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[ CAS No. 167484-18-6 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 167484-18-6
Chemical Structure| 167484-18-6
Chemical Structure| 167484-18-6
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Product Details of [ 167484-18-6 ]

CAS No. :167484-18-6 MDL No. :MFCD11007805
Formula : C20H22N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :XJUPGFXGJQIYQG-UHFFFAOYSA-N
M.W : 322.40 Pubchem ID :10914256
Synonyms :

Calculated chemistry of [ 167484-18-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 24
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.35
Num. rotatable bonds : 4
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 101.12
TPSA : 41.57 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.15
Log Po/w (XLOGP3) : 3.62
Log Po/w (WLOGP) : 2.68
Log Po/w (MLOGP) : 3.14
Log Po/w (SILICOS-IT) : 3.14
Consensus Log Po/w : 3.15

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.23
Solubility : 0.0192 mg/ml ; 0.0000595 mol/l
Class : Moderately soluble
Log S (Ali) : -4.18
Solubility : 0.0213 mg/ml ; 0.000066 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.02
Solubility : 0.000306 mg/ml ; 0.000000951 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.5

Safety of [ 167484-18-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H317 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 167484-18-6 ]

* 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 [ 167484-18-6 ]

[ 167484-18-6 ] Synthesis Path-Downstream   1~81

  • 1
  • [ 124-63-0 ]
  • [ 167484-18-6 ]
  • [ 184289-84-7 ]
YieldReaction ConditionsOperation in experiment
81% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; Compound A (3.03 g, 9.4 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0C. diisopropylethylamine (1.8 mL, 10.3 mmol) and methanesulfonyl chloride (0. 8 mL, 10.3 mmol) were added slowly. The reaction was stirred over night at room temperature. The solvent was removed under vacuum and the crude material was dissolved in dichloromethane, washed successively with aqueous HC1 (1N), saturated aqueous NaHC03 and brine. The organic layer was dried over Na2S04. The dichloromethane was removed by evaporation and the crude material was crystallised from hot ethanol and a drop of acetic acid to give 3.06g (81 %) of B as a beige solid.
81% With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; Synthesis of B:; Compound A (3.03 g, 9.4 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0C. diisopropylethylamine (1.8 mL, 10.3 mmol) and methanesulfonyl chloride (0.8 mL, 10.3 mmol) were added slowly. The reaction was stirred over night at room temperature. The solvent was removed under vacuum and the crude material was dissolved in dichloromethane, washed successively with aqueous HCI (IN), saturated aqueous NaHC03 and brine. The organic layer was dried over Na2S04. The dichloromethane was removed by evaporation and the crude material was crystallised from hot ethanol and a drop of acetic acid to give 3.06g (81 %) of B as a beige solid.
68% With triethylamine; In dichloromethane; at 0 - 25℃; for 3h; Methanesulfonyl chloride (0.145 mL, 1.861 mmol) was added to a solution of benzyl spiro[indoline-3,4?-piperidine]-l?-carboxylate (Compound of step 1 of Example 116, 0.5 g, 0. 1.55 1 mmol) and triethylamine (0.648 mL, 4.65 mmol) in DCM (20 mL) at 0-5 C. The reaction mixture was stirred at RT for 3h. After completion of reaction, water (20 mL) and DCM (20 mL) was added to the reaction mixture. The organic layer was separated and dried over Na2504. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel column, 1-70% EtOAc/petroleum ether as eluent) to obtain the title compound (0.42 g). Yield: 68%; 1H NMR (DMSO-d6, 300 MHz): 5 1.60 (s, 3H), 1.70- 1.74 (m, 2H), 2.93 (s, 3H), 2.97-3.02 (m, 1H), 3.87 (s, 2H), 4.25 (br s, 2H), 5.19 (s, 2H), 7.09 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.40 (brs, 6H); MS (mlz): [M] 400.1.
  • 3
  • [ 13139-17-8 ]
  • [ 171-75-5 ]
  • [ 167484-18-6 ]
YieldReaction ConditionsOperation in experiment
69% In tetrahydrofuran; at 20℃; for 1h; To a stirred solution of 49a (0.90 g, 4.78 mmol) in dry THF (25 mL) was added (N-benzyloxycarbonyloxy)-succinimide (1.2 g, 4.8 mmol) in THF (5 mL) over a 2-min period of time at rt under N2. The resulting mixture was stirred at rt for 1 h. EtOAc was added. It was washed with sat'd NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give pure 49b as colorless crystals (0.96 g, yield: 69%). LC-MS ESI 323.15 (M+H)+(tR=2.62 min, 10%-90% MeOH in H2O in a 4-min run).
69% In tetrahydrofuran; at 20℃; for 1.03333h; 6b. Spiro[3H-indole-3,4'-piperidine]-1'-carboxylic acid, 1,2-dihydro-, Phenylmethyl Ester:; To a stirred solution of 6a (0.90 g, 4.78 mmol) in dry THF (25 mL) was added (N-benzyloxycarbonyloxy)-succinimide (1.2 g, 4.8 mmol) in THF (5 mL) over a 2-min period of time at rt under N2. The resulting mixture was stirred at rt for 1 h. EtOAc was added. It was washed with saturated NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give pure 6b as colorless crystals (0.96 g, yield: 69%). LC-MS ESI 323.15 (M+H)+(tR=2.62 min, 10%-90% MeOH in H2O in a 4-min run).
  • 4
  • [ 252002-43-0 ]
  • [ 167484-18-6 ]
  • 5
  • [ 726198-18-1 ]
  • [ 167484-18-6 ]
  • 7
  • [ 10314-98-4 ]
  • [ 167484-18-6 ]
  • 9
  • [ 501-53-1 ]
  • (+-)-2.3-diamino-propionic acid [ No CAS ]
  • [ 167484-18-6 ]
  • 10
  • [ 10314-99-5 ]
  • [ 167484-18-6 ]
  • 11
  • [ 100-63-0 ]
  • 1.4-diphenyl-butanedione-(2.3) [ No CAS ]
  • [ 167484-18-6 ]
  • 12
  • [ 167484-18-6 ]
  • [ 159634-47-6 ]
  • 18
  • [ 138163-08-3 ]
  • [ 100-63-0 ]
  • [ 167484-18-6 ]
YieldReaction ConditionsOperation in experiment
84% Preparation 1; Benzyl spiro[in line-3,4'-piperidine]- 1 '-carboxylateA solution of phenyl hydrazine (1.29 g, 12.0 mmol) and trifluoroacetic acid (3.0 mL) in a 49/1 solution of toluene/acetonitrile (50 mL) is heated at 35 C. 4-Formyl- piperidine- l -carboxylic acid benzyl ester (2.7 g, 10.91 mmol) is dissolved in a 49/1 solution of toluene/acetonitrile (10 mL) and added dropwise to the mixture(WO2005046682). The mixture is stirred at 35 C overnight. The resulting solution is cooled to 0 C, and methanol (5 mL) is added. NaBFLt (0.619 g, 16.38 mmol) is added slowly to the solution and the mixture is stirred for 45 min. The mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL), dried over sodium sulfate, and evaporated to dryness to give a yellow solid. The crude solid is recrystallised from EtOAc to give a pale yellow solid (1.25 g, 1st crop). The mother liquor is evaporated and purified by flash chromatography, eluting with hexane:ethyl acetate (8:2) to give the title compound as a pale yellow solid (1.2 g, 2n crop) with a total yield (2.4 g, 84%). ESI/MS m/z 323 (M+H)+.
