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[ CAS No. 934178-97-9 ] {[proInfo.proName]}

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Chemical Structure| 934178-97-9
Chemical Structure| 934178-97-9
Structure of 934178-97-9 * Storage: {[proInfo.prStorage]}
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Product Details of [ 934178-97-9 ]

CAS No. :934178-97-9 MDL No. :MFCD17214383
Formula : C19H22BN3O4S Boiling Point : -
Linear Structure Formula :- InChI Key :ZYPOBLQBYBAHND-UHFFFAOYSA-N
M.W : 399.27 Pubchem ID :69326382
Synonyms :

Calculated chemistry of [ 934178-97-9 ]

Physicochemical Properties

Num. heavy atoms : 28
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.37
Num. rotatable bonds : 3
Num. H-bond acceptors : 6.0
Num. H-bond donors : 0.0
Molar Refractivity : 108.04
TPSA : 91.69 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.47 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 3.19
Log Po/w (WLOGP) : 3.36
Log Po/w (MLOGP) : 1.86
Log Po/w (SILICOS-IT) : 1.16
Consensus Log Po/w : 1.91

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.52
Solubility : 0.012 mg/ml ; 0.0000299 mol/l
Class : Moderately soluble
Log S (Ali) : -4.79
Solubility : 0.00652 mg/ml ; 0.0000163 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.06
Solubility : 0.000345 mg/ml ; 0.000000863 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.74

Safety of [ 934178-97-9 ]

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 [ 934178-97-9 ]

* 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 [ 934178-97-9 ]

[ 934178-97-9 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 934178-96-8 ]
  • [ 73183-34-3 ]
  • [ 934178-97-9 ]
YieldReaction ConditionsOperation in experiment
98% With potassium acetate In 1,2-dimethoxyethane at 150℃; for 0.166667h; microwave irradiation; 1a; 1.iv As shown in Figure 1-step iv, a mixture of compound 1004 (140 mg, 0.40 mmol), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane dimer (121 mg, 0.477 mmol), PdCl2 dppf2 (16 mg, 0.02 mmol) and potassium acetate (117 mg, 1.19 mmol) in 2 mL of DME were microwaved at 1500C for 10 minutes. The reaction mixture was filtered through a short pad of silica gel with 30% EtOAc-70% hexanes as eluent to provide, after concentration to dryness, 158 mg (98%) of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7-tosyl-7H- pyrrolo[2,3-d ]pyrimidine, compound 1005: ESMS M+l = 317.07.
61% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere; 1.6 Step 6: 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine A single-neck flask was charged with 5-bromo-7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (500 mg, 1.42 mmol) , bis (pinacolato) diboron (540 mg, 2.13 mmol) , potassium acetate (278 mg, 2.84 mmol) , Pd (dppf) Cl2(115 mg, 0.14 mmol) and 1, 4-dioxane (5 mL) . The mixture was stirred at 90 overnight under nitrogen protection. The mixture was cooled to rt and filtered through a celite pad. The filter cake was washed with ethyl acetate (10 mL) , and the combined filtrates were dried in vacuo. The residue was purified by silica gel chromatograph (PE/EtOAc (v/v) =5/1) to give the title compound as a white solid (285 mg, 61%) .MS (ESI, pos. ion) m/z: 400.0 [M+H]+.
50% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere; 21.2 Step 2: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine To a single-neck flask were added 5-bromo-7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (500 mg, 1.42 mmol) , bis (pinacolato) diboron (540 mg, 2.13 mmol) , potassium acetate (278 mg, 2.84 mmol) , Pd(dppf)Cl2 (115 mg, 0.14 mmol) and 1, 4-dioxane (5 mL) . The mixture was stirred at 90 overnight under nitrogen protection. The reaction mixture was cooled to rt and filtered through a celite pad, and the filter cake was washed with ethyl acetate (10 mL) . The filtrate was concentrated in vacuo to dry, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 5/1) to give the title compound as a white solid (285 mg, 50 %) . MS (ESI, pos. ion) m/z: 400.0 [M+H]+.
50% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere; 7.2 Step 2) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine Add 5-bromo-7-p-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (500 mg, to a single vial).1.42mmol),Benzoic acid pinacol ester(540mg, 2.13mmol),Potassium acetate (278 mg, 2.84 mmol),Pd(dppf)Cl2 (115mg, 0.14mmol)And 1,4-dioxane (5mL),The resulting mixture was heated to 90 ° C under nitrogen for reaction overnight.Then cool to room temperature,The reaction solution is filtered (diatomaceous earth aided filtration),The filter cake was washed with ethyl acetate (10 mL).The filtrate was concentrated to dryness.(PE/EtOAc(v/v)=5/1),The title compound obtained is a white solid(285 mg, 50%).
With tetrakis(triphenylphosphine) palladium(0); potassium acetate In 1,4-dioxane; water at 95℃; Inert atmosphere;
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 16h; Inert atmosphere; 18 Preparation of 18 A mixture of 5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (10 g, 28.39 mmol), bis(pinacolato)diboron (14.42 g, 56.79 mmol), potassium acetate (8.36 g, 85.18 mmol),Pd(dppf)C12 (1 g, 1.37 mmol) in 1 ,4-dioxane (170 mL, degassed with nitrogen) was heated at 80°C for 16 hours under nitrogen in a 500 mL round bottom flask equipped with a reflux condenser. The reaction mixture was cooled to room temperature, filtered through packed Celite and the solid was rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude was purified by silica column chromatography using an-heptane to ethyl acetate gradient. The desired fractions were collected and concentrated under reduced pressure to afford 18, 5-(4, 4, 5, 5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.33 (s, 12 H) 2.37 (s, 3 H) 7.47 (d, J=8.36 Hz, 2 H) 8.11 (d, J=8.58 Hz, 2 H) 8.14 (s, 1 H) 9.00 (s, 1 H) 9.10 (s, 1 H). LC-MS ES m/z = 318.1; Rt: 0.74 mm, method A.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 16h; Inert atmosphere; Preparation of Intermediate 3 A mixture of 5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (10 g, 28.39 mmol), bis(pinacolato)diboron (14.42 g, 56.79 mmol), potassium acetate (8.36 g, 85.18 mmol), Pd(dppf)Cl2 (1 g, 1.37 mmol) in 1,4-dioxane (170 mL, degassed with nitrogen) was heated at 80 °C. for 16 hours under nitrogen in a 500 mL round bottom flask equipped with a reflux condenser. The reaction mixture was cooled to room temperature, filtered through packed Celite and the solid was rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica column chromatography using a heptane to ethyl acetate gradient. The desired fractions were collected and concentrated under reduced pressure to afford 3,5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 12H) 2.37 (s, 3H) 7.47 (d, J=8.36 Hz, 2H) 8.11 (d, J=8.58 Hz, 2H) 8.14 (s, 1H) 9.00 (s, 1H) 9.10 (s, 1H). LC-MS ES+ m/z=318.1; Rt: 0.74 min, method A.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 16h; Inert atmosphere; Preparation of 57 A mixture of 5-bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (10 g, 28.39 mmol), bis(pinacolato)diboron (14.42 g, 56.79 mmol), potassium acetate (8.36 g, 85.18 mmol), Pd(dppf)C12 (1 g, 1.37 mmol) in 1,4-dioxane (170 mL, degassed with nitrogen) was heated at80°C for 16 hours under nitrogen in a 500 mL round bottom flask equipped with a reflux condenser. The reaction mixture was cooled to room temperature, filtered through packed Celite and the solid was rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude was purified by silica column chromatography using a n-heptane to ethyl acetate gradient. The desired fractions were collected and concentratedunder reduced pressure to afford 57, 5-(4 ,4 ,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.33 (s, 12 H) 2.37 (s,3 H) 7.47 (d, J=8.36 Hz, 2 H) 8.11 (d, J=8.58 Hz, 2 H) 8.14 (s, 1 H) 9.00 (s, 1 H) 9.10 (s,1 H). LC-MS ES m/z = 318.1; Rt: 0.74 mm, method A.

