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Chemical Structure| 858121-94-5 Chemical Structure| 858121-94-5

Structure of 858121-94-5

Chemical Structure| 858121-94-5

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Product Details of [ 858121-94-5 ]

CAS No. :858121-94-5
Formula : C7H11BrF2
M.W : 213.06
SMILES Code : FC1(F)CCC(CBr)CC1
MDL No. :MFCD11847776
InChI Key :VVBAHFKQTKRMAS-UHFFFAOYSA-N
Pubchem ID :53350361

Safety of [ 858121-94-5 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H315-H318-H335-H227
Precautionary Statements:P210-P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P332+P313-P362-P370+P378-P403+P233-P403+P235-P405-P501

Application In Synthesis of [ 858121-94-5 ]

* 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 [ 858121-94-5 ]

[ 858121-94-5 ] Synthesis Path-Downstream   1~19

  • 1
  • [ 178310-99-1 ]
  • [ 858121-94-5 ]
YieldReaction ConditionsOperation in experiment
With lithium bromide; In water; acetone; for 8h;Heating / reflux; In 15 ml of acetone, 1.5 g of 4,4- difluorocyclohexylmethyl p-toluenesulfonate was dissolved. Thereto 1.6 g of lithium bromide monohydrate was added and the mixture was heated under reflux for 8 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.76 g of 4-bromomethyl-1, 1-difluorocyclohexane. 4-Bromomethyl-l, l-difluorocyclohexane : 1H-NMR (CDC13, TMS) 5 (ppm): 1.33-1. 48 (2H, m), 1.64-1. 84 (3H, m), 1.90-2. 00 (2H, m), 2.14-2. 20 (2H, m), 3.31 (2H, d).
  • 2
  • [ 858121-94-5 ]
  • [ 474889-56-0 ]
  • 2-(4,4-difluorocyclohexyl)methyl-2-(3,3,3-trifluoropropyl)malononitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; 1.2 g of 2- (3, 3,3-trifluoropropyl) malononitrile and 0.76 g of 4-bromomethyl-1, 1-difluorocyclohexane were dissolved in 10 ml of N, N-dimethylformarnide, 0.99 g of potassium carbonate was added, and the mixture was stirred at room temperature overnight. Thereafter, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated'under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.51 g of 2- (4, 4-difluorocyclohexyl) methyl-2- (3, 3,3- trifluoropropyl) malononitrile (hereinafter, referred to as the present compound (83)). The present compound (83): 1H-NMR (CDCl3, TMS) 5 (ppm): 1. 42-1. 56 (2H, m), 1.71-1. 96 (5H, m), 1.99-2. 08 (2H, m), 2.10-2. 25 (4H, m), 2. 46-2. 60 (2H, m).
  • 3
  • [ 858121-94-5 ]
  • [ 949033-38-9 ]
YieldReaction ConditionsOperation in experiment
N-(5-chloropyridin-2-yl)-3-(4,4-difluorocyclohexyl)-2-(6-fluoro-4-oxoquinazolin-3(4H)-yl)propanamide Referring to the scheme above, to a solution of ethyl 2-(diphenylmethyleneamino)acetate (1.4 g, 5.6 mmol) in dry THF (15 ml) at -30 C. was added t-BuOK (0.69 g, 6.16 mmol) and the orange solution was stirred for 1 h at 0 C. To this mixture was added a solution (5 mL THF) of <strong>[858121-94-5]4-(bromomethyl)-1,1-difluorocyclohexane</strong> (1.1 g, 5.6 mmol) and the reaction was allowed to warm to RT overnight. The reaction was quenched by the addition of HCl (1 mL) followed by H2O (29 mL). This mixture was stirred at RT for 2 h and the solvent was removed. HPLC purification of the resultant crude residue afforded 217A as yellow oil (1.1 g). [M+H] calc'd for C11H190F2NO2, 236; found, 236. Compound 217A was further characterized after protection with Boc2O using common literature conditions. The resulting compound ethyl 2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propanoate possessed the following 1H NMR (400 MHz, CHLOROFORM-d) delta: 1.28 (t, J=7.07 Hz, 3H) 1.45 (s, 9H) 1.47-1.58 (m, 3H) 1.58-1.83 (m, 4H) 1.94 (d, J=13.14 Hz, 1H) 1.99-2.18 (m, J=13.20, 9.92, 6.76, 6.76, 3.54 Hz, 2H) 4.20 (qd, J=7.16, 1.52 Hz, 2H) 4.26-4.37 (m, 1H) 4.96 (d, J=8.59 Hz, 1H). [M+H] calc'd for C16H278F2NO4, 336; found 336.
