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[ CAS No. 1305208-37-0 ] {[proInfo.proName]}

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Chemical Structure| 1305208-37-0
Chemical Structure| 1305208-37-0
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Product Details of [ 1305208-37-0 ]

CAS No. :1305208-37-0 MDL No. :MFCD20926150
Formula : C4H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :HBGXGFLFLLDTML-UHFFFAOYSA-N
M.W : 103.12 Pubchem ID :53346589
Synonyms :

Calculated chemistry of [ 1305208-37-0 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 24.22
TPSA : 55.48 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.27 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.04
Log Po/w (XLOGP3) : -1.89
Log Po/w (WLOGP) : -1.29
Log Po/w (MLOGP) : -1.45
Log Po/w (SILICOS-IT) : 0.01
Consensus Log Po/w : -0.72

Druglikeness

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

Water Solubility

Log S (ESOL) : 0.78
Solubility : 618.0 mg/ml ; 5.99 mol/l
Class : Highly soluble
Log S (Ali) : 1.24
Solubility : 1810.0 mg/ml ; 17.6 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.16
Solubility : 150.0 mg/ml ; 1.46 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.11

Safety of [ 1305208-37-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1305208-37-0 ]

* 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 [ 1305208-37-0 ]

[ 1305208-37-0 ] Synthesis Path-Downstream   1~15

  • 1
  • [ 1446358-48-0 ]
  • [ 1305208-37-0 ]
  • [ 1628728-18-6 ]
YieldReaction ConditionsOperation in experiment
4% With triethylamine In tetrahydrofuran; water at 170℃; for 0.25h; Microwave irradiation; 1 General procedure: General procedure B A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.), and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1 ratio) at 90 °C until complete consumption of starting material was observed by LC/MS. The solution was diluted withiN hydrochloric acid and dichloromethane. The layers were then separated and thelayer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification yielded theproduct. The title compound was prepared following general procedure B, except (3-aminooxetan-3-yl)methanol was the amine reactant and the contents were heated at 170 °C for 15 mm in the microwave as a solution in THF/water (2:1). The contents were concentrated in vacuo, and the residue was purified via reverse phase HPLC utilizing a 5-75% acetonitrile/water gradient to deliver the desired compound, Compound 1-93 (0.6 mg, 4%) as a clear oil.1H-NMR (500 MHz, CD3OD) ö 8.85 (d, 1 H), 8.55 (s, 1 H), 7.69 (s, 1 H), 7.32 - 7.37 (m, 1 H),7.09 - 7.17 (m, 3 H), 6.97 (d, 1 H), 6.01 (s, 2 H), 5.00 (s, 2 H), 3.76 (q, 4 H).
  • 2
  • [ 1305208-37-0 ]
  • [ 1638268-79-7 ]
  • [ 1638265-47-0 ]
YieldReaction ConditionsOperation in experiment
767 mg With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; Compound 10: N-(4-fluoro-3-methyl-phenyl)-4-[[3 -(hydroxymethyl)oxetan-3-yll sulfamoyll- 1- methyl-pyrrole-2-carboxamide DIPEA (1.44 mL, 0.008 mol) was added to a stirring mixture of crude 5-[(4-fluoro-3-methyl- phenyl)carbamoyl] -1 -methyl-pyrrole-3 -sulfonyl chloride (obtained as described in the synthesis of compound 7, 1.38 g, 0.0042mo1) and CH2C12 (45 mL). (3-aminooxetan-3-yl)methanol, 0.47 g, 0.0046 mol ) was added, and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were evaporated. The residue was stirred in EtOAc (50 mL) and washedwith HC1 1M (25 mL). The separated organic layer was dried with Na2SO4, filtered off and evaporated. The obtained residue was dissolved in EtOAc (3 mL), and heptane (2 mL) was added. The resulting solution was left standing overnight. The formed precipitate was filtered off, washed with a minimum amount EtOAc (3x) and dried in vacuo.The obtained solid was recrystalyzed from CH3CN (20 mL) filtered off, washed with CH3CN (3x), and dried in vacuo, resulting in compound 10 (767 mg). Method A; Rt: 1.41 mi mlz : 395.9 (M-H) Exact mass:397.1. ‘H NMR (400 MHz, DMSO-d6) ö ppm 2.23 (d, J=1.8 Hz, 3 H), 3.61 (d, J5.7 Hz, 2 H),3.91 (s, 3 H), 4.39 (d, J=6.4 Hz, 2 H), 4.56 (d, J=6.4 Hz, 2 H), 5.08 (t, J=5.6 Hz, 1 H), 7.10 (t, J=9.2 Hz, 1 H), 7.33 (d, J=2.0 Hz, 1 H), 7.49 - 7.54 (m, 1 H), 7.57 (d, J=1.8 Hz, 1 H), 7.64 (dd =7.2, 2.3 Hz, 1 H), 7.88 (s, 1 H), 10.02 (s, 1 H).
