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[ CAS No. 1023595-11-0 ] {[proInfo.proName]}

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Chemical Structure| 1023595-11-0
Chemical Structure| 1023595-11-0
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Product Details of [ 1023595-11-0 ]

CAS No. :1023595-11-0 MDL No. :MFCD11227066
Formula : C13H24N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :XLEJZQHSRRYDFL-UHFFFAOYSA-N
M.W : 256.34 Pubchem ID :53439217
Synonyms :

Calculated chemistry of [ 1023595-11-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.92
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 76.74
TPSA : 50.8 Ų

Pharmacokinetics

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) : -7.38 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.95
Log Po/w (XLOGP3) : 0.68
Log Po/w (WLOGP) : 0.61
Log Po/w (MLOGP) : 0.88
Log Po/w (SILICOS-IT) : 1.21
Consensus Log Po/w : 1.26

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.66
Solubility : 5.61 mg/ml ; 0.0219 mol/l
Class : Very soluble
Log S (Ali) : -1.32
Solubility : 12.2 mg/ml ; 0.0475 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.12
Solubility : 1.95 mg/ml ; 0.0076 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.26

Safety of [ 1023595-11-0 ]

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 [ 1023595-11-0 ]

* 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 [ 1023595-11-0 ]

[ 1023595-11-0 ] Synthesis Path-Downstream   1~58

  • 3
  • [ 1023595-11-0 ]
  • [ 100-52-7 ]
  • tert-butyl 9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium tris(acetoxy)borohydride In 1-methyl-pyrrolidin-2-one
  • 6
  • [ 923595-50-0 ]
  • [ 1023595-11-0 ]
  • [ 1208069-64-0 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In pentan-1-ol at 150℃; for 24h; 7.2 Step 7.2. tert-Butyl 9-(2-methyl-3-pyridin-4-ylimidazo[1,2-b]pyridazin-6-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate In a reactor a solution of 0.50 g (2.0 mmol) of 6-chloro-3-(pyridin-4-yl)imidazo[1,2-b]-pyridazine, obtained in step 7.1., 0.90 g (3.1 mmol) of tert-butyl 1-oxa-4,9-diazaspiro[5.5]-undecane-4-carboxylate and 0.84 ml (5.1 mmol) of diisopropylethylamine in 5 ml of pentanol is heated at 150° C. for 24 hours. After cooling, the pentanol is removed by evaporation under reduced pressure and the residue is taken up with aqueous sodium bicarbonate solution. The product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and concentrated under reduced pressure and the residue is chromatographed, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (97/3/0.3), to give 0.17 g of orange oil, which is used as it is in the remainder of the synthesis.
  • 7
  • [ 1023595-11-0 ]
  • 5-fluoro-3-(3-fluorophenoxy)-2-methylbenzonitrile [ No CAS ]
  • tert-butyl 9-[3-cyano-5-(3-fluorophenoxy)-4-methylphenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
21% With potassium carbonate In dimethyl sulfoxide at 110 - 115℃; Sealed tube; 25.b Preparation 25: tert-butyl 9-[3-cyano-5-(3-fluorophenoxy)-4-methylphenyl]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P25) A mixture of 5-fluoro-3-(3-fluorophenoxy)-2-methylbenzonitrile (from step a, 27 mg, 0.11 mmol), tertbutyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (prepared according to p6, 56 mg, 0.22 mmol) and K2C03 (30 mg, 0.22 mmol) in DMSO (0.7 mL) in a sealed vial was heated at 110°C and shakenovernight. An additional amount of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (28 mg) was added; the reaction temperature was brought to 115 °C and the mixture was shaken for further 48 hrs. Ether and water were added, the organic phase was washed with water, dried and solvent removed under reduced pressure. The crude material was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 90/10) to give tert-butyl 9-[3-cyano-5-(3-fluorophenoxy)-4-methyl phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p25, 11 mg, y= 21%).MS (ES) (m/z): 482.3 [M÷H]
  • 8
  • [ 1023595-11-0 ]
  • 5-fluoro-3-(3-fluorophenoxy)-2-methylbenzonitrile [ No CAS ]
  • 3-(3-fluorophenoxy)-2-methyl-5-{1-oxa-4,9-diazaspiro[5.5]undecan-9-yl}benzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 110 - 115 °C / Sealed tube 2: trifluoroacetic acid / dichloromethane / 2 h
  • 9
  • [ 1023595-11-0 ]
  • 2-chloro-6-(3-fluorophenoxy)pyridine [ No CAS ]
  • tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% With potassium carbonate In dimethyl sulfoxide at 90 - 100℃; for 50.5h; Sealed tube; 57 Preparation 57: tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yI]-1-oxa-4,9-diazaspiro[5.5] undecane-4- carboxylate (P57) A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).MS (ES) (m/z): 444.2 [M÷H]
  • 10
  • [ 1023595-11-0 ]
  • 2-chloro-6-(3-fluorophenoxy)pyridine [ No CAS ]
  • 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 50.5 h / 90 - 100 °C / Sealed tube 2: trifluoroacetic acid / dichloromethane / 2 h
  • 11
  • [ 1023595-11-0 ]
  • 2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine [ No CAS ]
  • tert-butyl 9-[6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% With potassium carbonate In dimethyl sulfoxide at 90℃; for 2h; Sealed tube; 58 Preparation 58: tert-butyl 9-[6-(3-fI uorophenoxy)-4-(trifluoromethyl)pyridin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P58) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6,60 mg, 0.23 mmol) and 1-benzyl-3-bromobenzene (p27, 68 mg, 0.23 mmol) in analogous manner asdescribed in Preparation 57 (T= 90 °C, t= 2 hrs). tert-butyl 9-[6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p58, 75 mg, y= 64%).MS (ES) (m/z): 512.2 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).