Reference: [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2007/41130, 2007, A2 Location in patent: Page/Page column 40-41; Sheet 1/9
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2018/157830, 2018, A1 Location in patent: Paragraph 00234
[3]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2018/41091, 2018, A1 Location in patent: Paragraph 00291
[4]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN108727369, 2018, A Location in patent: Paragraph 0656; 0663-0665
[5]Farmer, Luc J.; Ledeboer, Mark W.; Hoock, Thomas; Arnost, Michael J.; Bethiel, Randy S.; Bennani, Youssef L.; Black, James J.; Brummel, Christopher L.; Chakilam, Ananthsrinivas; Dorsch, Warren A.; Fan, Bin; Cochran, John E.; Halas, Summer; Harrington, Edmund M.; Hogan, James K.; Howe, David; Huang, Hui; Jacobs, Dylan H.; Laitinen, Leena M.; Liao, Shengkai; Mahajan, Sudipta; Marone, Valerie; Martinez-Botella, Gabriel; McCarthy, Pamela; Messersmith, David; Namchuk, Mark; Oh, Luke; Penney, Marina S.; Pierce, Albert C.; Raybuck, Scott A.; Rugg, Arthur; Salituro, Francesco G.; Saxena, Kumkum; Shannon, Dean; Shlyakter, Dina; Swenson, Lora; Tian, Shi-Kai; Town, Christopher; Wang, Jian; Wang, Tiansheng; Wannamaker, M. Woods; Winquist, Raymond J.; Zuccola, Harmon J. [Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7195 - 7216]
[6]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/89518, 2017, A1 Location in patent: Page/Page column 18
[7]Current Patent Assignee: JOHNSON & JOHNSON INC - US2017/253600, 2017, A1 Location in patent: Paragraph 0048; 0054-0055
[8]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2017/125506, 2017, A1 Location in patent: Page/Page column 25; 26
  • 2
  • [ 934179-27-8 ]
  • [ 934178-97-9 ]
  • [ 934179-28-9 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate In 1,2-dimethoxyethane; water at 160℃; for 0.166667h; microwave irradiation; 35; 8.iv As shown in Figure 8-steps iv & v, compound 1038 (48 mg, 0.15 mmol),Pd(Ph3P)4 (17 mg, 0.015 mmol), and 1 mL of 2M of potassium acetate (aq) in 2 mL of DME were microwaved at 160°C for 10 minutes. The crude mixture was diluted with EtOAc, washed with water, and dried over sodium sulfate. The volatiles were removed in vacuo and the resulting crude product purified by reversed-phase HPLC [CH3CN/H20 (0.1%TFA) gradient] to produce compound 1039 (15 mg, 0.026 mmol). Compound 1039 was subsequently treated with 0.32 mL of IM tetrabutylammonium fluoride (0.032 mmol) in 1 mL of THF at room temperature. After 1 hour, the volatiles were removed in vacuo and the product purified by reversed-phase HPLC (CH3CN/H20 (0.1%TFA) gradient) to produce compound 108.
  • 3
  • [ 934179-14-3 ]
  • [ 934178-97-9 ]
  • (R)-2-(2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2,2,2-trifluoroethyl)-3-methylbutanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: C13H14ClF3N4O; 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(p-toluenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine With sodium carbonate In 1,2-dimethoxyethane; water at 150℃; for 0.166667h; microwave irradiation; Stage #2: With lithium hydroxide In 1,2-dimethoxyethane; water at 150℃; for 0.166667h; microwave irradiation; 36; 9.v As shown in Figure 9-step v, compound 1044 (45 mg, 0.13 mmol) was combined with 5-(4,4,5,5-tetramethyl-[l ,3,2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7H- pyrrolo[2,3-d]pyrimidine (compound 1005, 47 mg, 0.12 mmol), Pd(PPh3)4 (25 mg, 0.02 mmol), and 1 mL of 2M Na2CO3 in 2 mL of DME. The mixture was heated at 150 0C under microwave irradiation for 10 minutes. At this time, aqueous 1 M lithium hydroxide solution (2 mL) was added to the reaction mixture and microwave irradiation was continued at 150 0C for 10 min. The mixture was cooled and water (20 mL) was added. Purification by reversed- phase HPLC gave 27 mg of compound 110 as a yellow powder.
  • 4
  • [ 916176-99-3 ]
  • [ 934178-97-9 ]
  • C22H19F4N7O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In 1,2-dimethoxyethane; water at 150℃; for 0.166667h; microwave irradiation; 1b As shown in Figure 2-step iii, a mixture of compound 1005 (30 mg, 0.075 mmol), compound 1009 (23 mg, 0.075 mmol), Pd(Ph3P)4 (9 mg, 0.0078 mmol), and sodium carbonate 2M (115 uL, 0.23 mmol) in 1 mL of DME were microwaved at 150°C for 10 minutes. The reaction mixture was filtered through a short pad of silica gel using 30% EtOAc-70% hexanes as eluent to provide, after concentration to dryness, a crude intermediate tosylate that was used directly for the next step. The crude intermediate was dissolved in 1 mL of dry methanol and 200 uL of 25% sodium methoxide in methanol was added. The reaction mixture was stirred at 6O0C for 1 hour and quenched with 6N HCl (154 uL). After drying the reaction mixture under a flow of nitrogen, the product was purified by reversed- phase HPLC (gradient: 10-60% MeCN/ water with 0.5% TFA) to provide 19.6 mg (68%) of compound 6 (a compound of formula VIII, wherein R = F, R1 = CH3 with the S- configuration, and X = N).
  • 5
  • [ 934178-99-1 ]
  • [ 934178-97-9 ]
  • (S)-2-(6-phenyl-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-ylamino)-N-(2,2,2-trifluoroethyl)propanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-2-(2-chloro-6-phenylpyrimidin-4-ylamino)-N-(2,2,2-trifluoroethyl)propanamide; 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(p-toluenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine With sodium carbonate In 1,4-dioxane at 80℃; Stage #2: With lithium hydroxide In 1,4-dioxane; water at 60℃; for 1h; 21; 3.iii As shown in Figure 3-step i, a mixture of phenylboronic acid (1.22 g),2,4,6-trichloropyrimidine (compound 1011), tetrakis(triphenylphosphine) palladium(O) and 2N sodium carbonate (15 mL) in DME (25 mL) was heated at 80 0C overnight. After cooling to it, addition of water (30 mL), extraction with dichloromethane (3 x 20 mL), drying and evaporation, purification by column chromatography (SiO2, 10-20% ethyl acetate in hexane) afforded the desired product, 6-phenyl-2,4-dichloropyrimidine (compound 1012) (0.544 g). As shown in Figure 3-step ii, compound 1012 (0.34 g) was mixed with (,S)-2-amino-N-(2,2,2- trifluoroethylpropanamide (0.3 g) and diisopropylethylamine (0.63 mL) in isopropanol (5 mL) and the reaction mixture heated at 80 0C overnight. Evaporation gave a residue, which after aqueous workup and purification (SiO2, 20% ethyl acetate/hexane) produced 2-(2- chloro-6-phenyl-pyrimidin-4-ylamino)-ν-(2,2,2-trifluoro-ethyl)propionamide (compound 1013) (0.165 g). As shown in Figure 3-step iii, compound 1013 (29 mg), 5-(4,4,5,5- Tetramethyl-[l,3,2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 1005), PdCl2dppf2 (7 mg), and potassium phosphate (32 mg) were heated in 1,4- dioxane (2 mL) at 80 0C overnight. To the reaction was added aqueous lithium hydroxide solution (2 mL). After heating at 600C for Ih, water (20 mL) was added. Extraction with dichloromethane (3X), drying, evaporation and purification (SiO2, 50-100% ethyl acetate/hexane) gave 3.7 mg of 2-[6-phenyl-2-(7η-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin- 4-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide (compound 18).
  • 6
  • [ 934179-06-3 ]
  • [ 934178-97-9 ]
  • C24H20F3N7O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In 1,2-dimethoxyethane; water at 160℃; for 0.25h; microwave irradiation; 28; 5.iv As shown in Figure 5-step iii, 4-cyano-2,6-dichloropyridine (compound1021) (346 mg, 2.0 mmol), (S)-2~amino-N-(2,2,2-trifluoroethyl)propanamide (761 mg, 2.1 mmol), 2 mL of DIEA, and 1 mL of NMP was placed in a sealed tube. The reaction mixture was stirred at 120°C for 2 hours and concentrated to dryness. The residue was dissolved in DCM and washed with saturated aqueous NaHCθ3 solution. The organics were dried (Na2SO4) and concentrated in vacuo to give a residue that was purified by silica gel chromatography (50% EtOAc/ 50% hexanes) to provide 135 mg of compound 1022 (60% yield). As shown in Figure 5-step iv, compound 1022 (31 mg, 0.1 mmol), compound 1005 (52 mg, 0.12 mmol), Pd(Ph3P)4 (6.4 mg), and Na2CO3 2M (150 uL) in DME was heated at 160 0C for 15 minutes under microwave irradiation. The reaction mixture was filtered through a short pad of silica gel using EtOAc/hexanes as the eluent to provide, after concentration in vacuo, the crude intermediate tosylate. This intermediate was dissolved in 1 mL of dry methanol and 200 uL of 25% sodium methoxide in methanol was added. The reaction mixture was stirred at 6O0C for 1 hour and quenched with 6N HCl (154 uL). The volatiles were removed in vacuo and the product purified by silica gel chromatography (20% EtOAc/hexane, 100% EtOAc, and 5% MeOH/DCM) to provide 9 mg (19% yield) of compound 19.
  • 7
  • [ 478366-39-1 ]
  • [ 934178-97-9 ]
  • 6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl 6-bromo-5’,6’-dihydro-[2,4’-bipyridine]-1’(2’H)-carboxylate; 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(p-toluenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine With sodium carbonate In 1,2-dimethoxyethane; water at 90℃; Stage #2: With lithium hydroxide In 1,2-dimethoxyethane; water at 60℃; for 1h; 32; 7.iii As shown in Figure 7-step iii, a mixture of compound 1032 (0.18g), 5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7η-pyrrolo[2,3- d]ρyrimidine (compound 1005, 0.20 g), tetrakis (triphenylphosphine) palladium (50 mg), and 2N sodium carbonate (0.8mL) in DME (5 mL) was heated at 9O0C overnight. Saturated aqueous lithium hydroxide (2mL) was added and the reaction was heated at 60 0C for 1 hour. The reaction mixture was diluted with EtOAc and washed with brine. The organics were dried over sodium sulfate, concentrated, and purified by chromatography (SiO2, 50% ethyl acetate/hexane) to afford 6-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)-3',6'-dihydro-2lH- [2,4']bipyridinyl -1'-carboxylic acid tert-butyl ester (compound 1033, 81.6 mg).
