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[ CAS No. 173405-78-2 ] {[proInfo.proName]}

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Chemical Structure| 173405-78-2
Chemical Structure| 173405-78-2
Structure of 173405-78-2 * Storage: {[proInfo.prStorage]}
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Product Details of [ 173405-78-2 ]

CAS No. :173405-78-2 MDL No. :MFCD05861627
Formula : C14H26N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :YLKHACHFJMCIRE-UHFFFAOYSA-N
M.W : 254.37 Pubchem ID :15296367
Synonyms :

Calculated chemistry of [ 173405-78-2 ]

Physicochemical Properties

Num. heavy atoms : 18
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 : 80.16
TPSA : 41.57 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) : -6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.05
Log Po/w (XLOGP3) : 1.77
Log Po/w (WLOGP) : 1.63
Log Po/w (MLOGP) : 1.97
Log Po/w (SILICOS-IT) : 1.82
Consensus Log Po/w : 2.05

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.33
Solubility : 1.18 mg/ml ; 0.00463 mol/l
Class : Soluble
Log S (Ali) : -2.26
Solubility : 1.39 mg/ml ; 0.00548 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.66
Solubility : 0.559 mg/ml ; 0.0022 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.81

Safety of [ 173405-78-2 ]

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 [ 173405-78-2 ]

* 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 [ 173405-78-2 ]

[ 173405-78-2 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 59-67-6 ]
  • [ 173405-78-2 ]
  • [ 851324-35-1 ]
YieldReaction ConditionsOperation in experiment
77% With 1-methyl-pyrrolidin-2-one; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 20℃; for 1h; 5.a Example : 5; 3- (2-propoxybenzyl)-9- (pyridin-3-ylcarbonyl)-3, 9-diazaspiro [5. 5] undecane bis (trifluoroacetate); a) tert-butyl 9- (pyridin-3-ylcarbonyl)-3, 9-diazaspiro [5. 5] undecane-3-carboxylate; tert-Butyl 3,9-diazaspiro [5. 5] undecane-3-carboxylate (1.72 mmol, 500 mg), nicotinic acid (1.72 mmol, 212 mg), DIEA (3.44 mmol, 589 1) and HBTU (1.72 mmol, 652 mg) in NMP (2.5 ml) were mixed and vigorously stirred for 1 h at room temperature. Water was added and the mixture was extracted with EtOAc. Flash chromatography provided the title compound (476 g, 77 %). APCI-MS m/z: 304 [MH+]
  • 2
  • [ 65-85-0 ]
  • [ 173405-78-2 ]
  • [ 851322-37-7 ]
YieldReaction ConditionsOperation in experiment
92% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h; General procedure for the synthesisof compound G2 General procedure: Toa stirred solution of G1 (1.0 mmol) in CH2Cl2 (10 mL)was added benzoic acid (1.0 mmol), EDCI (1.3 mmol) and DMAP (0.6 mmol) at room temperature.The mixture was stirred for 8 h and concentrated. The residue was purified oversilica gel column (PE: EA = 1 : 1) to yield solid G2.
76% With 1-methyl-pyrrolidin-2-one; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 20℃; for 1h; 1.a Example 1; 3-benzoyl-9- (2-ethoxybenzyl)-3, 9-diazaspiro [5.5] undecane trifluoroacetate; a) tert-butyl 9-benzoyl-3, 9-diazaspiro [5. 5] undecane-3-carboxylate; tert-Butyl 3,9-diazaspiro [5.5] undecane-3-carboxylate (3.44 mmol, 1.00 g), benzoic acid (3.44 mmol, 0.42 g), DIEA (6. 88 mmol, 1. 18 ml) and HBTU (3.44 mmol, 1.31 g) in NMP (5 ml) were mixed and vigorously stirred for 1 h at room temperature. Water was added and the mixture was extracted with EtOAc. Flash chromatography provided the title compound (0.94 g, 76 %). APCI-MS m/z: 303.2, 359 [MH+]
  • 3
  • [ 5111-65-9 ]
  • tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate [ No CAS ]
  • [ 918653-16-4 ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: 2-Bromo-6-methoxynaphthalene; tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With sodium t-butanolate In toluene for 0.5h; Stage #2: With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene Heating / reflux; A A mixture of 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (500 mg, 1.97 mmol), 2-bromo-6-methoxynaphthalene (934 mg, 3.94 mmol) and sodium tert- butoxide (379 mg, 3.94 mmol) in dry toluene (10 ml_) was degassed with argon for 30 min. Palladium(ll) acetate (22 mg, 0.1 mmol) and 2,2'-bi(diphenylphosphino)-1 ,1'- binaphthalene (BINAP) (61.3 mg, 0.2 mmol) were added and the mixture heated to reflux over night. The mixture was filtered and the filtrate evaporated to dryness. Flash chromatography (ethyl acetate/heptane 1 :4) gave 666 mg (82%) of 3-(6-methoxy- naphthalen^-ylJ-S.Θ-diaza-spirotδ.δJundecane-S-carboxylic acid te/if-butyl ester.
  • 4
  • [ 50-00-0 ]
  • [ 173405-78-2 ]
  • [ 918653-13-1 ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: formalin; 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester In methanol; lithium hydroxide monohydrate at 0 - 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In methanol; lithium hydroxide monohydrate for 12h; 10.1 Step 1 : Preparation of tert-butyl 9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxylate To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.7 g, 2.75 mmol, 1 eq) in MeOH (12 mL) was added HCHO (1 .12 g, 13.7 mmol, 37% aqueous, 5 eq) at 0°C. The mixture was warmed to 20 °C and stirred for 0.5 hr, then NaBH(OAc)3 (1 .75 g, 8.26 mmol, 3 eq) was added into the mixture, and the mixture was stirred for another 12 hr. The reaction mixture was concentrated. The residue was diluted with H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a product (0.7 g, 95% yield) as a colorless oil. (0263) 1H NMR (400 MHz, CDCh-d) 53.43 - 3.34 (m, 4H), 3.31 - 2.79 (m, 4H), 2.71 (s, 3H), 1 .88 (s, 4H), 1.50 (s, 4H), 1.45 (s, 9H).
95% Stage #1: formalin; 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester In methanol; lithium hydroxide monohydrate at 0 - 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In methanol; lithium hydroxide monohydrate for 12h; 10.1 Step 1 : Preparation of tert-butyl 9-methyl-3,9-diazaspiro[5.5]undecane-3-carboxylate To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.7 g, 2.75 mmol, 1 eq) in MeOH (12 mL) was added HCHO (1 .12 g, 13.7 mmol, 37% aqueous, 5 eq) at 0°C. The mixture was warmed to 20 °C and stirred for 0.5 hr, then NaBH(OAc)3 (1 .75 g, 8.26 mmol, 3 eq) was added into the mixture, and the mixture was stirred for another 12 hr. The reaction mixture was concentrated. The residue was diluted with H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a product (0.7 g, 95% yield) as a colorless oil. (0263) 1H NMR (400 MHz, CDCh-d) 53.43 - 3.34 (m, 4H), 3.31 - 2.79 (m, 4H), 2.71 (s, 3H), 1 .88 (s, 4H), 1.50 (s, 4H), 1.45 (s, 9H).
79% Stage #1: formalin; 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester In methanol at 0 - 16℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In methanol at 16℃; for 12h; 23.23A Example 23A tert-butyl 9-methyl-3,9-diazaspiro[5.5]undecan-3-carboxylate At 0 deg.C, tert-butyl 3,9-diazaspiro[5.5]undecan-3-carboxylate (120 mg, 0.47 mmol) in methanol (5mL) was added 37% formaldehyde solution (71 mg , 2.36 mmol). The reaction mixture was stirred at 16 deg.C for 0.5 hours. Then sodium triacetoxyborohydride(299 mg, 1.42 mmol) was added to the reaction mixture, and stirred at 16 deg.C for 12 hours. LCMS showed the reaction was complete. The mixture was concentrated to remove the solvent, the residue was washed with water (10 mL) was diluted with dichloromethane (60mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a colorless oil (100 mg, 79% yield).
79% With sodium tris(acetoxy)borohydride In methanol; lithium hydroxide monohydrate at 0 - 16℃; for 12.5h; 17 Example 17 Tert-butyl-9-methyl-3,9-diazaspiro [5.5] undecane-3-carboxylate To a solution of tert-butyl-3,9-diazaspiro [5.5] undecane (120 mg, 1 eq.) In methanol (5 mL)was added 37% aqueous formaldehyde (5 equivalents)at 0 ° C, The mixture was warmed to 16 ° C and stirred for 0.5 hour.Sodium borohydrideacetate(89 mg, 3 eq.) Wasthen addedand stirred at 16 ° C for 12 hours.TLC to detect the total conversion of raw materials, concentrated at 35 under reduced pressure.Diluted withdichloromethane(50 mL), washed three times with water, twice with saturated brine (30 mL), dried over sodium sulfate, filtered and the organic phasewasconcentrated togive the title compound as a colorless oil (100 mg, 79% yield ).
78% Stage #1: formalin; 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester With methanol at 20℃; for 1h; Stage #2: With sodium tetrahydridoborate at 0 - 20℃; for 2h; 31.1 Preparation of tert-butyl 9-methyl-3,9-diazaspiro[5.5]undecan-3-carboxylate 2 g (6.88 mmol) of tert-butyl 3,9-diazaspiro[5.5]undecan-3-carboxylate was diluted with 20 ml of methanol 20 ml, and 2 ml of formaldehyde was added thereto and then stirred at room temperature for 1 hour 390 mg (10.3 mmol) of sodium borohydride was slowly added at 0 °C and then stirred at room temperature for 2 hours After the reaction was completed, the reaction mixture was diluted with ethyl acetate and then washed with sodium bicarbonate and distilled water. The resulting separated organic layer was dried with anhydrous sodium sulfate and then filtered under reduced pressure and distilled under reduced pressure to obtain 1.45 g of the compound of the title (Yield: 78 %). 1H-NMR (300MHz, CDCl3) δ 3.39 (m, 4H), 2.65 (m, 4H), 2.47 (s, 3H), 1.67 (m, 4H), 1.46 (s, 9H), 1.44 (m, 4H).
27% Stage #1: formalin; 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester In 1,1-dichloroethane at 0℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In 1,1-dichloroethane at 20℃; To an ice cooled solution of 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 ,55 g, 6 mmol) in dichloroethane (50 ml_) formaldehyde (0.68 ml_, 9 mmol) was added and stirred for 1 h at O0C. Sodium triacetoxyborohydride (2.54 g, 12 mmol) was added and the reaction stirred at room temperature over night. Aqueous sodium hydrogencarbonate (sat. 50 ml_) and water (50 ml_) were added and the aqueous phase extracted five times with dichloromethane. The combined organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated. Flash chromatography (dichloromethane/methanol 9:1 with 1% ammonium hydroxide) gave 435 mg (27%) θ-methyl-S.Θ-diaza-spirotδ.δjundecane-S-carboxylic acid tert-butyl ester.