76% Preparation 1Benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate A solution of phenyl hydrazine (1.29 g, 12.0 mmol) and trifluoroacetic acid (3.0 mL) in a 49:1 solution of toluene:acetonitrile (50 mL) is heated at 35 C. 4-Formyl-piperidine-1-carboxylic acid benzyl ester (2.7 g, 10.91 mmol) is dissolved in a 49:1 solution of toluene:acetonitrile (10 mL) and added dropwise to the mixture (WO2005046682). The mixture is stirred at 35 C. overnight. The resulting solution is cooled to 0 C., and methanol (5 mL) is added. NaBH4 (0.619 g, 16.38 mmol) is added portion wise to the solution and the mixture is stirred for 45 min. The reaction mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL), dried over sodium sulfate, and evaporated to dryness to give a yellow solid. The crude solid is recrystallised from EtOAc to give a yellow solid (1.25 g, 1st crop). The mother liquor is evaporated and purified by silica gel chromatography, eluting with hexane:ethyl acetate (8:2) to give the title compound as a pale yellow solid (1.2 g, 2nd crop) with a total yield of (2.4 g, 76%). ESI/MS m/z 323 (M+H)+.
75% A solution of phenylhydrazine (2.38 g, 22 mmol) and trifluoroacetic acid (5 mL) in Toluene/acetonitrile (49/1) (100 mL) was heated at 35C. N-benzyloxycarbonyl 4- formylpiperidine (4.94 g, 20 mmol) was dissolved in 20 mL of toluene/acetonitrile (49/1) and added dropwise to the mixture, which was stirred at 35C overnight. The resulting solution was then cooled to 0C, and methanol (10 mL) was added. NaBH4 (1.13 g, 30 mmol) was added very slowly to the solution which was stirred for a further 45 min. The reaction mixture was washed with aqueous NH40H 6% (40 mL). Methanol (2 mL) was added and the organic layer was washed with brine (40 mL) then dried over Na2S04 and evaporated. The crude material was purified by column chromatography on silica gel, eluting with ethyl acetate/cyclohexane (1/1) to give 4.85 g (75%) of A as a pale yellow solid.
75% Synthesis of advanced intermediate E Synthesis of A:; A solution of phenylhydrazine (2.38 g, 22 mmol) and trifluoroacetic acid (5 mL) in Toluene/acetonitrile (49/1) (100 mL) was heated at 35C. N-benzyloxycarbonyl 4- formylpiperidine (4.94 g, 20 mmol) was dissolved in 20 mL of toluene/acetonitrile (49/1) and added dropwise to the mixture, which was stirred at 35C overnight. The resulting solution was then cooled to 0C, and methanol (10 mL) was added. NaBH4 (1.13 g, 30 mmol) was added very slowly to the solution which was stirred for a further 45 min. The reaction mixture was washed with aqueous NH40H 6% (40 mL). Methanol (2 mL) was added and the organic layer was washed with brine (40 mL) then dried over Na2S04 and evaporated. The crude material was purified by column chromatography on silica gel, eluting with ethyl acetate/cyclohexane (1/1) to give 4.85 g (75%) of A as a pale yellow solid.
74% A solution of phenyl hydrazine (5.96 mmol) and trifluoroacetic acid (1.5 mL) in a solvent system of toluene: acetonitrile (49:1) (25 mL) was stirred at 35 C. To this reaction mixture, a solution of benzyl 4-formylpiperidine- 1 -carboxylate (5.46 mmol) in a solvent system of toluene: acetonitrile (49:1) (5 mL) was added drop wise. The reaction mixture was stirred overnight at 35 C. The reaction mixture was then cooled in ice bath and MeOH (2.5 mL) was added, followed by the addition of sodium borohydride (8.16 mmol) in portions. The reaction mixture was then stirred for 45 minutes. After the completion of reaction, the reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% aqueous ammonia, brine, dried over Na2504 and concentrated. The residue was purified by flash column chromatography (silica gel column, 10%-20% ethyl acetate/ petroleum ether). Yield: 74%; 1H NMR (CDC13, 300 MHz): 7.391 (m, 5H), 7.100 (m, 2H), 6.789 (t, J= 7.5, 1H), 6.686 (d, J = 7.5, 1H), 5.182 (s, 2H), 4.153 (bs, 2H), 3.501 (s, 2H), 3.067 (t, J = 14.1, 2H), 1.895 (m, 4H); MS (mlz): 323.1 (M+H) and 345.1 (M+Na).
49% To a solution of phenylmethyl 4-formyl-1-piperidinecarboxylate (81 mmol) in 200 mL of DCM cooled in an ice bath was added phenylhydrazine (81 mmol). After stirring for approximately 15 min, TFA (202.5 mmol) was added over a period of 5 min. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was then cooled in and ice bath and NaBH4 (121.5 mmol) was added in small portions over 15 min. The resulting solution was allowed to warm to room temperature and stir for one hour, whereupon a 10% solution of NH4OH (~100 mL) was added. After stirring for 30 min, the mixture was separated, and the aqueous layer extracted with DCM. The combine organic solutions were dried over Na2SO4 and concentrated. The residue was purified by column chromatography eluding with 0-10% MeOH in DCM. 12.72 g (39.4 mmol, 49% yield) of the desired product phenylmethyl 1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate was obtained. MS (ES) m/e 323 [M+H]+.
487 mg (Reference Example 33) 1'-benzyloxycarbonyl-1-tert-butyloxycarbonylspiro[indoline-3,4'-piperidine] <Step 1> First, 1-benzyloxycarbonyl-4-formylpiperidine (514.5 mg) was dissolved in chloroform (10 mL), phenylhydrazine (0.245 mL) and trifluoroacetic acid (0.478 mL) were added thereto, and the mixture was stirred at 35C for 14 hours. After that, sodium triacetoxyborohydride (881.9 mg) was added thereto, and the mixture was further stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried with anhydrous magnesium sulfate and was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 50/50) to obtain 1'-benzyloxycarbonylspiro[indoline-3,4'-piperidine] (487.0 mg). MS (ESI)m/z:323[M+H]+.