  • 4
  • [ 858121-94-5 ]
  • C23H41N3O4 [ No CAS ]
  • C30H51F2N3O4 [ No CAS ]
  • 5
  • [ 858121-94-5 ]
  • [ 58481-11-1 ]
  • [ 1251844-48-0 ]
YieldReaction ConditionsOperation in experiment
Zinc powder (1.43 g, 21.87 mmol) was added to a dried flask and was heated at 70 C. under vacuum for 30 minutes. Dry DMA (29 mL) and iodine (0.092 g, 0.37 mmol) were added and the mixture was heated at 70 C. until the red-brown colour had disappeared (approx. 5 minutes). 4-(Bromomethyl)-1,1-difluorocyclohexane (3.1 g, 14.55 mmol) was added and heating was continued for ca. 42 h. The resulting solution was used in the next transformation. To methyl-2-chloroisonicotinate (1.664 g, 9.7 mmol) and bis(tri-tert-butylphosphine)palladium(0) (198 mg, 0.38 mmol) under nitrogen was added tetrahydrofuran (10 mL). To the resulting solution was added freshly prepared ((4,4-difluorocyclohexyl)methyl)zinc(II) bromide (14.55 mmol, 0.5 M in 29 mL DMA) and the resulting brown mixture heated to 60 C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed with satd NaHCO3 (2 times), satd NH4Cl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH. The NH3/MeOH layer was evaporated leaving methyl 2-((4,4-difluorocyclohexyl)methyl)isonicotinate (2 g, 67%) as a yellow oil. 1H NMR (400 MHz, cdcl3) delta 1.30-1.46 (m, 2H), 1.58-1.79 (m, 4H), 1.87-2.14 (m, 3H), 2.82 (d, 2H), 3.96 (s, 3H), 7.65-7.73 (m, 2H), 8.70 (d, 1H). MS m/z 270 (M+H)+
  • 6
  • [ 178312-48-6 ]
  • [ 858121-94-5 ]
YieldReaction ConditionsOperation in experiment
96% With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 2h; To a stirred solution of (4,4-difluorocyclohexyl)methanol (2.00 g, 14.372 mmol, 1.0 eq) in DCM (20 mL), PBr3 (1.63 mL, 17.247 mmol, 1.2 eq) was added at 0 C. and the reaction mixture was then stirred at ambient temperature for 2 h. After completion of the reaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction was quenched with NaHCO3 solution (150 mL), extracted with DCM (3×150 mL), dried over Na2SO4 and concentrated to get 4-(bromomethyl)-1,1-difluorocyclohexane (2.80 g, 96%).
54% With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃;Inert atmosphere; (4,4-Difluorocyclohexyl)methanol (7.22 g, 48.08 mmol) and triphenylphosphine (25.2 g, 96.16 mmol) were dissolved in DCM (75 mL) and cooled to 0 C. under nitrogen atmosphere. Carbon tetrabromide (31.9 g, 96.16 mmol) was dissolved in DCM (75 mL) and added to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated. Pentane (250 mL) was added to the orange residue, which caused triphenylphosphineoxide to precipitate. The off-white solids were filtered off. The filtrate was evaporated and purified on a ISOLUTE Silica Flash column (50 g). Pentane followed by EtOAc:pentane (1% EtOAc) was used as eluent. 4-(Bromomethyl)-1,1-difluorocyclohexane (5.48 g, 54%) was isolated. 1H NMR (400 MHz, cdcl3) delta 1.32-1.46 (m, 2H), 1.64-1.84 (m, 3H), 1.90-1.99 (m, 2H), 2.05-2.18 (m, 2H), 3.31 (d, 2H).