Stage #1: formalin; 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester With hydrogen; toluene-4-sulfonic acid In lithium hydroxide monohydrate for 16h; Heating / reflux; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate 7 EXAMPLE 7 Preparation of 3-Methyl-3,9-diaza-spiro[5.5]undecane (30). A mixture of 0.625 g (2.5 mmol) of 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (28) (Syntech) and 0.470 g (2.5 mmol) of TsOH.H2O in 25 mL of water was sonicated with heating to afford a solution. To this solution was added 2.0 mL (24.6 mmol) of formaldehyde followed by 0.629 g of 10% Pd/C. The mixture was agitated under a 50 psi atmosphere of hydrogen for 16 h. The reaction mixture was filtered through Celite and the solution adjusted to pH 11 with 1 M NaOH. The mixture was extracted with CHCl3, dried over MgSO4, filtered and the solvent removed by rotary evaporation to afford compound 29. Stirring compound 29 in neat TFA for 15 min followed by removal of the TFA by rotary evaporation afforded compound 30.

  • 5
  • [ 2402-78-0 ]
  • [ 173405-78-2 ]
  • [ 918653-22-2 ]
YieldReaction ConditionsOperation in experiment
84% Stage #1: 2,6-dichloropyridine; tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With sodium carbonate In toluene for 0.5h; Stage #2: With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene Heating / reflux; B 3,9-Diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (300 mg, 1.18 mmol), 2.6-dichlororpyridine (349 mg, 2.36 mmol) and sodium carbonate (250 mg, 2.35 mmol) in dry toluene were stirred under argon for 30 min. Bisdibenzylideneacetone palladium (Pd2(dba)3) (4 mg, 0.06 mmol) and 9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene (Xantphos) (68 mg, 0.12 mmol) were added and the mixture warmed to reflux overnight. Both bisdibenzylideneacetone palladium (Pd2(dba)3) (54 mg, 0.06 mmol) EPO and 9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene (Xantphos) (68 mg, 0.12 mmol) were added again and the mixture warmed to reflux overnight. The mixture was filtered and the filtrate concentrated in vacuo. Flash chromatography (ethyl acetate/heptane 1 :20 - 1 :5) gave 383 mg (84%) of 3-(6-chloro-pyridin-2-yl)-3,9-diaza-spiro[5.5]- undecane-3-carboxylic acid terf-butyl ester.
  • 6
  • [ 7379-35-3 ]
  • [ 173405-78-2 ]
  • [ 336190-91-1 ]
YieldReaction ConditionsOperation in experiment
39% With triethylamine In butan-1-ol for 15h; Reflux; 2.i Stage (i): tert-Butyl 9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1 g, 3.931 mmol), 4-chloropyridinium chloride (1.765 g, 11.794 mmol) and triethylamine (2.2 ml, 15.725 mmol) were refluxed in 1-butanol (50 ml) for 15 h. Saturated sodium bicarbonate solution (30 ml) and ethyl acetate (80 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2*80 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane/methanol/ammonia (25% aq) 400/40/40/1. Yield: 0.52 g (39%) Alternatively, this reaction can also be carried out with 4-fluoropyridine (or the corresponding hydrochloride). The target compound also can alternatively be prepared via Hartwig-Buchwald coupling with 4-bromopyridine in the presence of a suitable palladium catalyst, such as e.g. tris(dibenzylidene-acetone)dipalladium/(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, in toluene and in the presence of a suitable base, for example sodium tert-butylate, at 90° C.
39% With triethylamine In butan-1-ol for 15h; Reflux; 5.F.12.i Amine F-12: 3-(Pyridin-4-yl)-3,9-diazaspiro[5.5]undecane dihydrochioride(i): Tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1 g, 3.931 mmol), 4-chloropyridinium chloride (1.765 g, 11.794 mmol) and triethylamine (2.2 ml, 15.725 mmol) were refluxed for 15 hours in 1-butanol (50 ml). Saturated sodium hydrogen carbonate solution (30 ml) and ethyl acetate (80 ml) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate (2×80 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexane/methanol/ammonia (25% aq.), 400:40:40:1). Yield: 0.52 g (39%).
39% With triethylamine In butan-1-ol for 15h; Reflux; 5.i tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1 g, 3.931 mmol), 4-chloropyridinium chloride (1.765 g, 11.794 mmol) and triethylamine (2.2 ml, 15.725 mmol) were refluxed for 15 h in 1-butanol (50 ml). Saturated sodium hydrogen carbonate solution (30 ml) and ethyl acetate (80 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×80 ml). The combined organic phases were dried over magnesium sulfate and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane/methanol/ammonia (25% eq.) 400/40/40/1. Yield: 0.52 g, 39%
39% With triethylamine In butan-1-ol for 15h; Reflux; 5.i tert-Butyl-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 g, 3.931 mmol), 4-chloro-pyridinium chloride (1.765 g, 11.794 mmol) and triethylamine (2.2 ml, 15.725 mmol) were refluxed for 15 h in 1-butanol (50 ml). Saturated sodium hydrogen carbonate solution (30 ml) and ethyl acetate (80 ml) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate (2×80 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/-hexane/methanol/ammonia (25% aq.), 400:40:40:1). Yield: 0.52 g (39%)
39% With triethylamine In butan-1-ol for 15h; Reflux; A.5.i Synthesis of the amine unit A M N -01 : 9-pyridin-4-yl-3,9- diazaspiro[5.5]undecane dihydrochloride (AMN-01); (i): tert-Butyl S.Θ-diazaspirotδ.Slundecane-S-carboxylate (1 g, 3.931 mmol), 4- chloropyridinium chloride (1.765 g, 11.794 mmol) and triethylamine (2.2 ml, 15.725 mmol) were refluxed in 1-butanol (50 ml) for 15 h. Saturated sodium bicarbonate solution (30 ml) and ethyl acetate (80 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 80 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate / hexane / methanol / ammonia (25 % aq.) 400 / 40 / 40 / 1. Yield: 0.52 g, 39 %

  • 7
  • [ 460-00-4 ]
  • [ 173405-78-2 ]
  • [ 1246508-51-9 ]
YieldReaction ConditionsOperation in experiment
43% With sodium t-butanolate In toluene for 4h; Inert atmosphere; Heating; Reflux; acid tert-butyl ester (AMN_CC-22) BINAP (350 mg, 0.47 mmol) and Pd2dba3 (317 mg, 1.57 mmol) was added to a mixture of 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (2 g, 7.87 mmol), 1-bromo-4-fluoro-benzene (1.3 g, 7.87 mmol) and sodium tert-butylate (2.26 g, 23.61 mmol) in toluene (25 ml) and the reaction mixture was degassed under argon for 20 minutes and heated under reflux for 4 h. The mixture was then diluted with ethyl acetate, stirred for 15 minutes and filtered over Celite. The reaction mixture was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 43%
  • 8
  • [ 65520-08-3 ]
  • [ 173405-78-2 ]
  • [ 1246508-50-8 ]
YieldReaction ConditionsOperation in experiment
31% With sodium t-butanolate In toluene for 4h; Inert atmosphere; Heating; Reflux; acid tert-butyl ester (AMN_CC-21) BINAP (147 mg, 0.23 mmol) and Pd(OAc)2 (159 mg, 0.74 mmol) was added to a mixture of 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (3 g, 11.81 mmol), 3-bromopyridine HCl (2.29 g, 11.81 mmol) and sodium tert-butylate (3.4 g, 35.45 mmol) in toluene and the reaction mixture was degassed under argon for 20 minutes and heated under reflux for 4 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, stirred for 15 minutes and filtered over Celite. The reaction mixture was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 31%
  • 9
  • [ 843673-58-5 ]
  • [ 173405-78-2 ]
  • [ 1246508-52-0 ]
YieldReaction ConditionsOperation in experiment
35% Stage #1: tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2h; Stage #2: 4-(bromomethyl)-pyridine hydrochloride In N,N-dimethyl-formamide; mineral oil at 20℃; for 16h; Synthesis of amine (AMN CC-23): 9-(Pyridin-4-yl-methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (AMN_CC-23) NaH (60% strength in mineral oil, 709 mg, 29.52 mmol) was added to a mixture of 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (2.5 g, 9.84 mmol) in DMF (50 ml) at 0° C., the mixture was stirred at room temperature for 2 h, 4-(bromomethyl)-pyridine HCl (2.42 mg, 14.76 mmol) was then added and the mixture was stirred at room temperature for 16 h. Finally, ice was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase methanol/methylene chloride). Yield: 35%
  • 10
  • [ 19524-06-2 ]
  • tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate [ No CAS ]
  • [ 336190-91-1 ]
YieldReaction ConditionsOperation in experiment
45% With (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); sodium t-butanolate In toluene at 90℃; for 4h; Inert atmosphere; 1. Sodium tert-butylate (4 mmol) was added to a solution of 4-bromopyridine hydrochloride (1.9 mmol) in dry toluene (10 ml) under argon, followed by 3,9- diazaspiro [5.5] undecane-3-carboxylic acid tert-butyl ester (1.6 mmol) in toluene (5 ml). Argon was added to the mixture for 15 min, then (S)-(-)-2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl (0.123 mmol) and tris(dibenzylidene acetone)dipalladium (0.041 mmol) were added. The mixture was heated at 9O0C for 4 h and the reaction progress was monitored by thin-layer chromatography. On completion of the reaction the mixture was diluted with ethyl acetate (100 ml) and extracted with water and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (3% methanol in DCM). Yield: 45%
  • 11
  • [ 1258070-82-4 ]
  • [ 173405-78-2 ]
  • [ 1258071-15-6 ]
YieldReaction ConditionsOperation in experiment
80.15% Stage #1: 2-(1-(((4-methoxy-2,6-dimethyl-phenyl)sulfonyl)-methyl-amino)-ethyl)-3H-benzoimidazole-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 0.25h; Stage #2: tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate In dichloromethane at 0 - 20℃; C.1.1 Library No. 2; Synthesis of the amine units (ASN CC):; Overview:; Synthesis of: N-(1 -(7-(3,9-diazaspiro[5.5]undecane-3-carbonyl)-1 H- benzo[d]imidazol-2-yl)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide(ASN_CC-01); Step 1 : 2-ϖ-rr(4-methoxv-2.6-dimethvl-phenvl)sulfonvll-methyl-aminol-ethvll-3H- benzoimidazole-4-carboxylic acid (ACI-02; 6.228 mol; 2.6g) was dissolved in dichlormethane (136 mL),1-hydroxybenzotriazolhydrat (1.557 mol, 0.204g) and N- ethyl-diisopropylamine (10.38 mol, 1.759 mL) were added at room temperature. The reaction mixture was cooled to O0C and 1-(3-dimethylaminopropyl)-3- ethylcarbdiimide hydrochloride (7.785 mol, 1.489g) was added stirring was continued at 00C for 15 min. Finally S.Θ-Diaza-spiro-IS.δl-undecane-S-carboxylic acid tert- butylester (5.19 mol, 1.32g) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with aqueous 0.5 M KOH solution for three times, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure.The crude product was purified by flash chromatography over silica with ethylacetate/ n-hexane (30:70 ->; 100:0) as mobile phase. Yield: 80.15 % (2.72g)
  • 12
  • [ 202336-25-2 ]
  • [ 173405-78-2 ]
  • [ 1643957-81-6 ]
YieldReaction ConditionsOperation in experiment
65% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; ieri-Butyl 9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phi diazaspiro[5.5]undecane-3-carboxylate ieri-Butyl 9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phi diazaspiro[5.5]undecane-3-carboxylate A mixture of (4-fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone (200 mg, 0.55 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (commercially available from for example Matrix Scientific) (279 mg, 1.1 mmol) was heated in a Biotage microwave at 130° C for 4 hours. The reaction mixture was cooled to room temperature, diluted with DMF (3 mL), and was then subjected directly to purification by mass-directed automated preparative HPLC (formic acid modifier) to afford the title compound (215 mg, 0.36 mmol, 65% yield). LCMS RT = 1.22 min, ES+ve m/z 599.5 [M+H]+.