  • 8
  • [ 123-75-1 ]
  • [ 934179-02-9 ]
  • [ 934178-97-9 ]
  • C26H27F3N8O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: pyrrolidine; (S)-2-(4,6-dichloropyrimidin-2-ylamino)-N-(2,2,2-trifluoroethyl)propanamide With N-ethyl-N,N-diisopropylamine In 1,2-dimethoxyethane at 160℃; for 0.0833333h; microwave irradiation; Stage #2: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(p-toluenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine With cesium fluoride In 1,2-dimethoxyethane; water at 160℃; for 0.0833333h; microwave irradiation; 23 As shown in Figure 4-step v, to a solution of compound 1019 (31.7 mg,0.100 mmol) in DME (0.50 mL) was added a nucleophilic amine (pyrrolidine, 10 μL, 0.11 mmol) and diisopropylethylamine (25.8 mg, 34.8 μL, 0.200 mmol). The mixture was heated at 160 0C with microwave for 5 min, followed by the addition of 5-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-7η-pyrrolo[2,3-d]ρyrimidine (compound 1005, 39.9 mg, 0.100 mmol) and a solution of CsF (30 mg, 0.20 mmol) in water (0.25 mL). The mixture was heated at 160 0C with microwave for 5 min. The reaction mixture was filtered through a EPO short pad of silica gel using EtOAc/hexanes as eluent to provide, after concentration in vacuo, the crude intermediate tosylate. This intermediate was dissolved in 1 mL of dry methanol and 200 uL of 25% sodium methoxide in methanol was added. The reaction mixture was stirred at 6O0C for 1 hour and quenched with trifluoroacetic acid. Purification by reversed- phase HPLC gave 35.0 mg of 2-[4-pyrrolidin-l-yl-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)- pyrimidin-2-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide TFA salt (a compound of formula IX where R10 is 1 -pyrrolidine).
  • 15
  • [ 98-59-9 ]
  • [ 934178-97-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium hydride / tetrahydrofuran / 20 °C 2: bromine / dichloromethane 3: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 95 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 0 - 20 °C 2.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 90 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 1.2: 20 °C 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 90 °C / Inert atmosphere
  • 16
  • [ 941685-26-3 ]
  • [ 934178-97-9 ]
  • 7-((2-(trimethylsilyl)ethoxy)methyl)-7H,7'H-4,5'-bipyrrolo[2,3-d]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
224 mg With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 3h;Inert atmosphere; Reflux; 4- chloro-7 - ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d] pyrimidine (Compound A, 500mg, 1.25mmol, 1.0eq) and5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane hetero-pentyl 2-yl) -7-tosyl--7H- pyrrolo [2,3-d] pyrimidine(Compound B, 392mg, 1.38mmol, 1.1eq) was dissolved in DME (10mL) mixture / 2M sodium carbonate solution (5mL) was added Pd (PPh3) 4 (144mg, 0.125mmol, 0.1eq) under N2 atmosphere, after addition was complete the reaction was warmed to reflux for 3h. TLC monitored the reaction was complete (Rf = 0.1, PE: EA = 3: 1), cooled to room temperature and added to H2O (30mL) and EA (50 mL) separated, aqueous phase extracted with EA three times, the combined organic phase was washed with saturated brine once, after the organic phase was dried over anhydrous magnesium sulfate, and column chromatography (PE: EA = 3: 1-1: 1) give 224 mg of a pale yellow solid (compound C).
  • 17
  • [ 934178-97-9 ]
  • 2-(3-(7H,7'H-[4,5'-bipyrrolo[2,3-d]pyrimidin]-7'-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 3 h / Inert atmosphere; Reflux 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 40 h / 32 - 36 °C 3: boron trifluoride diethyl etherate / acetonitrile / 20 h / 30 °C
  • 18
  • [ 934178-97-9 ]
  • 2-(1-(ethylsulfonyl)-3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H,7'H-[4,5'-bipyrrolo[2,3-d]pyrimidin]7'-yl)azetidin-3-yl)acetonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 3 h / Inert atmosphere; Reflux 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 40 h / 32 - 36 °C
  • 19
  • [ 934178-97-9 ]
  • C19H22ClFN4O2 [ No CAS ]
  • C32H32FN7O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,2-dimethoxyethane at 110℃; for 1h; Autoclave; Sealed tube; 19 Preparation of 19 In a sealed tube, a solution of 18(1.525 g, 3.82 mmol), 9(1.6 g, 4.073 mmol), and K2003 (5.73 mL, 2 M, 11.46 mmol) in DME (24 mL) was purged with N2 for 5 mm and then Pd(dppf)C12.CH2CI2 (313 mg, 0.38 mmol) was added. The mixture was stirred and heated in an autoclave at 11000 for 60 mm, then was filtered over dicalite and the filtrate was concentrated under reduced pressure. The crude was purified via silica columnchromatography using a n-heptane to 25%EtOAc in n-heptane gradient. The solvents of the best fractions were removed under reduced pressure to afford a solid. LC-MS ES m/z = 630.2; Rt: 1.28 mm, method A.
  • 21
  • [ 934178-97-9 ]
  • C24H26FN7O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane / 1 h / 110 °C / Autoclave; Sealed tube 2: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 25 °C
  • 22
  • [ 934178-97-9 ]
  • C30H29FN8O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane / 1 h / 110 °C / Autoclave; Sealed tube 2: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 25 °C 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / dimethyl sulfoxide / 1 h / 20 °C
  • 23
  • [ 934178-97-9 ]
  • C17H20ClFN4O2 [ No CAS ]
  • C30H30FN7O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,2-dimethoxyethane at 120℃; for 0.666667h; Inert atmosphere; Microwave irradiation; Preparation of compound A5 Preparation of compound A5 (0047) A solution of intermediate A4 [CAS-934178-97-9] (273 mg, 0.7 mmol), intermediate A3 (275.9 mg, 0.8 mmol) and K2CO3 (1 ml_, 2 M, 2.1 mmol) in DME (3 ml_) was purged with N2 flow for 5 min and then Pd(dppf)Cl2 (56 mg, 0.07 mmol) was added. The resulting mixture was stirred and heated at 120 °C using a singlemode microwave (Biotage initiator60) with a power output ranging from 0 to 400 W for 40 min. The mixture was poured out into water and DCM, the organic layer was separated with an hydrophobic frit and evaporated till dryness. Purification was carried out by flash chromatography over silica gel (irregular SiOH, 15-35μηη, 40 g, Heptane/EtOAc from 100/0 to 80/20). Pure fractions were collected and evaporated to intermediate A5 as colorless oil, 0.270 g, 65%.
  • 24
  • [ 934178-97-9 ]
  • C20H21FN6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane; water / 0.33 h / 150 °C / Inert atmosphere; Microwave irradiation 2: potassium acetate / acetonitrile / 0.17 h / 120 °C / Sealed tube
  • 25
  • [ 934178-97-9 ]
  • C18H14FN5O4S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0) / water / 2 h / 80 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane; methanol / 20 °C
  • 26
  • [ 934178-97-9 ]
  • C28H31FN6O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0) / water / 2 h / 80 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 70 °C
  • 27
  • [ 934178-97-9 ]
  • C19H21FN6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0) / water / 2 h / 80 °C / Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 70 °C 4: potassium <i>tert</i>-butylate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere
  • 28
  • [ 934178-97-9 ]
  • C17H19ClF4N2O2 [ No CAS ]
  • C23H23F4N5O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(p-toluenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine; C17H19ClF4N2O2 With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane; water at 150℃; for 0.166667h; Microwave irradiation; Stage #2: With potassium acetate In ethanol at 120℃; for 10h; Microwave irradiation; Preparation of 43 A mixture of 3 (400 mg, 0.98 mmol), 42 (400 mg, 0.983 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Xantphos (58 mg, 0.1 mmol), Na2CO3 (2.8 mL, 2 M aq., 5.77 mmol), and 1,4-dioxane (10 mL) was stirred at 150° C. for 10 minutes under microwave irradiation. The solvent was removed under reduced pressure. DCM was added, then the mixture was filtered through a silica plug and flushed with 5 volumes DCM. The solvent was removed under reduced pressure. KOAc (200 mg) and ethanol (7 mL) were added and heated to 120° C. for 10 min in the microwave. The residue was purified via silica column chromatography using a heptane to ethyl acetate gradient. The best fractions were collected and the solvent removed under reduced pressure, yielding 43.
  • 29
  • [ 934178-97-9 ]
  • C17H19ClF4N2O2 [ No CAS ]
  • C21H19F4N5O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane; water / 0.17 h / 150 °C / Microwave irradiation 1.2: 10 h / 120 °C / Microwave irradiation 2.1: lithium hydroxide / 1,4-dioxane; water / 1 h / Reflux
  • 30
  • [ 934178-97-9 ]
  • 2-chloro-5-fluoro-4-methylthiopyrimidine [ No CAS ]
  • C18H14FN5O2S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In water at 80℃; for 2h; Inert atmosphere; Preparation of 50 A mixture of 3 (4.39 g, 11 mmol), 2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (1.96 g, 11 mmol) and potassium phosphate (7 g, 33 mmol) was stirred in water (44 mL) and Me-THF (132 mL) at room temperature under a nitrogen atmosphere. Then Xantphos (629 mg, 1.32 mmol) and Pd2(dba)3 (302.19 mg, 0.33 mmol) were added and degassing was done for ten minutes with nitrogen bubbling through the mixture. The reaction was heated to 80° C. and stirred for two hours at this temperature in a closed vessel. The mixture was allowed to cool down for one hour, then reconstituted in 200 mL ethyl acetate and twice washed with brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified over silica with dichloromethane/methanol (99/1) as eluent. The desired fractions were evaporated and the residue was crystallized in acetonitrile. The crystals were collected by filtration and dried in vacuo, 50. LC-MS ES+ m/z=415; Rt: 2.00 min, method B.