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 26℃; for 16h; To a solution of (4,4-difluorocyclohexyl)methanol (1 g, 0.0066 mol, commercial source: J&W Pharma) in dichloromethane (5 mL), triphenyl phosphine (3.4 g, 0.0133 mol) was added at 26 C, followed by the addition of a solution of carbon tetrabromide (2.1 g, 0.0066 mol) in dichloromethane (5 mL) slowly in dropwise at 0 C. The reaction mixture was stirred at 26 C for 16 h. On completion, the reaction mixture was concentrated under reduced pressure at 26 C. The crude was stirred with n-pentane (100 mL) at 26 C for 10 min. The n-pentane layer was decanted and concentrated under reduced pressure to afford 4-(bromomethyl)-1 ,1-difluorocyclohexane (1.7 g) as a colorless liquid that was characterized by H-NMR. This crude was used without any purification in the next reaction.1H NMR (400 MHz, CDCI3) 5 3.31 (d, J = 6.4 Hz, 2H), 2.21 -2.06 (m, 2H), 2.00-1 .90 (m, 2H), 1.83-1.63 (m, 3H), 1.47-1.32 (m, 2H)
  • 7
  • [ 858121-94-5 ]
  • [ 74-96-4 ]
  • [ 1384875-65-3 ]
  • [ 1384875-15-3 ]
  • [ 1384875-16-4 ]
  • [ 1384875-17-5 ]
YieldReaction ConditionsOperation in experiment
Example 148 :N-[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 149 :N-[(4,4-difluorocyclohexyl)methyl]-N-ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 150 :N,N-bis[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazaspiro[2.5]octane-8-sulfonamide 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pynmidine-7-carboxylic acid tert-butyl ester (intermediate 2) (0.049 mmol) was dissolved in dry DMF (1 mL) and added Cs2C03 (0.147 mmol) and 4-(bromomethyl)-l,l-difluoro-cyclohexane (0.044 mmol) and stirred at 45C for 16h. The obtained reaction mixture was added bromoethane (0.098 mmol) and stirred at 45C for 2h before being filtered through a syringe filter. The obtained filtrate was added 2,2,2-trifluoroethanol (1 mL) and heated to 100C for lh. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.Example 148 :1H NMR (300 MHz, DMSO) delta 11.71 (s, 1H), 8.13 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.18 (dd, J = 3.5, 2.3 Hz, 1H), 6.59 (dd, J = 3.5, 1.8 Hz, 1H), 4.05 (t, J = 5.0 Hz, 2H), 3.84 (s, 2H), 3.55 (t, J = 5.2 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.07 - 1.91 (m, 2H), 1.84 - 1.64 (m, 3H), 1.29 - 1.07 (m, 4H), 1.06 - 0.78 (m, 4H) .LC-MS: 2.12 min, ES (+), m/z: 441.187 Example 149 :LC-MS: 2.31 min, ES (+), m/z: 469.220Example 150 :1H NMR (300 MHz, DMSO) delta 11.72 (s, 1H), 8.49 (s, 1H), 7.23 - 7.12 (m, 1H), 6.59 (dd, J = 3.7, 1.8 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.82 (s, 2H), 3.49 - 3.44 (m, 2H), 2.99 (d, J = 6.8 Hz, 4H), 2.10 - 1.66 (m, 14H), 1.35 - 1.07 (m, 4H), 1.00 - 0.79 (m, 4H).LC-MS: 2.49 min, ES (+), m/z: 537.260Example 148 :N-[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 149 :N-[(4,4-difluorocyclohexyl)methyl]-N-ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 150 :N,N-bis[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazaspiro[2.5]octane-8-sulfonamide 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pynmidine-7-carboxylic acid tert-butyl ester (intermediate 2) (0.049 mmol) was dissolved in dry DMF (1 mL) and added Cs2C03 (0.147 mmol) and 4-(bromomethyl)-l,l-difluoro-cyclohexane (0.044 mmol) and stirred at 45C for 16h. The obtained reaction mixture was added bromoethane (0.098 mmol) and stirred at 45C for 2h before being filtered through a syringe filter. The obtained filtrate was added 2,2,2-trifluoroethanol (1 mL) and heated to 100C for lh. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.Example 148 :1H NMR (300 MHz, DMSO) delta 11.71 (s, 1H), 8.13 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.18 (dd, J = 3.5, 2.3 Hz, 1H), 6.59 (dd, J = 3.5, 1.8 Hz, 1H), 4.05 (t, J = 5.0 Hz, 2H), 3.84 (s, 2H), 3.55 (t, J = 5.2 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.07 - 1.91 (m, 2H), 1.84 - 1.64 (m, 3H), 1.29 - 1.07 (m, 4H), 1.06 - 0.78 (m, 4H) .LC-MS: 2.12 min, ES (+), m/z: 441.187 Example 149 :LC-MS: 2.31 min, ES (+), m/z: 469.220Example 150 :1H NMR (300 MHz, DMSO) delta 11.72 (s, 1H), 8.49 (s, 1H), 7.23 - 7.12 (m, 1H), 6.59 (dd, J = 3.7, 1.8 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.82 (s, 2H), 3.49 - 3.44 (m, 2H), 2.99 (d, J = 6.8 Hz, 4H), 2.10 - 1.66 (m, 14H), 1.35 - 1.07 (m, 4H), 1.00 - 0.79 (m, 4H).LC-MS: 2.49 min, ES (+), m/z: 537.260Example 148 :N-[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 149 :N-[(4,4-difluorocyclohexyl)methyl]-N-ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 150 :N,N-bis[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazaspiro[2.5]octane-8-sulfonamide 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pynmidine-7-carboxylic acid tert-butyl ester (intermediate 2) (0.049 mmol) was dissolved in dry DMF (1 mL) and added Cs2C03 (0.147 mmol) and 4-(bromomethyl)-l,l-difluoro-cyclohexane (0.044 mmol) and stirred at 45C for 16h. The obtained reaction mixture was added bromoethane (0.098 mmol) and stirred at 45C for 2h before being filtered through a syringe filter. The obtained filtrate was added 2,2,2-trifluoroethanol (1 mL) and heated to 100C for lh. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.Example 148 :1H NMR (300 MHz, DMSO) delta 11.71 (s, 1H), 8.13 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.18 (dd, J = 3.5, 2.3 Hz, 1H), 6.59 (dd, J = 3.5, 1.8 Hz, 1H), 4.05 (t, J = 5.0 Hz, 2H), 3.84 (s, 2H), 3.55 (t, J = 5.2 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.07 - 1.91 (m, 2H), 1.84 - 1.64 (m, 3H), 1.29 - 1.07 (m, 4H), 1.06 - 0.78 (m, 4H) .LC-MS: 2.12 min, ES (+), m/z: 441.187 Example 149 :LC-MS: 2.31 min, ES (+), m/z: 469.220Example 150 :1H NMR (300 MHz, DMSO) delta 11.72 (s, 1H), 8.49 (s, 1H), 7.23 - 7.12 (m, 1H), 6.59 (dd, J = 3.7, 1.8 Hz, 1H), 4.11...
  • 8
  • [ 858121-94-5 ]
  • [ 74-96-4 ]
  • [ 1384875-65-3 ]
  • C26H38F2N6O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 148 :N-[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 149 :N-[(4,4-difluorocyclohexyl)methyl]-N-ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 150 :N,N-bis[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazaspiro[2.5]octane-8-sulfonamide 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pynmidine-7-carboxylic acid tert-butyl ester (intermediate 2) (0.049 mmol) was dissolved in dry DMF (1 mL) and added Cs2C03 (0.147 mmol) and 4-(bromomethyl)-l,l-difluoro-cyclohexane (0.044 mmol) and stirred at 45C for 16h. The obtained reaction mixture was added bromoethane (0.098 mmol) and stirred at 45C for 2h before being filtered through a syringe filter. The obtained filtrate was added 2,2,2-trifluoroethanol (1 mL) and heated to 100C for lh. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.Example 148 :1H NMR (300 MHz, DMSO) delta 11.71 (s, 1H), 8.13 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.18 (dd, J = 3.5, 2.3 Hz, 1H), 6.59 (dd, J = 3.5, 1.8 Hz, 1H), 4.05 (t, J = 5.0 Hz, 2H), 3.84 (s, 2H), 3.55 (t, J = 5.2 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.07 - 1.91 (m, 2H), 1.84 - 1.64 (m, 3H), 1.29 - 1.07 (m, 4H), 1.06 - 0.78 (m, 4H) .LC-MS: 2.12 min, ES (+), m/z: 441.187 Example 149 :LC-MS: 2.31 min, ES (+), m/z: 469.220Example 150 :1H NMR (300 MHz, DMSO) delta 11.72 (s, 1H), 8.49 (s, 1H), 7.23 - 7.12 (m, 1H), 6.59 (dd, J = 3.7, 1.8 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.82 (s, 2H), 3.49 - 3.44 (m, 2H), 2.99 (d, J = 6.8 Hz, 4H), 2.10 - 1.66 (m, 14H), 1.35 - 1.07 (m, 4H), 1.00 - 0.79 (m, 4H).LC-MS: 2.49 min, ES (+), m/z: 537.260Example 148 :N-[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 149 :N-[(4,4-difluorocyclohexyl)methyl]-N-ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 150 :N,N-bis[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazaspiro[2.5]octane-8-sulfonamide 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pynmidine-7-carboxylic acid tert-butyl ester (intermediate 2) (0.049 mmol) was dissolved in dry DMF (1 mL) and added Cs2C03 (0.147 mmol) and 4-(bromomethyl)-l,l-difluoro-cyclohexane (0.044 mmol) and stirred at 45C for 16h. The obtained reaction mixture was added bromoethane (0.098 mmol) and stirred at 45C for 2h before being filtered through a syringe filter. The obtained filtrate was added 2,2,2-trifluoroethanol (1 mL) and heated to 100C for lh. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.Example 148 :1H NMR (300 MHz, DMSO) delta 11.71 (s, 1H), 8.13 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.18 (dd, J = 3.5, 2.3 Hz, 1H), 6.59 (dd, J = 3.5, 1.8 Hz, 1H), 4.05 (t, J = 5.0 Hz, 2H), 3.84 (s, 2H), 3.55 (t, J = 5.2 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.07 - 1.91 (m, 2H), 1.84 - 1.64 (m, 3H), 1.29 - 1.07 (m, 4H), 1.06 - 0.78 (m, 4H) .LC-MS: 2.12 min, ES (+), m/z: 441.187 Example 149 :LC-MS: 2.31 min, ES (+), m/z: 469.220Example 150 :1H NMR (300 MHz, DMSO) delta 11.72 (s, 1H), 8.49 (s, 1H), 7.23 - 7.12 (m, 1H), 6.59 (dd, J = 3.7, 1.8 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.82 (s, 2H), 3.49 - 3.44 (m, 2H), 2.99 (d, J = 6.8 Hz, 4H), 2.10 - 1.66 (m, 14H), 1.35 - 1.07 (m, 4H), 1.00 - 0.79 (m, 4H).LC-MS: 2.49 min, ES (+), m/z: 537.260
  • 9
  • [ 858121-94-5 ]
  • [ 1384875-65-3 ]
  • C24H34F2N6O4S [ No CAS ]
  • C31H44F4N6O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 45℃; for 16h; Example 148 :N-[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 149 :N-[(4,4-difluorocyclohexyl)methyl]-N-ethyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazas iro[2.5]octane-8-sulfonamideExample 150 :N,N-bis[(4,4-difluorocyclohexyl)methyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8- diazaspiro[2.5]octane-8-sulfonamide 4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pynmidine-7-carboxylic acid tert-butyl ester (intermediate 2) (0.049 mmol) was dissolved in dry DMF (1 mL) and added Cs2C03 (0.147 mmol) and 4-(bromomethyl)-l,l-difluoro-cyclohexane (0.044 mmol) and stirred at 45C for 16h. The obtained reaction mixture was added bromoethane (0.098 mmol) and stirred at 45C for 2h before being filtered through a syringe filter. The obtained filtrate was added 2,2,2-trifluoroethanol (1 mL) and heated to 100C for lh. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.Example 148 :1H NMR (300 MHz, DMSO) delta 11.71 (s, 1H), 8.13 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.18 (dd, J = 3.5, 2.3 Hz, 1H), 6.59 (dd, J = 3.5, 1.8 Hz, 1H), 4.05 (t, J = 5.0 Hz, 2H), 3.84 (s, 2H), 3.55 (t, J = 5.2 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.07 - 1.91 (m, 2H), 1.84 - 1.64 (m, 3H), 1.29 - 1.07 (m, 4H), 1.06 - 0.78 (m, 4H) .LC-MS: 2.12 min, ES (+), m/z: 441.187 Example 149 :LC-MS: 2.31 min, ES (+), m/z: 469.220Example 150 :1H NMR (300 MHz, DMSO) delta 11.72 (s, 1H), 8.49 (s, 1H), 7.23 - 7.12 (m, 1H), 6.59 (dd, J = 3.7, 1.8 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.82 (s, 2H), 3.49 - 3.44 (m, 2H), 2.99 (d, J = 6.8 Hz, 4H), 2.10 - 1.66 (m, 14H), 1.35 - 1.07 (m, 4H), 1.00 - 0.79 (m, 4H).LC-MS: 2.49 min, ES (+), m/z: 537.260