  • 19
  • [ 1493-27-2 ]
  • [ 167484-18-6 ]
  • [ 870072-74-5 ]
YieldReaction ConditionsOperation in experiment
91% at 175℃; for 8h; 6c. Spiro[3H-indole-3,4'-piperidine]-1'-carboxylic acid, 1,2-dihydro-1-(2-nitrophenyl)-, Phenylmethyl Ester:; To 6b (200 mg, 0.62 mmol, 10025-B) was added 2-fluoro-nitrobenzene (400 mg, 2.8 mmol). The reaction was stirred at 175 C. for 8 h. The desired compound was purified by column chromatography using 0% to 40% EtOAc in hexanex as eluting gradient to afford 6c (250 mg, 91%). MS (ES) m/z 444 [M+H]+.
70% at 200 - 220℃; for 0.5h;microwave; 49b (0.25 g) and ortho-fluoronitrobenzene (0.40 mL) was heated with stirring at 200-220 C. for 30 min under microwave irradiation. The resulting mixture was purified via flash chromatography (silica gel, hexanes:EtOAc=1:0 to 1:1) to give 49c (0.24 g, yield: 70%). LC-MS (ESI) 444.
  • 20
  • [ 121-44-8 ]
  • [ 75-36-5 ]
  • [ 167484-18-6 ]
  • [ 167484-19-7 ]
YieldReaction ConditionsOperation in experiment
2.93 g (77%) With acetic acid;palladium-carbon; In ethanol; dichloromethane; 1-Acetyl-spiro(indoline-3,4'-piperidine) Acetyl chloride (1.4 mL, 19.9 mmol) was added to a solution of 5.35 g (16.6 mmol) of <strong>[167484-18-6]1'-benzyloxycarbonyl-spiro(indoline-3,4'-piperidine)</strong> in 33 mL of CH2 Cl2 and 3.2 mL (23.2 mmol) of Et3 N keeping the temperature between 0-5 C. by cooling in ice bath. After 10 min the cold bath was removed and reaction was stirred for 30 min at which time a TLC indicated complete reaction. The solution was diluted with CH2 Cl2 and washed with water, brine and dried over Na2 SO4. The filtrate was concentrated to a thick oil and the oil was dissolved in 40 mL of EtOH. Acetic acid (3 mL) and 0.8 g of 10% Pd/C were added to the solution and the resulting mixture was hydrogenated on a Parr apparatus for 3 h. The catalyst was filtered and washed with EtOAc and the combined filtrate was concentrated. The residue was partitioned between CH2 Cl2 and water and 2N NaOH was added to this mixture until the aqueous layer was basic. The layers were separated and the aqueous layer was extracted with CH2 Cl2. The combined organic layer was washed with brine, dried over Na2 SO4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.
2.93 g (77%) With acetic acid;palladium-carbon; In ethanol; dichloromethane; 1-Acetyl-spiro(indoline-3,4'-piperidine) Acetyl chloride (1.4 mL, 19.9 mmol) was added to a solution of 5.35 g (16.6 mmol) of <strong>[167484-18-6]1'-benzyloxycarbonyl-spiro(indoline-3,4'-piperidine)</strong> in 33 mL of CH2 Cl2 and 3.2 mL (23.2 mmol) of Et3 N keeping the temperature between 0-5 C. by cooling in ice bath. After 10 min the cold bath was removed and reaction was stirred for 30 min at which time a TLC indicated complete reaction. The solution was diluted with CH2 Cl2 and washed with water, brine and dried over Na2 SO4. The filtrate was concentrated to a thick oil and the oil was dissolved in 40 mL of EtOH. Acetic acid (3 mL) and 0.8 g of 10% Pd/C were added to the solution and the resulting mixture was hydrogenated on a Parr apparatus for 3 h. The catalyst was filtered and washed with EtOAc and the combined filtrate was concentrated. The residue was partitioned between CH2 Cl2 and water and 2N NaOH was added to this mixture until the aqueous layer was basic. The layers were separated and the aqueous layer was extracted with CH2 Cl2. The combined organic layer was washed with brine, dried over Na2 SO4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.
  • 22
  • [ 24391-41-1 ]
  • [ 167484-18-6 ]
  • benzyl 1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With potassium dihydrogenphosphate; phosphoric acid; In dimethyl sulfoxide; at 80℃; for 12h; A solution of <strong>[24391-41-1]4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile</strong> (1.0 g, 5.6 mmol), benzyl 1 ,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate (1.80 g, 5.6 mmol), phosphoric acid (0.11g, 1.1 mmol), and potassium dihydrogen phosphate (0.76 g, 5.6 mmol) in 3 mL of dimethyl sulfoxide has heated at 8O0C for 12 h. The mixture was poured into 25% sodium bicarbonate in water (by weight) and extracted 3x with ethyl acetate. The combined organics were dried over sodium sulfate. Chromatography on silica gel, eluting with 62-65% ethyl acetate / hexanes afforded 1.94 g (74%) of benzyl 1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1 ,2-dihydrc-1Eta-spiro[indole-3,4'-piperidine]-r-carboxylate; TR 7.54 min (HPLC Conditions H).
  • 23
  • [ 1618-36-6 ]
  • [ 167484-18-6 ]
  • benzyl 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% In ethyl acetate; at 100℃; for 48h; A suspension of 4-Chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.05 g, 0.30 mmol) and benzyl 1 ,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate (0.0961 g, 0.3 mmol) in ethyl acetate was heated to 1000C, boiling off the ethyl acetate. The mixture was heated at 1000C for 48 h. The cooled reaction was taken up in ethyl acetate and saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted three times with ethyl acetate, and the combined organics were washed with brine, dried over sodium sulfate and evaporated. The crude material was absorbed on silica gel and chromatographed with 1:1 ethyl acetate/ hexanes to afford 0.693 g (51%) of benzyl 1-(5-methyl-7H-pyrrolo[2,3- dlpyrimidin^-yO-i ^-dihydro-i'H-spirotindole-S^'-piperidinel-i'-carboxylate; TR 7.80 min (HPLC conditions H).
