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[ CAS No. 129540-21-2 ] {[proInfo.proName]}

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Chemical Structure| 129540-21-2
Chemical Structure| 129540-21-2
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Product Details of [ 129540-21-2 ]

CAS No. :129540-21-2 MDL No. :MFCD02089473
Formula : C10H12ClN Boiling Point : -
Linear Structure Formula :- InChI Key :AFXDPDJNNABZGP-UHFFFAOYSA-N
M.W : 181.66 Pubchem ID :3719582
Synonyms :

Calculated chemistry of [ 129540-21-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.4
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 55.44
TPSA : 12.03 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.68 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.42
Log Po/w (XLOGP3) : 2.44
Log Po/w (WLOGP) : 2.06
Log Po/w (MLOGP) : 2.66
Log Po/w (SILICOS-IT) : 3.15
Consensus Log Po/w : 2.54

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.81
Solubility : 0.283 mg/ml ; 0.00156 mol/l
Class : Soluble
Log S (Ali) : -2.34
Solubility : 0.838 mg/ml ; 0.00462 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.94
Solubility : 0.0208 mg/ml ; 0.000114 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.86

Safety of [ 129540-21-2 ]

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 [ 129540-21-2 ]

* 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 [ 129540-21-2 ]

[ 129540-21-2 ] Synthesis Path-Downstream   1~34

  • 1
  • [ 129540-21-2 ]
  • [ 109086-16-0 ]
  • 1-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-2-hydroxy-2-(4-methylsulfanyl-phenyl)-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
59%
  • 2
  • [ 129540-25-6 ]
  • [ 129540-21-2 ]
YieldReaction ConditionsOperation in experiment
86% With sodium tetrahydroborate
With methanol; sodium tetrahydroborate for 2h; Cooling with ice;
  • 3
  • [ 88-12-0 ]
  • [ 7335-25-3 ]
  • [ 129540-21-2 ]
  • 4
  • [ 129540-21-2 ]
  • MANDELIC ACID [ No CAS ]
  • 1-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-2-hydroxy-2-phenyl-ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
In xylene for 40h; Heating;
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; platinum Hydrogenation;
  • 6
  • [ 129540-21-2 ]
  • 10-Chloro-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 59 percent 2: 95 percent / polyphosphoric acid
  • 7
  • [ 129540-21-2 ]
  • trans-10-chloro-1,2,3,5,6,10b-hexahydro-6-<4-(methylthio)phenyl>pyrrolo<2,1-a>isoquinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 59 percent 2: 95 percent / polyphosphoric acid 3: BH3*THF
  • 8
  • [ 129540-21-2 ]
  • cis-10-chloro-1,2,3,5,6,10b-hexahydro-6-<4-(methylthio)phenyl>pyrrolo<2,1-a>isoquinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 59 percent 2: 95 percent / polyphosphoric acid 3: BH3*THF
  • 9
  • [ 7335-25-3 ]
  • [ 129540-21-2 ]
  • 10
  • [ 129540-21-2 ]
  • [ 24424-99-5 ]
  • [ 823190-03-0 ]
YieldReaction ConditionsOperation in experiment
92% With sodium hydrogencarbonate In tetrahydrofuran; water 291 Preparation 291 2-(2-chloro-phenyl)-pyrrolidine-1-carboxylic acid-tert-butyl ester Combine 2- (2-CHLORO-PHENYL)-PYRROLIDINE (2.0 g, 11.0 mmol) with di-t- butyldicarbonate (2.89 g, 13.2 mmol) in a mixture of THF (30 mL) and aqueous NAHC03 (30 mL) and stir at RT until the reaction is complete. Dilute the mixture with water and extract with EtOAc. Dry the combined extracts over NA2SO4, filter, and concentrate. Purify the residue by chromatography on silica gel to provide the title compound (92% yield). MS (ES) 282.3 (M+L) + ; Rf=0. 43 (CH2C12).