  • 10
  • [ 858121-94-5 ]
  • [ 1508310-56-2 ]
  • N-(4-((((4,4-difluorocyclohexyl)methyl)(propyl)amino)methyl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
10.6% With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Microwave irradiation; General procedure: 2-(4-(ethylsulfonyl)phenyl)-N-(4-((propylamino)methyl)phenyl)acetamide (50 mg, 0.13 mmol) was added sequentially to a 20 mL sealed tube.2-chlorobenzyl bromide (53 muL, 0.4 mmol),Anhydrous potassium carbonate (55 mg, 0.4 mmol),N,N-dimethylformamide 2mL,Heated at 60 C for 3 hours,TLC confirmed that the reaction was completed and washed with saturated brine.Purification of petroleum ether by column chromatography: ethyl acetate 2:1?3:2,Made a white solid 18mg,The yield was 27.8%.
  • 11
  • [ 858121-94-5 ]
  • N-(2-hydroxyethyl)-4-(2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
  • 4-(2-((4,4-difluorocyclohexyl)methyl)2H-tetrazol-5-yl)-N-(2-hydroxyethyl)benzenesuIfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 50℃; for 88h;Inert atmosphere; General procedure: DIPEA (778 muIota, 4.46 mmol) was added dropwise to a stirred solution of N-(2-hydroxyethyl)-4- (2H-tetrazol-5-yl)benzenesulfonamide (300 mg, 1.1 14 mmol, Intermediate 17') and 2- (bromomethyl)tetrahydro-2H-pyran (285 muIota, 2.228 mmol, commercial source: Aldrich) in N,N- Dimethylformamide (DMF) (3714 muIota) at rt under nitrogen. The mixture was stirred at rt for 3 days. As starting material remained, it was stirred at 70 C overnight. The mixture was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica; EtOAc-cyclohexane from 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to obtain the product as a racemic mixture N-(2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)benzenesulfonamide (49 mg, 0.133 mmol, 28%). NMR (400 MHz, Acetone-d6) delta 7.84-7.78 (m, 2H), 7.56-7.50 (m, 2H), 7.33 (t, J = 5.9 Hz, 1 H), 4.37-4.32 (m, 2H), 4.25 (t, J = 5.6 Hz, 1 H), 3.50-3.44 (m, 1 H), 3.38-3.32 (m, 1 H), 2.94-2.90 (m, 2H), 2.86-2.80 (m, 1 H), 2.41-2.37 (m, 2H), 1.40-1.25 (m, 2H), 1.12-0.85 (m, 4H). MS m/z [M-H]"= 366.2
  • 12
  • [ 858121-94-5 ]
  • (R)-N-(2-hydroxypropyl)-4-(2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
  • (R)-4-(2-((4,4-difluorocyclohexyl)methyl)2H-tetrazol-5-yl)-N-(2-hydroxypropyl)benzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 34h;Inert atmosphere; General procedure: DIPEA (778 muIota, 4.46 mmol) was added dropwise to a stirred solution of N-(2-hydroxyethyl)-4- (2H-tetrazol-5-yl)benzenesulfonamide (300 mg, 1.1 14 mmol, Intermediate 17') and 2- (bromomethyl)tetrahydro-2H-pyran (285 muIota, 2.228 mmol, commercial source: Aldrich) in N,N- Dimethylformamide (DMF) (3714 muIota) at rt under nitrogen. The mixture was stirred at rt for 3 days. As starting material remained, it was stirred at 70 C overnight. The mixture was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica; EtOAc-cyclohexane from 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to obtain the product as a racemic mixture N-(2- hydroxyethyl)-4-(2-((tetrahydro-2H-pyran-2-yl)methyl)-2H-tetrazol-5-yl)benzenesulfonamide (49 mg, 0.133 mmol, 28%). NMR (400 MHz, Acetone-d6) delta 7.84-7.78 (m, 2H), 7.56-7.50 (m, 2H), 7.33 (t, J = 5.9 Hz, 1 H), 4.37-4.32 (m, 2H), 4.25 (t, J = 5.6 Hz, 1 H), 3.50-3.44 (m, 1 H), 3.38-3.32 (m, 1 H), 2.94-2.90 (m, 2H), 2.86-2.80 (m, 1 H), 2.41-2.37 (m, 2H), 1.40-1.25 (m, 2H), 1.12-0.85 (m, 4H). MS m/z [M-H]"= 366.2