  • 31
  • [ 934178-97-9 ]
  • [ 28942-85-0 ]
  • C20H19FN6O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 150℃; for 0.25h; Microwave irradiation; Inert atmosphere; Preparation of 60 A mixture of 3 (798.6 mg, 2 mmol), 59 (379.24 mg, 2 mmol) and Na2CO3 (3 mL, 2 M, 6 mmol) was stirred in 1,4-dioxane (10 mL) at room temperature under a nitrogen atmosphere. Then Pd(PPh3)4 (115.56 mg, 0.1 mmol) and Xantphos (57.86 mg, 0.1 mmol) were added and degassing was done for ten minutes with nitrogen bubbling through the mixture. The reaction was heated to 150° C. under microwave radiation for 15 minutes. The mixture was diluted with water and twice extracted with ethyl acetate. The organic layer was once washed with brine, dried over MgSO4, filtered, and evaporated. The residue was crystallized in diisopropylether with about 10% acetonitrile. The off-white precipitate was collected by filtration and dried in vacuo, yielding 60. LC-MS ES+ m/z=426; Rt: 2.22 min, method B.
  • 32
  • [ 934178-97-9 ]
  • [ 28942-85-0 ]
  • C13H13FN6 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 0.25 h / 150 °C / Microwave irradiation; Inert atmosphere 2: sodium methylate / 1 h / 20 °C
  • 33
  • [ 934178-97-9 ]
  • methyl (+/-)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate [ No CAS ]
  • C25H27FN6O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 100℃; for 16h; Preparation of 68 In a pressure tube, a mixture of 3 (3.5 g, 8.766 mmol), Pd(PPh3)4 (1013 mg, 0.877 mmol), K2CO3 (2423 mg, 17.53 mmol)) and 67 (2.667 g, 9.204 mmol) in DME (50 mL) and water (15 mL) was heated to 100° C. and stirred for 16 hours. The reaction was completed and the solvent was removed under reduced pressure. The crude residue was taken in DCM and filtered. The filtrate was purified by flash column chromatography over silica (gradient: heptane-EtOAc (100-100)). The desired fractions were collected and evaporated to dryness. The residue was dissolved in a mixture of DCM/methanol (1/1) and purified via silica gel column chromatography (gradient: heptane-EtOAc (100-100)). The desired fractions were collected and the solvent was removed under reduced pressure, yielding 68. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (s, 9H) 2.65 (m, 1H) 2.78 (m, 1H) 3.44 (s, 3H) 4.76-4.94 (m, 1H) 7.41 (m, 1H) 8.07-8.27 (m, 2H) 8.82 (s, 1H) 9.73 (s, 1H) 12.47 (br. s., 1H). LC-MS ES+ m/z=372.2; Rt: 0.84 min, method A.
  • 34
  • [ 934178-97-9 ]
  • methyl (+/-)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate [ No CAS ]
  • C18H21FN6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,2-dimethoxyethane; water / 16 h / 100 °C 2: lithium hydroxide / 1,4-dioxane; water / 16 h / 20 °C
  • 35
  • [ 934178-97-9 ]
  • C18H17ClFN5O [ No CAS ]
  • C24H21FN8O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In 1,4-dioxane; water at 90℃; for 2h; Preparation of 98 A mixture of 3 (200 mg, 0.501 mmol), 97 (187 mg, 0.501 mmol), K3PO4 (33 mg, 0.0501 mmol), and [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (318 mg, 1.503 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was heated to 90° C. for 2 h. The reaction mixture was filtered over Celite and concentrated. Then, the reaction mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO4 and purified by reverse phase HPLC (Method: MG3BIC From 70% [Aq. phase]-30% [Organic phase] to 27% [AP]-73% [OP]. AP=25 mM aq. NH4HCO3, OP=acetonitrile:methanol 1:1). The desired fractions were collected and the solvent was removed under reduced pressure to afford 98. LC-MS ES+ m/z=457.2; Rt: 2.39 min, method C.
  • 36
  • [ 934178-97-9 ]
  • methyl 3-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)-bicyclo[2.2.2]-octane-2-carboxylate [ No CAS ]
  • C29H27FN6O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(p-toluenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine; methyl 3-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)-bicyclo[2.2.2]-octane-2-carboxylate In tetrahydrofuran; water at 20℃; for 0.166667h; Inert atmosphere; Stage #2: With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran; water at 120℃; for 12h; Inert atmosphere; Preparation of 100 A solution containing 3 (2.814 g, 7.049 mmol) and 99 (2 g, 54.92 mmol) in THF (40 mL) and water (10 mL) was stirred for 10 min under inert atmosphere at room temperature. Then were added Pd2(dba)3 (0.103 g, 0.141 mmol), tripotassium phosphate (3.753 g, 17.69 mmol), and XantPhos (0.336 g, 0.705 mmol) and the mixture was stirred at 120° C. for 12 h. The crude was concentrated under reduced pressure and 100 was used in the next step without further purification.
  • 37
  • [ 934178-97-9 ]
  • methyl 3-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)-bicyclo[2.2.2]-octane-2-carboxylate [ No CAS ]
  • C22H21FN6O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: water; tetrahydrofuran / 0.17 h / 20 °C / Inert atmosphere 1.2: 12 h / 120 °C / Inert atmosphere 2.1: sodium methylate / tetrahydrofuran / 3 h / 40 °C
  • 38
  • [ 934178-97-9 ]
  • (+/-)-N-((cis)-3-((6-chloro-5-cyano-3-fluoro-pyridin-2-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide [ No CAS ]
  • (+/-)-N-((cis)-3-((5-cyano-3-fluoro-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 100℃; for 16h; Preparation of 9 Into a thick-wall glass tube was placed a mixture of 3 (500 mg, 1.25 mmol), Pd(PPh3)4 (145 mg, 0.125 mmol), K2CO3 (346 mg, 2.51 mmol) and 8 (481 mg, 1.32 mmol) in DME (15 mL) and water (5 mL) was heated to 100° C. and stirred for 16 h. The solvent was removed under reduced pressure. The crude residue was stirred in DCM, filtered off and purified by silica flash column chromatography (first gradient: heptane-ethyl acetate; second gradient: DCM-DCM/CH3OH 100-90/10). The desired fractions were collected and evaporated to dryness to afford 9, (+/-)-N-((cis)-3-((5-cyano-3-fluoro-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.15-1.31 (m, 2H) 1.34-1.44 (m, 1H) 1.48 (q, J=11.93 Hz, 1H) 1.75-1.78 (m, 4H) 1.78-1.84 (m, 2H) 2.00 (d, J=11.30 Hz, 1H) 2.03-2.06 (m, 1H) 3.16-3.19 (m, 4H) 3.53-3.56 (m, 1H) 4.12-4.15 (m, 1H) 5.84 (d, J=7.92 Hz, 1H) 7.74 (d, J=7.04 Hz, 1H) 7.87 (d, J=11.30 Hz, 1H) 8.33 (s, 1H) 8.85 (s, 1H) 9.56 (s, 1H) 12.66 (br. s., 1H). LC-MS ES+ m/z=449.2; Rt: 1.55 min, method B.
  • 39
  • [ 934178-97-9 ]
  • (+/-)-N-((cis)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide [ No CAS ]
  • C28H31FN8O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 150℃; for 0.416667h; Inert atmosphere; Microwave irradiation; A mixture of 3 (799 mg, 2 mmol), 5 (684 mg, 2 mmol) and Na2CO3 (3 mL, 2 M, 6 mmol) was stirred in 1,4-dioxane (10 mL) at room temperature under a nitrogen atmosphere. Then tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol) and Xantphos (58 mg, 0.1 mmol) were added and the mixture was degassed for 10 minutes. The reaction was heated at 150° C. in the microwave for 15 min.
  • 40
  • [ 934178-97-9 ]
  • (+/-)-N-((cis)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyl)pyrrolidine-1-carboxamide [ No CAS ]
  • C21H25FN8O [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 0.42 h / 150 °C / Inert atmosphere; Microwave irradiation 2: sodium methylate / methanol / 1 h / Inert atmosphere
  • 41
  • [ 934178-97-9 ]
  • (+/-)-N-((cis)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide [ No CAS ]
  • C23H22FN9O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 100℃; for 18h; Sealed tube; Preparation of 12 Into a 20 mL thick-wall glass vial was placed 3 (0.25 g, 0.63 mmol), Pd(PPh3)4 (72 mg, 0.0626 mmol), K2CO3 (173 mg, 1.25 mmol), DME (5 mL), water (1.5 mL), and 11 (0.25 g, 0.63 mmol). The vial was sealed and heated in an oil bath at 100° C. for 18 h. The reaction mixture was brought to pH 6 via addition of conc. HCl. DMSO was added and the solution was filtered. The crude was purified by preparatory HPLC (RP SunFire Prep C18 OBD-10 μm, 30×150 mm, mobile phase 0.25% aq. ammonium carbonate, to CH3OH). The best fractions were pooled and the solvents were removed under reduced pressure to afford 12 as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.54 (m, 3H), 1.62 (q, J=11.7 Hz, 1H), 1.84 (d, J=10.8 Hz, 2H), 2.06 (t, J=14.2 Hz, 2H), 3.67 (s, 3H), 3.85 (d, J=8.6 Hz, 1H), 4.20 (dd, J=7.8, 3.6 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 7.63 (d, J=0.9 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.87 (d, J=11.2 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.86 (s, 1H), 9.59 (s, 1H), 12.65 (br. s., 1H). LC-MS ES+ m/z=460.1; Rt: 0.71 min, method A.