  • 11
  • [ 129540-21-2 ]
  • [ 823188-48-3 ]
  • [1-(3,5-bis-trifluoromethyl-benzyl)-5-(4-fluoro-phenyl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With dmap; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; 361 Example 361 [1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5- (4-FLUORO-PHENYL)-1 H- [1, 2,3] TRIAZOL-4-YL]- [2- (2- chloro-phenyl)-pyrrolidin-1-yl]-methanone Dissolve 1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5- (4-FLUORO-PHENYL)-1H- [1,2, 3] TRIAZOLE-4-CARBOXYLIC acid (100 mg, 0.23 mmol) in DMF (5 mL). Add 2-(2- chlorophenyl) -pyrrolidine (46 mg, 0.25 mmol), hydroxy-azabenzotriazole (HOAt) (50 mg, 0.25 mmol), EDCI (35 mg, 0.25 mmol), DMAP (5 mg) and TEA (0.1 mL, 0.69 mmol). Stir overnight at RT, then concentrate to dryness. Purify by radial chromatography using a MEOH/CHC13 gradient. Slurry the residue in ether/hexanes and concentrate to dryness to afford 87 mg (63%) of the title compound as a white foam. MS (ES) 597.0 (M+1) + ; Rf= 0.67 (5% MEOH/CHC13).
  • 12
  • [ 620534-18-1 ]
  • [ 129540-21-2 ]
  • C28H21ClF6N4O [ No CAS ]
  • C28H21ClF6N4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 24h; 515 Example 515 [1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5-PHENYL-IH- [1, 2,3] TRIAZOL-4-YL]- [2- (2-CHLORO- phenyl)-pyrrolidin-1-yl]-methanone Dissolve 1- (3, 5-bis-trifluoromethyl-benzyl)-5-phenyl-IH- [1, 2,3] triazole-4- carboxylic acid (2.13 g, 18.2 mmol), ()-2- (2-CHLORO-PHENYL)-PYRROLIDINE (0.93 g, 5.12 mmol), and HOBt (0.86 g, 6.4 mmol) in a mixture OF CH2CI2 (50 mL) and triethylamine (2.14 mL, 15.4 mmol). Add EDCI (1.23 g, 6.4 mmol) and stir the solution at RT. After 24 h, dilute with CH2CI2 (50 mL) and wash with 1 N HCI (100 mL), H20 (100 mL), and saturated NAHC03 (100 mL). Dry the organic layer over MGS04, filter, and concentrate to give a pale yellow foam. Crystallize from EtOAc/hexanes (-1 : 10) to provide 2.20 g (74%) of the title compound in two crops. The racemic mixture may be separated using using chiral chromatography (SS WHELK-01, 20% 3A alcohol/10% IPA/70% heptane) to give the (R)-ENANTIOMER (earlier eluting) and the (S) -enantiomer (later eluting). MS (ES) 579.1 (M+L) + ; RF= 0.18 (2: 1 hexanes/EtOAc).
  • 13
  • [ 129540-21-2 ]
  • [ 823189-31-7 ]
  • (+/-)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; 477 Example 477 (T)- [1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5-CHLORO-1H- [1, 2,3] triazol-4-yl]- [2- (2-chloro- PHENYL)-PYRROLIDIN-I-YL]-METHANONE Dissolve 1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5-CHLORO-I H- [1, 2,3] triazole-4- carboxylic acid (1.8 g, 4.8 MMOL), ()-2- (2-CHLORO-PHENYL)-PYRROLIDINE (1.1 g, 5.89 mmol) and DMAP (1. 4 g, 11.4 mmol) in CH2CI2 (45 mL) and add EDCI (1. 4 g, 7. 1 mmol). Stir the solution at RT for 24 h, then dilute with additional CH2CI2 (50 mL) and wash with saturated NH4CI (50 mL) and saturated NAHC03 (50 mL). Dry, filter, and concentrate the organic phase. Purify crude material by flash chromatography using a linear gradient of 10% to 50% EtOAc/hexanes to give the title compound (2.1 g, 83%) as a white foam upon concentration of solvent. MS (ES) 537.0 (M+L) + ; H NMR (400 MHz, CDCI3, mixture of amide ROTAMERS) No. 7.88 (s, 0. 5H), 7.84 (s, 0. 5H), 7.80 (s, 1H), 7.64 (s, 1H), 7.33 (m, 0. 5H), 7.16 (m, 2H), 7.00 (m, 1. 5H), 6.23 (M, 0. 5H), 5.64 (m, 1. 5H), 5.46 (s, 1H), 4.44 (m, 0.5H), 4.12 (m, 0. 5H), 4.01 (m, 0. 5H), 3.87 (m, 0. 5H), 2.43 (m, 1H), 2.00 (m, 2H), 1. 88 (m, 1H).
