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[ CAS No. 114012-41-8 ] {[proInfo.proName]}

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Chemical Structure| 114012-41-8
Chemical Structure| 114012-41-8
Structure of 114012-41-8 * Storage: {[proInfo.prStorage]}
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Product Details of [ 114012-41-8 ]

CAS No. :114012-41-8 MDL No. :MFCD08669505
Formula : C4H6O3 Boiling Point : -
Linear Structure Formula :- InChI Key :UWOTZNQZPLAURK-UHFFFAOYSA-N
M.W : 102.09 Pubchem ID :19847174
Synonyms :

Calculated chemistry of [ 114012-41-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.75
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 22.08
TPSA : 46.53 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) : -7.36 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.77
Log Po/w (XLOGP3) : -0.62
Log Po/w (WLOGP) : -0.28
Log Po/w (MLOGP) : -0.79
Log Po/w (SILICOS-IT) : 0.3
Consensus Log Po/w : -0.13

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -0.02
Solubility : 98.3 mg/ml ; 0.963 mol/l
Class : Very soluble
Log S (Ali) : 0.12
Solubility : 133.0 mg/ml ; 1.3 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.48
Solubility : 310.0 mg/ml ; 3.03 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.36

Safety of [ 114012-41-8 ]

Signal Word:Danger Class:N/A
Precautionary Statements:P280-P301+P312+P330-P305+P351+P338+P310 UN#:N/A
Hazard Statements:H302-H318 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 114012-41-8 ]

* 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 [ 114012-41-8 ]

[ 114012-41-8 ] Synthesis Path-Downstream   1~51

  • 1
  • [ 114012-41-8 ]
  • [ 1449278-36-7 ]
  • [ 1449276-91-8 ]
YieldReaction ConditionsOperation in experiment
10% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; 17 Example 17 8-amino-2-(3 -fluorophenyl)-N-( 1 -(oxetane-3 -carbonyl)azetidin-3 -yl)- 1 ,7-naphthyridine-5-carboxamide Example 17 8-amino-2-(3 -fluorophenyl)-N-( 1 -(oxetane-3 -carbonyl)azetidin-3 -yl)- 1 ,7-naphthyridine-5-carboxamide A solution of 34-3 (74 mg, 0.164 mmol), 17-2 (22.6 mg, 0.22 mmol), HATU (126 mg, 0.33 mmol) and DIPEA (115 mg, 0.89 mmol) in DMF (10 mL) was stirred at r.t. for 3 h. It was concentrated and the crude product was purified by prep-HPLC to give the pure product as yellow solid (9.0 mg, yield 10%). LCMS: (0-60AB, 2 min), 0.973 min, Ms = 422.1 (M + l) ; NMR (400MHz, MeOH-tW) δ 8.88 (d, J= 8.8 Hz, 1H), 8.28-8.26 (m, 1H), 8.20 (s, 1H), 8.09 (d, J= 8.8 Hz, 1H), 8.12-8.06 (m, 1H), 7.57-7.52 (m, 1H), 7.24-7.21 (m, 1H), 4.80-4.78 (m, 5H), 4.50-4.46 (m, 1H), 4.41-4.36 (m, 1H), 4.12-3.92 (m, 3H).
  • 2
  • [ 114012-41-8 ]
  • [ 1520888-97-4 ]
  • [ 1520889-62-6 ]
YieldReaction ConditionsOperation in experiment
46% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; 52 rac-2-[l-(Oxetane-3-carbonyl)-piperidin-4-yl]- 1,2,4, 10-tetrahydro-3-oxa-10-aza- phenanthren-9-one (I-52) In a 5 mL round-bottomed flask, 4-(6-oxo-3,4,5,6-tetrahydro-lH-pyrano[4,3- c]isoquinolin-3-yl)piperidinium (31.4 mg, 110 μηιο, Eq: 1.00), DIPEA (42.7 mg, 57.7 μ, 330 μηιο, Eq: 3.00) and oxetane-3-carboxylic acid (16.5 mg, 165 μηιο, Eq: 1.50) were combined with DMF (1 mL) to give an off-white suspension. l-(3-Dimethylaminopropyl-3- ethylcarbodiimide hydrochloride (31.6 mg, 165 μηιο, Eq: 1.50) was added. The mixture was stirred at RT overnight. The reaction mixture was distributed into 50 mL EtOAc, washed with 10 mL 0.2 N HCl, water and sat NaHC03. The aqueous layers were back-extracted with 2 x 20 mL EtOAc. The combined EtOAc layers were dried over MgS04, filtered and evaporated to a white solid. The crude material (adsorbed onto silica) was purified by flash chromatography (silica gel, 15 x 12 g, 0% to 100% 5% MeOH/EtOAc in hexanes). Fractions were pooled and evaporated to 18.6 mg (46%) of 2-[l-(oxetane-3-carbonyl)-piperidin-4-yl]-l ,2,4,10-tetrahydro-3-oxa-10-aza- phenanthren-9-one as a white solid. 1H NMR (DMSO-d6) δ: 11.20 (br. s., 1H), 8.19 (dd, J = 7.9, 1.1 Hz, 1H), 7.64 (td, J = 8.0, 1.0 Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 5.20 (m, 2H), 4.85 (m, 1H), 4.45 (m, 3H), 3.80 (m, 4H), 3.46 (m, 1H), 1.90 (m, 1H), 1.76 (m, 4H), 1.57 (m, 1H), 1.48 - 1.32 (m, 2H). MS calcd. for C21H24N2O4 [(M+H)+] 369.4, obsd. 369.0.
  • 3
  • [ 114012-41-8 ]
  • [ 1889326-74-2 ]
  • [ 1889325-97-6 ]
YieldReaction ConditionsOperation in experiment
25.8% Stage #1: oxetane-3-carboxylic acid With HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: ethyl 1-(6-(3,5-difluoro-2-((2-methyl-6-(piperidin-4-yl)pyridin-3-yl)methoxy)phenyl)pyridin-2-yl)piperidine-4-carboxylate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 12h; Cooling; 28 Example 28ethyl 1 -(6-(3,5-difluoro-2-((2-methyl-6-(1 -(oxetane-3-carbonyl)piperidin-4-yl)pyridin-3-yl) methoxy)phenyl)pyridin-2-yl) piperidine-4-carboxylate To a solution of oxetane-3-carboxylic acid (ill mg, 1.090 mmol) in DMF (4 mL) was added HATU (621 mg, 1.634 mmol) and the reaction mixture was stirred at room temperature for 5 minutes. After cooling, ethyl 1 -(6-(3,5-difluoro-2-((2-methyl-6-(piperidin-4-yl)pyridin-3- yl)methoxy)phenyl)pyridin-2-yl) piperidine-4-carboxylate (600 mg, 1.090 mmol) and then DIPEA (0.571 mL, 3.27 mmol) were slowly added and the resulting reaction mixture was stirred at 25 00 for 12 hours and then was diluted with cold water (60 mL) and extracted with EtOAc (3 x 5OmL). The combined organic phase was washed with brine solution (80 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure . The residue was purified by column chromatography (silica gel, eluted with EtOAc) . Collected fractions were concentrated under reduced pressure to afford the title compound (250mg, 25.8 % yield) as colorless sticky liquid.LCMS (f): Rt= 5.81 mi M/z= 634.9 (M+H)
  • 4
  • [ 114012-41-8 ]
  • [ 1889325-72-7 ]
  • [ 1889325-73-8 ]
YieldReaction ConditionsOperation in experiment
13.28% With triethylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 4 Example 4ethyl 1 -(6-(3, 5-difluoro-2-((2-methyl-4-(1 -(oxetane-3-carbonyl)piperidi n-4-yl)benzyl)oxy) phenyl) pyridin-2-yl)piperidine-4-carboxylate To a solution of ethyl 1-(6-(3,5-difluoro-2-((2-methyl-4-(piperidin-4- yl)benzyl)oxy) phenyl)pyridin-2-yl)piperidine-4-carboxylate (500 mg, 0.910 mmol) andoxetane-3-carboxylic acid (0.065 ml, 1.092 mmol) in N,N-Dimethylformamide (2 ml) were added HATU (519 mg, 1.365 mmol) followed by TEA (0.190 ml, 1.365 mmol) atO 00 and the reaction mixture was allowed to stirred at room temperature for 16 hours. After dilution with water (lOmL) and extraction with EtOAc (3x2OmL), the organic phase was washed with brine solution (25mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:Hexane, 1:9) and then by HPLC (gradient 0.1% Formic acid (Aq) : ACN:MeOH (1:1)). Fractions were collected and concentrated under reduced pressure to remove ACN, the aqueous layer was extracted with EtOAc (2x50m1). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with pentane (3x5mL), filtered and dried under high vacuo to afford the title compound (80 mg, 13.28 % yield).LCMS: Rt: 2.92mm, M/z = 634.37 (M+H)
  • 5
  • [ 114012-41-8 ]
  • [ 75-16-1 ]
  • [ 1507872-90-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: oxetane-3-carboxylic acid With N,O-dimethylhydroxylamine*hydrochloride; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 0 - 20℃; for 2h; Stage #2: methylmagnesium bromide In tetrahydrofuran; diethyl ether at 0℃; for 2h; 159 1 -(oxetan-3 -yl)ethanone(2): To a solution of compound 1(300mg, 80% purity) in DCM(5mL) was added MeNHOMe HC1 (229 mg,2.35 mmol), NEt3(594mg, 5.88mmol) and T3P(1.25g, 3.92mmol) at 0 °C. The resulting solution was stirred at room temperature for 2 hours. Evaporate the solvent to give crudeWeinreb amide. Diluted it in THF(5mL), MeMgBr in ether(0.83 mL, 2.48 mmol) was added at 0°C. Stirred for 2 hours and warmed it up to room temperature slowly. Quenched with saturated aqueous solution of NH4C1 and extracted with DCM (2OmLX3). The organic layer was combined and concentrated to give cmde compound 2 (200 mg, 80% purity) as oil. TLC: 10% MeOH /DCM (Rf: 0.8)
  • 6
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
56% With 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.16667h; 52.1 Step 1: 5-phenyl-N- jtrans-3 - j(oxetan-3-ylformohydrazido)carbonylj cyclobutyll isoxazole3-carboxamide: HCTU (1.16 g, 2.78 mmol, 2.00 eq.), oxetane-3-carboxylic acid (141 mg,1.38 mmol, 1.00 eq.) and DIEA (537 mg, 4.16 mmol, 3.00 eq.) were added to a solution of 5- phenyl-N-[trans-3 -(hydrazinecarbonyl)cyclobutyl] isoxazole-3 -carboxamide (417 mg, 1.39mmol, 1.00 eq.) in DMF (10 mL) and the mixture was stirred for 70 mm at room temperature. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.3 g (56%) of 5 -phenyl-N- [trans-3 -[(oxetan-3 - ylformohydrazido)carbonyl]cyclobutyl]isoxazole-3-carboxamide as an orange solid. LC-MSES, m/z): [M+H] = 385.1.
  • 7
  • [ 114012-41-8 ]
  • [ 1953131-83-3 ]
  • [ 1953131-85-5 ]
YieldReaction ConditionsOperation in experiment
66% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In tetrahydrofuran at 20℃; for 0.333333h; 22.2 Step 2: 3-phenyl-N-[fra/is-3-[(oxetan-3- ylformohydrazido)carbonyI]cyclobutyl]isoxazole-5-carboxamide oxetane-3-carboxylic acid (170 mg, 1.67 mmol, 1.00 eq.), T3P (5.3 g, 8.33 mmol, 5.00 eq., 50%) and TEA (838 mg, 8.3 mmol, 5.00 eq.) were added to a solution of 3-pheny-N-[trans-3- (hydrazinecarbonyl)cyclobutyl]isoxazole-5-carboxamide (500 mg, 1.66 mmol, 1.00 eq.) in THF (50mL). The resulting solution was stirred for 20 min at room temperature, then quenched by the addition of 200mL of water. The resulting solution was extracted with dichloromethane (3x200mL) and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue solid was washed with 2mL of methanol to afford 420 mg (66%) of 3-phenyl-N-[/rara- 3-[(oxetan-3-ylformohydrazido)carbonyl]cyclobutyl]isoxazole-5-carboxamide as an off-white solid; LC-MS (ES, m/z): [M+H]+ = 385.0.