  • 24
  • [ 167484-18-6 ]
  • [ 55052-28-3 ]
  • [ 908287-33-2 ]
YieldReaction ConditionsOperation in experiment
52% With trifluoroacetic acid; In N,N-dimethyl-formamide; at 65℃; for 48h; Benzyl 1 ,2-dihydro-1Eta-spiro[indole-3,4'-piperidine]-1'-carboxylate (2 g, 6.2 mmol) is mixed with 4-chloro-1H-pyrrolo[2,3-b]pyridine (prepared as described in WO 2003000690), DMF (1 mL) and TFA (0.478 mL). The suspension is heated to 650C for 2 days. The reaction is then cooled to room temperature and partitioned between EtOAc and a solution of saturated sodium bicarbonate in water. The EtOAc layer is removed and the water layer is extracted twice more. The combined organics are dried over sodium sulfate, filtered, and the solvent is removed in vacuo. The resulting solid is then purified by column chromatography (99% EtOAc + 1 % Et3N) to provide 1.41g (52% yield) of benzyl 1-(1 H-pyrrolo[2,3-b]pyridin-4-yl)- 1 ,2-dihydro-1Eta-spiro[indole-3,4'-piperidine]-1'-carboxylate as an orange solid. 1H NMR (500 EPO <DP n="75"/>MHz, DMSOd6) delta 11.56 (1H, br. s), 8.05 (1H1 d, J = 6.0 Hz), 7.38-7.40 (4H, m), 7.31-7.35 (2H, m), 7.27 (1 H, br. d, J = 7.0 Hz), 7.12 (1H1 td, J = 8.0, 1.0 Hz), 7.05 (1H, d, J = 8.0 Hz), 6.92 (1H1 d, J = 6.0 Hz), 6.85 (1H, t, J = 7.8 Hz)1 6.43-6.44 (1H, m), 5.11 (2H, br. s), 4.18 (2H, s), 3.98- 4.06 (2H, m), 2.98-3.19 (2H, m), 1.81 (2H, dt, J = 12.9, 4.7 Hz), 1.67-1.75 (2H, m); LRMS (M+): 439.2; HPLC retention time: 1.99 min. (HPLC method I).
  • 25
  • [ 3680-69-1 ]
  • [ 167484-18-6 ]
  • [ 908283-37-4 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 25.67h; 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.4 M, 300 ul, 120 umol) and benzyl 1,2-dihydro- I'H-spirotindole-S^'-piperidinel-r-carboxylate (0.4 M, 300 ul, 120 umol) in DMSO were mixed together. DIEA (neat, 75 ul, 431 umol) was added. The contents were concentrated to dryness in a Genevac and the reaction vial was capped and heated at 1000C for 25 h, 40 min to form benzyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 ,2-dihydro-1Eta-spiro[indole-3,4'-piperidine]-1'- carboxylate. THF (0.5 ml) was added to the mixture, followed by lithium aluminum hydride (1 M in THF, 0.24 ml, 240 umol). The resulting solution was shaken at room temperature for 2 h, 20 min. Water (2 ml) and dichloroethane (2 ml) were added to the reaction mixture and the layers EPO <DP n="71"/>were separated. The aqueous layer was re-extracted with dichloroethane (2 ml). The combined organic layers were concentrated to dryness to afford 27.5 mg of a crude product. The material was dissolved in DMSO (1 ml) and purified by HPLC to afford 9.4 mg of the title compound as a TFA salt (18% overall yield after two steps). APCI LCMS: Observed mass: 320.13 (M+1). Retention time: 1.9 min (Method E).
  • 26
  • [ 871335-85-2 ]
  • [ 167484-18-6 ]
  • benzyl 1-(3-methyl-1H-pyrazolo[2,3-d]pyrimidin-4-yl)-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% In ethyl acetate; at 100℃; for 4h; A mixture of 4-chloro-3-methyl-1 H-pyrazolo[3,4-d]pyrimidine (1.30 g, 7.7 mmol) and benzyl 1 ,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate (2.48 g, 7.7 mmol) in ethyl acetate was heated to 100 0C, boiling off the ethyl acetate. The mixture was heated at 1000C for 4 h and then cooled to rt. The mixture was taken up in 4:1 dichloromethane/ methanol and 2M ammonia in methanol was added until neutral. The mixture was evaporated to dryness and chromatographed on silica gel, eluting with 60-90 % ethyl acetate/ hexanes to afford 1.86 g (53%) of benzyl 1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1 ,2-dihydro-1'H-spiro[indole-3,4'- piperidine]-1'-carboxylate; TR 7.35 min (HPLC conditions H).
  • 27
  • 5-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
  • [ 167484-18-6 ]
  • benzyl 1-(5-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% In ethyl acetate; at 100℃; for 24h; A suspension of 5-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.0683 g, 0.28 mmol) and benzyl i^-dihydro-i'H-spirotindole-S^'-piperidineJ-i'-carboxylate (0.0904 g, 0.28 mmol) in ethyl acetate was heated to 10O0C, boiling off the ethyl acetate. The mixture was heated at 1000C for 24 h. The mixture was taken up in 4:1 dichloromethane/ methanol and 2M ammonia in methanol was added until neutral. The mixture was evaporated to dryness and chromatographed on silica gel, eluting with 2-2.3 % methanol/ methylene chloride to afford 0.075 g (50%) of benzyl 1-(5-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 ,2-dihydro-1'H- spiro[indole-3,4'-piperidine]-1'-carboxylate; TR 8.62 min (HPLC conditions H).