  • 13
  • [ 1629046-58-7 ]
  • [ 173405-78-2 ]
  • [ 1800219-07-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With triethylamine In ethanol at 25℃; for 3h; Stage #2: (R)-5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine In ethanol for 48h; Reflux; A Step A: (R ert-butyl 9-(2-(6-(lH-tetrazol-l-vnpyridin-3-vn-2-hvdroxyethvn-3.9- diazaspiro Γ5.51undecane-3 -carboxylate Step A: (R ert-butyl 9-(2-(6-(lH-tetrazol-l-vnpyridin-3-vn-2-hvdroxyethvn-3.9- diazaspiro Γ5.51undecane-3 -carboxylate : To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane- 3-carboxylate (11.6 g, 0.04 mol) in EtOH (104 mL) was added TEA (6 mL). The mixture was stirred for 3h at 25°C. (i?)-5-(oxiran-2-yl)-2-(lH-tetrazol-l-yl)pyridine (7.56 g, 0.04 mol) was added. The mixture was heated to reflux for 48h. The mixture was concentrated, washed with brines, dried over Na2S04, and concentrated to provide the crude product. Further purification by chiral SFC (Column: AD, 250x30mmI.D.20um; Mobile phase: A: Supercritical C02, B: EtOH (0.05%NH3.H2O); Flow rate: 80 mL/min; Back pressure: lOObar; Wavelength: 220nm; Colum temp: 38 °C) afforded the title compound.
Stage #1: tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With triethylamine In ethanol at 25℃; for 3h; Stage #2: (R)-5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine In ethanol for 48h; Reflux; A Step A: (R)-tert-butyl 9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate Step A: (R)-tert-butyl 9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate: To a solution of iert-butyl 3,9-diazaspiro[5.5]undecane- 3-carboxylate (1 1.6 g, 0.04 mol) in EtOH (104 niL) was added TEA (6 niL). The mixture was stirred for 3h at 25°C. (R)-5-(oxiran-2-yl)-2-(lH-tetrazol-l-yl)pyridine (7.56 g, 0.04 mol) was added. The mixture was heated to reflux for 48h. The mixture was concentrated, washed with brines, dried over Na2S04, and concentrated to provide the crude product. Further purification by chiral SFC (Column: AD, 250x30mmI.D.20um; Mobile phase: A: Supercritical C02, B: EtOH (0.05%NH3.H2O); Flow rate: 80 mL/min; Back pressure: lOObar; Wavelength: 220nm; Colum temp: 38 °C) afforded the title compound.
Stage #1: tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With triethylamine In ethanol at 25℃; for 3h; Stage #2: (R)-5-(oxiran-2-yl)-2-(1H-tetrazol-1-yl)pyridine In ethanol for 48h; Reflux; Step A: (R)-tert-butyl 9-(2-(6-(1H-tetrazol-1-yl)pyridin-3-yl)-2-hydroxyethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate: To a solution of tert-butyl 3, 9-diazaspiro [5.5] undecane-3-carboxylate (11.6 g, 0.04 mol) in EtOH (104 mL) was added TEA (6 mL) . The mixture was stirred for 3h at 25 degree. (R) -5- (oxiran-2-yl) -2- (1H-tetrazol-1-yl) pyridine (7.56 g, 0.04 mol) was added. The mixture was heated to reflux for 48 h., concentrated, washed with brines, dried over Na2SO4, and concentrated to provide the crude product. Further purified by chiral SFC (Column: AD, 250×30mmI.D. 20um Mobile phase: A: supercritical CO2, B: EtOH (0.05NH3. H2O) flow rate: 80 mL/min Back pressure: 100bar wavelength: 220nm column temperature: 38 ) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H) , 8.51 (d, J 1.6 Hz, 1H) , 8.08-8.02 (m, 2H) , 4.84 (dd, J1 10.8 Hz, J2 3.6 Hz, 1H) , 3.38 (t, J 2.4 Hz, 4H) , 2.74 (t, J 4.8 Hz, 2H) , 2.61 (dd, J1 12.4 Hz, J2 3.6 Hz, 1H) , 2.47-2.41 (m, 3H) , 1.55 (dd, J1 10.8 Hz, J2 6.8 Hz, 4H) , 1.42 (s, 13H) .
  • 14
  • [ 1711-09-7 ]
  • [ 173405-78-2 ]
  • [ 1993414-61-1 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In dichloromethane at 0 - 25℃; for 2h; tert-butyl 9-(3-bromobenzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (58) To a solution of 57 (150 mg, 0.590 mmol) in DCM (3 mL) was added Et3N (123 μL, 0.885 mmol), and then was added dropwise a solution of 3-bromobenzoyl chloride (129 mg, 0.590 mmol) in DCM (3 mL) at 0 oC. The resulting solution was allowed to warm to 25 oC. After 2 h, the reaction mixture was then diluted with DCM (20 mL), washed with saturated aqueous NaHCO3 (20 mL). The water layer was extracted with DCM (4 × 20 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (PE/EtOAc = 1:1, v/v) to afford the desired product. 302 mg, 80%; oil; 1H NMR (300 MHz, CDCl3) δ 7.61-7.51 (m, 2H), 7.36-7.28 (m, 2H), 3.84-3.56 (m, 2H), 3.54-3.35 (m, 6H), 1.66 -1.49 (m, 6H), 1.49 - 1.43 (m, 11H). MS (ESI): m/z 437.7 [M + H+], 459.4 [M + Na+].
  • 15
  • [ 330794-02-0 ]
  • [ 173405-78-2 ]
  • [ 1854943-89-7 ]
YieldReaction ConditionsOperation in experiment
72.82% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 12h; 20.20B Example 20B tert-butyl 9-(2-fluoro-5-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecan-3-carboxylate To Example 20A (120 mg, 0.48 mmol) in dioxane (10 mL) solution was added tert-butyl 3,9-diazaspiro[5.5]undecan-3-carboxylate (139.59 mg, 0.48 mmol), Pd2 (dba) 3 (43.95 mg, 0.048 mmol), Xantphos (22.85 mg, 0.048 mmol) and cesium carbonate (469.14 mg, 1.44 mmol); The reaction mixture at 100 deg.C under stirring for 12 hours. TLC (PE: ethyl acetate = 2: 1) indicated the reaction was complete. The mixture was diluted with EtOAc (20mL), washed successively with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a dark oil, which was purified by column chromatography (the PE: ethyl acetate = 30: 1 , 20: 1), yielding the title compound (148 mg, 72.82% yield) as a yellow solid.
  • 16
  • [ 153281-13-1 ]
  • [ 173405-78-2 ]
  • [ 1800507-01-0 ]
YieldReaction ConditionsOperation in experiment
70% With triethylamine In tetrahydrofuran at 20℃; for 4h; 5.1 (1) Preparation of tert-butyl 9-((2-chloropyrimidin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-carboxylate (1) Preparation of tert-butyl 9-((2-chloropyrimidin-5-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-carboxylate 5-(Bromomethyl)-2-chloropyrimidine (326 mg, 1.57 mmol) was dissolved in tetrahydrofuran(10 mL), and triethylamine (158 mg, 1.57 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecan-3-carboxylate (200 mg, 0.79 mmol) were added under stirring. The reaction mixture was stirred at room temperature for 4 h, and filtrated under suction. The filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane: methanol=30:1) to get the title compound (210 mg, yield: 70%).
  • 17
  • [ 105-36-2 ]
  • [ 173405-78-2 ]
  • [ 2085748-15-6 ]
YieldReaction ConditionsOperation in experiment
67% With potassium carbonate In acetonitrile at 20℃;
66% With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran; 1,4-dioxane; toluene at 100℃; for 36h; Inert atmosphere;
With potassium carbonate In N,N-dimethyl-formamide at 20 - 60℃; for 3h; 17.1 Step 1: Preparation of tert-butyl 9-(2-ethoxy-2-oxoethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate To a stirred mixture of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (200.00 mg, 0.786 mmol, 1.00 equiv) and ethyl bromoacetate (131.30 mg, 0.786 mmol, 1.00 equiv) in DMF (6.00 mL) was added K2CO3 (217.33 mg, 1.572 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 3 h at 60 degrees C. The mixture was allowed to cool down to room temperature and water (100.00 ml) was added. Following extraction with EtOAc (3 x 100 mL), the combined organic layers were washed with brine (2 x 30 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (310 mg, crude) as a light yellow oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 340.46
  • 18
  • [ 1642844-58-3 ]
  • [ 173405-78-2 ]
  • [ 1642844-84-5 ]
YieldReaction ConditionsOperation in experiment
78% In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; 11.1 (1) tert-butyl 9 - (2 - cyano - 5, 5 - dimethyl -10 - oxo - 5, 10 - dihydro - 4H - benzo [f] thieno [3,2 - the b] indole -7 - yl) - 3, 9 - diaza spiro [5.5] undecane -3 - formic ester preparation The according to an example embodiment 9 section (1) step of the preparation method 2 - cyano - 5, 5 - dimethyl -10 - oxo - 5, 10 - dihydro - 4H - benzo [f] thieno [3,2 - the b] indole -7 - settling of the phosphor material (100 mg, 0 . 23mmol) butyl 3, 9 - diaza spiro [5.5] undecane -3 - a ester (585 mg, 2 . 3mmol) added to the NMP (5 ml) in, 120 °C oil bath 3 hours, adding ethyl acetate (50 ml), water sequentially, saturated sodium chloride aqueous solution washing, anhydrous sodium sulfate drying, silica gel column chromatography (PE: EA=1:1) to obtain the product (100 mg, yield 78%).