  • 13
  • [ 858121-94-5 ]
  • tert-butyl (2-amino-2-oxoethyl)((4-(2-((4,4-difluorocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methoxyphenyl)sulfonyl)carbamate [ No CAS ]
  • 14
  • [ 858121-94-5 ]
  • 2-((4-(2-((4,4-difluorocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methoxyphenyl)sulfonamido)acetamide [ No CAS ]
  • 15
  • [ 858121-94-5 ]
  • [ 1122648-78-5 ]
YieldReaction ConditionsOperation in experiment
With sodium azide; In N,N-dimethyl-formamide; at 26 - 100℃; for 16h; To a solution of 4-(bromomethyl)-1 ,1-difluorocyclohexane (600 mg, 0.0028 mol, Intermediate 3) in Lambda/,/V-dimethylformamide (6 mL), sodium azide (549 mg, 0.0084 mol) was added at 26 C. The reaction mixture was heated to 100 C and stirred for 16 h at the same temperature. Upon completion, the reaction mixture was used for the next step without any further purification.1H NMR (400 MHz, CDCI3) 53.18 (t, J = 6.6 Hz, 2H), 2.17-1.98 (m, 2H), 1.85-1.57 (m, 5H), 1.37- 1.20 (m, 2H).
  • 16
  • [ 858121-94-5 ]
  • 2-methoxy-4-(2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
  • 4-(2-((4,4-difluorocyclohexyl)methyl)-2H-tetrazol-5-yl)-2-methoxybenzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 70℃;Inert atmosphere; N,N-diisopropylethylamine (164 muIota_, 0.940 mmol, commercial source: Aldrich) was added to a stirred solution of 2-methoxy-4-(2H-tetrazol-5-yl)benzenesulfonamide (120 mg, 0.470 mmol, Intermediate 51 ') and 4-(bromomethyl)-1 ,1-difluorocyclohexane (70.8 muIota_, 0.470 mmol, commercial source: Combi-Blocks) in Lambda/,/V-Dimethylformamide (DMF) (1.57 mL) under nitrogen atmosphere. The mixture was stirred at rt overnight and then at 70 C for 24 h. 4-(bromomethyl)- 1 , 1-difluorocyclohexane (14.17 muIota_, 0.094 mmol, commercial source: Combi-Blocks) and N,N- diisopropylethylamine (82 muIota_, 0.470 mmol) were added and the mixture was stirred at 70C for 6h. Upon completion, the reaction mixture was diluted with water and extracted with dichloromethane (twice). The combined organic solution was dried over anhydrous Na2S04, filtered and the filtrate was evaporated under reduced pressure to give 4-(2-((4,4-difluorocyclohexyl)methyl)-2H-tetrazol- 5-yl)-2-methoxybenzenesulfonamide (177 mg, crude) that was used in the next step without further purification.
  • 17
  • [ 858121-94-5 ]
  • [ 55919-82-9 ]
  • 1-((4,4-difluorocyclohexyl)methyl)-5-iodo-1H-indazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; To a stirred solution of 5-iodo-1H-indazole (0.83 g, 5.396 mmol, 0.8 eq) in DMF (15 mL) NaH (0.25 mg, 3.396 mmol, 1.2 eq, 50% by wt) was added at 0 C., followed by the addition of <strong>[858121-94-5]4-(bromomethyl)-1,1-difluorocyclohexane</strong> (0.90 g, 4.245 mmol, 1.0 eq) and the reaction mixture was stirred at ambient temperature for 16 h. After completion of the reaction (monitored by TLC, TLC system 5% MeOH/DCM, Rf-0.4), the reaction mixture was quenched with ice cold water (50 mL), extracted with EtOAc (3×50 mL), washed with brine (50 mL), dried over Na2SO4 and was then concentrated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 0 to 3% MeOH-DCM) to separate the two isomers. The major isomer was the desired 1-((4,4-difluorocyclohexyl)methyl)-5-iodo-1H-indazole which was confirmed by 1H-NMR to afford intermediate C7 (0.54 g, 32%).