  • 42
  • [ 934178-97-9 ]
  • C16H18BrF2N5O [ No CAS ]
  • C29H28F2N8O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 150℃; for 0.416667h; Inert atmosphere; Microwave irradiation; Intermediate 3 (0.20 g, 0.50 mmol) reacted with 15 (0.207 g, 0.50 mmol) under the same Suzuki reaction conditions as those described for the formation of compound 7.
  • 43
  • [ 934178-97-9 ]
  • C16H18BrF2N5O [ No CAS ]
  • C22H22F2N8O [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 0.42 h / 150 °C / Inert atmosphere; Microwave irradiation 2: sodium methylate / methanol / 1 h
  • 44
  • [ 934178-97-9 ]
  • (rac)-(2S,3S)-methyl 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • C27H27FN6O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane; water at 150℃; for 0.333333h; Inert atmosphere; Microwave irradiation; 24a (283 mg, 0.90 mmol) (for preparation see J. Med. Chem. 2014, DOI: 10.1021/jm5007275) was reacted with intermediate 3 (400 mg, 1.00 mmol) under the same conditions as described in the formation of 7.
  • 45
  • [ 934178-97-9 ]
  • C19H22ClFN4O2 [ No CAS ]
  • C32H32FN7O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,2-dimethoxyethane at 110℃; for 1h; Inert atmosphere; Autoclave; Sealed tube; Preparation of 58 In a sealed tube, a solution of 57 (1.525 g, 3.82 mmol), 31(1.6 g, 4.07 mmol), and K2003(5.73 mL, 2 M, 11.46 mmol) in DME (24 mL) was purged with N2 for 5 mm and thenPd(dppf)C12.CH2CI2 (313 mg, 0.38 mmol) was added. The mixture was stirred and heated inan autoclave at 110°C for 60 mm, then was filtered over dicalite and the filtrate wasconcentrated under reduced pressure. The crude was purified via silica columnchromatography using a n-heptane to 25%EtOAc in n-heptane gradient. The solvents of the best fractions were removed under reduced pressure to afford 58. LC-MS ES m/z = 630.2; Rt: 1.28 mm, method A
  • 46
  • [ 934178-97-9 ]
  • C24H26FN7O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane / 1 h / 110 °C / Inert atmosphere; Autoclave; Sealed tube 2: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 20 °C
  • 47
  • [ 934178-97-9 ]
  • C29H28ClFN8O2S [ No CAS ]
  • C29H28ClFN8O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane / 1 h / 110 °C / Inert atmosphere; Autoclave; Sealed tube 2: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 20 °C 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 20 - 60 °C
  • 48
  • [ 934178-97-9 ]
  • C29H29FN8O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane / 1 h / 110 °C / Inert atmosphere; Autoclave; Sealed tube 2.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 20 - 60 °C 3.2: 20 °C
  • 49
  • [ 934178-97-9 ]
  • C22H23FN8 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane / 1 h / 110 °C / Inert atmosphere; Autoclave; Sealed tube 2.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 20 - 60 °C 3.2: 20 °C 3.3: 1 h / 85 °C
  • 50
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((6-chloro-5-cyano-3-fluoro-4-phenylpyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-3-((5-cyano-3-fluoro-4-phenyl-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 3 h / 110 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide; water / tetrahydrofuran; methanol / 20 °C
  • 51
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((6-chloro-5-cyano-3-fluoro-4-phenylpyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((5-cyano-3-fluoro-4-phenyl-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Microwave irradiation; 21.3 Step 3: (+/-)-trans-methyl 3-((5-cyano-3-fluoro-4-phenyl-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate To a mixed solvent of 1, 4-dioxane (3 mL) and water (0.3 mL) were added (+/-) -trans-methyl 3- ( (6-chloro-5-cyano-3-fluoro-4-phenylpyridin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (70 mg, 0.17 mmol) , Pd(dppf)Cl2 (24 mg, 0.03 mmol) , potassium carbonate (70 mg, 0.50 mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H -pyrrolo [2, 3-d] pyrimidine (96 mg, 0.24 mmol) . A steam of nitrogen was bubbled through the mixture for 10 min to remove the air, and the resulting mixture was stirred at 110 for 3 h under a microwave heating condition. To the reaction mixture was added ethyl acetate (60 mL) . The mixture was filtered through a celite pad, and the filtrate was washed with a saturated aqueous sodium chloride solution (50 mL × 2) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to dry, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 10/1 4/1) to give the title compound as yellow oil (57 mg, 52 %) . MS (ESI, pos. ion) m/z: 651.2 [M+H]+ 1H NMR (400 MHz, CDCl3) δ (ppm) : 9.68 (s, 1H) , 9.12 (s, 1H) , 8.67 (s, 1H) , 8.18 (d, J 8.3 Hz, 2H) , 7.55 (d, J 3.4 Hz, 5H) , 7.35 (d, J 8.1 Hz, 2H) , 3.56 (s, 3H) , 2.41 (s, 3H) , 2.11 (s, 1H) , 2.01 (s, 1H) , 1.95 (s, 2H) , 1.78-1.63 (m, 6H) .
  • 52
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((6-chloro-5-cyano-3-fluoro-4-(furan-2-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-3-((5-cyano-3-fluoro-4-(furan-2-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 3 h / 110 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide; water / tetrahydrofuran; methanol / 20 °C
  • 53
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((6-chloro-5-cyano-3-fluoro-4-(furan-2-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((5-cyano-3-fluoro-4-(furan-2-yl)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Microwave irradiation; 23.2 Step 2: (+/-)-trans-methyl 3-((5-cyano-3-fluoro-4-(furan-2-yl)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate To a mixed solvent of 1, 4-dioxane (3 mL) and water (0.3 mL) were added (+/-) -trans-methyl 3- ( (6-chloro-5-cyano-3-fluoro-4- (furan-2-yl) pyridin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (92 mg, 0.23 mmol) , Pd(dppf)Cl2 (33 mg, 0.05 mmol) , potassium carbonate (94 mg, 0.68 mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan -2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (127 mg, 0.32 mmol) . A stream of nitrogen was bubbled through the mixture for 5 min to remove the air, and the resulting mixture was stirred at 110 for 3 h under a microwave heating. To the reaction mixture was added ethyl acetate (60 mL) . The mixture was filtered through a celite pad, and the filtrate was washed with a saturated aqueous sodium chloride solution (50 mL × 2) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to dry, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 10/1 4/1) to give the title compound as yellow oil (81 mg, 55 %) .
  • 54
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((6-chloro-5-cyano-4-cyclopropyl-3-fluoropyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-3-((5-cyano-4-cyclopropyl-3-fluoro-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 3 h / 110 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide; water / tetrahydrofuran; methanol / 20 °C
  • 55
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((6-chloro-5-cyano-4-cyclopropyl-3-fluoropyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((5-cyano-4-cyclopropyl-3-fluoro-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Microwave irradiation; 22.2 Step 2: (+/-)-trans-methyl 3-((5-cyano-4-cyclopropyl-3-fluoro-6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)amino)bicyclo[2.2.2]octane-2-carboxylate To a mixed solvent of 1, 4-dioxane (3 mL) and water (0.3 mL) were added (+/-) -trans-methyl 3- ( (6-chloro-5-cyano-4-cyclopropyl-3-fluoropyridin-2-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.26 mmol) , Pd(dppf)Cl2 (38 mg, 0.05 mmol) , potassium carbonate (109 mg, 0.78 mmol) and 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (148 mg, 0.37 mmol) . A stream of nitrogen was bubbled through the mixture for 10 min, and the resulting mixture was stirred at 110 for 3 h by microwave heating. To the reaction mixture was added ethyl acetate (60 mL) . The mixture was filtered through a celite pad, and the filtrate was washed with a saturated aqueous sodium chloride solution (50 mL × 2) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to dry, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) 10/1 4/1) to give the title compound as yellow oil (65 mg, 40 %) . MS (ESI, pos. ion) m/z: 461.3 [M+H]+.
  • 56
  • [ 934178-97-9 ]
  • [ 138647-49-1 ]
  • tert-butyl 4-[7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83 mg With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 120℃; for 18h; Microwave irradiation; Inert atmosphere; A3.1 Example A3.1 llustrative synthesis of tert-Butyl 4- j7-(p-tolylsulfonyl)pyrrolo j2,3-dJ pyrimidin-5-ylJ -3,6-dihydro-2H-pyridine- 1-carboxylate To the solution of 7-(p-tolylsulfonyl)-5 -(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)pyrrolo [2,3 -d]pyrimidine (127 mg, 1 equiv.), tert-butyl 4-(trifluoromethylsulfonyloxy)- 3,6-dihydro-2H-pyridine-1-carboxylate (105 mg, 1 equiv.), and potassium carbonate (60 mg, 1.4 equiv.) in degassed dioxane/H20 2:1 (4.0 mL), Pd(PPh3)4 (31 mg, 0.08 equiv.) wasadded and the solution degassed by bubbling argon for 5 minutes. The resulting mixture was sealed in microwave flask and heated at 120 °C for 18 h. The reaction mixture was cooled to RT, then transferred to a separatory funnel containing distilled water, and extracted with EtOAc (4 x 80 mL). The combined organic extracts were dried over Na2SO4, filtered, and solvent was removed in vacuo giving yellow oil which was purifiedby preparative TLC eluting with 70% EtOAc/cyclohexane to afford the expected product (83 mg). LCMS: MW (calcd): 454.54; MS (ES, m/z): 455.6 [M+H].