  • 19
  • [ 448-19-1 ]
  • [ 173405-78-2 ]
  • [ 1854943-65-9 ]
YieldReaction ConditionsOperation in experiment
94% With potassium carbonate In acetonitrile at 85℃; for 5h; 12 Tert-butyl ester 9- (3-Methoxy-4-nitrophenyl) -3,9-diazaspiro [5.5] undecane-3-carboxylate Tert-butyl-3,9-diazaspiro [5.5] undecane-3-carboxylate (5.00 g, 1 eq) and 4-fluoro-2-methoxy-1-nitrobenzene (4.04 (4.08 g, 29.49 mmol, 1.5equiv.)Was added to the solution of acetonitrile (50.00 mL)at 0 & lt; 0 & gt; C for 5 hours. TLC (DCM: MeOH = 10: 1, Rf = 0.5) The reaction was complete,water (30 mL) was added to the reaction solution and concentrated.Until the organic solvent evaporated after a solid precipitation.The mixture was filtered and the filter cake was filtered through apetroleum ether: ethyl acetate mixed solvent (volume ratio = 5: 1, 24 mL). The filter cake was washed with petroleum ether: ethyl acetate mixedsolvent (volume ratio = 20: 21 mL) was filtered and filtered, and the cake was dried to give the product (7.5 g, 94% yield) as a yellow solid.
93% With potassium carbonate In N,N-dimethyl-formamide at 60℃; 30.1 Step 2: Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (1-2) General procedure: 4-fluoro-2-methoxy-1-nitrobenzene (5.0 g, 29.22 mmol),A mixture of Boc-piperazine (6.5 g, 35.06 mmol) and potassium carbonate (6.0 g, 43.24 mmol) in N,N-dimethylformamide (43 mL) was stirred at room temperature. After stirring overnight, potassium carbonate (3.0 g) was added and the mixture was stirred for 2 days. Water was added to the reaction mixture, stirred, filtered, washed with water, and dried under vacuum to obtain the title compound (9.5 g, 96%).
With potassium carbonate In dimethyl sulfoxide at 90℃; for 12h; General procedure A: synthesis of compound 5 General procedure: A solution of Boc-protected spiro diamine, 4-fluoro-2-methoxy-1-nitrobenzene (1.3 eq) and K2CO3 (3 eq) in DMSO was stirred at 90°C for 12 h. LCMS showed the reaction was completed. The reaction mixture was diluted with H2O and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a residue, which was purified by p-TLC (PE: EtOAc = 1: 1) to give compound 5.
With potassium carbonate In dimethyl sulfoxide at 90℃; for 12h; General procedure A: synthesis of compound 5 General procedure: A solution of Boc-protected spiro diamine, 4-fluoro-2-methoxy-1-nitrobenzene (1.3 eq) and K2CO3 (3 eq) in DMSO was stirred at 90°C for 12 h. LCMS showed the reaction was completed. The reaction mixture was diluted with H2O and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a residue, which was purified by p-TLC (PE: EtOAc = 1: 1) to give compound 5.

  • 20
  • [ 2126803-73-2 ]
  • [ 173405-78-2 ]
  • [ 2143956-56-1 ]
YieldReaction ConditionsOperation in experiment
56.1% Stage #1: 6-(tert-butylsulfonyl)-7-(2-((2-chloropyrimidin-5-yl)oxy)ethoxy)-N-(3,4-dimethyl-1H-pyrazol-5-yl)quinazolin-4-amine With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 110℃; for 18h; Sealed tube; Stage #2: tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate In 1-methyl-pyrrolidin-2-one at 110℃; for 4h; Sealed tube; tert-butyl 9-(5-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7- yl)oxy)ethoxy)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate To 6-(tert-butylsulfonyl)-7-(2-((2-chloropyrimidin-5-yl)oxy)ethoxy)-N-(4,5-dimethyl-lH-pyrazol-3- yl)quinazolin-4-amine (81 mg, 0.152 mmol) in NMP (1 mL) was added tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate (58.1 mg, 0.228 mmol) and DIPEA (0.080 mL, 0.457 mmol). The reaction was stirred at 110 °C in a sealed tube for 18h. Additional tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate (58.1 mg, 0.228 mmol) was added and the reaction was stirred at 110 °C in a sealed tube for a further 4h. The reaction was concentrated, and the residue was subjected directly to purification by flash chromatography (12g pre-packed C-18 SNAP cartridge: 30% to 85% acetonitrile (0.1% formic acid) in water (0.1% formic acid)). The desired fractions were combined and concentrated to afford the title compound (64 mg, 0.085 mmol, 56.1 % yield). LCMS T= 1.09 min, ES+ve 750.
  • 21
  • [ 698-63-5 ]
  • [ 173405-78-2 ]
  • [ 2228842-70-2 ]
YieldReaction ConditionsOperation in experiment
65% Stage #1: 5-nitrofurane-2-carboxaldehyde; tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With acetic acid In dichloromethane at 20℃; for 0.166667h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane for 12h; 4 tert-butyl- 9-((5-nitrofuran-2-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-Carbo-xylate 11 The procedure for compound 11 was performed as the method for compound 3 by the reaction with compound 1 with compound 10. yellow solid, yield: 65%. mp: 95-97°C; 1H NMR (500M, CDCl3) 7.26 (d, J=3.4Hz, 1H), 6.45 (d, J=3.4Hz, 1H), 3.62 (s, 2H), 3.34, 2.47 (m, 4H), 1.53, 1.39 (m, 4H), 1.43 (s, 9H). HRMS-ESI(m/z): Calcd. for C19H30N3O5 (M+H)+: 380.2107; Found: 380.2115
  • 22
  • [ 1612172-54-9 ]
  • [ 173405-78-2 ]
  • [ 2230825-63-3 ]
YieldReaction ConditionsOperation in experiment
80.8% With triethylamine In isopropyl alcohol at 150℃; for 1h; 282.1 1. Step- Synthesis of Tert-butyl 9-(4-((1-isopropyl-2-methyl-1H-imidazo[4,5- c]pyridin-6-yl)amino)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate A mixture of N-(2-chloropyrimidin-4-yl)-1-isopropyl-2-methyl-1H-imidazo[4,5- c]pyridin-6-amine (150 mg, 0.47 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (125 mg, 0.49 mmol) and Et3N (142 mg, 1.4 mmol) in iPrOH(5 mL) was stirred at 150oC for 1 h. After cooling to rt, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography with MeOH/DCM (1:20) as eluent to afford the desired product Tert- butyl 9-(4-((1-isopropyl-2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)amino)pyrimidin-2-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate as a yellow solid (200 mg, 0.38 mmol, 80.8% yield). (2331) Chemical Formula: C28H40N8O2; Molecular Weight: 520.68. LC-MS: (ES+): m/z 521.3 [M+H]. tR = 3.33 min
  • 23
  • [ 75-44-5 ]
  • [ 173405-78-2 ]
  • [ 2252344-38-8 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In tetrahydrofuran at 20℃; for 24h; Inert atmosphere; Cooling with ice; tert-Butyl 9-(chlorocarbonyl)-3, 9-diazaspiro[5. 5]undecane-3-carboxylate Tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 0.32 mmol) was dissolved in tetrahydrofuran (6 ml) under an argon atmosphere then triethylamine (69 p1, 0.49 mmol) was added and cooled on ice/water. Phosgene (36.5 mg, 0.13 mmol) was added and the mixture was stirred on ice/water for 10 mm then RT for 21 h. Extra phosgene (15 mg, 0.05 mmol)was added and stirred at RT for 3 h. The mixture was poured into ice / water then extracted three times with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and the filtrate evaporated to provide tert-butyl 9-(chlorocarbonyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (96 mg, quantitative) as a yellow oil. 1H NMR (ODd3, 300 MHz) O 1.43 (5, 9H), 1.53 (m, 8H), 3.39 (m, 4H), 3.60 (m, 2H), 3.68 (m, 2H).
  • 24
  • [ 2888-06-4 ]
  • tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate [ No CAS ]
  • tert-butyl 9-((3-chlorophenyl)sulfonyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90.9% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (137 mg, 539 muetaiotaomicron, CAS RN 173405-78-2) and DIPEA (139 mg, 188 (iL, 1.08 mmol) in DCM (2 mL) was added dropwise 3-chlorobenzenesulfonyl chloride (1 14 mg, 75.8 iL, 539 muiotaetaomicron, CAS RN 2888-06-4) and the mixture was stirred at RT for 2 h. The reaction mixture was washed with 0 and the aqueous layer was extracted three times with DCM. The organic layers were dried over MgS04, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane : EtOAc (100 : 0 to 50 : 50) to get the desired compound as a light brown solid (0.210 g; 90.9%). MS (ESI): m/z = 373.2 [M- C4H8]-.
  • 25
  • [ 284027-27-6 ]
  • [ 173405-78-2 ]
  • [ 2313540-17-7 ]
YieldReaction ConditionsOperation in experiment
47% With caesium carbonate In acetonitrile at 70℃; for 12h;
47% With caesium carbonate In acetonitrile at 70℃; for 12h; Tert-butyl 9-(3-((4-methyl-5-phenyl-4H-l, 2, 4-triazol-3-yl)thio)propyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (6e). A mixture of 7 (1.0 mmol), tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate (1.1 mmol), and CS2CO3 (1.5 mmol) was stirred in acetonitrile (5 mL) at 70 °C for 12 h. The crude reaction mixture was then filtered, and solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluding with 10% 7 N ML in MeOH solution/CTLCh (1 : 10) affording 6e as an off- white solid (Yield 47%). NMR (500 MHz, CDCh) δ 7.55-7.54 (m, 2H), 7.42-7.40 (m, 3H), 3.52 (s, 3H), 3.28-3.26 (m, 4H), 3.21 (t, 7= 7.0 Hz, 2H), 2.51 (t, 7= 7.1 Hz, 2H), 2.42 (bs, 4H), 1.99-1.93 (quint, 7= 7.1 Hz, 2H), 1.48 (t, 7= 5.6 Hz, 4H), 1.36 (s, 9H), 1.34 (bs, 4H); 13C NMR (125 MHz, CDCb) δ 155.7, 154.8, 151.7, 129.9, 128.8, 128.4, 126.9, 79.1, 65.7, 56.9, 48.9, 39.6, 38.8, 34.8, 31.5, 30.9, 29.4, 28.3, 26.4, 15.2; LC-MS (ESI) m/z: 486.17 [M+H].