  • 28
  • [ 541-41-3 ]
  • [ 167484-18-6 ]
  • [ 937255-10-2 ]
YieldReaction ConditionsOperation in experiment
31% With triethylamine; In dichloromethane; at 20℃; for 18h; Preparation 1251 '-benzyl 1-ethyl 1'H-spiro?ndole-3.4'-piperidinel-1 ,1'(2H)-dicarboxylateBenzyl 1 ,2-dihydro-1eta-spiro[indole-3,4'-piperidine]-r-carboxylate [described in J. Xie et al., Tetrahedron, 2004, 60, 4875-4878] (251 mg, 0.78 mmol), ethyl chloroformate (93 mg, 0.86 mmol) and triethylamine (0.15 ml, 0.97 mmol) were stirred in dichloromethane (5 ml) at room temperature for 18 hours. The organic phase was washed with saturated aqueous sodium hydrogen carbonate (5 ml), dried (MgSO4), and loaded onto a silica gel column. Gradient elution with cydohexane:Et2O (90:10 - 50:50) yielded the title compound as a colourless gum (95 mg, 0.24 mmol, 31 %). MS m/z (APCI) 395 [MH]+
  • 29
  • [ 79-22-1 ]
  • [ 167484-18-6 ]
  • [ 937255-09-9 ]
YieldReaction ConditionsOperation in experiment
29% With triethylamine; In dichloromethane; at 20℃; for 18h; Preparation 1241'-benzyl 1-methyl 1'H-spiro?ndole-3,4'-piperidine1-1 ,1'(2H)-dicarboxylateBenzyl i ^-dihydro-i'H-spiroIindole-S^'-piperidineJ-i'-carboxylate [described in J. Xie et al., Tetrahedron, 2004, 60, 4875-4878] (251 mg, 0.78 mmol), methyl chloroformate (81 mg, 0.86 mmol) and triethylamine (0.15 ml, 0.97 mmol) were stirred in dichloromethane (5 ml) at room <n="184"/>temperature for 18 hours. The organic phase was washed with saturated aqueous sodium hydrogen carbonate (5 ml), dried (MgSO4), and loaded onto a silica gel column. Gradient elution with cyclohexane:Et2O (90:10 - 50:50) yielded the title compound as a colourless gum (85 mg, 0.22 mmol, 29%).MS m/z (APCI) 381 [MH]+
  • 30
  • [ 108-23-6 ]
  • [ 167484-18-6 ]
  • [ 937255-11-3 ]
YieldReaction ConditionsOperation in experiment
20% With triethylamine; In dichloromethane; at 20℃; for 18h; Preparation 126 1 '-Benzyl 1-isopropyl 1 'H-spirorindole-3,4'-piperidinel-1.1 '(2H)-dicarboxylate <n="185"/>Benzyl i^-dihydro-i'H-spiropndole-S^'-piperidineJ-i'-carboxylate [described in J. Xie et al., Tetrahedron, 2004, 60, 4875-4878] (251 mg, 0.78 mmol), isopropyl chloroformate (95 mg, 0.86 mmol) and triethylamine (0.15 ml, 0.97 mmol) were stirred in dichloromethane (5 ml) at room temperature for 18 hours. The organic phase was washed with saturated aqueous sodium hydrogen carbonate (5 ml), dried (MgSO4), and loaded onto a silica gel column. Gradient elution with cyclohexane/Et2O (90:10 - 50:50) yielded the title compound as a colourless gum (65 mg, 0.16 mmol, 20%). MS m/z (APCI) 409 [MH]+.
  • 31
  • [ 167484-18-6 ]
  • [ 171-75-5 ]
YieldReaction ConditionsOperation in experiment
78% With palladium on activated charcoal; ammonium formate; In methanol; for 2h;Reflux; Benzyl spiro[indoline-3,4?-piperidine] -1 ?-carboxylate (Compound of step 1 of Example 116, 0.7 g, 2.171 mmol) and ammonium formate (0.685 g, 10.86 mmol) were added to a suspension of Pd/C (0.231 g, 2.171 mmol) in MeOH (20 mL) at RT. The reaction mixture was refluxed for 2 h. After completion of reaction, the reaction mixture was filtered over celite bed. The filtrate was concentrated and the residue was purified by flash column chromatography (0-3 % MeOH chloroform with 0.5% aqueous ammonia as eluent, silica gel column) to obtain the title compound (0.32 g). Yield: 78%; H NMR (CDC13, 300 MHz):1.71-1.88 (m, 4H), 1.76 (t, J = 12.0 Hz, 2H), 3.09 (d, 12.0 Hz, 2H), 3.50 (s, 2H), 6.66 (d, J =7.2 Hz, 1H), 6.77 (t, J= 7.5 Hz, 1H), 7.05 (a, J= 7.5 Hz, 1H), 7.11 (a, J= 7.2 Hz, 1H); MS(mlz): [M+H]+ 189.1.
68% With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; A solution of <strong>[167484-18-6]phenylmethyl 1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate</strong> (12.72 g, 39.4 mmol) in 200 mL of MeOH in a 500-mL flask was purged with N2 for 15 min, after which time 10% Pd/C (5 g, approx 50% water) was added. The reaction flask was then purged with H2 and fitted with a balloon charged with H2. The reaction was allowed to stir at room temperature overnight. The mixture was then filtered through celite and the filtrate was concentrated. The celite/Pd/C mixture was stirred in 500 mL of MeOH for 30 min to extract remaining product that may have precipitated out of the reaction. The mixture was filtered through additional celite and the filtrate combined with the previous filtrate and concentrated. 5.05 g (26.7 mmol, 68% yield) of the desired product 1,2-dihydrospiro[indole-3,4'-piperidine] was obtained. MS (ES) m/e 189 [M+H]+.
  • 32
  • [ 115093-90-8 ]
  • [ 167484-18-6 ]
  • [ 908283-43-2 ]
  • 33
  • [ 594-44-5 ]
  • [ 167484-18-6 ]
  • [ 1185762-10-0 ]
  • 34
  • [ 167484-18-6 ]
  • [ 74-88-4 ]
  • [ 1093956-87-6 ]
YieldReaction ConditionsOperation in experiment
40% A 0 C. solution of <strong>[167484-18-6]phenylmethyl 1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate</strong> (100 mg, 0.3 mmol) in DMF (3 mL) was treated with NaH (95%, 10 mg, 0.4 mmol) and stirred at room temperature for 30 min. The solution was cooled to 0 C. and treated with CH3I (0.019 mL, 0.31 mmol) and stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were combined, concentrated and purified by FCC (0-25% EtOAc/hexanes) to afford the product (40 mg, 40%), MS (ES) m/e 337 [M+H]+.
  • 36
  • [ 167484-18-6 ]
  • [ 1292291-54-3 ]
  • 37
  • [ 167484-18-6 ]
  • [ 1292290-66-4 ]
  • 38
  • [ 108-86-1 ]
  • [ 167484-18-6 ]
  • [ 1292290-90-4 ]
YieldReaction ConditionsOperation in experiment
86.48% With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 0 - 100℃;Inert atmosphere; Preparation 14Benzyl 1-phenylspiro[indoline-3,4'-piperidine]-1'-carboxylate To a solution of <strong>[167484-18-6]benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate</strong> (1.5 g, 4.65 mmol) in 1-4, dioxane (5 mL) is added bromobenzene (0.803 g, 5.115 mmol), 4,5-(diphenyl-phosphino)-9,9-dimethyl xanthene (0.807 g, 1.395 mmol) and cesium carbonate (4.54 g, 13.95 mmol) at 0 C. The reaction mixture is purged with nitrogen gas for 15 minutes and palladium acetate (0.062 g, 0.279 mmol) is added. The mixture is stirred at 100 C. for 5 hours, filtered, diluted with ammonium chloride solution, extracted with EtOAc, dried with sodium sulphate, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (1.6 g, 86.48%). ESI/MS m/z 399.4 (M+H)+.