  • 14
  • [ 129540-21-2 ]
  • [ 823188-47-2 ]
  • [1-(3,5-bis-trifluoromethyl-benzyl)-5-pyrrol-1-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; 313 Example 313 [1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5-PYRROL-1-YL-IH- [1, 2,3] TRIAZOL-4-YL]- [2- (2-CHLORO- PHENYL)-PYRROLIDIN-1-YL]-METHANONE Combine EDCI (132 mg, 0.69 mmol) with a solution of 2-(2-chloro-phenyl)- pyrrolidine (125 mg, 0.69 mmol), 1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5-PYRROL-L-YL-LH- [1, 2,3] TRIAZOLE-4-CARBOXYLIC acid (200 mg, 0.50 mmol), and DMAP (85 mg, 0.69 mmol) in CH2Cl2 (10.0 mL) and stir at RT. After 24 h, dilute the solution with CH2CL2, wash with saturated aqueous NH4CI, saturated aqueous NAHC03, and water, then dry, filter, and concentrate the organic phase. Purification by flash chromatography eluting with a linear gradient of 15% to 30% EtOAc in hexanes gives the title compound in quantitative yield. MS (ES) 568. 3. 0 (M+L) + ; H NMR (400 MHz, CHCI3, 1: 1 mixture of amide rotamers) 8 7.82 (s, 0. 5H), 7.79 (s, 0.5H), 7.48 (s, 1H), 7.35 (s, 1H), 7.30 (M, 0. 5H), 7.21 (M, 0. 5H), 7.13 (M, 1H), 7.03 (M, 1H), 6.94 (M, 0. 5H), 6.69 (t, 1H, J= 2. 2), 6.43 (t, 1H, J= 2.2), 6.37 (t, 1H, J= 2.2), 6.34 (t, 1H, J= 2.2), 6.19 (dd, 0. 5H, J= 7.9, 2.9), 5.6 (dd, 0. 5H, J= 7.9, 4.0), 5.48 (M, 1H), 5.28 (M, 1H), 4.41 (M, 0. 5H), 3.95 (M, 1H), 3.83 (M, 1H), 2.32- 2.52 (M LH), 1.82-2. 01 (M, 3H).
  • 15
  • [ 129540-21-2 ]
  • [ 823189-37-3 ]
  • (+/-)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-2-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 60h; 327 Example 327 (~)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-2-yl-1H-[1, 2,3] TRIAZOL-4-YL]- [2- (2- CHLORO-PHENYL)-PYRROLIDIN-1-YL]-METHANONE Dissolve 1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5-PYRIDIN-2-YL-IH- [1, 2,3] triazole-4- carboxylic acid (413 mg, 0.99 mmol), ()-2- (2-chloro-phenyl)-pyrrolidine (196 mg, 1.08 mmol), and DMAP (250 mg, 2.05 mmol) in CH2CI2 (4.0 mL) and treat with EDCI (248 mg, 1.29 mmol). Stir the solution at RT for 60 h, then dilute with additional CH2CI2 (20mL) and wash with saturated NH4C1 (10 mL), H20 (10 mL), and saturated NAHC03 (10 mL). Dry, filter, and concentrate the organic phase. Purify the crude material by flash chromatography using a linear gradient of 15% to 40% EtOAc/hexanes to give the title compound (463 mg, 81%) as a white foam. MS (ES) 580.2 (M+1) +. H NMR (400MHZ, CDC13) : No. 8.68 (d, 0. 5H, J= 4.9), 8.57 (d, 0. 5H, J= 4.9), 7.90 (d, 0. 5H, J= 7.8), 7.80 (d, 0. 5H, J= 8.3), 7.66-7. 74 (M, SH), 7.11-7. 34 (M, 3H), 6.67-6. 95 (M, 2H), 5.97 (M, 1H), 5.88 (M, 0. 5H), 5.78 (M, 1H), 5.59 (m, 0. 5H), 4.29 (M, 0. 5H), 3.92 (M, 1. 5H), 2.43 (M, 1H), 1.92 (m, 3H).