  • 26
  • [ 2377643-33-7 ]
  • [ 173405-78-2 ]
  • [ 2377643-60-0 ]
YieldReaction ConditionsOperation in experiment
900 mg With 4-methyl-morpholine; 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 2.5h; Inert atmosphere; 1 Step 1 : tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-4-methoxybenzoyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (432 mg, 1 .698 mmol) and NMM (0.392 ml, 3.57 mmol) at RT under argon in DMF (4 ml) was added 3-(2,4- dioxotetrahydropyrimidin-1 (2H)-yl)-4-methoxybenzoic acid (intermediate 5, 471 mg, 1 .783 mmol), followed by HATU (743 mg, 1 .953 mmol). The RM was stirred at RT for 2.5 h and a saturated aq. solution of NaHC03was added. EtOAc was added and both phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with water and brine, dried over MgS04and concentrated to afford the title compound as a solid (900 mg).Method A: Rt = 0.91 min; [M+H]+= 501 .4.
900 mg With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In 1,2-dimethoxyethane at 20℃; for 2.5h; Inert atmosphere; 1 Step 1 : tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-4-methoxybenzoyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate At RT, to a stirred solution of 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (432 mg, 1 .698 mmol) and NMM (0.392 ml, 3.57 mmol) under argon in DMF (4 ml) was added intermediate 1 a (471 mg, 1 .783 mmol), followed by HATU (743 mg, 1 .953 mmol). The clear RM was stirred at RT for 2.5 h and then quenched with sat. aq. NaHC03, and diluted with EtOAc. Layers were separated and the aq. layer was extracted with EtOAc (1x). Combined organic layers were washed with brine/water 1 :1 (2x) and brine (1x), dried over MgS04, filtered and concentrated under reduced pressure to give 900 mg of the title compound. At RT, to a stirred solution of 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (432 mg, 1 .698 mmol) and NMM (0.392 ml, 3.57 mmol) under argon in DMF (4 ml) was added intermediate 1 a (471 mg, 1 .783 mmol), followed by HATU (743 mg, 1 .953 mmol). The clear RM was stirred at RT for 2.5 h and then quenched with sat. aq. NaHC03, and diluted with EtOAc. Layers were separated and the aq. layer was extracted with EtOAc (1x). Combined organic layers were washed with brine/water 1 :1 (2x) and brine (1x), dried over MgS04, filtered and concentrated under reduced pressure to give 900 mg of the title compound. LC-MS (Method A): Rt = 0.91 min, [M+H]+ = 501 .4
1.55 g With 4-methyl-morpholine; 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 2h; Inert atmosphere; Step 1: Preparation of 9-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl tert-butyl)-3,9-diazaspiro[5.5]undecyl-3-carboxylate At room temperature, under nitrogen protection, to 3-(2,HATU ( 1.66g, 4.37mmol),3,9-Diazaspiro[5.5]undecyl-3-carboxylate tert-butyl ester (0.96 g, 3.78 mmol) and N-methylmorpholine (0.8 g, 7.92 mmol). After stirring the reaction for 2 h, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was collected, washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography to obtain 1.55 g of the target product as a white solid.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 0 - 25℃; third step Compound H-5 (4.00g, 15.1mmol), compound F-2 (4.04g, 15.9mmol)and triethylamine (4.60g, 45.4mmol) were dissolved in dichloromethane (40mL), and then 1-propylphosphoric anhydride (14.5g, 22.7mmol) was added at 0°C.The reaction mixture was stirred at 25°C for 12 hours.First, the reaction mixture was concentrated under reduced pressure, and the obtained crude product was dissolved in ethyl acetate (40 mL), and the combined organic phases were washed with saturated aqueous sodium bicarbonate (20 mL×4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound H-6.

  • 27
  • [ 350-46-9 ]
  • [ 173405-78-2 ]
  • [ 1373417-50-5 ]
YieldReaction ConditionsOperation in experiment
87.2% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 90℃; 5.1 Step 1 : fer/-butyl 9-(4-nitrophenyl )-3.9-diazaspirc>r5.51undecane-3 -carboxyl ate. A mixture of 4-fluoronitrobenzene (554.7 mg, 3.93 mmol), DMF (20 mL), ethylbis(propan-2-yl)amine (2.74 mL, 15.7 mmol) and tert- butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1000 mg, 3.93 mmol) was allowed to stir at 90 °C overnight. EtOAc and H20 were added. The organic layer was dried with MgS04, filtered, concentrated and purified by MPLC (0-50% EtOAc in hexanes) to afford tert- butyl 9-(4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1287.00 mg, 87.2%). C20H29N3O4 requires 375, found: m/z = 376 [M+H]+.
87.2% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 90℃; 8 Synthesis of tert-butyl 9-(4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate A mixture of 4-fluoronitrobenzene (554.7 mg, 3.93 mmol), DMF (20 mL), ethylbis(propan-2-yl)amine (2.74 mL, 15.7 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane- 3-carboxylate (1000 mg, 3.93 mmol) was allowed to stir at 90 °C overnight. EtOAc and H2O were added. The organic layer was dried with MgSO4, filtered, concentrated, and purified by MPLC (0-50% EtOAc in hexanes) to afford tert-butyl 9-(4-nitrophenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (1287.00 mg, 87.2%). C20H29N3O4 requires 375, found: m/z = 376 [M+H]+.
With potassium carbonate In dimethyl sulfoxide at 120℃; for 2h; 3 Step 3: synthesis of compound I2-D Potassium carbonate (626.92 mg, 4.54 mmol) was added into compound I2-C (825.00 mg, 3.24 mmol) and p-fluoronitrobenzene (457.16 mg, 3.24 mmol, 343.73 µL) in dimethyl sulfoxide solution (10.00 mL) at r.t. The reaction mixture was stirred at 120°C for 2 hours. The reaction mixture was cooled down to r.t. and slowly added dropwise into water (50 mL) while stirring, solid precipitation appeared, then filtered to give the crude compound I2-D. MS m/z: 376.5 [M+H]+
  • 28
  • [ 929302-01-2 ]
  • [ 173405-78-2 ]
YieldReaction ConditionsOperation in experiment
With palladium on activated charcoal; hydrogen In tetrahydrofuran at 40℃; for 40h; 2 Step 2: synthesis of compound I2-C Under argon atmosphere, wet Pd/C (188.05 mg, 159.50 µmol, purity 10%) was added into the compound I2-B in THF solution (1.10 g, 3.19 mmol), after replacing the gas in the flask 3 times with hydrogen, the reaction was stirred at 40°C for 40 hours under 45 Psi. After completion of the reaction, the solution was filtered through diatomite, the filtrate was concentrated to give the crude compound I2-C. MS m/z: 255.1[M+H]+
  • 29
  • [ 4548-45-2 ]
  • [ 173405-78-2 ]
  • [ 2416133-44-1 ]
YieldReaction ConditionsOperation in experiment
90% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 16h; 50A.1 Step 1 : 2-Chloro-5-nitropyridine (1 eq; YA is N and Xx is CH) and /er/-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1 eq) were combined in DMF:DIEA solution (10:1 ratio, 0.1M). The reaction mixture was stirred at 70 °C for 16 h, then cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, and filtered. This solution was concentrated onto silica gel and chromatographed by silica (0-100% ethyl acetate in hexane) to afford /er/-butyl 9-(5-nitropyridin-2-yl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (90%). LCMS C19H28N4O4 requires: 376.5 found: m/z = 377.4 [M+H]+.
  • 30
  • [ 2434846-48-5 ]
  • [ 173405-78-2 ]
  • [ 2434848-60-7 ]
YieldReaction ConditionsOperation in experiment
59% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dimethyl sulfoxide at 25℃; for 0.5h; Inert atmosphere; Step 1 -Tert-butyl 9-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol- 4-yl] propanoyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate To a solution of 3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]propanoic acid (128 mg, 386 umol, Intermediate AKM), tert-butyl 3,9-diazaspiro[5.5]undecane- 3-carboxylate (98.2 mg, 386 umol, CAS 173405-78-2) in DMF (3.00 mL) was added HATU (220 mg, 579 umol) and DIPEA (149 mg, 1.16 mmol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was quenched with H2O (1.00 mL) and concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (130 mg, 59% yield) as a white solid.1H NMR (400MHz, DMSO-d6) d 11.11 (s, 1H), 7.03 - 6.88 (m, 3H), 5.43 - 5.31 (m, 1H), 3.58 (s, 3H), 3.47 - 3.40 (m, 3H), 3.34 - 3.32 (m, 1H), 3.31 - 3.25 (m, 4H), 3.18 - 3.11 (m, 2H), 2.97 - 2.83 (m, 1H), 2.78 - 2.62 (m, 4H), 2.03 - 1.92 (m, 1H), 1.39 (s, 9H), 1.36 - 1.24 (m, 8H).
  • 31
  • [ 2360518-87-0 ]
  • [ 173405-78-2 ]
  • [ 2434841-85-5 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: 1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde; tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With acetic acid In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere; 1 Step 1 - Tert-butyl 9-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]methyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate To a solution of 1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4- carbaldehyde (100 mg, 348 umol, Intermediate WW) and tert-butyl 3,9-diazaspiro[5.5]undecane- 3-carboxylate (88.5 mg, 348 umol, CAS 173405-78-2) in THF (3 mL) and DMF (3 mL) was added tetraisopropoxytitanium (296 mg, 1.04 mmol, 308 uL). The mixture was stirred at 80 °C for 2 hrs, then NaBH(OAc)3(147 mg, 696 umol) was added to the mixture. The reaction mixture was stirred at 20 °C for 16 hrs. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (145 mg, 79% yield) as a white solid.1H NMR (400MHz, DMSO-d6) d 11.10 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.90 - 6.85 (m, 1H), 5.37 (dd, J = 5.2, 12.4 Hz, 1H), 3.66 (s, 3H), 3.65 - 3.60 (m, 2H), 3.30 - 3.23 (m, 4H), 2.94 - 2.84 (m, 1H), 2.77 - 2.68 (m, 1H), 2.65 - 2.57 (m, 1H), 2.43 - 2.34 (m, 4H), 2.05 - 1.96 (m, 1H), 1.45 - 1.39 (m, 4H), 1.38 (s, 9H), 1.36 - 1.30 (m, 4H); LC-MS (ESI+) m/z 526.2 (M+H)+.