  • 8
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
28% Stage #1: oxetane-3-carboxylic acid With oxalyl dichloride In dichloromethane at 0 - 20℃; for 2h; Stage #2: methyl (R)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate With triethylamine In dichloromethane at 20℃; 45.1 Step-1 Methyl (R)-4-(oxetane-3-carbonyl)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate Into a 10-mL vial (vial A) purged and maintained with an inert atmosphere of nitrogen, were placed a solution of cyclobutanecarboxylic acid (25 mg, 0.25 mmol, 1 equiv) in CH2Cl2 (5 mL), then oxalyl chloride (13.1 mg, 0.5 equiv) was added at 0° C. and stirred at room temperature for 2 h. In vial B was added methyl (R)-3-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (30 mg, 0.11 mmol, 1 equiv) and Et3N (50 mg, 0.49 mmol, 6 equiv), then the solution of vial A was transferred to vial B dropwise. The resulting solution was stirred for 2 h at room temperature, then concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc/pet. ether, 1:1) to afford the title compound as a yellow oil (25 mg, 28% yield). MS: (ES, m/z): 360 [M+H]+.
  • 9
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; 51.1 Step-1 Methyl (R)-5-isopropyl-4-(oxetane-3-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate Into a 10-mL round-bottom flask, was placed the product from Example 45 Step 5 (methyl (R)-5-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.TFA) (50 mg, 0.20 mmol, 1 equiv) in DMF (3 mL), DIEA (103 mg, 0.80 mmol, 4 equiv), HATU (115 mg, 0.30 mmol, 1.5 equiv) and oxetane-3-carboxylic acid (24 mg, 0.24 mmol, 1.2 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched with H2O (20 mL) and extracted with EtOAc (3*15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the title compound as yellow oil (60 mg, 90% yield). MS: (ES, m/z): 334 [M+H]+.
  • 10
  • [ 114012-41-8 ]
  • [ 269078-82-2 ]
  • [ CAS Unavailable ]
  • [ 2023027-69-0 ]
YieldReaction ConditionsOperation in experiment
39% Stage #1: 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid; 4-aminomethyl-3-chlorobenzonitrile With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; Inert atmosphere; Stage #2: With methylamine In ethanol; dichloromethane at 20℃; Inert atmosphere; Stage #3: oxetane-3-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; 113 Example 113 N-[(2-Chloro-4-cyanophenyl)methyl]-2-[6-[4-(oxetane-3-carbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetamide To a solution of 2-[6-[4-(9H-fluoren-9-ylmethoxycarbonyl)piperazin-1-yl]-4-oxoquinazolin-3-yl]acetic acid (intermediate A-1; [CAS RN 269078-82-2]) (50 mg, 0.098 mmol) in dry DCM (2 mL) were added TBTU (47.2 mg, 0.15 mmol; [CAS RN 125700-67-6]) and DIPEA (50 µL, 0.29 mmol) under an atmosphere of nitrogen. Then, 4-(aminomethyl)-3-chlorobenzonitrile (20.4 mg, 0.12 mmol; [CAS RN 202521-97-9]) was added and the reaction mixture stirred at rt for 90 min. A solution of methanamine (2 mL, 16.0 mmol; 8.0 M solution in ethanol; [CAS RN 74-89-5]) was added and stirring at rt continued overnight. The crude reaction mixture was concentrated under reduced pressure and redissolved in dry DMF (2 mL). To this solution were added DIPEA (50 µL, 0.29 mmol), TBTU (47.2 mg, 0.15 mmol; [CAS RN 125700-67-6]) and oxetane-3-carboxylic acid (7.0 µL, 0.098 mmol; [CAS RN 114012-41-8]) and the reaction mixture stirred at rt for 2 h under an atmosphere of nitrogen. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile- water provided the title compound as light brown solid (20 mg, 39 %). MS: m/e = 521.3 [M+H]+.
  • 11
  • [ 114012-41-8 ]
  • [ 6638-79-5 ]
  • [ 1935978-87-2 ]
YieldReaction ConditionsOperation in experiment
14% With 1,1'-carbonyldiimidazole In dichloromethane at 25℃; for 12h; 40.1 Step 1: N-methoxy-N-methyl-oxetane-3-carboxamide A mixture of oxetane-3-carboxylic acid (300 mg, 2.94 mmol), Ι,Γ-carbonyldiimidazole (524 mg, 3.23 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (286 mg, 2.94 mmol) in dichloromethane (8 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by preparative TLC (60% ethyl acetate in petroleum ether, Rf= 0.3) to give N-methoxy-N-methyl- oxetane-3-carboxamide (60 mg, 14%) as a colorless oil. H NMR (400 MHz, CDCl3) δ 4.92 - 4.89 (m, 2H), 4.80 - 4.76 (m, 2H), 4.19 - 4.13 (m, 1H), 3.63 (s, 3H), 3.21 (s, 3H).
With 1,1'-carbonyldiimidazole In dichloromethane at 25℃; for 16h; 16.1 Step 1: N-Methoxy-N-methyloxetane-3-carboxamide Step 1: N-Methoxy-N-methyloxetane-3-carboxamide[0323][0324]To a solution of oxetane-3-carboxylic acid (0.500 g, 4.90 mmol) and N, O-dimethylhydroxylamine hydrochloride (0.478 g, 4.9 mmol) in DCM (10 mL) was added 1, 1-carbonyldiimidazole (0.874 g, 5.4 mmol) . The reaction mixture was stirred at 25 for 16 h. Then the reaction mixture was diluted with brine (5 mL) and extracted with ethyl acetate (3 x 5 mL) . The combined organic layers were washed with water (2 x 5 mL) , brine (2 x 5 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using gradient1-99of ethyl acetate in petroleum ether as eluent. The fractions containing desired product were combined and concentrated. The title compound was obtained as a liquid. MS (+ESI) m/z 146.2.
With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 16h; Inert atmosphere; 1.42.a 1.42 Scheme for preparation of tert-butyl 5-bromo-3-(oxetan-3-yl)indazole -1-carboxylate a. Preparation of N-methoxy-N-methyl-oxetane-3-carboxamide [0224] To a solution of oxetane-3-carboxylic acid (0.9 g, 8.82 mmol, 1 eq.) and N-methoxymethan amine; hydrochloride (859.93 mg, 8.82 mmol, 1 eq.) in DCM (20 mL) was added CDI (1.72 g, 10.58 mmol, 1.2 eq.) in portions at 20 °C under nitrogen. The reaction mixture was stirred at 20 °C for 16 h. TLC (PE:EtOAc=0:1) showed the starting material was consumed completely. The reaction was washed with 1N HCl (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (0.9 g, 5.58 mmol, 63.30% yield, 90% purity) as yellow liquid, which was used to next step without purification.
  • 12
  • [ 114012-41-8 ]
  • [ 2057507-67-0 ]
  • [ 2057509-95-0 ]
YieldReaction ConditionsOperation in experiment
32% With triethylamine; HATU In N,N-dimethyl acetamide at 17 - 25℃; for 16h; 19 N-((1R,3S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide HATU (118 mg, 0.31 mmol) was added to a solution of oxetane-3-carboxylic acid (32 mg, 0.31 mmol), (1S,3R)-3-amino-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide (100 mg, 0.26 mmol; prepared according to Example 14), and triethylamine (0.11 mL, 0.77 mmol) in DMA (2 mL). The mixture was stirred at r.t. for 16 h before being quenched with water (20 mL). The mixture was then extracted with DCM (50 mL), and the organic layer was washed with saturated aqueous sodium chloride (50 mL) before being passed through a phase separation cartridge. The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were concentrated under reduced pressure to afford N-((1R,3 S)-3-((5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide (39 mg, 32%) as a solid. 1H NMR (500 MHz, DMSO-d6, 30° C.) 1.06-1.14 (1H, m), 1.62-1.75 (9H, m), 1.72-1.81 (3H, m), 1.92 (1H, br. d), 2.59-2.7 (1H, m), 2.90 (2H, s), 3.56-3.73 (2H, m), 3.95 (2H, s), 4.53-4.66 (4H, m), 7.80 (1H, d), 8.00 (1H, s), 8.25 (1H, s), 8.35 (1H, s), 10.56 (1H, s). m/z: ES+[M+H]+ 472.
  • 13
  • [ 114012-41-8 ]
  • [ 2057507-90-9 ]
  • [ 2057509-91-6 ]
YieldReaction ConditionsOperation in experiment
19% With triethylamine; HATU In N,N-dimethyl-formamide at 17 - 25℃; for 4h; 18 N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide HATU (77 mg, 0.20 mmol) was added to a solution of oxetane-3-carboxylic acid (25 mg, 0.24 mmol), (1S,3R)-3-amino-N-(4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide (72 mg, 0.20 mmol; prepared according to Example 16), and triethylamine (0.085 mL, 0.61 mmol) in DMF (1 mL). The mixture was stirred at r.t. for 4 hh and then purified directly by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were concentrated under reduced pressure to afford N-((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide (17 mg, 19%) as a solid. 1H NMR (400 MHz, DMSO-d6, 30° C.) 1.06-1.17 (1H, m), 1.26-1.39 (9H, m), 1.77-1.86 (3H, m), 1.91-1.94 (1H, br d), 2.57-2.7 (1H, m), 2.93 (2H, s), 3.54-3.76 (2H, m), 3.90 (2H, s), 4.4-4.71 (4H, m), 7.21 (1H, dd), 7.82 (1H, d), 7.96 (1H, s), 8.21-8.24 (2H, m), 10.33 (1H, s). m/z: ES+[M+H]+ 438.
  • 14
  • [ 114012-41-8 ]
  • [ 2057513-88-7 ]
  • [ 2057513-94-5 ]
YieldReaction ConditionsOperation in experiment
47% With triethylamine; HATU In dichloromethane; N,N-dimethyl-formamide at 17 - 25℃; for 4h; 76 Preparation of N-((1R,3S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide HATU (219 mg, 0.58 mmol) was added to a solution of (1S,3R)-3-amino-N-(4-iodo-5-methylpyridin-2-yl)cyclohexanecarboxamide dihydrochloride (228 mg, 0.53 mmol; prepared according to Example 75), oxetane-3-carboxylic acid (59 mg, 0.58 mmol), TEA (0.24 mL, 1.7 mmol), DCM (2.8 mL) and DMF (2.8 mL) to give a colorless solution. The reaction turned yellow over time; after 4 h at r.t., the reaction was concentrated under reduced pressure and then diluted with DCM. The mixture was washed with water (3×50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by flash column chromatography, eluting with 0 to 10% MeOH and DCM to afford N-((1R,3 S)-3-((4-iodo-5-methylpyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide (112 mg, 47%) as a white solid. 1H NMR (300 MHz, DMSO-d6, 27° C.) 0.99-1.17 (1H, m), 1.20-1.37 (3H, m), 1.70-1.83 (3H, m), 1.84-1.94 (1H, m), 2.29 (3H, s), 2.54-2.64 (1H, m), 3.55-3.73 (2H, m), 4.54-4.64 (4H, m), 7.81 (1H, d), 8.16 (1H, s), 8.61 (1H, s), 10.45 (1H, s). m/z: ES+[M+H]+ 444.