  • 16
  • [ 129540-21-2 ]
  • [ 620534-16-9 ]
  • [1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; 473 Example 473 [1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5-PYRIDIN-3-YL-I H- [1, 2,3] TRIAZOL-4-YL]- [2- (2-CHLORO- PHENYL)-PYRROLIDIN-1-YL]-METHANONE Treat a solution of 1- (3, 5-BIS-TRIFLUOROMETHYL-BENZYL)-5-PYRIDIN-3-YL-LH- [1, 2,3] triazole-4-carboxylic acid (0.20 g, 0.49 mmol) in CH2CL2 (3.0 mL) with EDCI (0.20 g, 1.0 mmol), DMAP (0.13 g, 1. 1 mmol) and ()-2- (2-chloro-phenyl)-pyrrolidine (0.26 g, 0.95 mmol). Stir at RT overnight, then dilute with additional CH2C12 (20 mL) and wash with saturated NH4CI (10 mL), H20 (10 mL), and saturated NAHC03 (10 mL). Dry, filter, and concentrate the organic solution, then purify by flash chromatography using A linear gradient of 70% EtOAc/hexanes to 100% EtOAc. Purify again by flash chromatography using a linear gradient of 100% CH2CI2 to 10% MEOH/CH2CI2 to give the title compound (0.17 g, 65%). MS (ES+) 580.3 (M+l) + ; H NMR (400 MHZ, CDC13) 8 8.69 (M, 1H), 8.55 (M, 0. 5H), 8.20 (M, 0. 5H), 7.82 (s, 0. 5H), 7.79 (s, 0. 5H), 7.67 (m, 0. 5H), 7.54 (M, 0. 5H), 7.47 (M, 1H), 7.29-7. 40 (M, 3H), 7.10-7. 24 (M, 1. 5H), 7.06 (m, 0. 5H), 7.01 (m, 0. 5H), 6.90 (m, 0. 5H), 6.30 (m, 0. 5H), 5.60 (m, 1. 5H), 5.41 (m, I H), 4.55 (m, 0. 5H), 4.11 (m, 0. 5H), 3.90 (m, 0. 5H), 3.81 (m, 0. 5H), 2.50 (m, 0. 5H), 2.41 (m, 0. 5H), 1.84-2. 02 (m, 3. 5H).
  • 17
  • [ 129540-21-2 ]
  • [ 1210859-14-5 ]
YieldReaction ConditionsOperation in experiment
With isopentyl nitrite In tetrahydrofuran at 20℃; 16.A Example 16; A. 2-(2-Chloro-phenyl)-1-nitroso-pyrrolidine. To a solution of 2-(2-chloro-phenyl)pyrrolidine (1.0 g, 5.50 mmol) in THF (5.50 mL) was added isoamyl nitrite (0.95 mL, 7.16 mmol) and the reaction mixture was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo and purified by MPLC (SiO2, 20% EtOAc/hexanes) to give 2-(2-chloro-phenyl)-1-nitroso-pyrrolidine (976 mg). MS 211.5 (M+1)+.
  • 18
  • [ 129540-21-2 ]
  • [ 1210859-03-2 ]
  • 1-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-2-phenylamino-2-(4-trifluoromethyl-phenyl)-propan-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% With HATU In dichloromethane 5.E E. 1-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-2-phenylamino-2-(4-trifluoromethyl-phenyl)-propan-1-one. To a solution of Compound 5e (15 mg, 0.05 mmol) and HATU (30 mg, 0.08 mmol) in methylene chloride (5 mL) was added 2-(2-chloro-phenyl)-pyrrolidine (15 mg, 0.08 mmol). The mixture was stirred overnight, concentrated in vacuo, and subjected to preparative TLC (30% ethyl acetate/hexanes) to give Compound 80 (15.2 mg, 66%). MS 473 (M+1)+.
  • 19
  • [ 129540-21-2 ]
  • [ 1210859-12-3 ]
  • 1-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-3-phenylamino-2-(4-trifluoromethyl-phenyl)-propan-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With triethylamine; HATU In dichloromethane at 20℃; 14.C C. 1-[2-(2-Chloro-phenyl)-pyrrolidin-1-yl]-3-phenylamino-2-(4-trifluoromethyl-phenyl)-propan-1-one. To compound 14b (90 mg, 0.29 mmol) and Et3N (0.32 mL, 2.32 mmol) in CH2Cl2 (1.2 mL) was added racemic 2-(2-chloro-phenyl)-pyrrolidine (68 mg, 0.37 mmol) and HATU (221 mg, 0.58 mmol). The reaction mixture was stirred at rt overnight, partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by HPLC (C-18, 50-100 MeCN in water gradient) gave Compound 83 (60 mg, 44%) as a mixture of four stereoisomers. MS 473.3 (M+1)+.