  • 3
  • [ 1305208-37-0 ]
  • [ 1820865-50-6 ]
  • [ 1643467-18-8 ]
YieldReaction ConditionsOperation in experiment
6.1% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; 25 Example 258-Isopropoxy-7-methoxy-1-thiophen-2-yl-4H-5-oxa-29b-diaza-cyclopenta[a]naphthalene-3-carboxylic acid (3-hydroxymethyl-oxetan-3-yl)-amide (137) [00265] To 8-Isopropoxy-7-methoxy- 1 -thiophen-2-yl-4H-5 -oxa-2,9b-diaza-cyclopenta[a]naphthalene-3-carboxylic acid (80.00 mg; 0.21 mmol; 1.00 eq.) in DCM (3.00 ml; 46.80 mmol; 226.07 eq.), was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide (0.18 ml; 0.31 mmol; 1.50 eq.), (3-Amino-oxetan-3-yl)-methanol (32.02 mg; 0.31 mmol;1.50 eq.) and Ethyl-diisopropyl-amine (0.10 ml; 0.62 mmol; 3 eq.). The reaction was stuffed at RT for 1 hour. The mixture was concentrated and purified using prep-HPLC (20-37 % CH3CN in 0.1 % NH4OH in H20) to afford the desired product, 8-Isopropoxy-7-methoxy-1-thiophen-2-yl-4H-5-oxa-2,9b-diaza-cyclopenta[a] naphthalene-3-carboxylic acid (3-hydroxymethyl-oxetan-3- yl)-amide (6.00 mg; 0.01 mmol), as a yellow solid (6 mg, 6.1 %).mlz= 472 [M+H]‘H NMR (400 MHz, DMSO) 3 8.50 (s, 1H), 7.90 (d, J= 5.1 Hz, 1H), 7.46 (d, J= 3.5 Hz, 1H), 7.26 (dd, J = 5.0, 3.6 Hz, 1H), 6.89 (s, 1H), 6.50 (s, 1H), 5.43 (s, 2H), 5.14 (t, J= 5.9 Hz, 1H), 4.70 (d, J= 6.4 Hz, 2H), 4.51 (d, J= 6.5 Hz, 2H), 3.96-3.88 (m, 1H), 3.76 (s, 3H), 3.69 (d, J= 5.7 Hz, 2H), 1.07 (d, J= 6.1 Hz, 6H).