  • 12
  • [ 1023595-11-0 ]
  • 2-chloro-6-(3-fluorophenoxy)pyridine-4-carbonitrile [ No CAS ]
  • tert-butyl 9-[4-cyano-6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
67% With potassium carbonate In dimethyl sulfoxide at 80℃; for 18h; Sealed tube; 59 Preparation 59: tert-butyl 9-[4-cyano-6-(3-fluorophenoxy)pyridin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P59) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6,65 mg, 0.26 mmol) and 2-chloro-6-(3-fluorophenoxy)pyridine-4-carbonitrile (p28, 128 mg, 0.51 mmol) inanalogous manner as described in Preparation 57 (T= 80 °C, t= 18 hrs). tert-butyl 9-[4-cyano-6-(3- fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p59, 82 mg, y= 67%). MS (ES) (m/z): 469.1 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).
  • 13
  • [ 1023595-11-0 ]
  • 6-chloro-2-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile [ No CAS ]
  • tert-butyl 9-[5-cyano-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% With potassium carbonate In dimethyl sulfoxide at 100℃; for 2h; Sealed tube; 60 Preparation 60: tert-butyl 9-[5-cyano-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yI]-1-oxa-4,9-diazaspiro[5.5] undecane-4-carboxylate (P60) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 36 mg, 0.139 mmol) and a mixture of 2-chloro-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3- carbonitrile and 6-chloro-2-(3-fluorophenoxy)-4-(trifluoromethyl)pyridine-3-carbonitrile (p29, 53 mg,0.167 mmol) in analogous manner as described in Preparation 57 (T= 100 °C, t= 2 hrs). tert-butyl 9-[5- cyano-6-(3-fluorophenoxy)-4-(trifluoromethyl)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p60, 27 mg, y= 36%). MS (ES) (m/z): 537.3 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).
  • 14
  • [ 894416-95-6 ]
  • [ 1023595-11-0 ]
  • tert-butyl 9-[6-(3-fluorophenoxy)pyrazin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With potassium carbonate In dimethyl sulfoxide at 100℃; for 1h; Sealed tube; 62 Preparation 62: tert-butyl 9-[6-(3-fluorophenoxy)pyrazin-2-yI]-1-oxa-4,9-diazaspiro[5.5] undecane-4- carboxylate (P62) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4,50 mg, 0.195 mmol) and 2-chloro-6-(3-fluorophenoxy)pyrazine (p30, 44 mg, 0.195 mmol) in analogousmanner as described in Preparation 57 (T= 100 °C, t= 1 h). tert-butyl 9-[6-(3-fluorophenoxy)pyrazin-2-yl]- 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p62, 37 mg, y= 42%).MS (ES) (m/z): 445.3 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).
  • 15
  • [ 1023595-11-0 ]
  • 2-chloro-4-(3-fluorophenoxy)pyrimidine [ No CAS ]
  • tert-butyl 9-[4-(3-fluorophenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With potassium carbonate In dimethyl sulfoxide at 100℃; for 18h; Sealed tube; 63 Preparation 63: tert-butyl 9-[4-(3-fluorophenoxy)pyrimidin-2-yI]-1-oxa-4,9-diazaspiro[5.5]undecane-4- carboxylate (P63) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4,50 mg, 0.195 mmol) and 2-chloro-4-(3-fluorophenoxy)pyrimidine (p31, 44 mg, 0.195 mmol) in analogousmanner as described in Preparation 57 (T= 100 °C, t= 18 hrs). tert-butyl 9-[4-(3-fluorophenoxy)pyrimidin- 2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p63, 38 mg, y= 42%).MS (ES) (m/z): 445.2 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).MS (ES) (m/z): 444.2 [M÷H]
  • 16
  • [ 1023595-11-0 ]
  • 2-chloro-4-methyl-6-(3-methylphenoxy)pyrimidine [ No CAS ]
  • tert-butyl 9-[4-methyl-6-(3-methylphenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% With potassium carbonate In dimethyl sulfoxide at 90℃; for 18h; Sealed tube; 66 Preparation 66: tert-butyl 9-[4-methyl-6-(3-methyl phenoxy)pyrimidin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P66) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 53 mg, 0.21 mmol) and 2-chloro-4-methyl-6-(3-methylphenoxy)pyrimidine (p34, 54 mg, 0.23 mmol) inanalogous manner as described in Preparation 57 (T= 90 °C, t= 18 hrs). tert-butyl 9-[4-methyl-6-(3- methylphenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p66, 51 mg, y= 54%). MS (ES) (m/z): 455.3 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).