  • 15
  • [ 114012-41-8 ]
  • [ 2057506-31-5 ]
  • [ 2057511-36-9 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 17 - 25℃; for 3h; 67 N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide HATU (166 mg, 0.44 mmol) and DIPEA (0.18 mL, 1.0 mmol) were added sequentially to a solution of (1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide dihydrochloride (150 mg, 0.34 mmol; prepared according to Example 3 b) and oxetane-3-carboxylic acid (45 mg, 0.44 mmol) in DMF (1.2 mL). The reaction was stirred at r.t. for 3 h before being diluted with saturated aqueous sodium hydrogencarbonate and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude gum was purified by preparative HPLC (Waters XBridge Prep Phenyl OBD column, 5μ silica, 19 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium hydroxide, pH 10) and MeCN as eluents to afford N-((1R,3S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)-oxetane-3-carboxamide (20 mg). (1112) A second reaction was set up as follows: HATU (140 mg, 0.37 mmol) was added to a solution of (1S,3R)-3-amino-N-(5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)cyclohexanecarboxamide dihydrochloride (150 mg, 0.34 mmol), oxetane-3-carboxylic acid (45 mg, 0.44 mmol), DIPEA (0.18 mL, 1.0 mmol) and DMF (1.2 mL). The reaction was stirred at r.t. for 3 h. The reaction was diluted with EtOAc and washed with saturated NaHCO3 and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash silica chromatography, eluting with gradient 80 to 100% EtOAc in hexane, to afford N-((1R,3S)-3-((5-chloro-4-(4, 5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide (50 mg) as a white solid. This residue was combined with the product from the first reaction and repurified by preparative HPLC (Waters XBridge Prep Phenyl OBD column, 5μ silica, 19 mm diameter, 150 mm length) to afford N-((1R,3 S)-3-((5-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)oxetane-3-carboxamide (54 mg, 17%) as a white solid. 1H NMR (300 MHz, CDCl3, 27° C.) 1.10-1.26 (1H, m), 1.37-1.68 (3H, m), 2.17-1.84 (7H, m), 2.37-2.22 (1H, m), 2.57-2.43 (1H, m), 2.95 (2H, t), 3.67 (1H, tt), 3.85-4.00 (1H, m), 4.24 (2H, t), 4.89-4.78 (4H, m), 5.52 (1H, br d), 7.93 (1H, s), 8.27 (1H, s), 8.28 (1H, s), 8.60 (1H, br s). m/z: ES+[M+H]+ 458.
  • 16
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
66% With T3P; triethylamine In tetrahydrofuran at 20℃; for 0.333333h; 22.2 Step 2: 3-phenyl-N-jtrans-3-j(oxetan-3-ylformohydrazido)carbonylj cyclobutyll isoxazole-5-carboxamide: oxetane-3 -carboxylic acid(170 mg, 1.67 mmol, 1.00 eq.), T3P (5.3 g, 8.33 mmol, 5.00 eq., 50%) and TEA (838 mg, 8.3mmol, 5.00 eq.) were added to a solution of 3-phenyl-N-[trans-3-(hydrazinecarbonyl)cyclobutyljisoxazole-5 -carboxamide (500 mg, 1.66 mmol, 1.00 eq.) inTHF (5OmL). The resulting solution was stirred for 20 mm at room temperature, thenquenched by the addition of 200mL of water. The resulting solution was extracted withdichloromethane (3x200mL) and the organic layers combined. The resulting mixture waswashed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue solid was washed with 2mL of methanol to afford 420 mg (66%) of 3-phenyl-N-[trans- 3 -[(oxetan-3-ylformohydrazido)carbonylj cyclobutylj isoxazole-5 -carboxamide as an off-whitesolid; LC-MS (ES, m/z): [M+Hj= 385.0.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In tetrahydrofuran at 20℃; for 0.333333h; 22.2 Step 2: 3-phenyl-N-jtrans-3-j(oxetan-3-ylformohydrazido)carbonylj cyclobutyll isoxazole-5-carboxamide oxetane-3 -carboxylic acid(170 mg, 1.67 mmol, 1.00 eq.), T3P (5.3 g, 8.33 mmol, 5.00 eq., 50%) and TEA (838 mg, 8.3mmol, 5.00 eq.) were added to a solution of 3-phenyl-N-[trans-3-(hydrazinecarbonyl)cyclobutyljisoxazole-5 -carboxamide (500 mg, 1.66 mmol, 1.00 eq.) inTHF (5OmL). The resulting solution was stirred for 20 mm at room temperature, thenquenched by the addition of 200mL of water. The resulting solution was extracted withdichloromethane (3x200mL) and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue solid was washed with 2mL of methanol to afford 420 mg (66%) of 3-phenyl-N-[trans-3 -[(oxetan-3-ylformohydrazido)carbonylj cyclobutylj isoxazole-5 -carboxamide as an off-white solid; LC-MS (ES, m/z): [M+Hj= 385.0.
  • 17
  • [ 114012-41-8 ]
  • [ 1848239-83-7 ]
  • [ 1848240-65-2 ]
YieldReaction ConditionsOperation in experiment
56% With 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.16667h; 52.1 5-phenyl-N-[trans-3-[(oxetan-3-ylformohydrazido)carbonyl]cyclobutyl]isoxazole-3-carboxamide HCTU (1.16 g, 2.78 mmol, 2.00 eq.), oxetane-3-carboxylic acid (141 mg, 1.38 mmol, 1.00 eq.) and DIEA (537 mg, 4.16 mmol, 3.00 eq.) were added to a solution of 5-pheny-N-[trans-3- (hydrazinecarbonyl)cyclobutyl]isoxazole-3-carboxamide (417 mg, 1.39 mmol, 1.00 eq.) in DMF (10 mL) and the mixture was stirred for 70 min at room temperature. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.3 g (56%) of 5- phenyl-N-[fra ,-3-[(oxetan-3-ylformohydrazido)carbonyl]cyclobu†yl]isoxazole-3-carboxaniide as an orange solid. LC-MS ES, m/z): [M+H]+ = 385.1.
  • 18
  • [ 114012-41-8 ]
  • [ 2100845-95-0 ]
  • [ 2100845-96-1 ]
YieldReaction ConditionsOperation in experiment
64% With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; triethylamine In acetonitrile at 20℃; for 15h; Inert atmosphere; 5.1.9.3.4. (S)-N-(1-(Cyclobutylamino)-5-(oxetane-3-carboxamido)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (36). General procedure: Following the general procedure E describedabove, the crude amine 85 (20 mg, 0.04 mmol) and 3-oxetanecarboxylicacid (6 mg, 0.06 mmol) was used to give 36 (15 mg, 64%) as a whitesolid; 1H NMR (200 MHz, CDCl3) δ 1.40-2.80 (m, 19H), 3.60-3.90 (m,2H), 4.10-4.50 (m, 3H), 4.70-5.00 (m, 4H). 6.32 (br s, 1H), 6.71 (s, 1H),7.18 (br s, 1H), 7.28-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.90(m,1H), 8.15 (d, J = 8.8 Hz, 1H); LCMS (ESI) m/z: Calcd. forC29H36F3N5O4 575.27 [M]+, found: 576.2 [M+H]+.
64% With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; triethylamine In acetonitrile at 20℃; for 15h; Inert atmosphere; 5.1.9.3.4. (S)-N-(1-(Cyclobutylamino)-5-(oxetane-3-carboxamido)-1-oxopentan-3-yl)-1-cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide (36). General procedure: Following the general procedure E describedabove, the crude amine 85 (20 mg, 0.04 mmol) and 3-oxetanecarboxylicacid (6 mg, 0.06 mmol) was used to give 36 (15 mg, 64%) as a whitesolid; 1H NMR (200 MHz, CDCl3) δ 1.40-2.80 (m, 19H), 3.60-3.90 (m,2H), 4.10-4.50 (m, 3H), 4.70-5.00 (m, 4H). 6.32 (br s, 1H), 6.71 (s, 1H),7.18 (br s, 1H), 7.28-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.90(m,1H), 8.15 (d, J = 8.8 Hz, 1H); LCMS (ESI) m/z: Calcd. forC29H36F3N5O4 575.27 [M]+, found: 576.2 [M+H]+.
6 mg With N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate; triethylamine In acetonitrile at 20℃; for 18h; (5)-N-(l-(cyclobutylamino)-5-(oxetane-3-carboxamido)-l-oxopentan-3-yl)-l- cyclopentyl-5-(2-(trifluoromethyl)phenyl)-lH-pyrazole-3-carboxamide: (5)-N-(l-(cyclobutylamino)-5-(oxetane-3-carboxamido)-l-oxopentan-3-yl)-l- cyclopentyl-5-(2-(trifluoromethyl)phenyl)-lH-pyrazole-3-carboxamide: To a solution of (5)-N-(5- amino-l-(cyclobutylamino)- l-oxopentan-3-yl)-l-cyclopentyl-5-(2-(trifluoromethyl)phenyl)- lH- pyrazole-3-carboxamide (30 mg, 0.061 mmol) and 3-oxetanecarboxylic acid (13 mg, 0.122 mmol) in ACN (2 mL) was added anhydrous NEt3 (0.018 mL, 0.183 mmol) followed by TBTU (39 mg, 0.122 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with sat. NaHC03 (5 mL). The organic phase was extracted, added silica gel (100 mg) and purified using Combiflash Rf (EtOAc/hexanes) and the fractions containing the product (TLC) were pooled and evaporated to afford(S)-N-(l-(cyclobutylamino)-5-(oxetane-3-carboxamido)- l-oxopentan-3-yl)- l-cyclopentyl-5-(2-(trifluoromethyl)phenyl)- lH-pyrazole-3-carboxamide(6 mg) as a white solid; lH NMR (200 MHz, CDC1 ): δ 1.40-2.80 (m, 19H), 3.60-3.90 (m, 2H), 4.10-4.50 (m, 3H), 4.70-5.00 (m, 4H). 6.32 (br s, 1H), 6.71 (s, 1H), 7.18 (br s, 1H), 7.28-7.40 (m, 1H), 7.50-7.70 (m, 2H), 7.70-7.90 (m, 1H), 8.15 (d, 1H, = 8.8 Hz); LC-MS (ESI): m/z calculated for C29H37F3N504 [M+H+] : 576, Found: 576.2.
  • 19
  • [ 114012-41-8 ]
  • [ 1834480-75-9 ]
  • [ 1834481-72-9 ]
YieldReaction ConditionsOperation in experiment
23% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h; 118.1 Step 1 (Synthesis of 118) Step 1 (Synthesis of 118) (0629) Compound 118-1 (80 mg, 171.9 μmol, 1.0 eq.), 118-2 (35 mg, 343.8 μmol, 2.0 eq.) were dissolved in anhydrous DMF (2 mL), and at 20° C. were sequentially added HATU (130 mg, 343.8 umol, 2.0 eq.), TEA (87 mg, 859.6 umol, 5.0 eq.). After the addition, the mixture was stirred for 2 hours. With TLC showing completion of the reaction, the reaction mixture was quenched with water (10 mL), and extracted with DCM (20 mL) for 3 times. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by instrumental separation (aqueous ammonia system), to obtain 22 mg Example 118 as yellow solid, yield: 23%. (0630) NMR data of Example 118: 1H NMR (400 MHz, CDCl3) δ: 7.83 (d, J=3.3 Hz, 1H), 7.44-7.40 (m, 1H), 7.37 (dd, J=2.5, 8.3 Hz, 1H), 7.12 (dd, J=6.0, 8.8 Hz, 1H), 6.98 (dt, J=2.5, 8.3 Hz, 1H), 6.19-6.16 (m, 1H), 5.12 (d, J=16.1 Hz, 1H), 5.01-4.79 (m, 6H), 4.25-4.01 (m, 5H), 3.74-3.62 (m, 1H), 1.23-1.12 (m, 3H). (0631) LCMS (ESI) m/z: 551.1 [M+H+].
  • 20
  • [ 114012-41-8 ]
  • [ 2101217-44-9 ]
  • [ 2101211-61-2 ]
YieldReaction ConditionsOperation in experiment
41% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; 136 (R)-5-(2-methyl-4-phenoxyphenyl)-N-(1-(oxetane-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide A solution of (R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- thia-3,5,8-triazaacenaphthylene-2-carboxamide (Example 869, 100 mg, 0.2 mmol), oxetane-3- carboxylic acid (30 mg, 0.29 mmol), triethylamine (40 mg, 0.40 mmol), and HATU (150 mg, 0.40 mmol) in DMF (5 mL) was reacted at rt for 2 h, quenched with H20 (10 mL), extracted with DCM, dried over anhydrous Na2SC>4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound as an off white solid (48 mg, 41% yield). MS (ESI): mass calcd. for C31H29N5O5S, 583.7; m/z found, 584.2 [M+H]+.1H NMR (400 MHz, CD3OD and DMSO-d6): δ 8.41-8.34 (m, 1H), 7.50-7.41 (m, 2H), 7.38-7.33 (m, 1H), 7.27-7.18 (m, 1H), 7.17-7.09 (m, 3H), 7.06-6.97 (m, 1H), 6.12-6.05 (m, 1H), 5.08-4.89 (m, 1H), 4.89-4.75 (m, 4H), 4.28-4.18 (m, 1H), 4.04-3.78 (m, 1H), 3.68-3.38 (m, 1H), 3.01-2.93 (m, 1H), 2.85-2.75 (m, 1H), 2.20-2.11 (m, 3H), 2.09-2.03 (m, 1H), 1.93-1.81 (m, 1H), 1.76-1.64 (m, 1H), 1.63-1.52 (m, 1H).
41% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h; 136 Example 136: (R)-5-(2-Methyl-4-phenoxyphenyl) -N-(1- (oxetane-3-carbonyl) piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide . A solution of (R)-5-(2-methyl-4-phenoxyphenyl) -4-oxo-N-(piperidin-3-yl) -4,5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide (Example 869, 100 mg, 0.2 mmol), oxetane-3-carboxylic acid (30 mg, 0.29 mmol), triethylamine (40 mg, 0.40 mmol), and HATU (150 mg, 0.40 mmol) in DMF (5 mL) was reacted at rt for 2 h, quenched with H 2O (10 mL), extracted with DCM, dried over anhydrous Na 2SO 4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography to yield the title compound as an off white solid (48 mg, 41% yield). MS (ESI) : mass calcd. for C 31H 29N 5O 5S, 583.7 m/z found, 584.2 [M+H] +. 1H NMR (400 MHz, CD 3OD and DMSO-d 6) : δ 8.41-8.34 (m, 1H), 7.50-7.41 (m, 2H), 7.38-7.33 (m, 1H), 7.27-7.18 (m, 1H), 7.17-7.09 (m, 3H), 7.06-6.97 (m, 1H), 6.12-6.05 (m, 1H), 5.08-4.89 (m, 1H), 4.89-4.75 (m, 4H), 4.28-4.18 (m, 1H), 4.04-3.78 (m, 1H), 3.68-3.38 (m, 1H), 3.01-2.93 (m, 1H), 2.85-2.75 (m, 1H), 2.20-2.11 (m, 3H), 2.09-2.03 (m, 1H), 1.93-1.81 (m, 1H), 1.76-1.64 (m, 1H), 1.63-1.52 (m, 1H).
  • 21
  • [ 114012-41-8 ]
  • [ 2168558-98-1 ]
  • [ 2168532-76-9 ]
YieldReaction ConditionsOperation in experiment
0.05 g Stage #1: oxetane-3-carboxylic acid With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 15h; Stage #2: 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; 8.2 Step 2[0042j: To a solution of 3-oxetanecarboxylic acid [0041j (0.140 g, 1.38 mmol) in N,N-dimethylformamide was added 1-propanephosphonic acid cyclic anhydride ((1.3 17 g, 2.07 mmol), triethylamine (0.209 g, 2.07 mmol) at 0 °C and the reaction mixture was stirred at rt. After 15 mm, 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-amine [0040j (0.26 g, 0.69 mmol) was added to the reaction mixture at 0 °C and stirred at ft for 16 h. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford brown oil, which was purified in the Reveleris flash system using ethyl acetate in hexane followed by methanol in chloroform as eluents in 12 g column. The product was isolated at 07 % methanol in chloroform as eluent to afford N-((6-((4,4- difluorocyclohexyl)amino)-2-(3 -(fluoromethyl)- 1 H-pyrazol- 1 -yl)pyrimidin-4- yl)methyl)oxetane-3-carboxamide, Compound 333 [0042] as a white solid (0.05 g). MS(M+1)=425.2; ‘H NMR (400 MHz, DMSO-d6) 8.63 (bs, 1H), 8.54 (bs, 1H), 7.82 (s, 1H), 6.66 (s, 1H), 6.24 (s, 1H), 5.45 (d, IF = 48 Hz, 1H), 4.69 (d, I = 7.9 Hz, 4H), 4.19 (s, 3H), 3.92 - 3.82 (m, 1H), 2.12 - 1.92 (m, 7H), 1.57 (bs, 2H).
  • 22
  • [ 114012-41-8 ]
  • [ 1631137-51-3 ]
  • [ 1448188-80-4 ]
YieldReaction ConditionsOperation in experiment
53% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h;
  • 23
  • [ 114012-41-8 ]
  • [ 2209076-54-8 ]
  • [ 2209076-59-3 ]
YieldReaction ConditionsOperation in experiment
23.4% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 2h; B9 PREPARATION OF COMPOUND 95 To a solution of oxetane-3-carboxylic acid (35.0 mg, 0.335 mmol) in DCM (10 mL) was added HOBt (68.0 mg, 0.502 mmol), EDCI (96 mg, 0.502 mmol) and TEA (0.28 ml, 2.00 mmol). After stirring at room temperature, Compound 70C (300 mg, 0.335 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to give a residue which was purified by prep-HPLC (Waters 2767/Qda, Column: Waters Xbridge 19* 150mm lOum, Mobile Phase A: H20 (0794) (0.1%NH4OH), B: ACN) to yield Compound 95 (41 mg, 23.4% yield) as a white solid. (0795) ΝΜΡν CDsOD (400 MHz): δ 8.29 (s, 1H), 7.64 (s, 1H), 4.86-4.80 (m, 4H), 4.54-4.51 (m, 1H), 4.23-4.15 (m, 1H), 4.05-3.98 (m, 1H), 3.94-3.86 (m, 3H), 3.79-3.75 (m, 2H), 3.49-3.45 (m, 1H), 3.06-2.99 (m, 1H), 2.74-2.46 (m, 6H), 2.28-2.21 (m, 3H), 1.87-1.84 (m, 4H), 1.66-1.63 (m, 1H), 1.13-1.02 (m, 2H).
  • 24
  • [ 6246-06-6 ]
  • [ 114012-41-8 ]
YieldReaction ConditionsOperation in experiment
86% With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium hydrogencarbonate; potassium bromide In dichloromethane; water at 0 - 20℃; for 13h; 1.5 (5) 3-oxetane methanol to prepare 3-oxetanecarboxylic acid, the specific reaction formula is as follows: The white solid obtained in the step (4) (50 g, 0.57 mol) was dissolved in dichloromethane (1.2 L), and aqueous potassium bromide (13 g, 0.12 mol, water 430 mL) was added.Tempo (1.5 g, 0.012 mol), aqueous potassium hydrogencarbonate (115 g, 1.2 mol), stirred for 10 min after the addition.The system was ice-cooled, cooled to 0-5 ° C, and slowly added sodium hypochlorite aqueous solution (10%, 800 mL) to keep the system temperature below 10 ° C.After the completion of the dropwise addition, the temperature was maintained for 3 hours, and the temperature was naturally raised, and the reaction was continued at room temperature for 10 hours.After completion of the reaction, excess sodium hypochlorite was quenched with aqueous sodium thiosulfate (71 g, 0.29 mol, water 120 mL).The reaction system was adjusted to a pH of more than 12 with a 50% aqueous sodium hydroxide solution, and the aqueous phase was extracted once more with dichloromethane.The two dichloromethanes were discarded.The aqueous phase is adjusted to pH less than 2 with hydrochloric acid, then extracted three times with dichloromethane, and the organic phase is combined three times.The organic layer was concentrated to give 42 g of the desired compound, 3-oxetanecarboxylic acid, yield 86%.
81% With Dess-Martin periodane In dichloromethane at 20℃; for 2h; Cooling with ice; 1.6 (6) Preparation of 3-oxetanecarboxylic acid from 3-oxetane methanol, The specific reaction formula is as follows: The target obtained in the step (5) (20 g, 0.23 mol)Soluble in dichloromethane (2L),Ice bath, stirring,One part was added to Dess Martin oxidant (195g, 0.46mol).The system was naturally warmed to room temperature and stirring was continued for 2 hours.10% sodium thiosulfate (200 mL) was added dropwise.Add 2L of water,Layering, extracting the aqueous phase with dichloromethane, combining the organic phases,Washed three times,Washed with saturated brine, dried, concentrated,The residue was dissolved in 50 mL of petroleum ether.Ice bath,1 mL of ethyl acetate was added dropwise with stirring.After half an hour of filtration, 19 g of a white powder was obtained in a yield of 81%.
55% With ruthenium trichloride; sodium periodate In water; acetonitrile at 20℃; for 20h;
  • 25
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ 2089722-00-7 ]
YieldReaction ConditionsOperation in experiment
60% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h; 6 Example 6: Preparation of Compound I To a 100 mL reaction flask were sequentially added the above-obtained amine 8' (1 mmol), carboxylic acid (1 mmol, 1 eq.), condensation reagent HATU (1.2 mmol, 1.2 eq.) and solvent DMF (20 ml). A solution of DIEA (2 mmol, 2 eq.) in 5 ml of DMF was added dropwise with stirring at room temperature, and after addition the reaction was allowed to react for 2 hours with stirring at room temperature. The reaction mixture was diluted with ethyl acetate (150 m), washed with saturated aqueous sodium chloride (40 mL×4), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The final product I was obtained by flash column chromatography.
  • 26
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ 2231210-12-9 ]
YieldReaction ConditionsOperation in experiment
31.3% Stage #1: oxetane-3-carboxylic acid With triethylamine; HATU In dichloromethane at 20℃; for 1h; Stage #2: C13H18N2O*C2HF3O2 In dichloromethane at 20℃; for 16h; 10 Example 10. Synthesis of Compounds 21-Entl and 21-Ent2 A mixture of oxetane-3-carboxylic acid (78 mg, 0.76 mmol, 1.2 eq.); HATU (395 g, 0.95 mmol, 1.5 eq.) and TEA (191 mg, 1.89 mmol, 3.0 eq.) in DCM (5 mL) was stirred at 20 °C for 1 h. Then compound 12-J (200 mg racemate, 0.63 mmol, 1.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS showed the reaction was complete. The mixture was purified by prep-TLC (EtOAc) to give the racemic product (60 mg, 31.3% yield) as yellow oil which was further separated by SFC (Mobile phase: Supercritical C02/MeOH with 0.1% NH3.H20; Column: Chiralpak OD(250mm*30mm, 10 urn); Detection wavelength: 220 nm) to give single enantiomer 21-Entl (Rt = 5.034 min, 8.0 mg, 13.3% yield) as a white solid and single enantiomer 21-Ent2 (Rt = 5.754 min, 7.6 mg, 12.7% yield) as a white solid. The absolute stereochemistry for both enantiomers was not determined. Data for 21-Entl (0883) LCMS: (M+H: 303.2) (0884) HPLC: (98.95% purity) (0885) SFC: (ee%: 99.64%) (0886) 1HNMR: (400 MHz, MeOD) δ: 7.81 (s, 0.58H), 7.73 (s, 0.34H), 4.88 - 4.72 (m, 4H), 4.53 (d, = 12.6 Hz, 0.74H), 4.36 - 4.26 (m, 1H), 3.63 (d, = 11.8 Hz, 0.77H), 3.43 (d, = 12.0 Hz, 0.44H), 3.09 - 2.93 (m, 1H), 2.60 (d, = 12.8 Hz, 1H), 2.12 - 2.03 (m, 1H), 1.77 - 1.63 (m, 2H), 1.25 - 1.19 (m, 5H), 1.17 (s, 1H), 1.09 (s, 3H). (0887) Data for 21-Ent2 (0888) LCMS: (M+H: 303.2) (0889) HPLC: (98.32% purity) (0890) SFC: (ee%: 100%) (0891) 1HNMR: (400 MHz, MeOD) δ: 7.81 (s, 0.6H), 7.73 (s, 0.35H), 4.88 - 4.72 (m, 4H), 4.53 (d, = 12.6 Hz, 0.7H), 4.32 - 4.22 (m, 1H), 3.63 (d, = 13.6 Hz, 0.75H), 3.43 (d, = 13.0 Hz, 0.48H), 3.08 - 2.95 (m, 1H), 2.60 (d, J = 12.6 Hz, 1H), 2.13 - 2.02 (m, 1H), 1.78 - 1.63 (m, 2H), 1.24 - 1.19 (m, 5H), 1.17 (s, 1H), 1.09 (s, 3H).