  • 32
  • [ 1451362-50-7 ]
  • [ 173405-78-2 ]
  • [ 2460263-44-7 ]
YieldReaction ConditionsOperation in experiment
42.7% With triethylamine In N,N-dimethyl acetamide at 25 - 70℃; for 9h; 1 General procedure for preparation of compound 16d To a solution of compound 16b (1 g, 2.08 mmol) and compound 16c (600 mg, 2.36 mmol) in DMA (20 mL ) was added TEA (2.18 g, 21 .5 mmol, 3 mL , 10.4 eq) at 25 °C, the mixture was stirred at 70 °C for 9 hrs. The mixture was cooled to 25 - 30 °C, poured into water (50 mL ) , extracted with ethyl acetate (20 mL x 3), the organic phase was washed with brine (30 mL x 3), then separated and dried with Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give brown oil. The oil was purified by Prep- HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 38% - 68%, 1 1 5min), the fraction was concentrated under reduced pressure to give compound 16d (500 mg, 886 umol, 42.7% yield) as brown oil. 1H NMR: 400 MHz CDCI3 δ 7.30 (m, 5H), 5.92 (s, 1 H), 5.09 (s, 2H), 3.58 (m, 12H), 3.38 (m, 6H), 2.54 (m, 2H), 2.40 (m, 4H), 1 .49 (m, 4H), 1 .44 (s, 9H). LCMS: (method 1 ), Rt = 0.844 min, m/z (M + 1 ) = 564.5
  • 33
  • [ 2098983-15-2 ]
  • [ 173405-78-2 ]
  • [ 2460263-23-2 ]
YieldReaction ConditionsOperation in experiment
49% With potassium carbonate; potassium iodide In acetonitrile at 70℃; for 12h; Inert atmosphere; 1 General procedure for preparation of amine 4 To a solution of compound 6b (800 mg, 1.83 mmol) and compound 6c (500 mg, 1.97 mmol) in MeCN (10 mL ) was added Kl (700 mg, 4.22 mmol) and K2CO3 (800 mg, 5.79 mmol), the mixture was stirred at 70 °C under N2 for 12 hours. The mixture was cooled to 25 °C, the n poured into water (50 mL ), extracted with ethyl acetate (30 mL x 2), the combined organic phase was washed with brine (50 mL x 3), separated and dried with Na2SO4, filtered, the filtrate was concentrated under reduced pressure to give brown oil. The oil was purified by reversed phase chromatography (CH3CN:H20 (0.1 % NH3.H2O contained) = 0:1 - 45:1 ), the fraction was collected and concentrated under reduced pressure to give colourless oil. Compound 6d (500 mg, 962 mitioI, 49% yield) was obtained as yellow oil. 1H NMR: 400 MHz, CDCI3; δ 7.42-7.28 (m, 5H), 5.10 (s, 2H), 3.73-3.52 (m, 8H), 3.43-3.27 (m, 6H), 2.61 (t, J = 5.4 Hz, 2H), 2.48 (s, 4H), 1.53 (t, J= 5.3 Hz, 4H), 1.45 (s, 9H), 1.39 (s, 4H)
  • 34
  • [ 835616-61-0 ]
  • [ 173405-78-2 ]
  • [ 2476319-06-7 ]
YieldReaction ConditionsOperation in experiment
90% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; Inert atmosphere; 77.a a) tert-butyl 9-12-12.6-dio\o-3-piperidyl )- 1.3-dio\o-isoindolin-5-yl 1-3.9- diazaspiror5.51undecane-3-carboxylate To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l,3-dione (200 mg, 724 pmol, 1.0 eq) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (184 mg, 724 pmol, 1.0 eq) in DMSO (1.5 mL) at room temperature was added DIPEA (187 mg, 253 pL, 1.45 mmol, 2.0 eq). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was then poured into EtOAc/THF (1:1) and extracted sequentially with water and with brine. The organic phase was dried over Na2SC>4 and concentrated in vacuo. The crude material was purified on silica column (heptane/EtOAc 0-100%) to afford the title compound (334 mg, 654 pmol, 90% yield) as a green solid. MS (ESI): 455.4 ([M+H- C4H8]+).
88% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 80℃; for 5h; 77.1 The first step: 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro [5.5] Undecane-3-carboxylate tert-butyl ester (77b)tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate Dissolve tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (77a) (850 mg, 3.34 mmol) in 20 mL DMSO,2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (see WO2017197056 for the synthesis method) (1.38 g, 5.00 mmol) were added, The temperature was raised to 80°C for 5h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the solid was collected by filtration. The filter cake was washed with 50 mL of water, the solid was dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane). /methanol (v/v)=20:1) to obtain 77b (1.5 g, yield: 88%).
306 mg With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 65℃; for 2h; 20.1 Step 1 : tert-butyl 9-r2-(2.6-dioxopiperidin-3-yl)-1.3-dioxoisoindol-5-yl1-3.9- diazaspiror5.51undecane-3-carboxylate. A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-l,3-dione (218 mg, 0.79 mmol), z-Pr2NEt (412 pL, 2.37 mmol), and tert-butyl 3,9-diazaspiro[5.5]undecane-3- carboxylate (201 mg, 0.79 mmol) was dissolved in A-methylpyrrolidone (1 mL) and heated to 65 °C for 2 h before being cooled and purified (SiCh, 0 - 100% EtO Ac/Hexanes) to afford tert-butyl 9-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindol-5-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (306 mg). LCMS: C27H34N4O6 requires: 510, found: m/z = 511 [M+H]+.
  • 35
  • [ 766-11-0 ]
  • [ 173405-78-2 ]
  • [ 918653-36-8 ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate In dimethyl sulfoxide at 90℃; for 4h; 1 fert-butyl 9-(5-bromopyridin-2-vP-3.,9-diazaspiro[5.51tindecane-3-carboxylate of 13) To a stirred mixture of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate 1 (0.5 g, 1.96 mmol) and 5-bromo-2-fluoropyridine 2 (0.376 g, 2.16 mmol) in DMSO (20 mL), K2CO3 (0.678 g, 4.92 mmol) was charged and heated at 90 °C for 4 h. The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted into EtOAc (5 x 50 mL). Combined organic layers were washed with ice cold water (2 c 50 mL),.brine (1 c 30 mL). Organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure and crude product was purified by combiflash chromatography (-Hexanes: EtOAc = 90: 10) to afford 3 (0.560 g, 70%) as an off- white solid. NMR (400 MHz, CDCb): d ppm 8.17 (d, 7= 2.0 Hz, 1H), 7.50 (dd, 7=2.4, 9.2 Hz, 1H), 6.54 (d, 7=8.8 Hz, 1H), 3.49 (t, 7=6.0 Hz, 4 H), 3.41 (t, 7=5.6 Hz, 4 H), 1.48 - 1.59 (m, 8 H), 1.46 (s, 9 H).
  • 36
  • [ 1010100-26-1 ]
  • tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate [ No CAS ]
  • tert-butyl 9-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With caesium carbonate In 1,4-dioxane at 40 - 100℃; for 3h; Inert atmosphere; Intermediate 7a: tert-butyl 9-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-3,9-diazaspiro[5.5]undecane- 3-carboxylate Pd-PEPPSI-IHeptCl (0.53 g, 0.54 mmol) was added to a degassed mixture of 3-(5-Bromo-1-oxoisoindolin-2- yl)piperidine-2,6-dione (3.5 g, 10.8 mmol), 3-Boc-3,9-diazaspiro[5.5]undecane (3.6 g, 14.2 mmol) and cesium carbonate (10.6 g, 32.5 mmol) in 1,4-dioxane (100 mL) at 40°C under nitrogen. The resulting mixture was vacuum degassed, backfilling with nitrogen and stirred at 100 °C for 3 hours. The reaction mixture was diluted with DCM (150 mL) and 10% aq. AcOH (100 mL), the layers were separated, and the aqueous layer was extracted with DCM (150 mL). The combined organic layers were dried with MgSO4, filtered and evaporated to afford crude product. The crude solid was triturated with EtOAc (35 mL) to give a solid which was collected by filtration, washed sequentially with EtOAc (2x 15 mL) and EtOAc:Et2O (1:1; 20 mL) and dried under vacuum to give the title compound (4.14 g, 77 %) as a pale blue solid; 1H NMR (400 MHz, DMSO, 30°C) 1.40 (13H, s), 1.51- 1.64 (4H, m), 1.96 (1H, ddd), 2.27- 2.44 (1H, m), 2.59 (1H, dt), 2.90 (1H, ddd), 3.32 (8H, dd), 4.20 (1H, d), 4.32 (1H, d), 5.04 (1H, dd), 7.04 (2H, d), 7.50 (1H, d), 10.91 (1H, s); m/z: ES+ [M+H]+ 497.3.
  • 37
  • [ 835616-60-9 ]
  • [ 173405-78-2 ]
  • [ 2573306-54-2 ]
YieldReaction ConditionsOperation in experiment
88.6% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 130℃; for 3h; Inert atmosphere; 1 Step 1 - Tert-butyl 9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-3,9- diazaspiro[5.5] undecane-3-carboxylate To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (900 mg, 3.54 mmol, CAS 173405-78-2) and 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (782 mg, 2.83 mmol, Intermediate R) in DMSO (5 mL) was added to DIPEA (1.37 g, 10.6 mmol, 1.85 mL). The reaction mixture was stirred at 130 °C for 3 hrs. On completion, the reaction mixture was diluted with water (25 mL), and filtered to give the title compound (1.6 g, 88.6 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) d 11.08 (s, 1H), 7.72 - 7.59 (m, 1H), 7.41 - 7.23 (m, 2H), 5.16 - 5.01 (m, 1H), 3.37 - 3.34 (m, 2H), 3.27 (s, 4H), 2.92 - 2.81 (m, 1H), 2.63 - 2.53 (m, 4H), 2.06 - 1.98 (m, 1H), 1.63 (s, 4H), 1.42 (d, J = 5.6 Hz, 4H), 1.41 - 1.38 (m, 9H); LC-MS (ESI+) m/z 511.3 (M+H)+.
  • 38
  • [ 1150102-49-0 ]
  • [ 173405-78-2 ]
  • [ 2654056-53-6 ]
YieldReaction ConditionsOperation in experiment
59% With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos In toluene at 80℃; for 2h; Inert atmosphere; 1; 1 Step 1 - Tert-butyl 9-[3-methyl-2-oxo-1-(2-t benzimidazol-4-yl]- 3,9- diazaspiro[5.5]undecane-3-carboxylate To a solution of 4-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one (5.0 g, 13.9 mmol, Intermediate BED) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (3.74 g, 14.6 mmol, CAS 173405 -78-2) in toluene (50 mL) was added RuPhos (1.31 g, 2.80 mmol), Pd2(dba)3 (1.28 g, 1.40 mmol), and t-BuONa (3.36 g, 34.9 mmol). The reaction mixture was then stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (4.4 g, 59% yield) as yellow oil. LC-MS (ESI+) m/z 531.5(M+1)+.