  • 17
  • [ 1023595-11-0 ]
  • 3-[(2-chloro-6-methylpyrimidin-4-yl)oxy]benzonitrile [ No CAS ]
  • tert-butyl 9-[4-(3-cyanophenoxy)-6-methylpyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h; Sealed tube; 67 Preparation 67: tert-butyl 9-[4-(3-cyanophenoxy)-6-methylpyrimidin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P67) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4,55 mg, 0.21 mmol) and 3-[(2-chloro-6-methylpyrimidin-4-yl)oxy]benzonitrile (p35, 57 mg, 0.23 mmol) inanalogous manner as described in Preparation 57 (T= 100 °C, t= 3 hrs). tert-butyl 9-[4-(3-cyanophenoxy)- 6-methylpyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p67, 47 mg, y= 48%). MS (ES) (m/z): 466.1 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).
  • 18
  • [ 1023595-11-0 ]
  • 2-chloro-4-methyl-6-(2-methylphenoxy)pyrimidine [ No CAS ]
  • tert-butyl 9-[4-methyl-6-(2-methylphenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With potassium carbonate In dimethyl sulfoxide at 100℃; for 1.5h; Sealed tube; 72 Preparation 72: tert-butyl 9-[4-methyl-6-(2-methyl phenoxy)pyrimidin-2-yI]-1-oxa-4,9- diazaspiro[5.5] undecane-4-carboxylate (P72) The title compound was prepared from tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 50 mg, 0.195 mmol) and 2-chloro-4-methyl-6-(2-methylphenoxy)pyrimidine (p40, 55 mg, 0.234 mmol) inanalogous manner as described in Preparation 57 (T= 100 °C, t= 1.5 h). tert-butyl 9-[4-methyl-6-(2- methylphenoxy)pyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p72, 33 mg, y= 37%). MS (ES) (m/z): 455.3 [M÷H]; A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p6, 60 mg, 0.23 mmol), 2-chloro-6-(3-fluorophenoxy)pyridine (p26, 47 mg, 0.21 mmol) and K2C03 (38 mg, 0.27 mmol) in DMSO(0.8 mL) in a sealed vessel was heated at 90 °C and shaken 2.5 hrs at this temperature. The mixture was then shaken at 100 °C for 48 hrs. After cooling to RT, Et20 and water were added, the organic phase was washed with water, dried and evaporated; crude product was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 80/20) to give tert-butyl 9-[6-(3-fluorophenoxy)pyridin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p57, 19 mg, y= 20%).
  • 19
  • [ 43212-41-5 ]
  • [ 372-20-3 ]
  • [ 1023595-11-0 ]
  • tert-butyl 9-[4-(3-fluorophenoxy)-6-methoxypyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
17% 3-fluorophenol (0.023 mL, 0.251 mmol), <strong>[43212-41-5]2,4-dichloro-6-methoxypyrimidine</strong> (50 mg, 0.279 mmol) and K2C03 (50.13 mg, 0.363 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 2 hrs at RT. The mixture was diluted with EtOAC and water. The organic phase was washed several times with brine, dried, filtered and evaporated. Crude material was purified by FC on silica gel (eluent: Cy to Cy/EtOAc 90/10) affording a mixture of 2 regioisomers and starting material (65 mg); Mixture from step a (62 mg), tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 50 mg, 0.195 mmol) and K2C03 (35 mg, 0.254 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 2 hrs at RT. The mixture was diluted with EtOAc and water. The organic phase was washed several times with brine, dried, filtered and evaporated. Crude was purified by FC on silica gel (eluent: Cy to 10% EtOAc) togive a mixture of desired compound and chlorinated analogue (30 mg); 3-fluorophenol (7 ilL, 0.075 mmol), mixture from step b (30 mg) and K2C03 (13.54 mg, 0.098 mmol) were mixed in dry DMSO (0.5 mL) and stirred for 12 hrs at RT. Then further 2 eq of K2C03 were added and the reaction mixture was stirred at 100 C for 48 hrs. The mixture was diluted with EtOAc and water and theorganic phase was washed several times with brine, dried, filtered and evaporated. Crude was purified by FC on silica gel (eluent: Cy to Cy/EtOAc 90/10) affording tert-butyl 9-[4-(3-fluorophenoxy)-6- methoxypyrimidin-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p87, 20 mg, y= 17%) as colourless oil.MS (ES) (m/z): 475.3 [M÷H]
  • 20
  • [ 1018608-18-8 ]
  • [ 1023595-11-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 2: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
Multi-step reaction with 2 steps 1: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 2: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere
  • 21
  • [ 3612-20-2 ]
  • [ 1023595-11-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: sodium hydride / mineral oil; dimethyl sulfoxide / 1.17 h / 10 - 20 °C / Cooling with ice 1.2: 1.5 h / 20 °C 2.1: triethylamine / methanol; water / 36 h / 50 °C 3.1: sodium hydroxide / tetrahydrofuran; ethanol / 5 h / Reflux 4.1: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 5.1: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
Multi-step reaction with 7 steps 1.1: sodium hydride / mineral oil; dimethyl sulfoxide / 1.17 h / 10 - 20 °C / Cooling with ice 1.2: 1.5 h / 20 °C 2.1: ammonium hydroxide / methanol; water / 0 - 20 °C 3.1: triethylamine / dichloromethane / 0.92 h / 0 °C / Inert atmosphere 4.1: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 6.1: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 7.1: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