  • 39
  • [ 50-00-0 ]
  • [ 167484-18-6 ]
  • [ 1093956-87-6 ]
YieldReaction ConditionsOperation in experiment
98.3% Preparation 2; Benzyl 1 -methylspiro[indoline-3,4'-piperidine]- 1 '-carboxylate To a 0 C solution of benzyl l,2-dihydro- H-spiro[indole-3,4'-piperidine]- - carboxylate (315 g, 977.5 mmol), formaldehyde (40 % aqueous solution, 138 mL, 4.9 mol) and acetic acid (279 mL, 4.9 mol) in methanol (6.0 L), is added sodiumcyanoborohydride (184 g, 2.9 mol) in portions over a period of 2 h (some effervescence is observed). The reaction mixture is allowed warm to room temperature and stirred for 6 h. The pH of the mixture is adjusted to about 8 with 10% NaHC(¾ solution and extracted with EtOAc (3 x 5.0 L). The combined extracts are washed with water (2 x 2.5 L) and brine (2.5 L), dried over sodium sulfate, and evaporated to dryness to give the title compound as a pale yellow solid (310 g, 98.3%). ESI/MS m/z 337 (M+H)+.
92% With sodium cyanoborohydride; acetic acid; In methanol; at 0 - 25℃; Sodium cyanoborohydride (6.23 mmol) was added to the reaction mixture of benzyl spiro[indoline-3,4?-piperidine]-l?-carboxylate (compound of step 1, 2.078 mmol), acetic acid (10.39 mmol) and formaldehyde (8.31 mmol) in MeOH (20 mL) at 0 C. The reaction mixture was stirred overnight at RT. After the completion of reaction, the reaction mixture was poured into ice-cold water (100 mL) and basified by 10% sodium bicarbonate to obtain the crude product, which was filtered and washed with water to obtain the title compound. Yield: 92%; 1H NMR (CDC13, 300 MHz): 1.60 (s, 2H), 1.75 (bs, 2H), 2.78 (s, 3H), 3.03 (bs, 2H), 3.26 (s, 2H), 4.15 (bs, 2H), 5.18 (s, 2H), 6.53 (d, J= 7.5 Hz, 1H), 6.73 (t, J= 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.28-7.41 (m, 5H); MS: (mlz) 338.3 (M+H).
75% Preparation 7Benzyl 1-methylspiro[indoline-3,4'-piperidine]-1'-carboxylateTo a 0 C. solution of <strong>[167484-18-6]benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate</strong> (1.15 g, 3.56 mmol), formaldehyde (37% aqueous solution, 1.44 mL, 17.83 mmol) and acetic acid (1.02 mL, 17.83 mmol) in methanol (25 mL) is added sodium cyanoborohydride (0.67 g, 10.68 mmol). The reaction mixture is allowed to warm to room temperature overnight. The pH of the mixture is adjusted to approximately 8 with 10% NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined extracts are washed with water (50 mL) and brine (50 mL), dried, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography, eluting with hexane:ethyl acetate (85:15) to give the title compound as an off-white solid (0.9 g, 75%). ESI/MS m/z 337.2 (M+H)+.
  • 40
  • [ 167484-18-6 ]
  • [ 1309436-41-6 ]
  • 41
  • [ 6457-49-4 ]
  • [ 167484-18-6 ]
  • 42
  • [ 100-63-0 ]
  • [ 167484-18-6 ]
  • 43
  • [ 122860-33-7 ]
  • [ 167484-18-6 ]
  • 44
  • [ 823-85-8 ]
  • [ 138163-08-3 ]
  • [ 167484-18-6 ]
YieldReaction ConditionsOperation in experiment
To a mixture of 4-fluorophenylhydrazine hydrochloride (13.36 mmol,1.93 g), trifluoroacetic acid (40.06 mmol, 2.97 mL) in acetonitrile:toluene (49: 1, 25 mL), a solution of benzyl 4-formylpiperidine-l-carboxylate (12.14 mmol, 3 g) in acetonitrile:toluene (49:1, 10 mL) was added drop wise at room temperature. The reaction mixture was stirred at 35 C for 16 hr followed by 5 hr at 50 C. Then the reaction mixture cooled to 0 C, diluted with 3 mL MeOH, added NaBH4 (18.21 mmol, 688 mg) and continued stirring at room temperature for 3 hr. The reaction mixture was then diluted with sat. aq. NaHC03 solution, extracted with ethyl acetate, dried over anhydrous Na2S04, evaporated under reduced pressure and the residue was purified by flash column chromatography. The product eluted at 1 :2 hexane:ethyl acetate solvent mixture.
  • 45
  • [ 24424-99-5 ]
  • [ 167484-18-6 ]
  • [ 676607-30-0 ]
YieldReaction ConditionsOperation in experiment
To a solution of spiroindole (3.32 mmol, 1.07 g) in DMF (5 mL) at 0C, NaH (4.98 mmol, 119 mg) added and stirred for 10 min. Then to the mixture boc- anhydride (4.31 mmol, 942 mg) was added and stirred for 4 hr. The reaction mixture diluted with water (50 mL), extracted with ethylacetate (2 x 50 mL), the ethylacetate layer was washed with brine, dried over Na2S04, evaporated under reduced pressure and the crude was purified by flash column chromatography.
587.3 mg With dimethylaminopyridine; In chloroform; at 20℃; for 1h; The 1?-benzyloxycarbonylspiro[indoline-3,4?-piperidine] (487.0 mg) was dissolved in chloroform (15 mL), ditert-butyl dicarbonate (0.416 mL) and dimethylaminopyridine (221.5 mg) were added thereto, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried with anhydrous magnesium sulfate and was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 25/75) to obtain the title compound (587.3 mg). 1H-NMR (400MHz,CDCl3) delta: 1.58(br.s,9H),1.77-1.88(m,2H),2.90-3.03(m,2H),3.80-3.93(m,2 H),4.16-4.29(m,2H),5.17(s,2H),6.95-6.99(m,1H),7.06-7.09(m,1 H),7.16-7.22(m,1H),7.30-7.96(m,6H). MS (ESI)m/z:423[M+H]+.