59% With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos In toluene at 80℃; for 2h; 2 Step 2 - Tert-butyl 9-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate To a solution of 4-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one (5.0 g, 13.9 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (3.74 g, 14.6 mmol, CASNo. 173405-78-2) in toluene (50 mL) was added RuPhos (1.31 g, 2.80 mmol), Pd2(dba)3 (1.28 g, 1.40 mmol), t-BuONa (3.36 g, 34.9 mmol), and the reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (4.4 g, 59% yield) as yellow oil. LC-MS (ESI+) m/z 531.5(M+1)+.
59% With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos In toluene at 80℃; for 2h; 2 Step 2 - Tert-butyl 9-[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate To a solution of 4-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one (5.0 g, 13.9 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (3.74 g, 14.6 mmol, CASNo. 173405-78-2) in toluene (50 mL) was added RuPhos (1.31 g, 2.80 mmol), Pd2(dba)3 (1.28 g, 1.40 mmol), t-BuONa (3.36 g, 34.9 mmol), and the reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (4.4 g, 59% yield) as yellow oil. LC-MS (ESI+) m/z 531.5(M+1)+.
  • 39
  • [ 1092953-04-2 ]
  • [ 173405-78-2 ]
  • [ 2677040-99-0 ]
YieldReaction ConditionsOperation in experiment
39% With potassium carbonate; potassium iodide In acetonitrile at 75℃; for 1h; 4.1.6 General procedure for the synthesis of 4(d-r) General procedure: Intermediate 3 (0.608g, 1.21mmol), different spiro ring fragments (1.21mmol), potassium carbonate (0.25g, 1.82mmol) and potassium iodide (0.30g, 1.82mmol) were dissolved in 25mL acetonitrile and refluxed at 75°C for 1h. After completion of the reaction, the solvent was removed under reduced pressure. Water (50mL) and ethyl acetate (25mL×3) were added to the crude and extracted. The organic phases were collected and combined and extracted once more with saturated sodium chloride solution (25mL). The organic phases were dried with anhydrous magnesium sulfate. After filtering, it was purified by flash column chromatography with the solvent system of PE: EA=4:1. The obtained solid was recrystallized using a dichloromethane-n-hexane system to achieve the desired products 4(d-r). 4.1.6.1 Tert-butyl 9-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (4d) Yield: 39.0%; mp: 77-80°C; 1H NMR (400MHz, DMSO-d6): δ 9.69 (s, 1H, dihydropyrimidine-H), 8.00 (s, 1H, thiazole-H), 7.93 (s, 1H, thiazole-H), 7.56 (d, J=8.1Hz, 1H, Ph-H), 7.37 (m, 1H, Ph-H), 7.22 (s, 1H, Ph-H), 6.02 (s, 1H, dihydropyrimidine-CH), 4.08-3.79 (m, 4H, dihydropyrimidine-CH2, CH2CH3), 3.31 (s, 4H, 2×NCH2), 2.50 (s, 4H, 2×BocNCH2), 1.53 (s, 4H), 1.39 (s, 9H, Boc), 1.23 (s, 2H, CCH2), 1.05 (t, J=6.9Hz, 3H, CH2CH3), 0.85 (s, 2H, CCH2); 13C NMR (100MHz, DMSO-d6): δ 165.65, 162.54, 161.25 (d, J=248.3Hz), 154.45, 147.45, 144.44, 144.07, 140.69 (d, J=3.3Hz), 131.32 (d, J=8.8Hz), 125.14, 123.05 (d, J=9.9Hz), 120.05 (d, J=24.2Hz), 115.93 (d, J=20.9Hz), 97.23, 78.86, 59.80, 58.68, 56.42, 49.26, 38.71, 35.72, 29.48, 28.58, 14.46; EI-MS: 676.97 [M+H]+, C31H39BrFN5O4S [675.19].
39% With potassium carbonate; potassium iodide In acetonitrile at 75℃; for 1h; 4 Example 4. Preparation of compound 4(d-r) General procedure: Take Intermediate 3 (0.608g, 1.21mmol), different spiro ring fragments (1.21mmol), potassium carbonate (0.25g, 1.82mmol) and potassium iodide (0.30g, 1.82mmol),Dissolve in 25mL acetonitrile solution and reflux at 75°C for one hour.After the reaction is complete, spin off the excess solvent, add water (30mL), and extract with ethyl acetate (20mL×3).Collect and combine the organic phases, extract once with saturated sodium chloride (25 mL), and dry the organic phase with anhydrous magnesium sulfate.Filter, add 200 mesh silica gel, mix the sample, and separate by fast column chromatography.The target compound 4(d-r) was obtained by recrystallization using dichloromethane-n-hexane system.
  • 40
  • [ 56961-27-4 ]
  • [ 173405-78-2 ]
  • [ 2480124-26-1 ]
YieldReaction ConditionsOperation in experiment
64.7% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h; 95.1 Step 1: To a solution of compound 94a (200 mg, 786.26 mmol) and 3-bromo-2-chlorobenzoic acid (224.32 mg,1.02 mmol) in DMF (3 mL), N,N-diisopropylethylamine and HATU (298.96 mg, 786.26 mmol) was added. The mixturewas stirred at room temperature for 16 h. The resulting mixture was added with water (20 mL) and extracted with ethylacetate (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated.The residue was purified by prep-TLC to give compound 95a (240 mg, 508.67 mmol, yield 64.7%) as light yellow oil. MS(ESI): m/z 471.3 (M+H)+.
64.7% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h; 95.1 Step 1: To a solution of compound 94a (200 mg, 786.26 mmol) and 3-bromo-2-chlorobenzoic acid (224.32 mg,1.02 mmol) in DMF (3 mL), N,N-diisopropylethylamine and HATU (298.96 mg, 786.26 mmol) was added. The mixturewas stirred at room temperature for 16 h. The resulting mixture was added with water (20 mL) and extracted with ethylacetate (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated.The residue was purified by prep-TLC to give compound 95a (240 mg, 508.67 mmol, yield 64.7%) as light yellow oil. MS(ESI): m/z 471.3 (M+H)+.
  • 41
  • [ 19230-27-4 ]
  • [ 173405-78-2 ]
  • [ 2480124-35-2 ]
YieldReaction ConditionsOperation in experiment
71.6% With tris-(dibenzylideneacetone)dipalladium(0); [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane; sodium t-butanolate In toluene at 100℃; for 16h; Inert atmosphere; 96.1 Step 1: To a solution of compound 94a (200 mg, 786.26 µmol) and 1,3-dibromo-2-chlorobenzene (212.57 mg, 786.26 µmol) in Toluene (3 mL), Pd2(dba)3 (36.00 mg, 39.31 µmol), BINAP (48.93 mg, 78.62 µmol) and sodium tert-butoxide (75.56 mg, 786.26 µmol) was added. The mixture was stirred under a nitrogen atmosphere at 100°C for 16 h. The resulting mixture was added with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC to give compound 96a (250 mg, 563.31 µmol, yield 71.6%) as light yellow oil. MS (ESI): m/z 443.3 (M+H)+.
71.6% With tris-(dibenzylideneacetone)dipalladium(0); [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane; sodium t-butanolate In toluene at 100℃; for 16h; Inert atmosphere; 96.1 Step 1: To a solution of compound 94a (200 mg, 786.26 µmol) and 1,3-dibromo-2-chlorobenzene (212.57 mg, 786.26 µmol) in Toluene (3 mL), Pd2(dba)3 (36.00 mg, 39.31 µmol), BINAP (48.93 mg, 78.62 µmol) and sodium tert-butoxide (75.56 mg, 786.26 µmol) was added. The mixture was stirred under a nitrogen atmosphere at 100°C for 16 h. The resulting mixture was added with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC to give compound 96a (250 mg, 563.31 µmol, yield 71.6%) as light yellow oil. MS (ESI): m/z 443.3 (M+H)+.
  • 42
  • [ 1197050-28-4 ]
  • [ 173405-78-2 ]
  • [ 2480124-15-8 ]
YieldReaction ConditionsOperation in experiment
55.6% Stage #1: 3-bromo-2-chloro-benzaldehyde; tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With acetic acid In dichloromethane at 20℃; for 16h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 3h; 94.1 Step 1: To a solution of compound 94a (200 mg, 786.26 µmol) in DCM (3 mL), 3-bromo-2-chlorobenzaldehyde (224.32 mg, 1.02 mmol) and acetic acid (94.43 mg, 1.57 mmol) was added. The mixture was stirred at room temperature for 16 h followed by the addition of sodium triacetoxyborohydride (666.56 mg, 3.15 mmol) and further stirred at room temperature for 3 h. The resulting mixture was added with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC to give compound 94b (200 mg, 436.84 µmol, yield 55.6%) as light yellow solid. MS (ESI): m/z 457.4 (M+H)+.
55.6% Stage #1: 3-bromo-2-chloro-benzaldehyde; tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate With acetic acid In dichloromethane at 20℃; for 16h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 3h; 94.1 Step 1: To a solution of compound 94a (200 mg, 786.26 µmol) in DCM (3 mL), 3-bromo-2-chlorobenzaldehyde (224.32 mg, 1.02 mmol) and acetic acid (94.43 mg, 1.57 mmol) was added. The mixture was stirred at room temperature for 16 h followed by the addition of sodium triacetoxyborohydride (666.56 mg, 3.15 mmol) and further stirred at room temperature for 3 h. The resulting mixture was added with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC to give compound 94b (200 mg, 436.84 µmol, yield 55.6%) as light yellow solid. MS (ESI): m/z 457.4 (M+H)+.