Multi-step reaction with 7 steps 1.1: sodium hydride / mineral oil; dimethyl sulfoxide / 1.16 h / 10 - 20 °C / Inert atmosphere 1.2: 1.5 h / 20 °C / Inert atmosphere 2.1: ammonium hydroxide / water; methanol / 0 - 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 1.17 h / 0 - 20 °C / Inert atmosphere 4.1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 - 20 °C / Inert atmosphere 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 6.1: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 7.1: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere
  • 22
  • [ 23804-68-4 ]
  • [ 1023595-11-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 0.92 h / 0 °C / Inert atmosphere 2: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 3: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 4: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 5: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 1.17 h / 0 - 20 °C / Inert atmosphere 2: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 - 20 °C / Inert atmosphere 3: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 4: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 5: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere
  • 23
  • [ 19867-34-6 ]
  • [ 1023595-11-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine / methanol; water / 36 h / 50 °C 2: sodium hydroxide / tetrahydrofuran; ethanol / 5 h / Reflux 3: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 4: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
Multi-step reaction with 6 steps 1: ammonium hydroxide / methanol; water / 0 - 20 °C 2: triethylamine / dichloromethane / 0.92 h / 0 °C / Inert atmosphere 3: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 4: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 5: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 6: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
Multi-step reaction with 6 steps 1: ammonium hydroxide / water; methanol / 0 - 20 °C / Inert atmosphere 2: triethylamine / dichloromethane / 1.17 h / 0 - 20 °C / Inert atmosphere 3: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 - 20 °C / Inert atmosphere 4: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 5: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 6: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere
  • 24
  • 9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • [ 1023595-11-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 2: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 3: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
Multi-step reaction with 3 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 2: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 3: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere
  • 25
  • N-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]-2-chloroacetamide [ No CAS ]
  • [ 1023595-11-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium hydride / mineral oil; tetrahydrofuran / 1 h / 0 - 20 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux 3: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 4: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
Multi-step reaction with 4 steps 1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 - 20 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 0.67 h / 0 °C / Reflux; Inert atmosphere 3: sodium carbonate / tetrahydrofuran; water / 1 h / 0 - 20 °C / Inert atmosphere 4: palladium 10% on activated carbon; ammonium formate / methanol / 1 h / 20 °C / Reflux; Inert atmosphere
  • 26
  • (2-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]amino}ethoxy)sulfonic acid [ No CAS ]
  • [ 1023595-11-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium hydroxide / tetrahydrofuran; ethanol / 5 h / Reflux 2: sodium carbonate / water; tetrahydrofuran / 1 h / 0 °C 3: ammonium formate; palladium 10% on activated carbon / methanol / 1 h / Reflux
  • 27
  • tert-butyl 9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
  • [ 1023595-11-0 ]
YieldReaction ConditionsOperation in experiment
96% With palladium 10% on activated carbon; ammonium formate In methanol for 1h; Reflux; 4; 6 Preparation 4: tert-butyl 1-oxa-4,9-diazaspiro[5.5] undecane-4-carboxylate (P4) To a solution of tert-butyl 9-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (2.26 g, 6.52 mmol, p3) in MeOH (45 mL) ammonium formate (2.47 g, 39.14 mmol) and 10% Pd/c (650 mg) were added atRT then the mixture was stirred under reflux for 1 h. The mixture was cooled down to RT and filtered through a pad of celite washing with MeOH. Solvent was eliminated under reduced pressure affording tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 1.6 g, y= 96%) as white wax.MS (ES) (m/z): 257.2 [M÷H]
With palladium 10% on activated carbon; ammonium formate In methanol at 20℃; for 1h; Reflux; Inert atmosphere; P69 Preparation 69: tert-butyl 1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate (P69) Preparation 69: tert-butyl 1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate (P69) To a solution of ieri-butyl 9-benzyl-l-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p68, 186 mg, 0.537 mmol) in MeOH (4 mL) ammonium formate (133 mg, 2.11 mmol) and 10% Pd/C (57 mg) were added at RT then the mixture was stirred under reflux for 1 h. The mixture was cooled down to RT and filtered through a pad of celite washing with MeOH. Solvent was eliminated under reduced pressure affording ieri-butyl l-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p69, 159 mg, crude material) as white wax.MS (ES) (m/z): 257.2 [M+H]+.