  • 4
  • [ 1305208-37-0 ]
  • [ 66222-29-5 ]
  • [ 1688652-65-4 ]
YieldReaction ConditionsOperation in experiment
57% Stage #1: (3-amino-oxetan-3-yl)-methanol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: tri-n-butylstannylmethyl iodide In N,N-dimethyl-formamide at 0 - 50℃; for 18h;
  • 5
  • [ 1195684-52-6 ]
  • [ 1305208-37-0 ]
YieldReaction ConditionsOperation in experiment
3.73 g With 20% palladium hydroxide-activated charcoal; hydrogen In methanol at 20℃; for 16h;
  • 6
  • [ 3764-01-0 ]
  • [ 1305208-37-0 ]
  • [ 1865786-09-9 ]
YieldReaction ConditionsOperation in experiment
4.03 g With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 48h;
  • 7
  • [ 1305208-37-0 ]
  • [ 501-53-1 ]
  • [ 2023006-73-5 ]
YieldReaction ConditionsOperation in experiment
77% With sodium hydrogencarbonate In dichloromethane; water at 25℃; 229.1 Step 1: benzyl N-[3-(hydroxymethyl)oxetan-3-yl]carbamate To a stirred solution of (3-amino-3-oxetanyl)methanol (103 mg, 1 mmol) in DCM (4.5 mL) was added a solution of sodium bicarbonate (252 mg, 3 mmol) in water (4.5 mL). Benzyl chloroformate (0.17 mL, 1.2 mmol) was added and the biphasic mixture stirred vigorously at 25 °C overnight. The mixture was diluted with water (5 mL) and extracted with DCM (3 x 15 mL). The combined organics were dried (phase separator) and concentrated and the crude product purified by column chromatography (SiO2, eluting with 50-100% EtOAc in Pet. Ether) to give benzyl N-[3-(hydroxymethyl)oxetan-3-yl]carbamate (182 mg, 0.77 mmol, 77% yield) as a colourless oily solid. LC-MS (ES+, Method C): 1.74 min, m/z 260.0 [M+Na]+.1H NMR (400 MHz, CDCl3): δ 7.41-7.30 (m, 5H), 5.34 (s, 1H), 5.10 (s, 2H), 4.71 (d, J = 6.5 Hz, 2H), 4.53 (d, J = 6.5 Hz, 2H), 4.04 (s, 2H), 2.48 (s, 1H).
65.6% With sodium hydrogencarbonate In dichloromethane; water at 25℃; for 16h; Inert atmosphere; 72 Benzyl (3 -(hydroxymethyl)oxetan-3 -yl)carbamate Benzyl chloroformate (7.48 mL, 52.37 mmol) was added to (3-aminooxetan-3-yl)methanol (4.5 g, 43.64 mmol) and sodium bicarbonate (11.00 g, 130.92 mmol) in DCM (180 mL)and water (180 mL) at 25°C under nitrogen. The resulting solution was stirred at 25 °C for 16 hours. The reaction mixture extracted with DCM (3 x 20 mL) and the organic layer driedover Na2SO4, filtered and evaporated to afford colourless oil. The crude product was purified by flash silica chromatography, elution gradient 40 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford benzyl (3- (hydroxymethyl)oxetan-3-yl)carbamate (6.79 g, 65.6 %) as a white solid. ‘H NMR (400 MHz, CDC13, 24.4 °C) 2.59 (1H, s), 4.04 (2H, s), 4.53 - 4.55 (2H, d), 4.71 - 4.73 (2H, d),5.12 (2H, s), 5.41 (1H, s), 7.31 - 7.41 (5H, m). mlz (ES+), [M+H]+ = 238.
  • 8
  • [ 1305208-37-0 ]
  • [ 2231627-93-1 ]
  • [ 2231628-77-4 ]
YieldReaction ConditionsOperation in experiment