  • 57
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chloro-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((6-(phenylethynyl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Sealed tube; 12.3 Step 3: (+/-) -trans-methyl 3- ( (6- (phenylethynyl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl)pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a sealed tube were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (140 mg, 0.35 mmol) , (+/-) -trans-methyl 3- ( (2-chloro-6- (phenylethynyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.25 mmol) , potassium carbonate (104 mg, 0.76 mmol) , Pd (dppf) Cl2(41 mg, 0.05 mmol) , 1, 4-dioxane (3 mL) and water (0.2 mL) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in the sealed tube was stirred at 110 for 3 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (80 mg, 50%) .MS (ESI, pos. ion) m/z: 633.2 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm) : 9.92 (s, 1H) , 9.07 (s, 1H) , 8.63 (s, 1H) , 8.17 (d, J = 8.3 Hz, 2H) , 8.12 (d, J = 8.4 Hz, 1H) , 7.70 -7.62 (m, 2H) , 7.44 -7.41 (m, 2H) , 7.35 (s, 1H) , 7.33 (s, 1H) , 6.54 (s, 1H) , 3.75 (s, 3H) , 2.41 (s, 3H) , 2.11 (s, 1H) , 1.96 (s, 2H) , 1.80 -1.64 (m, 8H) .
  • 58
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chloro-6-(phenylethynyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-3-((6-(phenylethynyl)-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 110 °C / Inert atmosphere; Sealed tube 2: sodium hydroxide; water / tetrahydrofuran; methanol / 30 °C
  • 59
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-methyl 3-((5-fluoro-6-phenyl-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) In 1,4-dioxane; water at 100℃; for 12h; 13.3 Step 3: (+/-) -trans-methyl 3- ( (5-fluoro-6-phenyl-2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl)pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of 1, 4-dioxane (10 mL) and H2O (1 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (342 mg, 1.43 mmol, 60%) , potassium phosphate (570 mg, 3.06 mmol) , Pd (dtbpf) Cl2(83 mg, 0.10 mmol) and (+/-) -trans-methyl 3- ( (2-chloro-5-fluoro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane -2-carboxylate (400 mg, 1.02 mmol) . The mixture was heated to 100 and stirred for 12 h. After the reaction was completed, the mixture was filtered to remove the solid impuries, and the filtrate was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 8/1) to give the title compound as a light yellow solid (160 mg, 25 %) .MS (ESI, pos. ion) m/z: 627.3 [M+H]+.
  • 60
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-5-fluoro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-3-((5-fluoro-6-phenyl-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / 1,4-dioxane; water / 12 h / 100 °C 2: sodium hydroxide; water / tetrahydrofuran; methanol / 20 °C
  • 61
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-methyl 3-((6-(1-methyl-1H-pyrazol-4-yl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% With palladium diacetate; potassium carbonate; XPhos In tetrahydrofuran; water at 80℃; for 12h; 14.3 Step 3: (+/-) -trans-methyl 3- ( (6- (1-methyl-1H-pyrazol-4-yl) -2- (7-tosyl-7H-pyrrolo [2, 3-d]pyrimidin-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of THF (20 mL) and H2O (1 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (595 mg, 1.49 mmol) , potassium carbonate (588 mg, 4.26 mmol) , palladium acetate (47 mg, 0.21 mmol) , X-Phos (203 mg, 0.40 mmol) and (+/-) -trans-methyl 3- ( (2-chloro -6- (1-methyl-1H-pyrazol-4-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (400 mg, 1.06 mmol) . Then the resulting mixture was heated to 80 and stirred for 12 h. After the reaction was completed, the mixture was filtered to remove the solid impuries, and the filtrate was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (DCM/EtOAc (v/v) = 4/1) to give the title compound as a light yellow solid (320 mg, 49 %) .MS (ESI, pos. ion) m/z: 613.3 [M+H]+.
  • 62
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-3-((6-(1-methyl-1H-pyrazol-4-yl)-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: XPhos; potassium carbonate; palladium diacetate / tetrahydrofuran; water / 12 h / 80 °C 2: sodium hydroxide; water / tetrahydrofuran; methanol / 20 °C
  • 63
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-6-(p-cyanophenyl)-pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-methyl 3-((6-(4-cyanophenyl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Sealed tube; Inert atmosphere; 15.3 Step 3: (+/-) -trans-methyl 3- ( (6- (4-cyanophenyl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl)pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of dioxane (3 mL) and water (0.2 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (140 mg, 0.35 mmol) , (+/-) -trans-methyl 3- ( (2-chloro-6- (4-cyanophenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.25 mmol) , potassium carbonate (104 mg, 0.76 mmol) and Pd (dppf) Cl2(41 mg, 0.05 mmol) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in the sealed tube was stirred at 110 for 3 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (78 mg, 49 %) .
  • 64
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-6-(p-cyanophenyl)-pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-3-((6-(4-cyanophenyl)-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 110 °C / Sealed tube; Inert atmosphere 2: sodium hydroxide; water / tetrahydrofuran; methanol / 30 °C
  • 65
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-methyl 3-((6-(4-methoxyphenyl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Sealed tube; 16.3 Step 3: (+/-) -trans-methyl 3- ( (6- (4-methoxyphenyl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of dioxane (3 mL) and water (0.2 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (139 mg, 0.35 mmol) , (+/-) -trans-methyl 3- ( (2-chloro-6- (4-methoxyphenyl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.25 mmol) , potassium carbonate (103 mg, 0.75 mmol) and Pd (dppf) Cl2(40 mg, 0.05 mmol) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in the sealed tube was stirred at 110 for 3 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (69 mg, 43 %) .MS (ESI, pos. ion) m/z: 439.4 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm) : 10.00 (s, 1H) , 9.08 (s, 1H) , 8.63 (s, 1H) , 8.18 (d, J = 8.3 Hz, 2H) , 8.10 (d, J = 8.7 Hz, 2H) , 7.33 (d, J = 8.3 Hz, 2H) , 7.05 (d, J = 8.7 Hz, 2H) , 6.71 (s, 1H) , 5.20 (s, 1H) , 4.54 (s, 1H) , 3.91 (s, 3H) , 3.75 (s, 3H) , 2.46 (d, J = 4.5 Hz, 1H) , 2.41 (s, 3H) , 2.10 (s, 1H) , 1.97 (s, 2H) , 1.83-1.70 (m, 6H) .
  • 66
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-6-(4-methoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-3-((6-(4-methoxyphenyl)-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 110 °C / Inert atmosphere; Sealed tube 2: sodium hydroxide; water / tetrahydrofuran; methanol / 30 °C
  • 67
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((5-chlorothiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((5-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
27% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Sealed tube; 17.2 Step 2: (+/-) -trans-methyl 3- ( (5- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl)thiazolo [5, 4-d] pyrimidin-7-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of dioxane (3 mL) and water (0.2 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (158 mg, 0.40 mmol) , (+/-) -trans-methyl 3- ( (5-chlorothiazolo [5, 4-d] pyrimidin-7-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.28 mmol) , potassium carbonate (117 mg, 0.85 mmol) and Pd (dppf) Cl2(42 mg, 0.06 mmol) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in the sealed tube was stirred at 110 for 3 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (45 mg, 27 %) .MS (ESI, pos. ion) m/z: 590.1 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm) : 9.96 (s, 1H) , 9.09 (s, 1H) , 8.78 (s, 1H) , 8.66 (s, 1H) , 8.21 (d, J = 8.3 Hz, 2H) , 7.35 (d, J = 8.3 Hz, 2H) , 6.33 (d, J = 6.5 Hz, 1H) , 4.99 (s, 1H) , 3.75 (s, 3H) , 2.55 (d, J = 5.7 Hz, 1H) , 2.42 (s, 3H) , 2.11 (d, J = 11.8 Hz, 2H) , 2.05-1.64 (m, 8H) .
  • 68
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chloroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 2h; Inert atmosphere; Sealed tube; 18.2 Step 2: (+/-) -trans-methyl 3- ( (2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) quinazolin-4-yl)amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of dioxane (3 mL) and water (0.2 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (143 mg, 0.36 mmol) , (+/-) -trans-methyl 3- ( (2-chloroquinazolin-4-yl) amino) bicyclo [2.2.2] octane -2-carboxylate (89 mg, 0.26 mmol) , potassium carbonate (106 mg, 0.77 mmol) and Pd (dppf) Cl2(42 mg, 0.05 mmol) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in the sealed tube was stirred at 110 for 2 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (56 mg, 37 %) .[0796]1H NMR (400 MHz, CDCl3) δ (ppm) : 10.11 (s, 1H) , 9.09 (s, 1H) , 8.71 (s, 1H) , 8.22 (d, J = 8.3 Hz, 2H) , 7.91 (d, J = 8.4 Hz, 1H) , 7.78 (d, J = 8.0 Hz, 1H) , 7.72 (d, J = 8.2 Hz, 1H) , 7.47 (t, J =7.5 Hz, 1H) , 7.34 (d, J = 8.2 Hz, 2H) , 5.89 (d, J = 6.5 Hz, 1H) , 4.99 (s, 1H) , 3.76 (s, 3H) , 2.53 (d, J = 5.2 Hz, 1H) , 2.41 (s, 3H) , 2.13 (d, J = 3.0 Hz, 2H) , 2.00-1.95 (m, 2H) , 1.89-1.70 (m, 6H) .