  • 28
  • [ 1023595-11-0 ]
  • 1-bromo-4,5-difluoro-2-(3-fluorophenoxy)benzene [ No CAS ]
  • tert-butyl 9-[4,5-difluoro-2-(3-fluorophenoxy)phenyl]-1-oxa-4,9diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77 mg With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 100℃; Inert atmosphere; 1.a To a stirred solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (p4, 150 mg, 0.585mmol) in Toluene (5 mL) at RT, BINAP (36 mg, 0.0585 mmol), sodium tert-butoxide (112 mg, 1.17 mmol)and 1-bromo-4,5-difluoro-2-(3-fluorophenoxy)benzene (p7, 178 mg, 0.585 mmol) were added and argon was purged for 10 mm. Eventually, Pd2(dba)3 (16 mg, 0.017 mmol) was added and the reaction mixture was shaken at 100 °C overnight. The reaction mixture was concentrated, water was added and then the mixture was extracted with EtOAc. The organic phase was dried, filtered and the solvent was eliminatedunder reduced pressure. The crude material was purified by FC on silica gel (eluent: Cy to 15% EtOAc) affording tert-butyl 9-[4,5-difluoro-2-(3-fluorophenoxy)phenyl]-1-oxa-4,9diazaspiro[5.5]undecane-4- carboxylate (77 mg) as yellow oil.
  • 29
  • [ 1023595-11-0 ]
  • 1-bromo-4,5-difluoro-2-(3-fluorophenoxy)benzene [ No CAS ]
  • 9-[4,5-difluoro-2-(3-fluorophenoxy)phenyl]-1-oxa-4,9-diazaspiro[5.5]undecane [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 100 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
  • 30
  • [ 1023595-11-0 ]
  • 9-[bis(4-fluorophenyl)methyl]-1-oxa-4,9-diazaspiro[5,5]undecane [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 20 °C / Reflux; Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C / Inert atmosphere
  • 31
  • [ 27064-94-4 ]
  • [ 1023595-11-0 ]
  • tert-butyl 9-[bis(4-fluorophenyl)methyl]-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In acetonitrile at 20℃; Reflux; Inert atmosphere; E31.a Step a Step a To a solution of tert-butyl 9-benzyl-1-oxa-4,9-diazaspiro[5,5]undecane-4-carboxylate (p69, 30 mg, 0.117 mmol) in Acetonitrile (1 mL), l-[chloro(4-fluorophenyl)methyl]-4-fluorobenzene (27 μ, 0.14 mmol) was added followed by K2C03(41 mg, 0.29 mmol). The mixture was heated to reflux for 7 hrs, then 0.2 eq of l-[chloro(4-fluorophenyl)methyl]-4-fluorobenzene were further added, the mixture refluxed for further 1 h, and then left stirring at T overnight. The day after, solid was filtered off washing with AcOEt and solvent was eliminated under reduced pressure affording ieri-butyl 9-[bis(4-fluorophenyl)methyl]-l-oxa- 4,9-diazaspiro[5.5]undecane-4-carboxylate (60 mg) used as such in next step.
  • 32
  • [ 1023595-11-0 ]
  • pentafluorophenyl (2R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl carbonate [ No CAS ]
  • 4-tert-butyl 9-{(2R)-1,1,1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl} 1-oxa-4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
11.2 g With triethylamine In acetonitrile at 0 - 25℃; for 15h; 7.1 Step 1. Synthesis of 4-tert-butyl 9-{(2R)-1 , 1 , 1-trifluoro-3-[(4-methoxybenzyl)oxy]propan-2-yl} 1- oxa-4, 9-diazaspiro[5.5]undecane-4, 9-dicarboxylate ( C30). Triethylamine (9.28 g, 91.7 mmol) was added to a 0 °C solution of te/ -butyl 1-oxa-4,9- diazaspiro[5.5]undecane-4-carboxylate (4.70 g, 18.3 mmol) in acetonitrile (60 mL); C2 (reaction solution in acetonitrile, containing 27.5 mmol) was then added drop-wise, and the reaction mixture was stirred at 0 °C few minutes. It was then allowed to warm to 25 °C and stir for 15 hours, whereupon it was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 100% dichloromethane in petroleum ether). The product (11.2 g) was isolated as a yellow oil, which by LCMS analysis was impure; this material was used without additional purification. LCMS m/z 555.1 [M+Na+].