  • 20
  • [ 129540-21-2 ]
  • [ 1210858-97-1 ]
  • C25H21ClF4N2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h;
  • 21
  • [ 129540-21-2 ]
  • [ 1428670-06-7 ]
  • C25H21ClF4N2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h;
  • 22
  • [ 129540-21-2 ]
  • [ 1428670-07-8 ]
  • C25H21ClF4N2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 16h;
  • 23
  • [ 129540-21-2 ]
  • 1-chloro-7-methoxy-9H-β-carboline [ No CAS ]
  • 1-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-methoxy-9H-β-carboline [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% In neat (no solvent) at 170℃; for 24h; Sealed tube;
  • 24
  • [ 129540-21-2 ]
  • 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine [ No CAS ]
  • C20H21ClN6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 120℃; 39 Example 39 To a solution of compound 1 (125 mg, 0.53 mmol) in iPA (2.5 mL) was added 2-(2-chlorophenyl)pyrrolidine (105.99 mg, 0.58 mmol), and DIPEA (0.14 mL, 0.80 mmol) at room temperature and the mixture was stirred at 120° C. for overnight. TLC was taken and the reaction was complete. The crude reaction mixture was concentrated and the residue was subjected to flash column chromatography on silica gel using 0-5% MeOH in DCM (v/v) as eluent to obtain compound 39 as beige solid (117 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 11.88 (br, 1H), 9.06 (br, 1H), 7.98 (br, 1H), 7.46 (m, 1H), 7.25 (m, 2H), 7.01 (m, 1H), 5.71 (br, 1H), 5.02 (br, 1H), 3.72 (m, 2H), 2.40 (m, 1H), 2.08-1.75 (m, 4H), 0.90 (m, 2H), 0.63 (m, 2H); ESI-MS: calcd for (C20H21ClN6) 380, found 381 (MH+).
  • 25
  • [ 129540-21-2 ]
  • C10H12ClN5O [ No CAS ]
  • C20H23ClN6O [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With potassium fluoride In dimethyl sulfoxide at 180℃; for 1.5h; Microwave irradiation; 53 Example 53 The mixture of compound 9 (95 mg, 0.37 mmol), 2-(2-chlorophenyl)pyrrolidine (78 mg, 0.43 mmol) and KF (66 mg, 1.12 mmol) DMSO (3.5 mL) was heated at 180° C. with Biotage microwave initiator for 90 min. TLC was checked and the starting material was almost consumed. The reaction mixture was added to half-saturated ammonium chloride in water (75 mL) and stirred for 30 min. The solids were collected by filtration, washed by water. The crude product was purified by column chromatography (0-10% MeOH in DCM) to give compound 53 as yellow solids. (47 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.68 (br, 1H), 9.47 (s, 1H), 8.04 (br, 1H), 7.50-6.80 (m, 4H), 5.80-5.00 (m, 3H), 4.50 (br, 1H), 3.80-3.40 (br, 2H), 2.40 (m, 1H), 2.00-1.70 (m, 3H), 1.25 (d, J=5.6 Hz, 6H); ESI-MS: calcd for (C20H23ClN6O) 398, found 399 (MH+).
  • 26
  • [ 129540-21-2 ]
  • C11H12ClN5O [ No CAS ]
  • C21H23ClN6O [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With potassium fluoride In dimethyl sulfoxide at 180℃; for 1.5h; Microwave irradiation; 54 Example 54 The mixture of compound 10 (100 mg, 0.38 mmol), 2-(2-chlorophenyl)pyrrolidine (78 mg, 0.43 mmol) and KF (66 mg, 1.12 mmol) DMSO (3.5 mL) was heated at 180° C. with Biotage microwave initiator for 90 min. TLC was checked and the starting material was almost consumed. The reaction mixture was added to half-saturated ammonium chloride in water (75 mL) and stirred for 30 min. The solids were collected by filtration, washed by water. The crude product was purified by column chromatography (0-10% MeOH in DCM) to give compound 54 as yellow solids. (61 mg, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.10 (br, 1H), 9.14 (s, 1H), 8.00 (br, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.25 (m, 2H), 7.00 (d, J=9.6 Hz, 1H), 6.4 (br, 1H), 6.0 (br, 1H), 5.35 (br, 1H), 4.80 (br, 1H), 4.00-3.20 (m, 4H), 2.38 (br, 1H), 3.18 (m, 1H), 2.00-1.70 (m, 6H); ESI-MS: calcd for (C21H23ClN6O) 410, found 411 (MH+).