  • 69
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chlorobenzo[g]quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[g]quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Microwave irradiation; 19.2 Step 2: (+/-) -trans-methyl 3- ( (2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) benzo [g] quinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of dioxane (3 mL) and water (0.2 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (141 mg, 0.35 mmol) , (+/-) -trans-methyl 3- ( (2-chlorobenzo [g] quinazolin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.25 mmol) , potassium carbonate (104 mg, 0.76 mmol) and Pd (dppf) Cl2(41 mg, 0.05 mmol) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 for 3 h by microwave heating. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (106 mg, 66 %) .1H NMR (400 MHz, CDCl3) δ (ppm) : 10.18 (s, 1H) , 9.10 (s, 1H) , 8.75 (s, 1H) , 8.43 (s, 1H) , 8.28 (s, 1H) , 8.23 (d, J = 8.4 Hz, 2H) , 8.03 (t, J = 7.4 Hz, 2H) , 7.62-7.57 (m, 1H) , 7.55-7.50 (m, 1H) , 7.34 (d, J = 8.2 Hz, 2H) , 6.22 (d, J = 6.5 Hz, 1H) , 5.06 (s, 1H) , 3.78 (s, 3H) , 2.61 (s, 1H) , 2.41 (s, 3H) , 2.20 (s, 1H) , 2.15 (s, 1H) , 2.04 (s, 2H) , 1.88-1.70 (m, 6H) .
  • 70
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chlorobenzo[g]quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-3-((2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[g]quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 110 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide; water / tetrahydrofuran; methanol / 30 °C
  • 71
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 2h; Inert atmosphere; Sealed tube; 20.2 Step 2: (+/-) -trans-methyl 3- ( (2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) thieno [2, 3-d]pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of dioxane (3 mL) and water (0.2 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (197 mg, 0.49 mmol) , ( (+/-) -trans-methyl 3- ( (2-chlorothieno [2, 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (124 mg, 0.35 mmol) , potassium carbonate (146 mg, 1.06 mmol) and Pd (dppf) Cl2(57 mg, 0.07 mmol) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in the sealed tube was stirred at 110 for 2 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (100 mg, 48 %) .MS (ESI, pos. ion) m/z: 589.3 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm) : 9.99 (s, 1H) , 9.08 (s, 1H) , 8.66 (s, 1H) , 8.20 (d, J = 8.3 Hz, 2H) , 7.32 (dd, J = 11.8, 7.1 Hz, 3H) , 7.19 (d, J = 6.0 Hz, 1H) , 5.31 (s, 1H) , 4.96 (s, 1H) , 3.74 (s, 3H) , 2.49 (d, J = 5.8 Hz, 1H) , 2.41 (s, 3H) , 2.11 (d, J = 2.7 Hz, 2H) , 1.88-1.62 (m, 8H) .
  • 72
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-3-((2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)thieno[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 2 h / 110 °C / Inert atmosphere; Sealed tube 2: sodium hydroxide; water / tetrahydrofuran; methanol / 30 °C
  • 73
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((6-(4-tert-butylphenyl)-2-chloro-pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-methyl 3-((6-(4-(tert-butyl)phenyl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 2h; Inert atmosphere; Microwave irradiation; 21.3 Step 3: (+/-) -trans-methyl 3- ( (6- (4- (tert-butyl) phenyl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of dioxane (3 mL) and water (0.2 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (139 mg, 0.35 mmol) , (+/-) -trans-methyl 3- ( (6- (4- (tert-butyl) phenyl) -2-chloropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.23 mmol) , potassium carbonate (96 mg, 0.70 mmol) and Pd (dppf) Cl2(38 mg, 0.05 mmol) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 for 2 h by microwave heating. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (74 mg, 48 %) .MS (ESI, pos. ion) m/z: 665.2 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm) : 10.02 (s, 1H) , 9.08 (s, 1H) , 8.63 (s, 1H) , 8.18 (d, J = 8.3 Hz, 2H) , 8.05 (d, J = 8.3 Hz, 2H) , 7.55 (d, J = 8.4 Hz, 2H) , 7.33 (d, J = 8.3 Hz, 2H) , 6.75 (s, 1H) , 3.76 (s, 3H) , 2.45 (s, 1H) , 2.41 (s, 3H) , 2.10 (s, 1H) , 1.83 (s, 2H) , 1.72 (d, J = 14.9 Hz, 6H) , 1.40 (s, 9H) .
  • 74
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((6-(4-tert-butylphenyl)-2-chloro-pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-3-((6-(4-(tert-butyl)phenyl)-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 2 h / 110 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide; water / tetrahydrofuran; methanol / 30 °C
  • 75
  • [ 934178-97-9 ]
  • (2S,3S)-ethyl 3-((2-chloroquinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (2S,3S)-ethyl 3-((2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 2h; Inert atmosphere; Microwave irradiation; 22.3 Step 3: (2S, 3S) -ethyl 3- ( (2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) quinazolin-4-yl) amino)bicyclo [2.2.2] octane-2-carboxylate To a mixed solvent of dioxane (3 mL) and water (0.2 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (138 mg, 0.35 mmol) , (2S, 3S) -ethyl 3- ( (2-chloroquinazolin-4-yl) amino) bicyclo [2.2.2] octane -2-carboxylate (83 mg, 0.23 mmol) , potassium carbonate (96 mg, 0.69 mmol) and Pd (dppf) Cl2(41 mg, 0.05 mmol) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 for 2 h by microwave heating. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (52 mg, 38%) .MS (ESI, pos. ion) m/z: 597.7 [M+H]+.
  • 76
  • [ 934178-97-9 ]
  • (2S,3S)-ethyl 3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (2S,3S)-ethyl 3-((6-(furan-2-yl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Sealed tube; 23.3 Step 3: (2S, 3S) -ethyl 3- ( (6- (furan-2-yl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a sealed tube were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (200 mg, 0.48 mmol, 80%) , (2S, 3S) -ethyl 3- ( (2-chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (130 mg, 0.34 mmol) , potassium carbonate (191 mg, 1.38 mmol) , Pd (dppf) Cl2(50 mg, 0.07 mmol) , dioxane (10 mL) and water (1 mL) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in the sealed tube was stirred at 110 for 3 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (170 mg, 80%) .MS (ESI, pos. ion) m/z: 613.2 [M+H]+.
  • 77
  • [ 934178-97-9 ]
  • (±)-trans-3-((5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)thiazolo[5,4-d]pyrimidin-7-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 3 h / 110 °C / Inert atmosphere; Sealed tube 2: sodium hydroxide; water / tetrahydrofuran; methanol / 30 °C
  • 78
  • [ 934178-97-9 ]
  • (±)-trans-3-((2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinazolin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / 1,4-dioxane; water / 2 h / 110 °C / Inert atmosphere; Sealed tube 2: sodium hydroxide; water / tetrahydrofuran; methanol / 30 °C
  • 79
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chloro-6-(pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((6-(pyridin-3-yl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Inert atmosphere; Microwave irradiation; 1.9 Step 9: (+/-) -trans-methyl 3- ( (6- (pyridin-3-yl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl)pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a microwave tube were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7 -tosyl-7H-pyrrolo [2, 3-d] pyrimidine (103 mg, 0.26 mmol) , (+/-) -trans-methyl 3- ( (2-chloro-6- (pyridin-3-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (80 mg, 0.21 mmol) , potassium carbonate (88 mg, 0.64 mmol) , Pd (dppf) Cl2(35 mg, 0.04 mmol) , 1,4-dioxane (3 mL) and water (0.2 mL) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture was stirred at 110 for 3 h by microwave heating. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (67 mg, 51%) .MS (ESI, pos. ion) m/z: 610.2 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm) : 9.96 (s, 1H) , 9.27 (s, 1H) , 9.09 (s, 1H) , 8.74 (d, J = 3.7 Hz, 1H) , 8.65 (s, 1H) , 8.47 (d, J = 7.8 Hz, 1H) , 8.19 (d, J = 8.2 Hz, 2H) , 7.49 (dd, J = 7.8, 4.9 Hz, 1H) , 7.34 (d, J = 8.2 Hz, 2H) , 6.81 (s, 1H) , 4.60 (s, 1H) , 3.76 (s, 3H) , 2.46 (s, 1H) , 2.42 (s, 3H) , 1.99 (s, 1H) , 1.70 (m, 10H) .