  • 33
  • [ 1023595-11-0 ]
  • 2-fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)-4-(2-hydroxypropan-2-yl)benzamide [ No CAS ]
  • tert-butyl 9-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.42 g Stage #1: tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate; 2-fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)-4-(2-hydroxypropan-2-yl)benzamide In tetrahydrofuran at 60℃; Stage #2: With sodium cyanoborohydride In tetrahydrofuran at 60℃; 1 Step 1 : Tert-butvl 9-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2- methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)-1 -oxa-4,9-diazaspiro[5.5]undecane-4- carboxylate A mixture of tert-butyl 1 -oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (155 mg, 0.605 mmol) and 2-fluoro-N-(5-fluoro-3-(6-(4-formylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)- 4-(2-hydroxypropan-2-yl)benzamide (intermediate 3, 350 mg, 0.665 mmol) in THF (6 ml) was stirred overnight at 60°C. Solid NaBH(OAc)3(384 mg, 1 .814 mmol) was added and stirring was continued at 60°C for 9 h and at RT overnight. The RM was diluted with EtOAc, and washed with an aq. solution of NaHC03and brine. The organic phase was dried over Na2S04and concentrated to afford the title compound as a solid (0.42 g).Method A: Rt = 0.90 min; [M+H]+ = 767.5.
  • 34
  • [ 1023595-11-0 ]
  • 4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde [ No CAS ]
  • tert-butyl 9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% Stage #1: tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate; 4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde In methanol at 20℃; for 0.5h; Stage #2: With methanol; sodium cyanoborohydride at 20℃; for 2h; 60.5 Step 5: Preparation of tert-butyl 9-[[4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6- dimethoxyphenyl]methyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (i60-6) A solution of 4-(7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde(100 mg, 0.295 mmol, 1.00 equiv) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (83.1 mg, 0.324 mmol, 1.1 equiv) in MeOH (1.5 mL) was stirred for 30 minutes at room temperature. Then NaBH3CN (125 mg, 1.989 mmol, 6.75 equiv) was added. The resulting mixture was stirred for 2 hours at room temperature. The reaction solution was purified by Prep-TLC (DCM/ MeOH 20:1) to afford tert-butyl 9-[[4- (7-hydroxy-2-methyl-1-oxoisoquinolin-4-yl)-2,6-dimethoxyphenyl]methyl]-1-oxa-4,9- diazaspiro[5.5]undecane-4-carboxylate (134 mg, 78%) as a light brown foam. LCMS (ESI) m/z: [M+H]+ = 580.
  • 35
  • [ 835616-61-0 ]
  • [ 1023595-11-0 ]
  • C26H32N4O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With 1-methyl-pyrrolidin-2-one; diisopropylamine at 20 - 90℃; for 6h; Inert atmosphere; 78.1 Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3- dione (i78-2) To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.50 g, 5.430 mmol, 1.00 equiv) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (1.67 g, 6.516 mmol, 1.20 equiv) in NMP (10.00 mL) was added DIEA (1.40 g, 10.861 mmol, 2.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 6 hours at 90 °C under nitrogen atmosphere. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 20 minutes; detector, UV 254 nm). This resulted in tert-butyl 9-(2- (2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (2 g, 72%) as a green oil. LCMS (ESI) m/z: [M+H]+ = 513.