  • 46
  • [ 167484-18-6 ]
  • [ 676607-31-1 ]
  • 47
  • [ 167484-18-6 ]
  • [ 1416892-49-3 ]
  • 48
  • [ 167484-18-6 ]
  • [ 1416892-51-7 ]
  • 49
  • C25H27F2N3O2 [ No CAS ]
  • [ 167484-18-6 ]
  • 50
  • C21H19F2N3O2 [ No CAS ]
  • [ 167484-18-6 ]
  • 51
  • [ 167484-18-6 ]
  • benzyl 1-(2-(3-(4-(Trifluoromethoxy)phenyl)ureido)phenyl)-spiro[indoline-3,4′-piperidine]-1′-carboxylate [ No CAS ]
  • 52
  • [ 167484-18-6 ]
  • [ 870072-22-3 ]
  • 53
  • [ 167484-18-6 ]
  • 2-(1-(2-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)spiro[indoline-3,4'-piperidine]-1'-yl)acetic acid [ No CAS ]
  • 54
  • [ 167484-18-6 ]
  • 1-(2-(1'-(2-hydroxyethyl)spiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea [ No CAS ]
  • 55
  • [ 167484-18-6 ]
  • 1-(2-(1'-(2-methoxyethyl)spiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea [ No CAS ]
  • 56
  • [ 167484-18-6 ]
  • methyl 1-(2-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate [ No CAS ]
  • 57
  • [ 167484-18-6 ]
  • N-isopropyl-1-(2-(3-(4-(trifluoromethoxy)phenyl)ureido)phenyl)spiro[indoline-3,4'-piperidine]-1'-carboxamide trifluoroacetic acid [ No CAS ]
  • 58
  • [ 167484-18-6 ]
  • 1-(2-(1'-Methylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea [ No CAS ]
  • 59
  • [ 167484-18-6 ]
  • 1-(2-(1'-isopropylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea trifluoroacetic acid [ No CAS ]
  • 60
  • [ 167484-18-6 ]
  • 1-(2-(1′-isobutylspiro[indoline-3,4′-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea [ No CAS ]
  • 61
  • [ 167484-18-6 ]
  • [ 870072-29-0 ]
  • 62
  • [ 167484-18-6 ]
  • 1-(2-(1′-neopentylspiro[indoline-3,4′-piperidine]-1-yl)-phenyl)-3-(4-(trifluoromethoxy)phenyl)urea [ No CAS ]
  • 63
  • [ 167484-18-6 ]
  • benzyl 1-(2-aminophenyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate [ No CAS ]
  • 64
  • [ 167484-18-6 ]
  • C34H40N2O4 [ No CAS ]
  • 65
  • [ 167484-18-6 ]
  • ethyl 2-(3-(4-((4-((1-(methylsulfonyl)spiro[indoline-3,4’-piperidin]-1‘-yl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate [ No CAS ]
  • 66
  • [ 167484-18-6 ]
  • 1‘-(methylsulfonyl)spiro[indoline-3,4’-piperidine] [ No CAS ]
  • 67
  • [ 167484-18-6 ]
  • ethyl 2-(3-(4-((4-((1‘-(methylsulfonyl)spiro[indoline-3,4’-piperidin]-1-yl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate [ No CAS ]
  • 68
  • [ 167484-18-6 ]
  • 2-(3-(4-((4-((1‘-(methylsulfonyl)spiro[indoline-3,4’-piperidin]-1-yl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid [ No CAS ]
  • 69
  • [ 167484-18-6 ]
  • ethyl 2-(3-(4-((3-((1-methylspiro[indoline-3,4’-piperidin]-1‘-yl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate [ No CAS ]
  • 70
  • [ 167484-18-6 ]
  • ethyl 2-(3-(4-((6-((1-methylspiro[indoline-3,4’-piperidin]-1‘-yl)methyl)pyridin-2-yl)methoxy)phenyl)oxetan-3-yl)acetate [ No CAS ]
  • 71
  • ethyl 2-(3-(4-((4-(bromomethyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate [ No CAS ]
  • [ 167484-18-6 ]
  • benzyl 1-(4-((4-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl)phenoxy)methyl)benzyl)spiro[indoline-3,4’-piperidine]-1‘-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h; A reaction mixture of benzyl spiro[indoline-3 ,4?-piperidine] -1 ?-carboxylate (Compound of step 1, 0.1 g, 0.3 10 mmol), ethyl 2-(3-(4-((4-(bromomethyl)benzyl) oxy)phenyl)oxetan-3-yl)acetate (Intermediate 7, 0.156 g, 0.372 mmol) and K2C03 (0.094 g, 0.682 mmol) in DMF (5 mL) was heated to 80C for 3 h. After completion of reaction, the solvent was removed and the residue was extracted with EtOAc (15 mL), washed with water, brine and concentrated. The residue was purified by column chromatography (silica gel column, 1-50% EtOAc/petroleum ether as eluent) to obtain the title compound (0.17 g). Yield: 78%; 1H NMR (CDC13, 300 MHZ): 5 1.17 (t, J= 7.2 Hz, 3H), 1.72-1.85 (m, 4H), 2.95 (br s, 2H), 3.11 (s, 2H), 3.28 (s, 2H), 4.05 (q, J= 7.2 Hz, 2H), 4.14 (q, J= 7.2 Hz, 2H), 4.32 (s, 2H), 4.86 (d, J = 6.0 Hz, 2H), 5.00 (d, J = 6.0 Hz, 2H), 5.05 (s, 2H), 5.17 (s, 2H), 6.53 (d, J = 7.8 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 7.2 Hz, 1H), 7.09-7.13 (m, 3H), 7.28-7.35 (m, 9H); MS (mlz): [M+H] 661.2.
  • 72
  • [ 167484-18-6 ]
  • [ 167484-48-2 ]
  • 73
  • [ 124150-87-4 ]
  • [ 167484-18-6 ]
  • (R)-1'-benzyloxycarbonyl-1-{3-[(tert-butyldimethylsilyl)oxy ]-2-hydroxypropyl}spiro[indoline-3,4'-piperidine] [ No CAS ]
  • C29H42N2O4Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In ethanol; at 90℃; for 18.6667h; (Reference Example 35) (R)-1'-benzyloxycarbonyl-1-{3-[(tert-butyldimethylsilyl)oxy ]-2-hydroxypropyl}spiro[indoline-3,4'-piperidine] First, the 1'-benzyloxycarbonyl-1-spiro[indoline-3,4'-piperidine] (90.9 mg) was dissolved in ethanol (1 mL), (R)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane (261.4 mg) and potassium carbonate (126.7 mg) were added thereto, and the mixture was stirred at 90 ºC for 18 hours 40 minutes. Water was added to the reaction solution, followed by four times of extraction with ethyl acetate. The organic layer was washed with saturated brine, then was dried with anhydrous sodium sulfate, and was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 0/100 to 40/60) to obtain 115.4 mg of the title compound (a mixture of isomers at about 3:2). 1H-NMR(270MHz, CDCl3) delta: 0.09 (s, 3H), 0.10 0.12 (3:2) (s, 3H), 0.919 0.924 (2:3) (s, 9H), 1.63-1.93 (m, 4H), 2.48 (br.d, J=4.6Hz, 1H), 2.90 -3.09 (m, 2H), 3.18 3.20 (2:3) (s, 2H) , 3.30-3.47 (m,2H), 3.59-3.75 (m,2H), 3.88-4.01 (m , 1H), 4.07-4.22 (m, 2H), 5.17 (s,2H), 6.49-6.56 (m, 1H), 6.66-6.76 (m , 1H), 6.97-7.04 (m, 1H), 7.10 (td, J=7.6, 7.6, 1.3Hz, 1H), 7.28-7.43 ( m, 5H). MS (ESI) m/z:511 [M+H]+.