  • 80
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-methyl 3-((6-(furan-2-yl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Sealed tube; Inert atmosphere; 2.3 Step 3: (+/-) -trans-methyl 3- ( (6- (furan-2-yl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl)pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a sealed tube were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (214 mg, 0.54 mmol) , (+/-) -trans-methyl 3- ( (2-chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (139 mg, 0.38 mmol) , potassium carbonate (159 mg, 1.15 mmol) , Pd (dppf) Cl2(56 mg, 0.08 mmol) , 1, 4-dioxane (3 mL) and water (0.2 mL) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in sealed tube was stirred at 110 for 3 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (160 mg, 70%) .[0509]MS (ESI, pos. ion) m/z: 559.2 [M+H]+;[0510]1H NMR (400 MHz, CDCl3) δ (ppm) : 9.95 (s, 1H) , 9.07 (s, 1H) , 8.59 (s, 1H) , 8.17 (d, J = 8.3 Hz, 2H) , 7.59 (s, 1H) , 7.33 (d, J = 8.3 Hz, 2H) , 6.68 (s, 1H) , 6.60 (dd, J = 3.3, 1.7 Hz, 1H) , 4.53 (s, 1H) , 3.75 (s, 3H) , 2.44 (d, J = 5.3 Hz, 1H) , 2.41 (s, 3H) , 2.09 (s, 1H) , 1.98 (d, J = 8.6 Hz, 2H) , 1.90 -1.67 (m, 8H) .
  • 81
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • C30H31N7O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 115℃; for 3h; Inert atmosphere; Microwave irradiation; 3.3 Step 3: (+/-) -trans-3- ( (7-methyl-7'-tosyl-7H, 7'H- [2, 5'-bipyrrolo [2, 3-d] pyrimidin] -4-yl)amino) bicyclo [2.2.2] octane-2-carboxylic acid To 1, 4-dioxane (3 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (160 mg, 0.40 mmol) , K2CO3(118 mg, 0.86 mmol) , PdCl2(dppf) (41 mg, 0.06 mmol) and (+/-) -trans-methyl 3- ( (2-chloro-7-methyl-7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.29 mmol) . Then H2O (0.2 mL) was added to the mixture, and the air in the mixture was exchanged with nitrogen by bubbling for 10 min. Ten the mixture was stirred for 3 h at 115 by microwave heating. The mixture was filtered to remove the solid impuries, and the filtrate was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (84 mg, 50 %) .MS (ESI, pos. ion) m/z: 586.6 [M+H]+;1H NMR (600 MHz, DMSO-d6) δ (ppm) : 12.27 (s, 1H) , 8.67 (s, 1H) , 8.29 (s, 2H) , 7.73 (d, J =4.8 Hz, 2H) , 7.48 (s, 1H) , 7.26 -7.17 (m, 1H) , 6.68 (s, 1H) , 4.58 (s, 1H) , 1.94 (d, J = 25.2 Hz, 2H) , 1.84 -1.38 (m, 8H) .
  • 82
  • [ 934178-97-9 ]
  • (±)-trans-methyl 3-((2-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
  • (±)-trans-methyl 3-((7-isopropyl-7'-tosyl-7H,7'H-[2,5'-bipyrrolo[2,3-d]pyrimidin]-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 115℃; for 3h; Inert atmosphere; Microwave irradiation; 4.3 Step 3: (+/-) -trans-methyl 3- ( (7-isopropyl-7'-tosyl-7H, 7'H- [2, 5'-bipyrrolo [2, 3-d] pyrimidin]-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To 1, 4-dioxane (3 mL) were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (182 mg, 0.45 mmol, 50%) , K2CO3(99 mg, 0.64 mmol) , PdCl2(dppf) (48 mg, 0.06 mmol) and (+/-) -trans-methyl 3- ( (2-chloro-7-isopropyl -7H-pyrrolo [2, 3-d] pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (120 mg, 0.32 mmol) . Then H2O (0.5 mL) was added to the mixture, and the air in the mixture was exchanged with nitrogen by bubbling for 10 min. Then the mixture was stirred for 3 h at 115 by microwave heating. The mixture was filtered to remove the solid impurities, and the filtrate was concentrated to remove the solvent. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as colorless oil (143 mg, 73 %) .MS (ESI, pos. ion) m/z: 614.3 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm) : 10.03 (s, 1H) , 9.06 (s, 1H) , 8.60 (s, 1H) , 8.19 (d, J = 8.3 Hz, 2H) , 7.33 (d, J = 8.3 Hz, 2H) , 7.08 (d, J = 3.5 Hz, 1H) , 6.41 (d, J = 3.1 Hz, 1H) , 4.89 (s, 1H) , 3.74 (s, 3H) , 2.49 (d, J = 5.3 Hz, 1H) , 2.41 (s, 3H) , 2.16 -2.09 (m, 1H) , 1.67 (s, 11H) , 1.56 (d, J = 6.8 Hz, 6H) .
  • 83
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-6-phenylpyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-methyl 3-((6-phenyl-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Microwave irradiation; Inert atmosphere; Sealed tube; 5.3 Step 3: (+/-) -trans-methyl 3- ( (6-phenyl-2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a microwave tube were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (193 mg, 0.48 mmol) , (+/-) -trans-methyl 3- ( (2-chloro-6-phenylpyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (150 mg, 0.40 mmol) , potassium carbonate (167 mg, 1.21 mmol) , Pd (dppf) Cl2(65 mg, 0.08 mmol) , 1, 4-dioxane (3 mL) and water (0.2 mL) . The air in the mixture was removed by bubbling with nitrogen for 10 min and the mixture in sealed tube was stirred at 110 for 3 h. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (n-hexane/EtOAc (v/v) = 1/1) to give the title compound as a yellow solid (200 mg, 82%) .[0564]MS (ESI, pos. ion) m/z: 609.1 [M+H]+.
  • 84
  • [ 934178-97-9 ]
  • (±)-cis-N-(3-((2-chloro-6-(furan-2-yl)pyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide [ No CAS ]
  • (±)-cis-N-(3-((6-(furan-2-yl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)cyclohexyl)-1-methyl-1H-imidazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 120℃; for 4h; Microwave irradiation; Inert atmosphere; 6.6 Step 6: (+/-) -cis-N- (3- ( (6- (furan-2-yl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl)pyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazole-4-carboxamide To a microwave tube were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan -2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (103 mg, 0.26 mmol) , (+/-) -cis-N- (3- ( (2-chloro-6- (furan-2-yl) pyrimidin-4-yl) amino) cyclohexyl) -1-methyl-1H-imidazo le-4-carboxamide (75 mg, 0.19 mmol) , potassium carbonate (77 mg, 0.56 mmol) , Pd (dppf) Cl2(30 mg, 0.04 mmol) , 1, 4-dioxane (3 mL) and water (0.2 mL) . The air in the mixture was exchanged with nitrogen by bubbling for 10 min, then the mixture was stirred at 120 with microwave heating for 4 hours. The mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL) . The filtrate was washed with saturated brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 10/1) to give the title compound as a yellow solid (62 mg, 52%) .[0590]MS (ESI, pos. ion) m/z: 638.2 [M+H]+;[0591]1H NMR (400 MHz, CDCl3) δ (ppm) : 9.91 (s, 1H) , 9.07 (s, 1H) , 8.57 (s, 1H) , 8.17 (d, J = 8.3 Hz, 2H) , 7.60 (s, 1H) , 7.54 (s, 1H) , 7.37 (s, 1H) , 7.33 (d, J = 8.3 Hz, 2H) , 7.05 (d, J = 8.4 Hz, 1H) , 6.64 -6.58 (m, 2H) , 5.00 (s, 1H) , 3.74 (s, 3H) , 2.55 (d, J = 11.8 Hz, 1H) , 2.41 (s, 3H) , 2.23 (d, J = 8.1 Hz, 1H) , 2.14 (d, J = 15.9 Hz, 1H) , 1.97 (d, J = 14.4 Hz, 1H) , 1.32 (m, 6H) .
  • 85
  • [ 934178-97-9 ]
  • (+/-)-trans-3-((2-chloro-5-fluoro-6-(furan-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid methyl ester [ No CAS ]
  • (±)-trans-methyl 3-((5-fluoro-6-(furan-2-yl)-2-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 110℃; for 3h; Microwave irradiation; Inert atmosphere; 7.3 Step 3: (+/-) -trans-methyl 3- ( (5-fluoro-6- (furan-2-yl) -2- (7-tosyl-7H-pyrrolo [2, 3-d] pyrimidin-5-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate To a microwave tube were added 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan -2-yl) -7-tosyl-7H-pyrrolo [2, 3-d] pyrimidine (147 mg, 0.37 mmol) , (+/-) -trans-methyl 3- ( (2-chloro-5-fluoro-6- (furan-2-yl) pyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylate (100 mg, 0.26 mmol) , water (0.2 mL) , 1, 4-dioxane (3 mL) , potassium carbonate (109 mg, 0.79 mmol) and Pd (dppf) Cl2(38 mg, 0.05 mmol) . The air in the mixture was exchanged with nitrogen by bubbling for 10 min. The mixture was stirred for 3 h at 110 with microwave heating. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) =1/1) to give the title compound as yellow oil (123 mg, 76%) .MS (ESI, pos. ion) m/z: 617.2 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm) : 9.99 (s, 1H) , 9.08 (s, 1H) , 8.56 (s, 1H) , 8.19 (d, J = 8.4 Hz, 2H) , 7.71 (s, 1H) , 7.34 (d, J = 8.2 Hz, 2H) , 7.23 (s, 1H) , 6.63 (dd, J = 3.3, 1.7 Hz, 1H) , 5.34 (d, J = 5.5 Hz, 1H) , 4.80 (s, 1H) , 3.77 (s, 3H) , 2.48 (d, J = 5.0 Hz, 1H) , 2.41 (s, 3H) , 2.11 (s, 1H) , 2.02 (s, 1H) , 1.97 (s, 2H) , 1.80 -1.67 (m, 6H) .
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