  • 36
  • [ 1023595-11-0 ]
  • 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1-methyl-pyrrolidin-2-one; diisopropylamine / 6 h / 20 - 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
  • 37
  • [ 1023595-11-0 ]
  • methyl 5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-methyl-pyrrolidin-2-one; diisopropylamine / 6 h / 20 - 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3: sodium cyanoborohydride; methanol / 2 h / 20 °C
  • 38
  • [ 1023595-11-0 ]
  • 5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]pentanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 1-methyl-pyrrolidin-2-one; diisopropylamine / 6 h / 20 - 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3: sodium cyanoborohydride; methanol / 2 h / 20 °C 4: hydrogenchloride / water / 2 h / 20 °C
  • 39
  • [ 1023595-11-0 ]
  • N-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl]-5-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-N-methylpentanamide formic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 1-methyl-pyrrolidin-2-one; diisopropylamine / 6 h / 20 - 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3: sodium cyanoborohydride; methanol / 2 h / 20 °C 4: hydrogenchloride / water / 2 h / 20 °C 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C
  • 40
  • [ 1023595-11-0 ]
  • tert-butyl N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 1-methyl-pyrrolidin-2-one; diisopropylamine / 6 h / 20 - 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3: sodium cyanoborohydride / N,N-dimethyl-formamide / 5 h / 20 °C
  • 41
  • [ 1023595-11-0 ]
  • 5-[4-(4-aminobutyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 1-methyl-pyrrolidin-2-one; diisopropylamine / 6 h / 20 - 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3: sodium cyanoborohydride / N,N-dimethyl-formamide / 5 h / 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C
  • 42
  • [ 1023595-11-0 ]
  • 2-([[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl](methyl)amino)-N-(4-[9-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]butyl)acetamide formic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 1-methyl-pyrrolidin-2-one; diisopropylamine / 6 h / 20 - 90 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3: sodium cyanoborohydride / N,N-dimethyl-formamide / 5 h / 20 °C 4: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C
  • 43
  • [ 1023595-11-0 ]
  • 4-(3,5-dimethoxy-4-[1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl]phenyl)-2-methyl-7-(methylamino)-2,6-naphthyridin-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium cyanoborohydride; methanol / 2 h / 25 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C
  • 44
  • [ 1023595-11-0 ]
  • 4-([5-[9-([2,6- dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1-oxa-4,9- diazaspiro[5.5]undecan-4-yl]-5-oxopentyl]oxy)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione formic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium cyanoborohydride; methanol / 2 h / 25 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 25 °C 3: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 2 h / 25 °C
  • 45
  • [ 1023595-11-0 ]
  • 2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]benzaldehyde [ No CAS ]
  • tert-butyl 9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin- 4-yl]phenyl]methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65.5% With methanol; sodium cyanoborohydride at 25℃; for 2h; 26.1 To a solution of 2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4- yl]benzaldehyde (100 mg, 0.283 mmol, 1.00 equiv) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4- carboxylate (87.1 mg, 0.340 mmol, 1.20 equiv) in MeOH (2.00 mL) was added NaBH3CN (35.6 mg, 0.566 mmol, 2.00 equiv), and the resulting solution was stirred at 25 °C for 2 hours. The resulting mixture was concentrated. The residue was applied onto a silica gel column with DCM/MeOH (20:1). This resulted in tert-butyl 9-([2,6-dimethoxy-4-[2-methyl-7-(methylamino)-1-oxo-2,6-naphthyridin-4-yl]phenyl]methyl)-1- oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (110 mg, 65.5%) as a yellow solid. LCMS (ESI) m/z: [M+H]+ = 594.
  • 46
  • [ 1023595-11-0 ]
  • 2-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]ethyl 4-methylbenzenesulfonate [ No CAS ]
  • tert-butyl 9-[2-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy] ethyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With N-ethyl-N,N-diisopropylamine; potassium iodide In acetonitrile at 100℃; for 12h; 4 Step 4 To a solution of 2-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy]ethyl 4- methylbenzenesulfonate (300 mg, 0.68 mmol, 1 eq) and tert-butyl l-oxa-4,9- diazaspiro[5.5]undecane-4-carboxylate (209 mg, 0.81 mmol, 1.2 eq) in acetonitrile (3 mL) was added N,N-diisopropylethylamine (263 mg, 2.03 mmol, 3 eq) and potassium iodide (113 mg, 0.68 mmol, 1 eq). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by addition water 10 mL, and then further diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (dichloromethane: methanol = 100: 1 to 20: 1). The desired compound tert-butyl 9-[2-[3-[(5-bromo-2-pyridyl)oxy]cyclobutoxy] ethyl]-l- oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (300 mg, 0.55 mmol, 81% yield) was obtained as a light yellow oil.
  • 47
  • [ 446273-59-2 ]
  • [ 1023595-11-0 ]
  • tert-butyl 9-(3-amino-6-chloropyridazin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With potassium carbonate In N,N-dimethyl acetamide at 110℃; for 20h; Inert atmosphere; 2.a a) tert-butyl 9-(3-amino-6-chloropyridazin-4-yl)-1-oxa-4.9-diazaspiro[5.5]undecane-4-carboxylate To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (600 mg, 2.88 mmol, 1.0 eq) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (812 mg, 3.17 mmol, 1.1 eq) in DMA (8 mL) was added potassium carbonate (1.19 g, 8.64 mmol, 3.0 eq). The reaction mixture was heated to 110 °C and stirred for 20 h. The reaction mixture was poured in water and extracted with EtOAc. The organic layers were combined, washed with sat NaHCO3, WATER and brine. The organic layers were dried over Na2SO4and concentrated in vacuo. The crude material was purified on silica column (heptane/EtOAc 0-100%) to afford the title compound (1.02 g, 2.66 mmol, 92% yield) as a light brown solid. MS (ESI): 384.2 ([M+H]+).