  • 27
  • [ 129540-21-2 ]
  • C17H23ClN6O2 [ No CAS ]
  • C27H34ClN7O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
9% With potassium fluoride In dimethyl sulfoxide at 180℃; for 1.5h; Microwave irradiation; 55 Example 55 The mixture of compound 11 (230 mg, 0.61 mmol), 2-(2-chlorophenyl)pyrrolidine (127 mg, 0.70 mmol) and KF (106 mg, 1.82 mmol) DMSO (3.5 mL) was heated at 180° C. with Biotage microwave initiator for 90 min. TLC was checked and the starting material was almost consumed. The reaction mixture was added to half-saturated ammonium chloride in water (75 mL) and stirred for 30 min. The solids were collected by filtration, washed by water. The crude product was purified by column chromatography (0-10% MeOH in DCM) to give compound 55 as yellow solids. (29 mg, 9% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.94 (br, 1H), 9.07 (s, 1H), 7.99 (br, 1H), 7.45 (d, J=9.2 Hz, 1H), 7.24 (m, 2H), 7.01 (d, J=9.2 Hz, 1H), 6.20-5.60 (br, 2H), 5.40 (br, 1H), 4.20-3.40 (m, 6H), 2.73 (m, 3H), 2.39 (m, 1H), 2.00-1.60 (m, 5H), 1.41 (s, 9H); ESI-MS: calcd for (C27H34ClN7O2) 523, found 524 (MH+).
  • 28
  • [ 129540-21-2 ]
  • C11H8ClN5O [ No CAS ]
  • C21H19ClN6O [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With potassium fluoride In dimethyl sulfoxide at 180℃; for 1.5h; Microwave irradiation; 56 Example 56 The mixture of compound 12 (150 mg, 0.57 mmol), 2-(2-chlorophenyl)pyrrolidine (115 mg, 0.63 mmol) and KF (99 mg, 1.71 mmol) DMSO (3.5 mL) was heated at 180° C. with Biotage microwave initiator for 90 min. TLC was checked and the starting material was almost consumed. The reaction mixture was added to half-saturated ammonium chloride in water (75 mL) and stirred for 30 min. The solids were collected by filtration, washed by water. The crude product was purified by column chromatography (0-10% MeOH in DCM) to give compound 56 as yellow solids. (71 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 9.32 (s, 1H), 8.04 (s, 1H), 7.50-6.40 (m, 8H), 5.30 (br, 1H), 3.80-3.40 (br, 2H), 2.39 (m, 1H), 2.00-1.70 (m, 3H); ESI-MS: calcd for (C21H19ClN6O) 406, found 407 (MH+).