14% With bis(η3-allyl-μ-chloropalladium(II)); t-BuBrettPhos; caesium carbonate In 1,4-dioxane; toluene at 60℃; for 72h; 147 Exam le 147 (General Procedure X (1288) N-(3-(6-(difluoromethoxy)-2,4-dihydrospiro[benzo[b][l,4]oxazine-3,3'-oxetan]-7-yl)-l- methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide A degassed mixture of N-[3-[4-bromo-5-chloro-2-(difluoromethoxy)phenyl]-l-methyl- lH-pyrazol-4-yl]pyrazolo[l,5-a]pyrimidine-3-carboxamide (60.0 mg, 0.121 mmol, (1289) Intermediate 19), (3-aminooxetan-3-yl)methanol (25.0 mg, 0.242 mmol), [Pd(allyl)Cl]2 (4.50 mg, 0.0123 mmol), t-BuBrettPhos (12.0 mg, 0.0246 mmol) and Cs2C03 (79 mg, 0.242 mmol) in toluene (2.0 mL) and dioxane (0.50 mL) was heated at 60 °C for 3 days. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (30/1 ~ 20/1). Appropriate fractions were combined and concentrated under reduced pressure. The crude product was further purified by Prep-HPLC with the following conditions: Column, XBridge Shield RPig OBD Column, 5um, (1290) 19* 150mm; mobile phase, Water (0.05% NH3H20) and CH3CN (15.0% CH3CN up to 35.0% in 7 min); Detector, UV 254/220nm give 8.3 mg (14%) of N-[3-[7-(difluoromethoxy)-2,4- dihydrospiro[ 1 ,4-benzoxazine-3,3-oxetane]-6-yl]- 1 -methyl- lH-pyrazol-4-yl]pyrazolo[ 1 ,5- a]pyrimidine-3-carbox amide as an off-white solid. LC/MS (Method N, ESI): [M+H]+ = 484.2, fix = 1.42 min. 1H NMR (400 MHz, DMSO-^): δ 9.74 (s, 1H), 9.35 (dd, J= 6.8, 1.6 Hz, 1H), 8.66 (s, 1H), 8.63 (dd, J= 4.4, 1.6 Hz, 1H), 8.22 (s, 1H), 7.31 (dd, J= 6.8, 4.4 Hz, 1H), 7.30 (s, 1H), 6.93 (t, J= 74.6 Hz, 1H), 6.87 (s, 1H), 6.62 (s, 1H), 4.59 (d, J= 6.8 Hz, 2H), 4.51 (d, J= 6.4 Hz, 2H), 4.32 (s, 2H), 3.87 (s, 3H).
  • 9
  • [ 1305208-37-0 ]
  • [ 1240304-80-6 ]
  • [ 1359948-93-8 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h; (1S)-2,3,4,6-Tetra-O-acetyl-1-[2-(acetyloxy)-5-[(4-{(1E)-3,3-dimethyl-4-[(2-methyl-1-oxopropan-2-yl)amino]-4-oxobut-1-en-1-yl}-2-methylphenyl)methyl]-4-(propan-2-yl)phenyl]-1,5-anhydro-D-glucitol (24a) General procedure: Compound 22a(184 mg, 2.07 mmol), 1-hydroxy-1H-benzotriazole hydrate(242 mg), water soluble carbodiimide hydrochloride (342 mg)were added to a solution of compound 18 (1.0 g, 1.38 mmol) inN,N-dimethylformamide solution (30 mL). The reaction solutionwas stirred at the room temperature for 18 h. Water was addedand the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over anhydrousmagnesium sulfate. After the desiccant was filtered off, the solventwas distilled off under reduced pressure to obtain the crudeintermediate (1.05 g). A chloroform suspension (20 mL) of obtainedintermediate (660 mg, 0.830 mmol) and Dess-Martin periodinane(422 mg, 1.25 mmol) was stirred at room temperature for3 h. After the solvent was distilled off under reduced pressure,the residue was purified by silica gel column chromatography(hexane : ethyl acetate = 4 : 1 to 1 : 4) to obtain the title compound(602 mg, 85% over 2 steps) as a yellow amorphous.
  • 10
  • [ 1305208-37-0 ]
  • [ 2696340-46-0 ]
  • [ 2696340-47-1 ]
YieldReaction ConditionsOperation in experiment
55.56% With caesium carbonate In 1,4-dioxane; toluene at 90℃; Inert atmosphere; 1.3 Step 3: To a solution of intermediate 3 (75 mg, 0.19 mmol) in 1,4-dioxane (1 mL) and toluene (4 mL) were added CS2CO3 (146 mg, 0.45 mmol), t-BuBrettPhos (44 mg, 0.092 mmol) and allylpalladium chloride dimer (21 mg, 0.058 mmol) at 0 °C under N2 atmosphere, followed by addition of compound 3A (50 mg, 0.49 mmol). The reaction was stirred at 90 °C overnight. The mixture was cooled to room temperature and was poured into iced-water and extracted with EtOAC twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-TLC (PE : EtOAc= 1 : 1) to give intermediate 4 (40 mg, yield 55.56%) as yellow solid. LC/MS (ESI) m/z : 373 (M+H)+.