  • 43
  • [ 41841-16-1 ]
  • [ 173405-78-2 ]
  • [ 2789679-87-2 ]
YieldReaction ConditionsOperation in experiment
54.95% With RuPhos Pd G3; Cs2CO3 In toluene at 20 - 110℃; for 16h; Inert atmosphere;
54.95% With chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II); Cs2CO3 In toluene at 110℃; for 16h; Inert atmosphere; aa.i [00401] Step i: Preparation of tert-butyl 9-(4-(2-methoxy-2-oxoethyl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate. To a solution of methyl 2-(4-bromophenyl)acetate (9.73 g, 42.457 mmol, 1.2 equiv.) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (9.00 g, 35.381 mmol, 1.0 equiv.) in toluene (100 mL) were added CS2CO3 (23.06 g, 70.762 mmol, 2 equiv.) and RuPhos Pd G2 (2.75 g, 3.538 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The reaction was stirred at 110 °C for 16 hours. The resulting reaction was concentrated under reduced pressure, re-dissolved with EA (200 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0 ~ 20% EA in PE. The fractions containing desired product were combined and concentrated under reduced pressure to afford tert-butyl 9-(4-(2-methoxy-2-oxoethyl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (8.6 g, 54.95% yield) as a light yellow solid. MS ESI (m/z) = 403.20 [M + H]+. H-NMR (300 MHz, Chloroform-d): δ 7.21- 7.09 (m, 2H), 6.92 - 6.89 (m, 2H), 3.68 (s, 3H), 3.54 (s, 2H), 3.42 -3.31 (m, 4H), 3.18 -3.14 (m, 4H), 1.68 -1.64 (m, 4H), 1.50 -1.46 (m,13H).
  • 44
  • [ 109-04-6 ]
  • [ 173405-78-2 ]
  • [ 2149046-15-9 ]
YieldReaction ConditionsOperation in experiment
55.4% With tris-(dibenzylideneacetone)dipalladium(0); potassium-t-butoxide; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine In toluene at 110℃; for 8h; Inert atmosphere; 1.1 Intermediate: Preparation of 9-(pyridin-2-yl)-3,9-diazaspiro[5.5]undecan-3-carboxylate tert-butyl ester I-1c (first step) Commercially available I-1a (316.0 mg, 2.0 mmol, 1.0 eq) and I-1b (508.0 mg, 2.0 mmol, 1.0 eq), Pd2(dba)3(183.0 mg, 0.2 mmol, 0.1 eq), BINAP (186.6mg, 0.3mmol, 0.15eq), a mixture of tBuOK (672.0mg, 6.0mmol, 3.0eq), TEA (606.0mg, 6.0mmol, 3.0eq) and Toluene (20mL)was heated to 110 under N2protection °C and stirred for 8 h, cooled to ambient temperature.The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (elution with EA/n-Hexane (v/v)=1/4-1/2), and then concentrated to obtain yellow solid I-1c.(367.0 mg, 55.4% yield).
  • 45
  • [ 1089280-66-9 ]
  • [ 173405-78-2 ]
  • [ 1854943-98-8 ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate In N,N-dimethyl-formamide at 100℃; 96.1 Step 1: tert-butyl 9- (2-chloro-5-methoxy-4-nitrophenyl) -3, 9-diazaspiro [5.5] undecane-3-carboxylate A mixture of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene (500 mg, 2.4 mmol) , tert-butyl 3, 9-diazaspiro [5.5] undecane-3-carboxylate (681 mg, 2.7 mmol) and K2CO3(673 mg, 4.8 mmol) in DMF (15 mL) was stirred in a round bottom flask at 100 overnight. The reaction was cooled to room temperature, the mixture was poured into water (60 mL) and stirred for 10 mins. The solid was filtered and washed with water (30 mL x 2) , dried to give the product (950 mg, 89%) . [M+H]+= 440.2.
With potassium carbonate In dimethyl sulfoxide at 90℃; for 12h;
  • 46
  • [ 144493-38-9 ]
  • [ 173405-78-2 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
73% Stage #1: 6-(1H-benzimidazol-2-yl)pyridine-2-carboxylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: 3,9-diaza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester In N,N-dimethyl-formamide at 20℃; Cooling with ice; 9.1 1. Synthesis of 9-(6-(1H-benzo[d]imidazol-2-yl)pyridyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester under ice bath, 6-(1H-benzimidazole-2-)pyridinecarboxylic acid (1 g, 4.2 mmol),1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96g, 5mmol), 1-hydroxybenzotriazole (0.66g, 5mmol) and N,N-diiso Propylethylamine (1.19g, 9.2mmol) was dissolved in N,N-dimethylformamide 20mL,After stirring for 0.5 h, tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.92 g, 4.6 mmol) was added, and the mixture was stirred for 0.5 h and returned to room temperature for overnight reaction. The reaction solution was poured into 80 mL of water, extracted with ethyl acetate (80 mL x 3), washed with saturated brine, combined with the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure by silica gel column chromatography (PE:EA=5:1) to obtain Off-white solid (1.3 g, 3 mmol), 73% yield
  • 47
  • [ 2416718-57-3 ]
  • [ 173405-78-2 ]
  • [ 2776895-15-7 ]
YieldReaction ConditionsOperation in experiment
95% With Potassium bicarbonate In N,N-dimethyl-formamide at 60℃; for 3h; 27.1 The first step: 9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methan (27a)tert-butyl 9-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3 ,9-diazaspiro[5.5]undecane-3-carboxylate 3-Chloro-2-(2-chloroethoxy)-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzyl Nitrile (4a) (see WO2020081999 for the synthesis method) (350 mg, 0.73 mmol) was dissolved in 20 mL of DMF,3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (320 mg, 1.26 mmol) and potassium bicarbonate (147 mg, 1.47 mmol) were sequentially added, and the temperature was raised to 60° C. to react for 3 h. Cooled to room temperature, 50 mL of water was added to the reaction system, extracted with ethyl acetate (40 mL×3), the organic phase was washed with water (50 mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (Petroleum ether/ethyl acetate (v/v)=2:1) to obtain 27a (480 mg, yield: 95%)
  • 48
  • [ 2776894-62-1 ]
  • [ 173405-78-2 ]
  • [ 2776898-36-1 ]
YieldReaction ConditionsOperation in experiment
80% With Potassium bicarbonate In N,N-dimethyl-formamide at 75℃; for 4h; 68.1 The first step: 9-(4-((4-(2-(3-chloro-5-cyanophenyl)prop-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3, tert-Butyl 9-diazaspiro[5.5]undecan-3-carboxylate (68a)tert-butyl 9-(4-((4-(2-(3-chloro-5-cyanophenyl)propan-2-yl)phenoxy)methyl)pyrimidin-2-yl)-3,9-diazaspiro[5.5]undecane -3-carboxylate 3-Chloro-5-(2-(4-((2-chloropyrimidin-4-yl)methoxy)phenyl)propan-2-yl)benzonitrile (9d) (1.7 g, 4.28 mmol) Dissolved in 20mL DMF,3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.1 g, 4.32 mmol) and solid potassium bicarbonate (0.87 g, 8.70 mmol) were sequentially added, and the temperature was raised to 75° C. to react for 4 h. The reaction solution was cooled to room temperature, 30 mL of water was added, extracted twice with 60 mL of ethyl acetate, the organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum Ether/ethyl acetate (v/v) = 1:1) to give 68a (2.1 g, yield: 80%).
  • 49
  • [ 1352244-77-9 ]
  • [ 173405-78-2 ]
  • [ 1854943-93-3 ]
YieldReaction ConditionsOperation in experiment
97% With potassium carbonate In dimethyl sulfoxide at 100℃; for 1h; 2.1 Step 1: Preparation of tert-butyl 9-(2-bromo-5-methoxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1 eq.), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2 eq.) ), K2CO3 (5 equivalents) was dissolved in DMSO (0.17 M), followed by stirring at 100 °C for 1 hour. The yellow solid obtained by adding water was used in the next reaction without further purification (yield: 97 %).
  • 50
  • [ 2357109-91-0 ]
  • [ 173405-78-2 ]
  • [ 2654056-55-8 ]
YieldReaction ConditionsOperation in experiment
29% With dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); Cs2CO3 In 1,4-dioxane at 100℃; for 10h; Inert atmosphere; 1 Step 1 - 3-[4-(3,9-Diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6 -dione To a solution of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4- methoxyphenyl)methyl] piperidine-2,6-dione (1.00 g, 2.18 mmol, synthesized via Steps 1-4 of Intermediate HP) and tert-butyl-3,9-diazaspiro[5.5]undecane- 3-carboxylate (666 mg, 2.62 mmol, CAS 173405-78-2) in dioxane (15 mL) was added Pd-PEPPSI-IHEPTCl 3-Chloropyridine (212 mg, 218 umol) and Cs2CO3(1.42 g, 4.36 mmol). Then the mixture was stirred at 100 °C for 10 hours. On completion, the mixture was filtered and concentrated in vacuo to give the residue. The residue was purified by reverse-phase (0.1% FA) to give the title compound (400 mg, 29% yield) as yellow solid.1H NMR (400 MHz, CDCl3-d) δ 7.40 - 7.35 (m, 2H), 6.93 - 6.86 (m, 2H), 6.86 - 6.80 (m, 2H), 6.28 (d, J = 7.2 Hz, 1H), 5.21 (dd, J = 5.4, 13.0 Hz, 1H), 5.02 - 4.92 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.47 - 3.39 (m, 4H), 3.04 - 2.90 (m, 5H), 2.87 - 2.77 (m, 1H), 2.68 - 2.55 (m, 1H), 2.18 - 2.11 (m, 1H), 1.74 (s, 2H), 1.65 - 1.63 (m, 4H), 1.48 (s, 9H), 1.43 (s, 2H). LC-MS (ESI+) m/z 632.4 (M+H)+
29% With dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); Cs2CO3 In 1,4-dioxane at 100℃; for 10h; Inert atmosphere; 1 Step 1 - 3-[4-(3,9-Diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6 -dione To a solution of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4- methoxyphenyl)methyl] piperidine-2,6-dione (1.00 g, 2.18 mmol, synthesized via Steps 1-4 of Intermediate HP) and tert-butyl-3,9-diazaspiro[5.5]undecane- 3-carboxylate (666 mg, 2.62 mmol, CAS 173405-78-2) in dioxane (15 mL) was added Pd-PEPPSI-IHEPTCl 3-Chloropyridine (212 mg, 218 umol) and Cs2CO3(1.42 g, 4.36 mmol). Then the mixture was stirred at 100 °C for 10 hours. On completion, the mixture was filtered and concentrated in vacuo to give the residue. The residue was purified by reverse-phase (0.1% FA) to give the title compound (400 mg, 29% yield) as yellow solid.1H NMR (400 MHz, CDCl3-d) δ 7.40 - 7.35 (m, 2H), 6.93 - 6.86 (m, 2H), 6.86 - 6.80 (m, 2H), 6.28 (d, J = 7.2 Hz, 1H), 5.21 (dd, J = 5.4, 13.0 Hz, 1H), 5.02 - 4.92 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.47 - 3.39 (m, 4H), 3.04 - 2.90 (m, 5H), 2.87 - 2.77 (m, 1H), 2.68 - 2.55 (m, 1H), 2.18 - 2.11 (m, 1H), 1.74 (s, 2H), 1.65 - 1.63 (m, 4H), 1.48 (s, 9H), 1.43 (s, 2H). LC-MS (ESI+) m/z 632.4 (M+H)+
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