  • 27
  • [ 1638760-80-1 ]
  • [ 114012-41-8 ]
YieldReaction ConditionsOperation in experiment
83.7% With ethanol; potassium hydroxide for 1h; Reflux; Large scale; 3.3 3. Hydrolysis reaction 1 kg of compound 3 was added to a solution of potassium hydroxide in ethanol (1010 g of potassium hydroxide, 7.3 L of ethanol) at room temperature, and the mixture was heated to reflux for 1 hour, and detected by TLC. After the reaction was completed, the reaction mixture was concentrated, and 5 L of water was added. The pH of the hydrochloric acid was adjusted to 2, ethyl acetate was evaporated, and the organic phase was combined, washed with brine, dried over sodium sulfate, and concentrated to afford 740 g of compound 4 (3-oxetanecarboxylic acid), yield 83.7%.
  • 28
  • [ 114012-41-8 ]
  • [ 2251711-97-2 ]
  • [ 2251712-10-2 ]
YieldReaction ConditionsOperation in experiment
12% Stage #1: oxetane-3-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 5-{6-[2-(4-bromo-phenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-N-hydroxy-thiophene-2-carboxamidine In N,N-dimethyl-formamide at 20 - 120℃; I.142 Example 142 : [2-(4-Bromo-phenyl)-ethyl]-{6-[4-ethoxy-5-(5-oxetan-3-yl-[1,2,4]oxadiazol-3-yl)-thiophen-2- yl]-pyrimidin-4-yl}-amine Oxetane-3-carboxylic acid (9.27 mg, 0.0908 mmol) is dissolved in DMF (0.746 mL) and TBTU (29.2 mg, 0.0908 mmol) and DIPEA (0.0311 mL, 0.182 mmol) are added in succession. After 5min stirring at RT, 5-{6-[2-(4-bromo- phenyl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-N-hydroxy-thiophene-2-carboxamidine (Example 129, 40 mg, 0.0606 mmol) is added and the RM is stirred at RT overnight, then at 120°C for 1 h40min. Once cooled at RT, the RM is purified directly by prep. HPLC, affording the title compound as a yellow solid (4 mg, 12%). LC-MS B: tR = 0.95 min; [M+H]+ = 527.95.
  • 29
  • [ 114012-41-8 ]
  • [ 2304684-61-3 ]
  • [ 2304685-19-4 ]
YieldReaction ConditionsOperation in experiment
1.2 mg Stage #1: C25H31FN6O3 With trifluoroacetic acid In dichloromethane at 20℃; for 0.5h; Stage #2: oxetane-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; 115 Example 115: Synthesis of Compound SL-E49 Compound SL-E2 (10 mg) was dissolved in 3 mL dichloromethane (DCM) and 1 mLTrifluoroacetic acid (TFA), stirred at room temperature for 30 min, and the solvent was concentrated to dryness.Dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA),Add HATU (30 mg) and oxetane-3-carboxylic acid (9 mg) at room temperature.After 1 h of reaction, TLC showed the end of the reaction, and the reaction mixture was poured into water and extracted with ethyl acetate.Dried and concentrated, separated by column chromatography,The title compound SL-E49 (1.2 mg) was obtained.
  • 30
  • [ 114012-41-8 ]
  • [ 2304684-73-7 ]
  • [ 2304684-80-6 ]
YieldReaction ConditionsOperation in experiment
1.5 mg With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; 87 Example 87: Synthesis of Compound SL-E19 Compound SL-E12 (19 mg, 0.05 mmol) was dissolved in 1 mL DMF and 0.1 mL of diisopropylethylamine (DIEPA), stir and dissolve, add at room temperatureHATU (38 mg, 0.1 mmol) and acid(oxetane-3-carboxylic acid) (10 mg, 0.1 mmol), reaction for 1 h,TLC showed the end of the reaction, the reaction solution was poured into water, and a large amount of ethyl acetate was extracted.Dried and concentrated, separated by column chromatography,The title compound SL-E19 (1.5 mg) was obtained.
  • 31
  • [ 114012-41-8 ]
  • [ 2304683-87-0 ]
  • [ 2304684-69-1 ]
YieldReaction ConditionsOperation in experiment
2.5 mg With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; 76 Example 76: Synthesis of Compound SL-E8 Compound E-Y10 (20 mg) was dissolved in 1 mL DMF and 0.1 mL diisopropylethylamine(DIEPA), stir and dissolve, add HATU (38mg, 0.1mmol) at room temperatureAnd acid(oxetane-3-carboxylic acid)(10 mg, 0.1 mmol), reacted for 1 h, TLC showed the reaction was completed.The reaction solution was poured into water, extracted with a large amount of ethyl acetate, and dried and concentrated.The title compound SL-E8 (2.5 mg) was obtained by column chromatography.
  • 32
  • [ 114012-41-8 ]
  • [ 2304683-78-9 ]
  • [ 2304684-98-6 ]
YieldReaction ConditionsOperation in experiment
0.7 mg Stage #1: C24H27FN6O3 With palladium 10% on activated carbon In methanol at 20℃; for 3h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 0.5h; Stage #3: oxetane-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; 105 Example 105: Synthesis of Compound SL-E39 Compound E-Y3 (10 mg) was dissolved in 2 mL of methanol.Add 10% Pd/C (4 mg) for 3 hours at room temperature, filter through celite, and spin the filtrate.Dissolved in 3 mL of dichloromethane (DCM) and 1 mL of trifluoroacetic acid (TFA).Stir at room temperature for 30 min, and concentrate the solvent after drying.Dissolved again in 1 mL DMF and 0.1 mL diisopropylethylamine (DIEPA).Add HATU (15 mg) and oxetane-3-carboxylic acid (9 mg) at room temperature.After reacting for 1 h, the reaction solution was poured into water, extracted with a large amount of ethyl acetate, and dried and concentrated.The title compound SL-E39 (0.7 mg) was obtained by column chromatography.
  • 33
  • [ 114012-41-8 ]
  • [ 2311944-56-4 ]
  • [ 2311941-63-4 ]
YieldReaction ConditionsOperation in experiment
31% Stage #1: oxetane-3-carboxylic acid With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In dichloromethane at 0 - 20℃; for 1h; Stage #2: 4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2h; 1 Example 1 (0423) N- { 3- [3-(4-Chlorophenyl)- 1 - { [ 1 -(3-chloropyridin-2-yl)- 1 H- 1 ,2,4-triazol-3-yl] methyl } -5-oxo- 1 dihydro-4H- 1 ,2,4-triazol-4-yl] -1,1,1 -trifluoropropan-2-yl } oxetane-3-carboxamide (Racemate) At 0°C, a solution of oxetane-3-carboxylic acid (153 mg, 1.50 mmol) in dichloromethane (4.3 ml) was treated with l-chloro-N,N,2-trimethylprop-l -en- 1 -amine (320 μ, 2.4 mmol) and stirred 1 h at room temperature. 4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{ [l-(3-chloropyridin-2- yl)-lH-l,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (Example 11 A, 150 mg, 300 μιηο), N,N-diisopropylethylamine (370 μ, 2.1 mmol) and 4-dimethylaminopyridine (184 mg, 1.50 mmol) were added to the reaction mixture at 0°C. The resulting mixture was stirred 2 h at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 54.1 mg (31% of th.) of the title compound. (0425) LC-MS (Method 3): Rt = 1.54 min; MS (ESIpos): m/z = 583.1 [M+H]+ (0426) -NMR (400 MHz, DMSO-d6) δ [ppm] : 9.05 (s, 1H), 8.73-8.48 (m, 2H), 8.29 (dd, 1H), 7.80-7.50 (m, 5H), 5.24-5.01 (m, 2H), 4.85-4.63 (m, 1H), 4.62-4.35 (m, 4H), 4.23 (dd, 1H), 4.00 (dd, 1H), 3.73-3.50 (m, 1H).
  • 34
  • [ 114012-41-8 ]
  • [ 2364603-00-7 ]
  • [ 2364602-77-5 ]
YieldReaction ConditionsOperation in experiment
11% Stage #1: oxetane-3-carboxylic acid With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.666667h; Inert atmosphere; Stage #2: 4-(7-morpholinoquinazolin-5-yl)oxycyclohexanamine In N,N-dimethyl-formamide 1 Preparation of Compound 34: N-((1s,4s)-4-((7-morpholinoquinazolin-5- yl)oxy)cyclohexyl)oxetane-3-carboxamide 1-hydroxybenzotriazole monohydrate (18 mg, 0.133 mmol), 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (Hydrochloric Acid (1) (38 mg, 0.198 mmol), and oxetane-3-carboxylic acid (13 mg, 0.127 mmol) and triethylamine (15 µL, 0.1076 mmol) were combined in DMF (1 mL) under nitrogen at room temperature and allowed to stir for 40min.4-(7-morpholinoquinazolin-5- yl)oxycyclohexanamine (27 mg, 0.0822 mmol) was added, and the reaction was allowed to stir overnight. Saturated sodium bicarbonate was added and extracted with EtOAc (2x). The combined organics were washed with water (2x), brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography over 4g silica gel using a 0-10% methanol/DCM gradient to yield N-((1s,4s)-4-((7-morpholinoquinazolin-5-yl)oxy)cyclohexyl)oxetane-3- carboxamide (4mg, 11% yield). 1H NMR (300 MHz, CDCl3) δ 9.42 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 6.79 (d, J = 1.9 Hz, 1H), 6.57 (d, J = 2.1 Hz, 1H), 5.51 (d, J = 8.1 Hz, 1H), 4.95 - 4.72 (m, 5H), 4.10 - 3.84 (m, 5H), 3.70 (tt, J = 8.3, 6.7 Hz, 1H), 3.39 (dd, J = 5.8, 4.0 Hz, 5H), 2.30 - 2.15 (m, 3H), 1.98 - 1.58 (m, 4H). ESI-MS m/z = 413.46 (M+1)+.
  • 35
  • [ 114012-41-8 ]
  • [ 2364571-27-5 ]
  • [ 2364565-45-5 ]
YieldReaction ConditionsOperation in experiment
49% With triethylamine; sodium iodide In acetone at 70℃; for 16h; 21 Example 21: 1- (oxetane-3-carboxyloyloxy) ethyl (S) -1- (2-chlorophenyl) -2-oxocyclohexylmethylcarbamate (A-21) To a solution of compound 2 (86 mg, 0.25 mmol) , NaI (75 mg, 0.5 mmol) and oxetane-3-carboxylic acid (77 mg, 0.75 mmol) in acetone (3 mL) was added Et 3N (0.18 mL, 1.25 mmol) . The reaction was heated to 70 for 16 h. The reaction was concentrated and re-dissolved in DCM (5 mL) , washed with aqueous saturated NaHCO 3 solution (5 mL) and brine (5 mL) . The organic layer was dried over MgSO 4, filtered and concentrated to get an oil, which was purified on silica gel column eluting with hexane/EA (7/3) to afford 40 mg (49%yield) of the titled compound (A-21) as a light yellow oil. [0446] 1HNMR (600 MHz, acetone-d 6) δ = 1.33-1.64 (m, 3H) , 1.68-1.90 (m, 4H) , 2.34-2.53 (m, 2H) , 2.65-2.77 (m, 1H) , 3.04-3.06 (m, 3H) , 3.20-3.34 (m, 1H) , 3.82-3.94 (m, 1H) , 4.55-4.82 (m, 4H) , 6.75-6.82 (m, 1H) , 7.02-7.11 (m, 1H) , 7.26-7.36 (m, 2H) , 7.41-7.48 (m, 1H) . [0447] MS (ESI) : [M + H] + = 409.9.
  • 36
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; 15.C C. Preparation of 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-l-((ls,3s)-3-(3,3- dimethylpyrrolidin- 1 -yl)cyclobutyl)- 1 '-(oxetane-3 -carbonyl)spiro[indoline-3 ,4'- piperidin]-2-one In a flask was placed 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-l-((ls,3s)-3-(3,3-dimethylpyrrolidin-l-yl)cyclobutyl)spiro[indoline-3,4'-piperidin]-2-one (82 mg, 0.14 mmol), oxetane-3-carboxylic acid (17 mg, 0.17 mmol), and DIPEA (0.70 ml, 0.12 mmol) in DMF (1 mL). To this mixture was added HATU (80 mg, 0.21 mmol). The mixture was stirred at room temperature for 1 h, then quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na2S04), concentrated, and purified by reverse phase HPLC to give 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6- yl)-l-((ls,3s)-3-(3,3-dimethylpyrrolidin-l-yl)cyclobutyl)-l'-(oxetane-3-carbonyl)spiro[indoline- 3,4'-piperidin]-2-one.