  • 11
  • [ 1305208-37-0 ]
  • [ 2681297-88-9 ]
  • [ 2752479-04-0 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; 1 Step 2. Synthesis of 2-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3- yl]cyclobutyl]methylamino]ethanol (374) General procedure: A 1 mL vial was charged with a magnetic stir bar, 3-[3-(bromomethyl)cyclobutyl]- 5,7-difluoro-2-(4-fluorophenyl)-1H-indole S4 (25 mg, 0.06342 mmol), DMF (317.1 µL), ethanolamine (approximately 3.874 mg, 3.828 µL, 0.06342 mmol), and K2CO3 (approximately 17.52 mg, 0.1268 mmol). The reaction was then heated to 80 °C with stirring for 12 hours before being allowed to cool to room temperature. The reaction mixture was diluted with DMSO (~0.5 mL) and this mixture was purified via reverse phase HPLC using a mobile phase of 5 to 95% MeCN in Water (0.1% TFA). The pure fractions which combined and concentrated in vacuo to afford pure title compound as its TFA salt.
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; 1 Step 2. Synthesis of 2-[[3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3- yl]cyclobutyl]methylamino]ethanol (374) General procedure: A 1 mL vial was charged with a magnetic stir bar, 3-[3-(bromomethyl)cyclobutyl]- 5,7-difluoro-2-(4-fluorophenyl)-1H-indole S4 (25 mg, 0.06342 mmol), DMF (317.1 µL), ethanolamine (approximately 3.874 mg, 3.828 µL, 0.06342 mmol), and K2CO3 (approximately 17.52 mg, 0.1268 mmol). The reaction was then heated to 80 °C with stirring for 12 hours before being allowed to cool to room temperature. The reaction mixture was diluted with DMSO (~0.5 mL) and this mixture was purified via reverse phase HPLC using a mobile phase of 5 to 95% MeCN in Water (0.1% TFA). The pure fractions which combined and concentrated in vacuo to afford pure title compound as its TFA salt.
  • 12
  • [ 473477-02-0 ]
  • [ 1305208-37-0 ]
  • [ 2760916-04-7 ]
YieldReaction ConditionsOperation in experiment
160 mg With [(2-di-tert-butylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2’-amino-1,1‘-biphenyl)] palladium(II) methanesulfonate; sodium tertiary butoxide In 1,4-dioxane at 90℃; for 16h; Intermediate 180: 5-[[3-(hydroxymethyl)oxetan-3-yl]amino]-N,N,2-trimethyl-benzenesulfonamide [00887] A mixture of 5-bromo-N,N,2-trimethyl-benzenesulfonamide (Intermediate 156, 500 mg, 1.80 mmol), (3-aminooxetan-3-yl)methanol (CAS 1305208-37-0, 278.03 mg, 2.70 mmo), sodium tert-butoxide (518.24 mg, 5.39 mmol) and tBuXphos-Pd-G3 (142.79 mg, 179.75 umol) in dioxane (5 mL) was stirred at 90°C for 16 hours. The mixture was cooled to room temperature, volatiles removed under reduced pressure and the residue purified by prep-HPLC (TFA condition) to give the title compound as a white solid (160 mg). [00888] LCMS: Rt=0.750 min, [M+H]+= 301.2 [00889] 1H NMR (400 MHz, DMSO-d6) δ = 7.11 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.55 - 6.36 (m, 2H), 5.28 - 5.10 (m, 1H), 5.15 (br t, J = 4.9 Hz, 1H), 4.73 - 4.43 (m, 4H), 3.67 (br d, J = 4.8 Hz, 2H), 2.71 (s, 6H), 2.37 (s, 3H)