92% With potassium carbonate In N,N-dimethyl acetamide at 110℃; for 20h; Inert atmosphere; Intermediate 12a: tert-butyl 9-(3-amino-6-chloro-pyridazin-4-yl)-1-oxa-4,9- diazaspiro[5.5]undecane-4-carboxylate To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (600 mg, 2.88 mmol, 1.0 eq) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (812 mg, 3.17 mmol, 1.1 eq) in DMA (8 mL) was added potassium carbonate (1.19 g, 8.64 mmol, 3.0 eq). The reaction mixture was heated to 110 °C and stirred for 20 h. The reaction mixture was poured in H2O and extracted with EtOAc. The organic layers were combined, washed with sat NaHCO3, H2O and brine. The organic layers were dried over Na2SO4and concentrated in vacuo. The crude material was purified by flash chromatography (Heptane/EtOAc 0- 100) to afford the title compound (1.02 g, 2.66 mmol, 92% yield) as a light brown solid. MS (ESI): 384.2 ([M+H]+).
  • 48
  • [ 1023595-11-0 ]
  • 4-[4-[3-[9-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-3-oxo-propyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere 3: hydrogenchloride / water; dichloromethane; 1,4-dioxane / 16 h / 0 - 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere
  • 49
  • [ 1023595-11-0 ]
  • tert-butyl 9-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere
  • 50
  • [ 1023595-11-0 ]
  • 2-[6-amino-5-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyridazin-3-yl]phenol hydrochloride salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere 3: hydrogenchloride / water; dichloromethane; 1,4-dioxane / 16 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 16 h / 0 - 20 °C / Inert atmosphere
  • 51
  • [ 1023595-11-0 ]
  • (2S,4R)-1-[(2S)-2-[[4-[9-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-4-oxobutanoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 16 h / 0 - 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
  • 52
  • [ 1023595-11-0 ]
  • (2S,4R)-1-[(2S)-2-[[7-[9-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-7-oxoheptanoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 16 h / 0 - 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
  • 53
  • [ 1023595-11-0 ]
  • (2S,4R)-1-[(2S)-2-[[12-[9-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-12-oxododecanoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 16 h / 0 - 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
  • 54
  • [ 1023595-11-0 ]
  • (2S,4R)-1-[(2S)-2-[[14-[9-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl]-14-oxo-tetradecanoyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl acetamide / 20 h / 110 °C / Inert atmosphere 2: potassium carbonate; methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II) / water; 1,4-dioxane / 16 h / 120 °C / Inert atmosphere 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 16 h / 0 - 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere
  • 55
  • [ 1023595-11-0 ]
  • 2-[4-(4-chlorophenyl)-5-(pyridin-4-yl)-1H-imidazol-1-yl]acetic acid 2,2,2-trifluoroacetic acid [ No CAS ]
  • tert-butyl 9-{2-[4-(4-chlorophenyl)-5-(pyridin-4-yl)-1H-imidazol-1-yl]acetyl}-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85 mg With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 1h; 1.8 Synthesis of tert-butyl 9-{2-[4-(4-chlorophenyl)-5-(pyridin-4-yl)-1H-imidazol-1-yl]acetyl}-1-oxa-4,9- diazaspiro[5.5]undecane-4-carboxylate / Intermediate 61 tert-Butyl 1-oxa-4,9- diazaspiro[5.5]undecane-4-carboxylate (50 mg, 0.195 mmol) and 2-[4-(4-chlorophenyl)-5-(4- pyridyl)imidazol-1-yl]acetic acid;2,2,2-trifluoroacetic acid (Intermediate 2a) (100 mg, 0.183 mmol) were dissolved in a solution of EtOAc (2 mL) and DIPEA (160 uL, 0.916 mmol) then T3P (50%, 220 uL, 0.370 mmol) was added. The mixture was stirred at RT for 1 h. The reaction was concentrated in vacuo. The crude product was purified via preparative HPLC (Method A1) to afford the title compound (85 mg, 83% yield) as a brown solid. 1HNMR(400 MHz, DMSO-d6) δ 8.67 - 8.61 (m, 2H), 7.78 (s, 1H), 7.41 - 7.36 (m, 2H), 7.31 - 7.25 (m, 4H), 4.86 (s, 2H), 3.83 - 3.69 (m, 1H), 3.63 - 3.57 (m, 2H), 3.51 - 3.39 (m, 1H), 3.36 - 3.32 (m, 2H), 3.20 (s, 4H), 1.70 - 1.62 (m, 2H), 1.44 (s, 9H), 1.32 - 1.23 (m, 2H). LCMS (Analytical Method H) Rt = 0.57 min, MS (ESIpos): m/z 552.5, 554.3 [M+H]+, Purity = 100%.
  • 57
  • [ 1023595-11-0 ]
  • [ 59986-44-6 ]
  • [ 76-05-1 ]
  • C22H26N2O3*C2HF3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate; 4-fluorobenzoic acid benzyl ester With potassium carbonate In N,N-dimethyl-formamide Stage #2: trifluoroacetic acid
  • 58
  • [ 1023595-11-0 ]
  • [ 59986-44-6 ]
  • C27H34N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide
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