  • 37
  • [ 114012-41-8 ]
  • [ 2256822-63-4 ]
  • [ 2256822-43-0 ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine In dichloromethane at 0℃; for 0.25h; 49 Step 1: synthesis of the compound WX091 General procedure: The compound BA-3 (300.00 mg, 538.26 μmol, 1.00 eq) was dissolved in dichloromethane (4.00 mL), followed by addition of triethylamine (108.93 mg, 1.08 μmol, 2.00 eq), DMAP (131.52 mg, 1.08 μmol, 2.00 eq) and the compound tert-butylsulfinyl chloride (90.83 mg, 645.91 μmol, 1.20 eq) were added sequentially at 0°C. The reaction was stirred at 0°C for 15 minutes. After completion of the reaction, the reaction mixture was added into water (30 mL) and extracted with dichloromethane (60 mL3). The organic phases were combined and washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness by rotary evaporation to give a crude product. The crude product was purified by preparative TLC (PE/EA=1/2) to give the compound WX091. MS m/z: 662.0 [M+H]+
  • 38
  • [ 114012-41-8 ]
  • [ 2137975-96-1 ]
  • [ 2446685-49-8 ]
YieldReaction ConditionsOperation in experiment
7.18% With N-ethyl-N,N-diisopropylamine; HATU In 1-methyl-pyrrolidin-2-one at 20℃; for 1h; 23 Example 23 Synthesis of 2-(oxetane-3-carboxamido)-l-propyl-lF/-benzo[
  • 39
  • [ 114012-41-8 ]
  • [ 2446310-88-7 ]
  • [ 2446309-15-3 ]
YieldReaction ConditionsOperation in experiment
16.6% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; 15 Synthesis of compound I-45 To a solution of ox etane-3 -carboxylic acid (23.85 mg, 0.234 mmol, 1.20 eq) in DMF (1 mL) were added HATU (148.06 mg, 0.389 mmol, 2.00 eq), DIEA (75.49 mg, 0.584 mmol, 3.0 eq). Then 10.3 (100.00 mg, 0.195 mmol, 1.00 eq) was added in portions at RT. The mixture was stirred for 1 h at RT. Then diluted with 20 mL of water, extracted with 3x20 mL of ethyl acetate and the organic layers were combined and concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, Cl 8 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to yield 26.7mg (16.6%) of 1-45 as a light brown solid. (ES, m/z): 598 (M+H)+; 1H-NMR (300 MHz, DMSO -d6,ppm) d 12.81 (s, 1H), 12.58 (s, 1H), 8.00-7.93 (m, 2H), 7.76-7.75 (d, 1H), 7.54- 7.53 (d, 1H), 7.38-7.35 (d, 2H), 7.09-7.05 (t, 1H), 6.96-6.95 (d, 1H), 6.62 (s, 1H), 4.72-4.53 (m, 6H), 4.34-4.23 (m, 4H), 3.82-3.68 (m, 1H), 2.54 (s, 3H), 2.13 (s, 3H), 1.82-1.73 (m, 4H), 1.32- 1.30 (t, 3H).
  • 40
  • [ 114012-41-8 ]
  • [ 2640025-70-1 ]
  • [ 2640027-59-2 ]
YieldReaction ConditionsOperation in experiment
72% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; 135.a Step a To a stirred solution of HATU (0.42 g, 1.09 mmol) and oxetane-3-carboxylic acid (75 mg, 0.73 mmol) in DMF (3 mL) were added Et3N (0.12 g, 1.09 mmol) and a solution of N- [[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2,2,2-trifluoroacetamide (0.15 g, 0.36 mmol) in DMF (2 mL) at room temperature under nitrogen atmosphere. After stirring for additional 2 h at room temperature, the reaction solution was quenched with water (20 mL) at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford N-[[4,5-dichloro-2-(prop-2-en-1- yloxy)phenyl][1-(oxetane-3-carbonyl)piperidin-4-yl]methyl]-2,2,2-trifluoroacetamide as a yellow solid (0.13 g, 72%): LCMS (ESI) calc’d for C21H23Cl2F3N2O4 [M + H]+: 495, 497 (3 : 2), found 495, 497 (3 : 2).
72% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; 135.a Step a To a stirred solution of HATU (0.42 g, 1.09 mmol) and oxetane-3-carboxylic acid (75 mg, 0.73 mmol) in DMF (3 mL) were added Et3N (0.12 g, 1.09 mmol) and a solution of N- [[4,5-dichloro-2-(prop-2-en-1-yloxy)phenyl](piperidin-4-yl)methyl]-2,2,2-trifluoroacetamide (0.15 g, 0.36 mmol) in DMF (2 mL) at room temperature under nitrogen atmosphere. After stirring for additional 2 h at room temperature, the reaction solution was quenched with water (20 mL) at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford N-[[4,5-dichloro-2-(prop-2-en-1- yloxy)phenyl][1-(oxetane-3-carbonyl)piperidin-4-yl]methyl]-2,2,2-trifluoroacetamide as a yellow solid (0.13 g, 72%): LCMS (ESI) calc’d for C21H23Cl2F3N2O4 [M + H]+: 495, 497 (3 : 2), found 495, 497 (3 : 2).
  • 41
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
3% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at -30 - 0℃; for 2h; 75.b Step b: To a stirred mixture of oxetane-3-carboxylic acid (41 mg, 0.40 mmol) and HATU (0.23 g, 0.61 mmol) in DMF (1 mL) were added 2-[2-(aminomethyl)piperidin-4-yl]-3,4- dichlorophenol cis isomer (0.20 g, 0.40 mmol) and Et3N (81 mg, 0.80 mmol) at -30oC. The reaction mixture was allowed to warm to 0oC and stirred for 2 h. The reaction solution was filtered and the filtrate was purified with Prep-HPLC with the following conditions: Column: Xselect CSH OBD Column 30 x 150 mm 5 μm; Mobile Phase A: Water (plus 0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35% B in 7 min; Detector: UV 254/220 nm; Retention time: 6.42 min. The fractions containing the desired product were collected and concentrated under reduced pressure to afford Compound 104 ((2R,4S)-rel-N-[[4- (2,3-dichloro-6-hydroxyphenyl)piperidin-2-yl]methyl]oxetane-3-carboxamide (cis isomer)) as an off-white solid (5 mg, 3%): LCMS (ESI) calc’d for C16H20Cl2N2O3 [M + H]+: 359, 361 (3 : 2), found 359, 361 (3 : 2);1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.77-8.60 (m, 1H), 8.53-8.34 (m, 1H), 8.20-8.10 (m, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.71- 4.59 (m, 4H), 3.83-3.69 (m, 1H), 3.64-3.46 (m, 2H), 3.31-3.17 (m, 2H), 3.17-2.97 (m, 1H), 2.63- 2.51 (m, 1H), 2.41-2.27 (m, 1H), 1.68 (dd, J = 28.1, 13.6 Hz, 2H).
  • 42
  • [ 114012-41-8 ]
  • [ 2699030-12-9 ]
  • [ 2699029-53-1 ]
YieldReaction ConditionsOperation in experiment
21.8% With triethylamine; HATU In dichloromethane at 20℃; for 18h; 31 Example 31: Synthesis of Compound 4249, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)- N-(3-fluorophenyl)-1-(oxetan-3-carbonyl)piperidine-4-sulfonamide N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)- N-(3-fluorophenyl)piperidine-4-sulfonamide (0.050 g, 0.099 mmol) prepared in step 3 of Example 18, oxetane-3-carboxylic acid (0.020 g, 0.197 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.056 g, 0.148 mmol), and triethylamine (0.028 mL, 0.197 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. An aqueous N-sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, and filtered through a plastic filter to remove a solid residue and an aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 plate, 20 x 20 x 1 mm; methanol/dichloromethane = 0% to 7 %) and concentrated to obtain the title compound (0.013 g, 21.8 %) as a yellow solid. 1H NMR (400 MHz, CDCl 3) δ 8.33-8.28 (m, 1H), 8.24 (dd, J = 1.0, 7.1Hz, 1H), 7.71 (s, 1H), 7.57 (dd, J = 1.7, 7.1Hz, 1H), 7.38-7.20 (m, 3H), 7.10-6.81 (m, 2H), 5.11 (s, 2H), 4.92 (ddd, J = 5.8, 7.1, 16.4 Hz, 2H), 4.81 (dd, J = 5.9, 8.7 Hz, 2H), 4.72 (d, J = 13.8 Hz, 1H), 4.00 (tt, J = 7.1, 8.7 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 3.35 (tt, J = 3.8, 11.6 Hz, 1H), 2.98 (ddd, J = 2.8, 12.2, 14.2 Hz, 1H), 2.66 (td, J = 2.9, 12.9, 13.7 Hz, 1H), 2.20 (d, J = 13.0 Hz, 1H), 1.81 (dtt, J = 6.1, 13.0, 20.0 Hz, 3H); LRMS (ES) m/z 591.0 (M + + 1).
  • 43
  • [ 114012-41-8 ]
  • [ 2699030-15-2 ]
  • [ 2699029-73-5 ]
YieldReaction ConditionsOperation in experiment
10.2% With triethylamine; HATU In dichloromethane at 20℃; for 18h; 51 Example 51: Synthesis of Compound 4269, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-(oxetan-3-carbonyl)- N-phenylpiperazine-1-sulfonamide N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)- N-phenylpiperazine-1-sulfonamide (0.050 g, 0.102 mmol) prepared in step 6 of Example 38, oxetane-3-carboxylic acid (0.016 g, 0.153 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.058 g, 0.153 mmol), and triethylamine (0.043 mL, 0.306 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. An aqueous N-sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove a solid residue and an aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2 plate, 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated, and then the obtained product was again purified by chromatography (SiO 2 plate, 20 x 20 x 1 mm; methanol/1%-dichloromethane aqueous solution = 0% to 7%) and concentrated to obtain the title compound (0.006 g, 10.2 %) as a white solid. 1H NMR (400 MHz, CDCl 3) δ 8.32 (s, 1H), 8.22 (dd, J = 0.9, 7.2 Hz, 1H), 7.71 (s, 1H), 7.56 (dd, J = 1.7, 7.2 Hz, 1H), 7.49-7.42 (m, 2H), 7.40-7.33 (m, 2H), 7.35-7.27 (m, 1H), 6.96 (t, J = 51.7 Hz, 1H), 5.08 (s, 2H), 4.89 (dd, J = 5.9, 7.1Hz, 2H), 4.79 (dd, J = 5.9, 8.7 Hz, 2H), 3.97 (tt, J = 7.0, 8.7 Hz, 1H), 3.64 (t, J = 5.2 Hz, 2H), 3.28-3.10 (m, 6H); LRMS (ES) m/z 574.1 (M + + 1).
  • 44
  • [ 114012-41-8 ]
  • [ 2699030-17-4 ]
  • [ 2699029-93-9 ]
YieldReaction ConditionsOperation in experiment
10.8% With triethylamine; HATU In dichloromethane at 20℃; for 18h; 71 Example 71: Synthesis of Compound 4310, N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)- N-(3-fluorophenyl)-4-(oxetane-3-carbonyl)piperazine-1-sulfonamide N-((7-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)methyl)- N-(3-fluorophenyl)piperazine-1-sulfonamide (0.050 g, 0.099 mmol) prepared in step 3 of Example 58, oxetane-3-carboxylic acid (0.015 g, 0.148 mmol), triethylamine (0.041 mL, 0.296 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.056 g, 0.148 mmol) were dissolved in dichloromethane (1 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. An aqueous N-sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove a solid residue and an aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by chromatography (SiO 2 plate, 20 x 20 x 1 mm; methanol/dichloromethane = 0% to 7 %) and concentrated to obtain the title compound (0.006 g, 10.8 %) as a white solid. 1H NMR (400 MHz, CDCl 3) δ 8.32 (s, 1H), 8.23 (d, J = 7.1Hz, 1H), 7.71 (s, 1H), 7.57 (d, J = 7.1Hz, 1H), 7.36-7.22 (m, 3H), 7.11-6.81 (m, 2H), 5.06 (s, 2H), 4.89 (t, J = 6.6 Hz, 2H), 4.79 (dd, J = 6.2, 8.5 Hz, 2H), 3.97 (p, J = 7.7, 8.2 Hz, 1H), 3.64 (t, J = 5.0 Hz, 2H), 3.24 (dt, J = 4.8, 10.2 Hz, 4H), 3.16 (d, J = 5.4 Hz, 2H); LRMS (ES) m/z 592.5 (M + + 1).