  • 74
  • [ 23147-58-2 ]
  • [ 167484-18-6 ]
  • 2-(1'-benzyloxycarbonylspiro[indoline-3,4'-piperidine]-1-yl)ethan-1-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.3 mg With sodium tris(acetoxy)borohydride; In chloroform; at 20℃; for 14h; (Reference Example 34) 2-(1'-benzyloxycarbonylspiro[indoline-3,4'-piperidinel-1-yl )ethan-1-ol First, the <strong>[167484-18-6]1'-benzyloxycarbonylspiro[indoline-3,4'-piperidine]</strong> (74.2mg) was dissolved in chloroform, glycol aldehyde dimer (41.5 mg) and sodium triacetoxyborohydride (146.3 mg) were added thereto, and the mixture was stirred at room temperature for 14 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried with anhydrous magnesium sulfate and was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 50/50) to obtain the title compound (80.3 mg). MS(ESI)m/z:367[M+H]+.
  • 75
  • [ 167484-18-6 ]
  • [ 1939-99-7 ]
  • benzyl 1-(benzylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
16.6% With pyridine at 100℃; for 16h; 17 Example 17 - Synthesis of benzyl 1-(benzylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate (I-80) [0305] Phenylmethanesulfonyl chloride (0.066 g, 0.346 mmol) was added to the vial containing benzyl 1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate (0.101 g, 0.313 mmol) in dry pyridine (1 mL). The reaction mixture was heated at 100 °C with stirring for 16 h. After cooling to the room temperature the mixture was evaporated. The residue was dissolved in DMSO (2 mL), filtered from non-soluble impurities. The resulting filtrate was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded benzyl 1-(benzylsulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate, I-80. Yield: 28.8 mg, 16.6%; Appearance: Pink solid; 1H NMR (400 MHz, DMSO-d6) - 7.23 (m, 10H), 7.13 (dd, J = 15.1, 7.6 Hz, 3H), 7.03 - 6.88 (m, 1H), 5.06 (s, 2H), 4.50 (s, 2H), 4.02 (d, J = 13.7 Hz, 2H), 3.68 (s, 2H), 1.71 (td, J = 13.0, 4.5 Hz, 2H), 1.54 (d, J = 13.5 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C27H28N2O4S2: 476.59; Observed: 475.0 [M-H]-.
  • 76
  • 4-(difluoromethyl)benzene-1-sulfonyl chloride [ No CAS ]
  • [ 167484-18-6 ]
  • benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94.5% With pyridine In acetonitrile at 20℃; for 18h; 46.2; 18 [0467] Step-2. Synthesis of benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate : [0468] Pyridine (2.57 g, 32.5 mmol) and 4-(difluoromethyl)benzene-1-sulfonyl chloride (5.89 g, 26.0 mmol) were added to a solution of benzyl 1,2-dihydrospiro[indole-3,4'-piperidine]-1'- carboxylate (7 g, 21.7 mmol) in acetonitrile (200 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure. Flash chromatography (hexane/chloroform/MTBE) purification of the residue afforded benzyl 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxylate as beige solid (10.5 g, 20.4 mmol, 100% purity, 94.5% yield).
  • 77
  • [ 167484-18-6 ]
  • 1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4'-piperidine] [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: pyridine / acetonitrile / 18 h / 20 °C 2: hydrogen; palladium on carbon / tetrahydrofuran; methanol / 18 h / 20 °C / 760.05 Torr
  • 78
  • [ 167484-18-6 ]
  • (1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4'-piperidin]-1'-yl)(pyrrolidin-1-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: pyridine / acetonitrile / 18 h / 20 °C 2: hydrogen; palladium on carbon / tetrahydrofuran; methanol / 18 h / 20 °C / 760.05 Torr 3: triethylamine / dichloromethane / 18 h / 20 °C
  • 79
  • [ 167484-18-6 ]
  • pyridin-2-ylmethyl 1-((4-(difluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: pyridine / acetonitrile / 18 h / 20 °C 2.1: hydrogen; palladium on carbon / tetrahydrofuran; methanol / 18 h / 20 °C / 760.05 Torr 3.1: N,N-dimethyl-formamide / 8 h / 60 °C / Sealed tube 3.2: 16 h / 60 °C
  • 80
  • [ 167484-18-6 ]
  • N-cyclopropyl-1-[4-(difluoromethyl)benzenesulfonyl]-1,2-dihydrospiro[indole-3,4'-piperidine]-1'-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: pyridine / acetonitrile / 18 h / 20 °C 2: hydrogen; palladium on carbon / tetrahydrofuran; methanol / 18 h / 20 °C / 760.05 Torr 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 16 h / 80 °C
  • 81
  • 4-(cyclopropyldifluoromethyl)benzene-1-sulfonyl chloride [ No CAS ]
  • [ 167484-18-6 ]
  • benzyl 1-((4-(cyclopropyldifluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45.1 mg With pyridine In acetonitrile at 20℃; for 12h; 49.6 [0507] Step-6. Synthesis of benzyl 1-((4-(cyclopropyldifluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate : [0508] 4-(Cyclopropyldifluoromethyl)benzene-1-sulfonyl chloride (0.18 g, 0.674 mmol) was added to a mixture of benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate (0.217 g, 0.674 mmol) and pyridine (0.266 g, 3.37 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford benzyl 1-((4-(cyclopropyldifluoromethyl)phenyl)sulfonyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate (I-139). Yield: 45.1 mg, 11.5 %; Appearance: Pink solid; NMR (400 MHz, DMSO-d6) (d, J = 8.1Hz, 2H), 7.76 (d, J = 8.1Hz, 2H), 7.51 (d, J = 8.1Hz, 1H), 7.36 (s, 6H), 7.31 - 7.19 (m, 3H), 7.05 (t, J = 7.3 Hz, 1H), 5.07 (s, 2H), 3.93 (s, 2H), 3.86 (d, J = 14.3 Hz, 2H), 2.95 (s, 2H), 1.67 (s, 1H), 1.56 (s, 2H), 1.03 (s, 2H), 0.63 (d, J = 11.6 Hz, 4H); HPLC purity: 100%; LCMS Calculated for C30H30F2N2O4S: 552.64; Observed: 554.2 [M+H]+.
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