 g, 15.5 mmol) in ethyl acetate (30 ml) was slowly added (15 minutes) at 0 C. and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with aqueous buffer (pH3) while the pH was allowed to reach 5-6 and two phases were separated. The organic layer was washed with aqueous buffer (pH3) (2×20 ml) and then brine (20 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as orange foam. The urea was dissolved in MeOH (20 ml), NaOMe (0.41 g, 7.75 mmol) was added and the reaction mixture was stirred for 15 minutes at r.t. The mixture was quenched with an aqueous saturated solution of ammonium chloride (25 ml) and diluted with ethyl acetate (50 ml). Two phases were separated and the organic layer was washed with brine (2×20 ml), dried (Na2SO4), filtered and evaporated. The residue was triturated with Et2O (10 ml) and the solid collected affording the title compound (1.22 g) as a beige solid. LC/MS: QC-3_MIN: Rt=1.341 min; 255 [M+H]+.
  • 24
  • [ 67-56-1 ]
  • [ 3059-97-0 ]
  • [ 118725-00-1 ]
YieldReaction ConditionsOperation in experiment
93% With thionyl chloride for 3h; Reflux; 2.1 (1) Esterification reaction: 117 g (1 mol) of D-isoproline was suspended in 1500 mL of methanol.Stir well,To the suspension, 179 g (1.5 mol) of thionyl chloride was slowly added.After the addition, the temperature was refluxed for 3 h.The resulting reaction mixture was cooled to room temperature and filtered.The filter cake was washed several times with methanol.The filtrate and the methanol wash were combined and concentrated under reduced pressure. Toluene was added to the obtained residue, followed by stirring. The toluene was removed to give the desired product D-isoproline methyl ester hydrochloride 156 g (yield: 93%).
  • 25
  • [ 118725-00-1 ]
  • R-2-(3,5-dichloro-4-methylphenyl)-4-ethyl-4-methyl-5-methylene-4,5-dihydrooxazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 0.5 h / 0 °C 1.2: 0.5 h / 0 °C 2.1: acetic anhydride / 1 h / Reflux 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 20 °C 3.2: 6 h / Reflux
  • 26
  • [ 118725-00-1 ]
  • R-5-chloromethylene-2-(3,5-dichloro-4-methylphenyl)-4-ethyl-4-methyl-4,5-dihydrooxazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 0.5 h / 0 °C 1.2: 0.5 h / 0 °C 2.1: acetic anhydride / 1 h / Reflux 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 20 °C 3.2: 6 h / Reflux 4.1: N-chloro-succinimide / 1 h / -10 °C
  • 27
  • [ 118725-00-1 ]
  • (-)-R-zoxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: 0.5 h / 0 °C 1.2: 0.5 h / 0 °C 2.1: acetic anhydride / 1 h / Reflux 3.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0.5 h / 20 °C 3.2: 6 h / Reflux 4.1: N-chloro-succinimide / 1 h / -10 °C 5.1: hydrogenchloride / 6 h / 60 °C
  • 28
  • [ 118725-00-1 ]
  • [ 113485-46-4 ]
  • C14H17Cl2NO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% Stage #1: methyl (R)-2-amino-2-methyl-butyrate hydrochloride; 3,5-dichloro-4-methylbenzoyl chloride at 0℃; for 0.5h; Stage #2: With triethylamine at 0℃; for 0.5h; 2.2 (2) Amidation reaction: L-isoproline methyl ester hydrochloride prepared in the previous step 140 g (0.83 mol)And 3,5-dichloro-4-methylbenzoyl chloride 190.5 g (0.853 mol)And 1.0 L of each of methyl isobutyl ketone was added dropwise to the reaction vessel, the temperature was lowered to 0 ° C, the reaction was stirred at 0 ° C for 30 min, 270 mL of triethylamine was added dropwise, the temperature of the reaction mixture was controlled at 0 ° C, and the reaction was continued for 30 min.The temperature was raised to room temperature by heating, and the progress of the reaction was followed by liquid chromatography.After completion of the reaction, the mixture was washed successively with a 2% aqueous hydrochloric acid solution, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution.The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated.getMethyl R-2-(3,5-dichloro-4-methylbenzoyl)-2-methylbutanoate242 g (yield: 89%).
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