  • 29
  • [ 129540-21-2 ]
  • methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoate [ No CAS ]
  • cis-methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)benzoate [ No CAS ]
  • trans-methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-(2-(2-chlorophenyl)pyrrolidin-1-yl)cyclohexyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-(2-chlorophenyl)pyrrolidine; methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-oxocyclohexyl)benzoate With acetic acid In methanol at 20℃; for 1h; Stage #2: With sodium cyanoborohydride In methanol for 1h; D1a.5; D1b.5 Step 5: (cis-or trans-) methyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-4-(4- (2- (2-chlorophenyl) pyrrolidin-1-yl) cyclohexyl) benzoate; (trans-or cis-) methyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-4-(4- (2- (2-chlorophenyl) pyrrolidin-1-yl) cyclohexyl) benzoate The mixture of methyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-4-(4-oxocyclohexyl) benzoate (437 mg, 1.20 mmol), 2- (2-chlorophenyl) pyrrolidine (262 mg, 1.44 mmol), AcOH (0.2mL) in MeOH was stirred for 1 hour at room temperature. To the reaction was added NaCNBH 3 (276 mg, 4.40 mmol) and stirred for another 1 hour. Then the reaction mixture was concentrated in vacuum and purified by chromatography column on silica: with the eluent of EA/PE = 1/5 to give the faster isomer P1 (130 mg, 20.43%) as a white solid. 1H NMR (400 MHz, CDCl 3) δ ppm: 9.29 (br, 1H), 8.19-8.15 (m, 1H), 7.86 (d, J = 8.0, 1H), 7.68-7.65 (m, 1H), 7.53-7.49 (m, 1H), 7.36-7.27 (m, 1H), 7.21-7.18 (m, 1H), 6.98-6.93 (m, 3H), 6.71 (s, 1H), 6.47-6.42 (m, 1H), 4.22 (d, J = 8.0, 1H), 3.84 (s, 3H), 3.24-3.18 (m, 1H), 2.60-2.53 (m, 2H), 2.43-2.38 (m, 2H), 2.19-2.15 (m, 1H), 1.83-1.71 (m, 5H), 1.49-1.43 (m, 4H), 1.36-1.24 (m, 2H). MS (ESI, m/e) [M+1] + 530.1; then with the eluent of EA/PE = 1/1 to give the slower isomer P2 (70 mg, 11.00%) as a white solid. 1H NMR (400 MHz, CDCl 3) δ ppm: 8.86 (br, 1H), 8.15-8.11 (m, 1H), 7.84 (d, J = 8.0, 1H), 7.70 (d, J = 8.0, 1H), 7.52-7.47 (m, 1H), 7.34-7.25 (m, 2H), 7.21 (t, J = 8.0, 1H), 7.11 (t, J = 8.0, 1H), 6.95 (d, J = 8.0, 1H), 6.66 (s, 1H), 6.46-6.42 (m, 1H), 4.22-4.17 (m, 1H), 3.84 (s, 3H), 3.24-3.15-3.10 (m, 1H), 2.60-2.53 (m, 2H), 2.37-2.29 (m, 2H), 2.21-2.08 (m, 1H), 1.81-1.72 (m, 5H), 1.56-1.50 (m, 2H), 1.32-1.2 1 (m, 4H). MS (ESI, m/e) [M+1] + 530.1.
  • 30
  • [ 129540-21-2 ]
  • [ 1118787-14-6 ]
  • [2-(2-chlorophenyl)pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
18.7 mg With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 12h; General procedure for preparation of CDK8 inhibitors General procedure: Compound 13 (0.1 mmol, 1 equiv) was added to a screw-top test tube that was equipped with a magnetic stirbar. The test tube was sealed with a screw-top septum and parafilm. The reaction vessel was evacuated (ca. 100 mtorr) and backfilled with argon 3 times. The reaction vessel was cooled to 0 °C. KOH (0.2 mmol, 2 equiv) inMeOH (0.3 mL) was then added via syringe. After 10 min, the reaction was warmed to rt, and was allowed to stir for an additional 12 h. The reaction mixture was diluted with water, and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over Na2SO4, and solvent was removed under reduced pressure to provide the crude deprotected product. To the crude product, 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (14 mg, 0.08 mmol), N-(3-(dimethylamino)propyl)-N’-ethylcarbodiimide (29.4 μl, 0.16 mmol), and 1-hydroxybenzotriazole hydrate (10.8 mg, 0.08 mmol) were added, followed by N,N-dimethylformamide(0.4 mL). 4-Methylmorpholine (26.4 μl, 0.24 mmol) was added atrt, and the reaction mixture was allowed to stir for 12 h at rt. The mixture was diluted with ethyl acetate (2 mL), washed with water (3 x 3 mL) followed by brine (2 x 3 mL),and dried over Na2SO4. The solvent was removed under reduced pressure and dried invacuo to provide the crude product. The crude reaction product was purified by flash column chromatography (9:1:0.1 ethyl acetate: MeOH: triethylamine) to afford pure14.