160 mg With [(2-di-tert-butylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2’-amino-1,1‘-biphenyl)] palladium(II) methanesulfonate; sodium tertiary butoxide In 1,4-dioxane at 90℃; for 16h; Intermediate 180: 5-[[3-(hydroxymethyl)oxetan-3-yl]amino]-N,N,2-trimethyl-benzenesulfonamide [00887] A mixture of 5-bromo-N,N,2-trimethyl-benzenesulfonamide (Intermediate 156, 500 mg, 1.80 mmol), (3-aminooxetan-3-yl)methanol (CAS 1305208-37-0, 278.03 mg, 2.70 mmo), sodium tert-butoxide (518.24 mg, 5.39 mmol) and tBuXphos-Pd-G3 (142.79 mg, 179.75 umol) in dioxane (5 mL) was stirred at 90°C for 16 hours. The mixture was cooled to room temperature, volatiles removed under reduced pressure and the residue purified by prep-HPLC (TFA condition) to give the title compound as a white solid (160 mg). [00888] LCMS: Rt=0.750 min, [M+H]+= 301.2 [00889] 1H NMR (400 MHz, DMSO-d6) δ = 7.11 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.55 - 6.36 (m, 2H), 5.28 - 5.10 (m, 1H), 5.15 (br t, J = 4.9 Hz, 1H), 4.73 - 4.43 (m, 4H), 3.67 (br d, J = 4.8 Hz, 2H), 2.71 (s, 6H), 2.37 (s, 3H)
  • 13
  • [ 1977-06-6 ]
  • [ 7287-40-3 ]
  • [ 1305208-37-0 ]
  • [ 2776166-29-9 ]
  • [ 2776166-61-9 ]
YieldReaction ConditionsOperation in experiment
1: 325 mg 2: 170.9 mg Stage #1: ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate With 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In acetonitrile at 20℃; for 16h; Inert atmosphere; Stage #2: 4-methyl-5-(hydroxymethyl)-thiazole With tributylphosphine; 1,1'-(azodicarboxylic)dipiperidide In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; Stage #3: (3-aminooxetan-3-yl)methanol Further stages; [0402] Step 4: To a stirred solution of a mixture of 4-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid compound and 6-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid (1:1) (550 mg, 1.71 mmol) in DMF (10 ml), were added DIPEA (1.2 ml, 6.84 mmol), HATU (970 mg, 2.57 mmol) and (3-(methylamino)oxetan-3-yl)methanol (260 mg, 2.57 mmol) at 0 °C and the reaction mixture was stirred for 2 h at RT. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude compound (715 mg, LCMS: 37% & 23% ratio). The crude compound was purified by reverse phase prep-HPLC purification (column: INERTSIL-ODS 2 (250*19 mm), 5 μm, mobile phase: A: 10 mM Ammonium Bi Carbonate in H2O, B: MeCN, Gradient: 0/30, 8/55, 9/55, 9.1/98,11/98,11.1/30,14/30; flow rate: 18 mL/min; diluent: MeCN+H2O+THF) to afford cpd.328 (325 mg) and cpd.362 (170.9 mg) as an off-white solid.
1: 325 mg 2: 170.9 mg Stage #1: ethyl 5-hydroxy-2-methylbenzofuran-3-carboxylate With 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) In acetonitrile at 20℃; for 16h; Inert atmosphere; Stage #2: 4-methyl-5-(hydroxymethyl)-thiazole With tributylphosphine; 1,1'-(azodicarboxylic)dipiperidide In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; Stage #3: (3-aminooxetan-3-yl)methanol Further stages; [0402] Step 4: To a stirred solution of a mixture of 4-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid compound and 6-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid (1:1) (550 mg, 1.71 mmol) in DMF (10 ml), were added DIPEA (1.2 ml, 6.84 mmol), HATU (970 mg, 2.57 mmol) and (3-(methylamino)oxetan-3-yl)methanol (260 mg, 2.57 mmol) at 0 °C and the reaction mixture was stirred for 2 h at RT. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude compound (715 mg, LCMS: 37% & 23% ratio). The crude compound was purified by reverse phase prep-HPLC purification (column: INERTSIL-ODS 2 (250*19 mm), 5 μm, mobile phase: A: 10 mM Ammonium Bi Carbonate in H2O, B: MeCN, Gradient: 0/30, 8/55, 9/55, 9.1/98,11/98,11.1/30,14/30; flow rate: 18 mL/min; diluent: MeCN+H2O+THF) to afford cpd.328 (325 mg) and cpd.362 (170.9 mg) as an off-white solid.