  • 45
  • [ 114012-41-8 ]
  • [ 2654741-56-5 ]
  • [ 2654743-04-9 ]
YieldReaction ConditionsOperation in experiment
37.4% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 1h; 11-1 EXAMPLE 11-1 (R)-(4-(1-methyl-4-((N-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone [0530] To a solution of (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)phthalazin-1-amine (20.0 mg, 46.6 pmol, 1.00 eq.) and oxetane-3-carboxylic acid (5.70 mg, 55.9 pmol, 1.20 eq.) in DMF (0.50 mL) was added HATU (21.3mg, 55.9 pmol, 1.20 eq.) and N, X-di i sopropyl ethyl amine (18.1 mg, 140 pmol, 24.3 pL, 3.00 eq.). The mixture was stirred at 25 °C for 1 hour then purified by prep-HPLC (Waters Xbridge 150 25 mm x 5 um; mobile phase: mobile phase A: [water (10 mM NH4HCO3), mobile phase B: acetonitrile]; B%: 27%-57%) to give (R)-(4-(1-methyl-4-((N-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone (9.00 mg, 17.4 pmol, 37.4% yield, 99.4% purity) as a off-white solid. LCMS [M+l] +: 514.3. [0531] NMR (400 MHz, CD3OD) d = 8.02 (d, J= 9.2 Hz, 1H), 7.73-7.63 (m, 3H), 7.50 (d, J= 7.6 Hz, 1H), 7.25 (t, J= 8.0 Hz, 1H), 5.63 (q, J= 7.2 Hz, 1H), 4.89 (br s, 4H), 4.33-4.22 (m, 1H), 3.89 -3.78 (m, 2H), 3.69 -3.58 (m, 4H), 3.55-3.47 (m, 2H), 2.67 (s, 3H), 2.61 (s, 3H), 1.64 (d, J= 6.8 Hz, 3H).
  • 46
  • [ 114012-41-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
35% Stage #1: (+/-)-benzyl ((5-(4-((3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate With glacial acetic acid at 25℃; Stage #2: oxetane-3-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 0.0833333h; Inert atmosphere; Stage #3: In N,N-dimethyl-formamide at 25℃; for 0.0833333h; Inert atmosphere; 33 Preparation of (+/-)-2-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)-N-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine hydrogen bromide: General procedure: To a solution of (+/-)-benzyl ((5-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol- 2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (1 g, 1.73 mmol, 1 eq) was added hydrogen bromide in acetic acid (37.25 g, 151.9 mmol, 25 mL, 33%wt, 87.60 eq). The mixture was stirred at 25 °C for 1 h, and completion of the reaction was confirmed using TLC analysis. The reaction mixture was poured into a saturated aqueous sodium carbonate solution (150 mL) to adjust the pH of the mixture to 9. The mixture was stirred for 15 mins and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried with anhydrous sodium sulfate, and filtered.4M HCl in EA (4 M, 15 mL) was added to the filtrate, and the filtrate solution was concentrated in vacuo. The crude product was triturated with methyl tert-butyl ether (MTBE) (40 mL) at 25 oC for 10 min and filtered to give (+/-)-2-(5- (aminomethyl)-1,3,4-thiadiazol-2-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-amine (650 mg, crude, HCl salt) in 78 % yield as a yellow solid. LC-MS (ES+, m/z): 443.0. [0396] Preparation of (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}oxetane-3-carboxamide (Compound 36B), (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2-trifluoroethyl)-1H- indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}cyclobutanecarboxamide (Compound 37B), and (+/-)-N- [5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)- 1,3,4-thiadiazol-2-yl]methyl}-1-methylpiperidine-4-carboxamide (Compound 40B):To a solution of RCOOH (1 eq) in DMF were added TEA (5 eq) and HATU (2 eq) in one portion at 25 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 5 min, and (+/-)-2-(5-(aminomethyl)-1,3,4- thiadiazol-2-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (1 eq, HCl) was added to the reaction at 25 °C. The mixture was stirred for 5 min, and completion of the reaction was confirmed using LC-MS analysis. The residue was poured into ice water (w/w = 1/1) (50 mL) and stirred for 5 min. The aqueous phase was extracted with EA (20 mL x 3), and the combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative-TLC (DCM:MeOH = 4:1) or preparative-HPLC to afford (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}oxetane-3-carboxamide (Compound 36B) in 35 % yield (LC-MS (ES+, m/z): 568.3); (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4- yl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}cyclobutanecarboxamide (Compound 37B) in 38 % yield (LC-MS (ES+, m/z): 525.2); and (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1- methylpiperidin-4-yl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}-1- methylpiperidine-4-carboxamide (Compound 40B) in 32 % yield (LC-MS (ES+, m/z): 527.2).
35% Stage #1: (+/-)-benzyl ((5-(4-((3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate With glacial acetic acid at 25℃; Stage #2: oxetane-3-carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 0.0833333h; Inert atmosphere; Stage #3: In N,N-dimethyl-formamide at 25℃; for 0.0833333h; Inert atmosphere; 33 Preparation of (+/-)-2-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)-N-((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine hydrogen bromide: General procedure: To a solution of (+/-)-benzyl ((5-(4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(2,2,2-trifluoroethyl)-1H-indol- 2-yl)-1,3,4-thiadiazol-2-yl)methyl)carbamate (1 g, 1.73 mmol, 1 eq) was added hydrogen bromide in acetic acid (37.25 g, 151.9 mmol, 25 mL, 33%wt, 87.60 eq). The mixture was stirred at 25 °C for 1 h, and completion of the reaction was confirmed using TLC analysis. The reaction mixture was poured into a saturated aqueous sodium carbonate solution (150 mL) to adjust the pH of the mixture to 9. The mixture was stirred for 15 mins and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried with anhydrous sodium sulfate, and filtered.4M HCl in EA (4 M, 15 mL) was added to the filtrate, and the filtrate solution was concentrated in vacuo. The crude product was triturated with methyl tert-butyl ether (MTBE) (40 mL) at 25 oC for 10 min and filtered to give (+/-)-2-(5- (aminomethyl)-1,3,4-thiadiazol-2-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(2,2,2- trifluoroethyl)-1H-indol-4-amine (650 mg, crude, HCl salt) in 78 % yield as a yellow solid. LC-MS (ES+, m/z): 443.0. [0396] Preparation of (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}oxetane-3-carboxamide (Compound 36B), (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2-trifluoroethyl)-1H- indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}cyclobutanecarboxamide (Compound 37B), and (+/-)-N- [5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)- 1,3,4-thiadiazol-2-yl]methyl}-1-methylpiperidine-4-carboxamide (Compound 40B):To a solution of RCOOH (1 eq) in DMF were added TEA (5 eq) and HATU (2 eq) in one portion at 25 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 5 min, and (+/-)-2-(5-(aminomethyl)-1,3,4- thiadiazol-2-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine (1 eq, HCl) was added to the reaction at 25 °C. The mixture was stirred for 5 min, and completion of the reaction was confirmed using LC-MS analysis. The residue was poured into ice water (w/w = 1/1) (50 mL) and stirred for 5 min. The aqueous phase was extracted with EA (20 mL x 3), and the combined organic phase was washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative-TLC (DCM:MeOH = 4:1) or preparative-HPLC to afford (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]amino}-1-(2,2,2- trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}oxetane-3-carboxamide (Compound 36B) in 35 % yield (LC-MS (ES+, m/z): 568.3); (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1-methylpiperidin-4- yl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}cyclobutanecarboxamide (Compound 37B) in 38 % yield (LC-MS (ES+, m/z): 525.2); and (+/-)-N-[5-(4-[(3R,4S)-3-fluoro-1- methylpiperidin-4-yl]amino}-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1,3,4-thiadiazol-2-yl]methyl}-1- methylpiperidine-4-carboxamide (Compound 40B) in 32 % yield (LC-MS (ES+, m/z): 527.2).
  • 47
  • [ 114012-41-8 ]
  • [ 2346579-39-1 ]
  • [ 2749439-26-5 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; 2 Example 2: Preparation of 2-[(2,6-difluoro-4-pyridyl)-(oxetane-3-carbonyl)amino]-N-(2,2- dimethylcyclobutyl)-5-methyl-thiazole-4-carboxamide (Example P-4, Table 2) A solution of 2-[(2,6-difluoro-4-pyridyl)amino]-N-(2,2-dimethylcyclobutyl)-5-methyl-thiazole-4- carboxamide (0.050 g, 1.0, 0.14 mmol, prepared as described in WO 2019/105933) in DMF (1.4 mL) was treated with oxetane-3-carboxylic acid (0.019 g, 1.2, 0.17 mmol), N,N-diisopropylethylamine (0.048 g, 0.064 mL, 0.37 mmol), and HATU (0.082 g, 0.21 mmol). The resulting pale brown solution was stirred for 4 hours at RT. After this time, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with water. It was then extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous Na SC , filtered and concentrated in vacuo to give a pale brown oil. The crude product was purified by reversed phase chromatography eluting with acetonitrile/water to give the title compound as a beige powder. 1H NMR (400 MHz, CDCh) d ppm 0.97 (s, 3 H) 1.14 (s, 3 H) 1.50 - 1.65 (m, 2 H) 1.65 - 1.81 (m, 1 H) 2.19 - 2.34 (m, 1 H) 2.84 (s, 3 H) 3.86 - 4.01 (m, 1 H) 4.13 - 4.26 (m, 1 H) 4.51 - 4.65 (m, 2 H) 4.92 - 5.06 (m, 2 H) 6.82 (s, 2 H) 6.91 - 7.08 (br s, 1 H); LC-MS (Method A): 437 [M+H], Rt: 1 .05 min.
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; 2 Example 2: Preparation of 2-[(2,6-difluoro-4-pyridyl)-(oxetane-3-carbonyl)amino]-N-(2,2- dimethylcyclobutyl)-5-methyl-thiazole-4-carboxamide (Example P-4, Table 2) A solution of 2-[(2,6-difluoro-4-pyridyl)amino]-N-(2,2-dimethylcyclobutyl)-5-methyl-thiazole-4- carboxamide (0.050 g, 1.0, 0.14 mmol, prepared as described in WO 2019/105933) in DMF (1.4 mL) was treated with oxetane-3-carboxylic acid (0.019 g, 1.2, 0.17 mmol), N,N-diisopropylethylamine (0.048 g, 0.064 mL, 0.37 mmol), and HATU (0.082 g, 0.21 mmol). The resulting pale brown solution was stirred for 4 hours at RT. After this time, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with water. It was then extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous Na SC , filtered and concentrated in vacuo to give a pale brown oil. The crude product was purified by reversed phase chromatography eluting with acetonitrile/water to give the title compound as a beige powder. 1H NMR (400 MHz, CDCh) d ppm 0.97 (s, 3 H) 1.14 (s, 3 H) 1.50 - 1.65 (m, 2 H) 1.65 - 1.81 (m, 1 H) 2.19 - 2.34 (m, 1 H) 2.84 (s, 3 H) 3.86 - 4.01 (m, 1 H) 4.13 - 4.26 (m, 1 H) 4.51 - 4.65 (m, 2 H) 4.92 - 5.06 (m, 2 H) 6.82 (s, 2 H) 6.91 - 7.08 (br s, 1 H); LC-MS (Method A): 437 [M+H], Rt: 1 .05 min.