  • 31
  • 1-[2-(2-chlorophenyl)-1-pyrrolidinyl]-2,2,2-trifluoro-ethanone [ No CAS ]
  • [ 129540-21-2 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide In methanol at 0 - 20℃; for 12.1667h; Sealed tube; Inert atmosphere; General procedure for preparation of CDK8 inhibitors General procedure: Compound 13 (0.1 mmol, 1 equiv) was added to a screw-top test tube that was equipped with a magnetic stirbar. The test tube was sealed with a screw-top septum and parafilm. The reaction vessel was evacuated (ca. 100 mtorr) and backfilled with argon 3 times. The reaction vessel was cooled to 0 °C. KOH (0.2 mmol, 2 equiv) inMeOH (0.3 mL) was then added via syringe. After 10 min, the reaction was warmed to rt, and was allowed to stir for an additional 12 h. The reaction mixture was diluted with water, and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over Na2SO4, and solvent was removed under reduced pressure to provide the crude deprotected product. To the crude product, 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (14 mg, 0.08 mmol), N-(3-(dimethylamino)propyl)-N’-ethylcarbodiimide (29.4 μl, 0.16 mmol), and 1-hydroxybenzotriazole hydrate (10.8 mg, 0.08 mmol) were added, followed by N,N-dimethylformamide(0.4 mL). 4-Methylmorpholine (26.4 μl, 0.24 mmol) was added atrt, and the reaction mixture was allowed to stir for 12 h at rt. The mixture was diluted with ethyl acetate (2 mL), washed with water (3 x 3 mL) followed by brine (2 x 3 mL),and dried over Na2SO4. The solvent was removed under reduced pressure and dried invacuo to provide the crude product. The crude reaction product was purified by flash column chromatography (9:1:0.1 ethyl acetate: MeOH: triethylamine) to afford pure14.
  • 32
  • [ 4530-20-5 ]
  • [ 129540-21-2 ]
  • tert-butyl N-{2-[2-(2-chlorophenyl)pyrrolidin-1-yl]-2-oxoethyl}carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% Stage #1: BOC-glycine With pivaloyl chloride; triethylamine In dichloromethane at 0℃; for 1h; Stage #2: 2-(2-chlorophenyl)pyrrolidine With triethylamine In dichloromethane at 0 - 20℃; tert-butyl N-{2-[2-(2-chlorophenyl)pyrrolidin-1-yl]-2-oxoethyl}carbamate Pivaloyl chloride (0.2 ml_, 1 .54 mmol) was added to a solution of Boc-glycine (270 mg, 1.54 mmol) and EbN (0.5 ml_, 3.47 mmol) in DCM (5 ml) at 0 °C. The reaction was stirred for 1 h, where after Et3N (0.5 ml_, 3.47 mmol) and 2-(2-Chlorophenyl)- pyrrolidine (308 mg, 1.70 mmol) were added in succession. The reaction was allowed to warm to room temperature and react overnight. The reaction mixture was washed with aqueous 0.5 M citric acid, sat. NaCI and sat. NaHCC>3. The DCM phase was dried with anhydrous MgS04 and evaporated. 500 mg, 96%. 1H NMR (400 MHz, DMSO-de) d 7.42 (td, J = 6.0, 5.5, 2.9 Hz, 2H), 7.31 - 7.19 (m, 2H), 7.19 - 7.10 (m, 1 H), 6.77 (t, J = 5.8 Hz, 1 H), 3.83 (qt, J = 12.3, 5.9 Hz, 2H), 3.75 - 3.49 (m, 2H), 2.31 - 2.19 (m, 1 H), 2.01 - 1.63 (m, 4H), 1.21 (s, 9H).
  • 33
  • [ 129540-21-2 ]
  • 3-{2-[2-(2-chlorophenyl)pyrrolidin-1-yl]-2-oxoethyl}-1-[(4-nitrophenyl)methyl]-1-( prop-2-yn-1-yl)urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: pivaloyl chloride; triethylamine / dichloromethane / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: 2-chloropyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.83 h / 20 °C 2.2: 20 h / 20 °C
  • 34
  • [ 129540-21-2 ]
  • 3-{2-[2-(2-chlorophenyl)pyrrolidin-1-yl]-2-oxoethyl}-1-[(1-methyl-1H-1,2,3-triazol-4-yI)methyl]-1-[(4-nitrophenyl)methyl]urea [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: pivaloyl chloride; triethylamine / dichloromethane / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: 2-chloropyridine; trifluoromethylsulfonic anhydride / dichloromethane / 0.83 h / 20 °C 2.2: 20 h / 20 °C 3.1: sodium azide; sodium carbonate; ascorbic acid; copper(II) sulfate pentahydrate / water; N,N-dimethyl-formamide / 20 °C
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