  • 14
  • [ 1305208-37-0 ]
  • [ 2810819-49-7 ]
  • [ 2810811-68-6 ]
YieldReaction ConditionsOperation in experiment
24% Stage #1: (3-aminooxetan-3-yl)methanol With sodium hydride In N,N-dimethyl acetamide; mineral oil at 50℃; for 0.0833333h; Stage #2: N-(5-(5-fluoro-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide In N,N-dimethyl acetamide; mineral oil at 90℃; for 2h; 144 Example 136: endo-N-(5-(5-(((1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)-2- methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide General procedure: To a small vial containing endo-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (255 mg, 1.42 mmol, 2.2 eq) dissolved in DMA (2.58 mL, 0.64 mmol, 0.25 M) was added sodium hydride (60 wt% dispersion in mineral oil, 258 mg, 6.45 mmol, 10 eq) portion-wisely while stirring at rt. The suspension was heated at 50 °C for 5 min, then N-(5-(5- fluoro-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 6, 200 mg, 0.64 mmol, 1.0 eq) was added. The mixture was stirred at 90 °C for 2 hours, then quenched with water. The aqueous layer was extracted several times with 10% MeOH / DCM, and the organic extracts were dried over sodium sulfate. The product was purified over FCC (10% 2M NH3 in MeOH / DCM) to provide the title compound (282 mg, 100%). MS (ESI): mass calcd. for C24H27N5O3, 433.2; m/z found, 434.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.57 - 8.51 (m, 1H), 8.28 (s, 1H), 8.08 - 8.05 (m, 1H), 7.37 (s, 1H), 7.17 (dd, J = 7.3, 2.0 Hz, 1H), 6.85 (s, 1H), 4.76 - 4.54 (m, 1H), 3.61 - 3.54 (m, 2H), 3.50 (d, J = 10.6 Hz, 2H), 2.96 - 2.88 (m, 2H), 2.45 (s, 3H), 2.32 - 2.24 (m, 2H), 1.97 - 1.88 (m, 1H), 1.71 - 1.61 (m, 2H), 0.87 - 0.77 (m, 4H).
24% Stage #1: (3-aminooxetan-3-yl)methanol With sodium hydride In N,N-dimethyl acetamide; mineral oil at 50℃; for 0.0833333h; Stage #2: N-(5-(5-fluoro-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide In N,N-dimethyl acetamide; mineral oil at 90℃; for 2h; 144 Example 136: endo-N-(5-(5-(((1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)-2- methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide General procedure: To a small vial containing endo-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (255 mg, 1.42 mmol, 2.2 eq) dissolved in DMA (2.58 mL, 0.64 mmol, 0.25 M) was added sodium hydride (60 wt% dispersion in mineral oil, 258 mg, 6.45 mmol, 10 eq) portion-wisely while stirring at rt. The suspension was heated at 50 °C for 5 min, then N-(5-(5- fluoro-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 6, 200 mg, 0.64 mmol, 1.0 eq) was added. The mixture was stirred at 90 °C for 2 hours, then quenched with water. The aqueous layer was extracted several times with 10% MeOH / DCM, and the organic extracts were dried over sodium sulfate. The product was purified over FCC (10% 2M NH3 in MeOH / DCM) to provide the title compound (282 mg, 100%). MS (ESI): mass calcd. for C24H27N5O3, 433.2; m/z found, 434.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.57 - 8.51 (m, 1H), 8.28 (s, 1H), 8.08 - 8.05 (m, 1H), 7.37 (s, 1H), 7.17 (dd, J = 7.3, 2.0 Hz, 1H), 6.85 (s, 1H), 4.76 - 4.54 (m, 1H), 3.61 - 3.54 (m, 2H), 3.50 (d, J = 10.6 Hz, 2H), 2.96 - 2.88 (m, 2H), 2.45 (s, 3H), 2.32 - 2.24 (m, 2H), 1.97 - 1.88 (m, 1H), 1.71 - 1.61 (m, 2H), 0.87 - 0.77 (m, 4H).