  • 48
  • [ 114012-41-8 ]
  • [ 2778219-36-4 ]
  • [ 2778161-68-3 ]
YieldReaction ConditionsOperation in experiment
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 25℃; for 0.5h; 86 General procedure: To a solution of Example 29-b [100 mg, 0.23 mmol, (Sa)-N-[6-(5-chloro-1,3-benzoxazol- 2-yl)spiro[3.3]heptan-2-yl]-5-(propanoylsulfamoyl)furan-2-carboxamide, or (Ra)-N-[6-(5-chloro- 1,3-benzoxazol-2-yl)spiro[3.3]heptan-2-yl]-5-(propanoylsulfamoyl)furan-2-carboxamide)], DMAP (1 mg, 8.19 μmol) and triethylamine (46.4 mg, 0.46 mmol) in DCM (5 mL) was added propionyl chloride (31.8 mg, 0.34 μmol) dropwise at 0oC. Then the reaction was stirred at 25oC for 30 min. The reaction solution was diluted with DCM (15 mL), washed with HCl (1 M, 10 mL). The organic layer was dried over Na2SO4and purified by flash column (eluting with MeOH/DCM = 1/50 to 1/30) to give Example 68 as a white solid [75 mg, 65.8 %, (Sa) -N-[6-(5- chloro-1,3-benzoxazol-2-yl)spiro[3.3]heptan-2-yl]-5-(propanoylsulfamoyl)furan-2-carboxamide, or (Ra)-N-[6-(5-chloro-1,3-benzoxazol-2-yl)spiro[3.3]heptan-2-yl]-5-(propanoylsulfamoyl)furan- 2-carboxamide ]. (MS obsd. (ESI+) [(M+H)+]: 492.6.1H NMR (400 MHz, DMSO-d6) δ ppm:12.44 (br s, 1 H), 8.80 (d, J = 7.3 Hz, 1 H), 7.80 (d, J = 2.0 Hz, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.40 (dd, J = 8.7, 2.1 Hz, 1 H), 7.35 (d, J = 3.7 Hz, 1 H), 7.29 (d, J = 3.8 Hz, 1 H), 4.27 (sxt, J = 8.0 Hz, 1 H), 3.74 (quin, J = 8.5 Hz, 1 H), 2.52 - 2.68 (m, 3 H), 2.40 - 2.48 (m, 2 H), 2.09 - 2.35 (m, 5 H), 0.92 (t, J = 7.4 Hz, 3 H)
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 25℃; for 0.5h; 86 General procedure: To a solution of Example 29-b [100 mg, 0.23 mmol, (Sa)-N-[6-(5-chloro-1,3-benzoxazol- 2-yl)spiro[3.3]heptan-2-yl]-5-(propanoylsulfamoyl)furan-2-carboxamide, or (Ra)-N-[6-(5-chloro- 1,3-benzoxazol-2-yl)spiro[3.3]heptan-2-yl]-5-(propanoylsulfamoyl)furan-2-carboxamide)], DMAP (1 mg, 8.19 μmol) and triethylamine (46.4 mg, 0.46 mmol) in DCM (5 mL) was added propionyl chloride (31.8 mg, 0.34 μmol) dropwise at 0oC. Then the reaction was stirred at 25oC for 30 min. The reaction solution was diluted with DCM (15 mL), washed with HCl (1 M, 10 mL). The organic layer was dried over Na2SO4and purified by flash column (eluting with MeOH/DCM = 1/50 to 1/30) to give Example 68 as a white solid [75 mg, 65.8 %, (Sa) -N-[6-(5- chloro-1,3-benzoxazol-2-yl)spiro[3.3]heptan-2-yl]-5-(propanoylsulfamoyl)furan-2-carboxamide, or (Ra)-N-[6-(5-chloro-1,3-benzoxazol-2-yl)spiro[3.3]heptan-2-yl]-5-(propanoylsulfamoyl)furan- 2-carboxamide ]. (MS obsd. (ESI+) [(M+H)+]: 492.6.1H NMR (400 MHz, DMSO-d6) δ ppm:12.44 (br s, 1 H), 8.80 (d, J = 7.3 Hz, 1 H), 7.80 (d, J = 2.0 Hz, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.40 (dd, J = 8.7, 2.1 Hz, 1 H), 7.35 (d, J = 3.7 Hz, 1 H), 7.29 (d, J = 3.8 Hz, 1 H), 4.27 (sxt, J = 8.0 Hz, 1 H), 3.74 (quin, J = 8.5 Hz, 1 H), 2.52 - 2.68 (m, 3 H), 2.40 - 2.48 (m, 2 H), 2.09 - 2.35 (m, 5 H), 0.92 (t, J = 7.4 Hz, 3 H)
  • 49
  • [ 114012-41-8 ]
  • [ 2771010-69-4 ]
  • [ 2771006-02-9 ]
YieldReaction ConditionsOperation in experiment
22% With 1-propanephosphonic acid cyclic anhydride; triethylamine In dichloromethane; ethyl acetate at 18 - 22℃; Inert atmosphere; 57 General procedure 3 General procedure: To a solution of Intermediates 117-128 (1 mmol) in dry DCM (0.2 M) at rtunder nitrogenatmosphere, was added TEA (20 mmol) and T3P - 50% in EtOAc (10 mmol), followed by the corresponding either commercially available or prepared carboxylic acid (1 .5 mmol). The reaction mixture was stirred at rt upon completion. The reaction mixture was quenched with sat. aq. NaHCO3. The reaction mixture was diluted in DCM, the phases were separated, and the aqueous phase extracted with DCM (2 times), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude was: a) purified by reverse-phase column chromatography (water/acetonitrile from water 100% to acetonitrile 100%) b) purified by flash column chromatography (Heptane/EtOAc or DCM/MeOH) c) purified by reverse chromatography (water/acetonitrile from water 100% (with 0.1 % AcOH) to acetonitrile 100%) d) Chiral separation (Chiralpak IB 5 μm, 250 x 4.6 mm, CO2/EtOH 70/30) e) Chiral separation (Chiralcel OJ-H 5pm, 250 x 21 mm, CO2/EtOH 80/20) f) Chiral separation (Pirkle (R, R) Whelk-01 5pm, 250 x 21 .1 mm, CO2/EtOH 65/35) g) Chiral separation (Xbridge BEH C18 10 μm, 250x50 mm, H2O /MeCN + HCOONH4)
22% With 1-propanephosphonic acid cyclic anhydride; triethylamine In dichloromethane; ethyl acetate at 18 - 22℃; Inert atmosphere; 57 General procedure 3 General procedure: To a solution of Intermediates 117-128 (1 mmol) in dry DCM (0.2 M) at rtunder nitrogenatmosphere, was added TEA (20 mmol) and T3P - 50% in EtOAc (10 mmol), followed by the corresponding either commercially available or prepared carboxylic acid (1 .5 mmol). The reaction mixture was stirred at rt upon completion. The reaction mixture was quenched with sat. aq. NaHCO3. The reaction mixture was diluted in DCM, the phases were separated, and the aqueous phase extracted with DCM (2 times), dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude was: a) purified by reverse-phase column chromatography (water/acetonitrile from water 100% to acetonitrile 100%) b) purified by flash column chromatography (Heptane/EtOAc or DCM/MeOH) c) purified by reverse chromatography (water/acetonitrile from water 100% (with 0.1 % AcOH) to acetonitrile 100%) d) Chiral separation (Chiralpak IB 5 μm, 250 x 4.6 mm, CO2/EtOH 70/30) e) Chiral separation (Chiralcel OJ-H 5pm, 250 x 21 mm, CO2/EtOH 80/20) f) Chiral separation (Pirkle (R, R) Whelk-01 5pm, 250 x 21 .1 mm, CO2/EtOH 65/35) g) Chiral separation (Xbridge BEH C18 10 μm, 250x50 mm, H2O /MeCN + HCOONH4)
  • 50
  • [ 114012-41-8 ]
  • [ 40372-61-0 ]
  • [ 2632998-58-2 ]
YieldReaction ConditionsOperation in experiment
Stage #1: oxetane-3-carboxylic acid; 2-amino-5-bromo-4-chlorophenol With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 3h; Stage #2: With potassium carbonate In methanol; lithium hydroxide monohydrate at 25℃; for 2h; 4.1 Step 1: Synthesis of compound 5-1 Compound 3-3 (1.01 g, 4.52 mmol) and solvent N,N-dimethylformamide (10 mL) were added to a reaction flask, then reagents 3-oxetanecarboxylic acid (0.6 g, 5.88 mmol), N,N-diisopropylethylamine (1.17 g, 9.04 mmol) and HATU (2.58 g, 6.78 mmol) were added at 25 °C, and the mixture was reacted at 25 °C for 3 hours. The reaction mixture was quenched with 10 mL of water, extracted with ethyl acetate (15 mL×2), and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was dissolved in methanol (20 mL) and water (7 mL), then potassium carbonate (1.2 g, 8.70 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was adjusted to pH = 4-5 with 1 mol/L hydrochloric acid, and then 10 mL of saturated sodium bicarbonate solution was added to adjust pH = 7-8; the resulting mixture was diluted with 20 mL of ethyl acetate, and the phases were separated; the aqueous phase was extracted with ethyl acetate (20 mL×2), and the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered, and concentrated to obtain compound 5-1. 1H NMR (400 MHz, CDCl3) δ ppm 9.40 (s, 1 H), 8.27 (s, 1 H), 7.16 (s, 1 H), 4.69- 4.64 (m, 4 H), 4.18 - 4.11 (m, 1 H).
Stage #1: oxetane-3-carboxylic acid; 2-amino-5-bromo-4-chlorophenol With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 3h; Stage #2: With potassium carbonate In methanol; lithium hydroxide monohydrate at 25℃; for 2h; 4.1 Step 1: Synthesis of compound 5-1 Compound 3-3 (1.01 g, 4.52 mmol) and solvent N,N-dimethylformamide (10 mL) were added to a reaction flask, then reagents 3-oxetanecarboxylic acid (0.6 g, 5.88 mmol), N,N-diisopropylethylamine (1.17 g, 9.04 mmol) and HATU (2.58 g, 6.78 mmol) were added at 25 °C, and the mixture was reacted at 25 °C for 3 hours. The reaction mixture was quenched with 10 mL of water, extracted with ethyl acetate (15 mL×2), and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was dissolved in methanol (20 mL) and water (7 mL), then potassium carbonate (1.2 g, 8.70 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was adjusted to pH = 4-5 with 1 mol/L hydrochloric acid, and then 10 mL of saturated sodium bicarbonate solution was added to adjust pH = 7-8; the resulting mixture was diluted with 20 mL of ethyl acetate, and the phases were separated; the aqueous phase was extracted with ethyl acetate (20 mL×2), and the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered, and concentrated to obtain compound 5-1. 1H NMR (400 MHz, CDCl3) δ ppm 9.40 (s, 1 H), 8.27 (s, 1 H), 7.16 (s, 1 H), 4.69- 4.64 (m, 4 H), 4.18 - 4.11 (m, 1 H).
  • 51
  • [ 114012-41-8 ]
  • [ 18107-18-1 ]
  • [ 1638760-80-1 ]
YieldReaction ConditionsOperation in experiment
94.7 % With acetic acid In methanol; dichloromethane at 0 - 20℃; 112.1 [0606] Step 1: [0607] At 0 °C, oxetane-3-carboxylic acid 81 (1.3 g, 12.73 mmol) was dissolved in a mixture of methanol (10 mL) and dichloromethane (10 mL), and trimethylsilyldiazomethane (2 M, 12.73 mL, 25.46 mmol) was slowly added. After the dropwise addition, the mixture was warmed to room temperature and stirred for 3 h. After the reaction was completed, acetic acid (0.05 mL) was added to the reaction mixture. The mixture was poured into water, and extracted with dichloromethane (2330 mL). The organic phases were combined, and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford crude compound 82 (1.4 g, yield: 94.7%) as a colorless oil.
94.7 % With acetic acid In methanol; dichloromethane at 0 - 20℃; 112.1 [0606] Step 1: [0607] At 0 °C, oxetane-3-carboxylic acid 81 (1.3 g, 12.73 mmol) was dissolved in a mixture of methanol (10 mL) and dichloromethane (10 mL), and trimethylsilyldiazomethane (2 M, 12.73 mL, 25.46 mmol) was slowly added. After the dropwise addition, the mixture was warmed to room temperature and stirred for 3 h. After the reaction was completed, acetic acid (0.05 mL) was added to the reaction mixture. The mixture was poured into water, and extracted with dichloromethane (2330 mL). The organic phases were combined, and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford crude compound 82 (1.4 g, yield: 94.7%) as a colorless oil.
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