  • 18
  • [ 858121-94-5 ]
  • tert-butyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate [ No CAS ]
  • tert-butyl (5RS)-2-[(4,4-difluorocyclohexyl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With caesium carbonate; In acetonitrile; at 20℃; tert-Butyl (5RS)-2-[(4,4-difluorocyclohexyl)methyl]-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (Racemate) To tert-butyl (5RS)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (racemate) (67.4 mg, 282 mumol) and caesium carbonate (138 mg, 422 mumol) in 4.0 ml of acetonitrile was added <strong>[858121-94-5]4-(bromomethyl)-1,1-difluorocyclohexane</strong> (72.0 mg, 338 mumol), then the reaction mixture was stirred at room temperature over a weekend. For workup, the precipitate present was filtered off, the filtrate was concentrated, and the residue was taken up and extracted with ethyl acetate/water. The aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried with sodium sulphate, filtered, and concentrated and dried under reduced pressure. The residue was separated by preparative HPLC (column: Kromasil C18, 125*30 mm, 10 mum, eluent: acetonitrile (B)/water+0.1% TFA (A), gradient: 0 min 90% A, 6 min 90% A, 18 min 5% A, 20 min 5% A, 21 min 90% A, flow rate: 75 ml/min, detector: 210 nm). By combining the product-containing fractions, after removal of the solvents under reduced pressure, 41.0 mg (39% of theory) of the title compound were obtained. LC-MS (Method 6): Rt=1.76 min; MS (ESIpos): m/z=372 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.396 (16.00), 2.072 (2.01), 3.528 (1.35), 3.545 (1.33), 4.399 (0.62).
  • 19
  • [ 858121-94-5 ]
  • 3-(5-(((1S,2S)-2-aminocyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
  • 3-(5-(((1S,2S)-2-(((4,4-difluorocyclohexyl)methyl)amino)cyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
14% Example 151 3-(5-(((1S,2S)-2-(((4,4-difluorocyclohexyl)methyl)amino)cyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-173) To a solution of 3-(5-(((1S,2S)-2-aminocyclopentyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-12, 100 mg, 0.291 mmol) in MeCN (1.5 mL) was added <strong>[858121-94-5]4-(bromomethyl)-1,1-difluorocyclohexane</strong> (151-1, 68 mg, 0.32 mmol) and DIPEA (153 muL, 0.874 mmol) and the resulting mixture was stirred at 140 C. for 45 minutes in the muW. NaI (48 mg, 0.32 mmol) was added and stirring was continued at 140 C. for 2 h and 45 minutes in the muW. The reaction mixture was then added to a saturated solution of aqueous sodium hydrogen carbonate (20 mL) and extracted with 20% i-PrOH in DCM (*2). The combined organic phases were passed through a phase separating column and concentrated to dryness. The crude material was purified via silica gel chromatography eluting with 0-15% i-PrOH (with 0.1% NEt3) in DCM (with 0.1% NEt3) to afford I-173 (20 mg, 0.040 mmol, 14% yield) as a cream-colored solid. MS [M+H]+=476.4. H NMR (400 MHz, DMSO-d6) delta (ppm): 10.95 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.17 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.11-4.97 (m, 1H), 4.65-4.52 (m, 1H), 4.44-4.19 (m, 2H), 3.18-3.03 (m, 1H), 2.90 (ddd, J 18.3, 13.6, 5.4 Hz, 1H), 2.59 (d, J=17.6 Hz, 1H), 2.47-2.28 (m, 2H), 2.17-2.05 (m, 1H), 2.04-1.87 (d, J=13.0 Hz, 4H), 1.86-1.58 (m, 8H), 1.56-1.38 (m, 2H), 1.21-1.07 (m, 2H).
 

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