  • 15
  • [ 1305208-37-0 ]
  • [ 2810819-55-5 ]
  • [ 2810816-21-6 ]
YieldReaction ConditionsOperation in experiment
15% Stage #1: (3-aminooxetan-3-yl)methanol With sodium hydride In N,N-dimethyl acetamide; mineral oil at 50℃; for 0.0833333h; Stage #2: N-(5-(5-fluoro-2-(prop-1-yn-1-yl)pyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide In N,N-dimethyl acetamide; mineral oil at 90℃; for 2h; 433 Example 136: endo-N-(5-(5-(((1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)-2- methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide General procedure: To a small vial containing endo-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (255 mg, 1.42 mmol, 2.2 eq) dissolved in DMA (2.58 mL, 0.64 mmol, 0.25 M) was added sodium hydride (60 wt% dispersion in mineral oil, 258 mg, 6.45 mmol, 10 eq) portion-wisely while stirring at rt. The suspension was heated at 50 °C for 5 min, then N-(5-(5- fluoro-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 6, 200 mg, 0.64 mmol, 1.0 eq) was added. The mixture was stirred at 90 °C for 2 hours, then quenched with water. The aqueous layer was extracted several times with 10% MeOH / DCM, and the organic extracts were dried over sodium sulfate. The product was purified over FCC (10% 2M NH3 in MeOH / DCM) to provide the title compound (282 mg, 100%). MS (ESI): mass calcd. for C24H27N5O3, 433.2; m/z found, 434.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.57 - 8.51 (m, 1H), 8.28 (s, 1H), 8.08 - 8.05 (m, 1H), 7.37 (s, 1H), 7.17 (dd, J = 7.3, 2.0 Hz, 1H), 6.85 (s, 1H), 4.76 - 4.54 (m, 1H), 3.61 - 3.54 (m, 2H), 3.50 (d, J = 10.6 Hz, 2H), 2.96 - 2.88 (m, 2H), 2.45 (s, 3H), 2.32 - 2.24 (m, 2H), 1.97 - 1.88 (m, 1H), 1.71 - 1.61 (m, 2H), 0.87 - 0.77 (m, 4H).
15% Stage #1: (3-aminooxetan-3-yl)methanol With sodium hydride In N,N-dimethyl acetamide; mineral oil at 50℃; for 0.0833333h; Stage #2: N-(5-(5-fluoro-2-(prop-1-yn-1-yl)pyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide In N,N-dimethyl acetamide; mineral oil at 90℃; for 2h; 433 Example 136: endo-N-(5-(5-(((1R,5S,7s)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxy)-2- methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide General procedure: To a small vial containing endo-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (255 mg, 1.42 mmol, 2.2 eq) dissolved in DMA (2.58 mL, 0.64 mmol, 0.25 M) was added sodium hydride (60 wt% dispersion in mineral oil, 258 mg, 6.45 mmol, 10 eq) portion-wisely while stirring at rt. The suspension was heated at 50 °C for 5 min, then N-(5-(5- fluoro-2-methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (Intermediate 6, 200 mg, 0.64 mmol, 1.0 eq) was added. The mixture was stirred at 90 °C for 2 hours, then quenched with water. The aqueous layer was extracted several times with 10% MeOH / DCM, and the organic extracts were dried over sodium sulfate. The product was purified over FCC (10% 2M NH3 in MeOH / DCM) to provide the title compound (282 mg, 100%). MS (ESI): mass calcd. for C24H27N5O3, 433.2; m/z found, 434.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.57 - 8.51 (m, 1H), 8.28 (s, 1H), 8.08 - 8.05 (m, 1H), 7.37 (s, 1H), 7.17 (dd, J = 7.3, 2.0 Hz, 1H), 6.85 (s, 1H), 4.76 - 4.54 (m, 1H), 3.61 - 3.54 (m, 2H), 3.50 (d, J = 10.6 Hz, 2H), 2.96 - 2.88 (m, 2H), 2.45 (s, 3H), 2.32 - 2.24 (m, 2H), 1.97 - 1.88 (m, 1H), 1.71 - 1.61 (m, 2H), 0.87 - 0.77 (m, 4H).
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