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[ CAS No. 874473-14-0 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 874473-14-0
Chemical Structure| 874473-14-0
Chemical Structure| 874473-14-0
Structure of 874473-14-0 * Storage: {[proInfo.prStorage]}
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Product Details of [ 874473-14-0 ]

CAS No. :874473-14-0 MDL No. :MFCD11111713
Formula : C4H9NO Boiling Point : -
Linear Structure Formula :- InChI Key :NQVWMPOQWBDSAI-UHFFFAOYSA-N
M.W : 87.12 Pubchem ID :46835725
Synonyms :

Calculated chemistry of [ 874473-14-0 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 23.06
TPSA : 35.25 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) : -7.43 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.29
Log Po/w (XLOGP3) : -0.84
Log Po/w (WLOGP) : -0.27
Log Po/w (MLOGP) : -0.57
Log Po/w (SILICOS-IT) : 0.64
Consensus Log Po/w : 0.05

Druglikeness

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

Water Solubility

Log S (ESOL) : 0.15
Solubility : 123.0 mg/ml ; 1.41 mol/l
Class : Highly soluble
Log S (Ali) : 0.58
Solubility : 331.0 mg/ml ; 3.8 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.36
Solubility : 37.7 mg/ml ; 0.433 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 874473-14-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 874473-14-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 874473-14-0 ]

[ 874473-14-0 ] Synthesis Path-Downstream   1~55

  • 1
  • [ 874473-14-0 ]
  • [ 1246924-68-4 ]
  • [ 1246924-18-4 ]
YieldReaction ConditionsOperation in experiment
8% Example 176-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-N-(3-methyl-oxetan-3-yl)-nicotinamide; To a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) in DMF (3.3 mL) was added 1,1'-carbonyl-diimidazole (58.2 mg, 0.35 mmol). The reaction mixture was stirred for 1 h at 60 C. 3-Methyl-3-oxetanamine (27.8 mg, 0.32 mmol) was then added at room temperature and the mixture was stirred overnight. Extraction with water/ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 1:1) afforded the title compound (10 mg, 8%) as a white solid. MS: m/e=414.2 [M+H]+.
  • 2
  • [ 874473-14-0 ]
  • N-(2,4-dimethylphenyl)-3-hydroxy-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide [ No CAS ]
  • N-(2,4-dimethylphenyl)-3-hydroxy-4-[2-hydroxy-1-(morpholin-4-yl)ethyl]-N-(2-methylpropyl)benzene-1-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
11.2 mg In ethanol; at 25 - 50℃; for 12h; c) Example 109: N-(2,4-dimethylphenyn-3-hydroxy-4-(2-hydroxy-l-morpholinoethyn-N- isobutylbenzenesulfonamide To a stirred solution of N-(2,4-dimethylphenyl)-3-hydroxy-N-isobutyl-4-(oxiran-2- yl)benzenesulfonamide (60 mg, 0.160 mmol) in ethanol (1 ml.) at 25 C was added morpholine (30.6 mg, 0.352 mmol) and the reaction mixture stirring at 50 C for 12 hours. The reaction mixture was then concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give a single regioisomer of the desired product, 11.2 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 463 (M+H).
  • 3
  • [ 874473-14-0 ]
  • N-(4-ethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide [ No CAS ]
  • N-(4-ethylphenyl)-4-{1-hydroxy-2-[(3-methyloxetan-3-yl)amino]ethyl}-N-(2-methylpropyl)benzene-1-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
170.7 mg In ethanol; at 50℃; for 16h; d) Example 112: N-(4-ethylphenyn-4-(l-hydroxy-2-((3-methyloxetan-3-ynamino)ethyl)-N- isobutylbenzenesulfonamide A solution of N-(4-ethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (400 mg, 1.113 mmol) was prepared in ethanol (6 mL) and <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (388 mg, 4.45 mmol) added. The reaction mixture was heated at 50 C and stirred 16 hours. The solvent was evaporated in vacuo to give the crude product which was then purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane+0-20% methanol). The appropriate fractions were combined and evaporated in vacuo to give the required product, 170.7 mg, as a white solid. LCMS [LCMS2] Rt 1.21 min, m/z (ES+) 447 (M+H).
170.7 mg In ethanol; at 50℃; for 16h; A solution of N-(4-ethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (400 mg, 1.113 mmol) was prepared in ethanol (6 mL) and <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (388 mg, 4.45 mmol) added. The reaction mixture was heated at 50 C. and stirred 16 hours. The solvent was evaporated in vacuo to give the crude product which was then purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane+0-20% methanol). The appropriate fractions were combined and evaporated in vacuo to give the required product, 170.7 mg, as a white solid. LCMS [LCMS2] Rt 1.21 min, m/z (ES+) 447 (M+H).
  • 4
  • [ 874473-14-0 ]
  • N-(2,4-dimethylphenyl)-3-fluoro-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide [ No CAS ]
  • N-(2,4-dimethylphenyl)-3-fluoro-4-{1-hydroxy-2-[(3-methyloxetan-3-yl)amino]ethyl}-N-(2-methylpropyl)benzene-1-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
11.2 mg In ethanol; at 25 - 50℃; for 26h; Example 106: N-(2,4-dimethylphenyn-3-fluoro-4-(l-hydroxy-2-((3-methyloxetan-3-ynamino)ethyn- N-isobutylbenzenesulfonamide To a stirred solution of N-(2,4-dimethylphenyl)-3-fluoro-N-isobutyl-4-(oxiran-2- yl)benzenesulfonamide (20 mg, 0.053 mmol) in ethanol at 25 C was added 3-methyloxetan-3- amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50 C for 18 hours. Another portion of <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50 C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 11.2 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 465 (M+H).
11.2 mg In ethanol; at 25 - 50℃; for 26h; To a stirred solution of N-(2,4-dimethylphenyl)-3-fluoro-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.053 mmol) in ethanol at 25 C. was added <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50 C. for 18 hours. Another portion of <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50 C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 11.2 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 465 (M+H).
  • 5
  • [ 874473-14-0 ]
  • N-(2,4-dimethylphenyl)-2-methyl-N-(2-methylpropyl)-4-(oxiran-2-yl)benzene-1-sulfonamide [ No CAS ]
  • N-(2,4-dimethylphenyl)-4-{1-hydroxy-2-[(3-methyloxetan-3-yl)amino]ethyl}-2-methyl-N-(2-methylpropyl)benzene-1-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
9.3 mg In ethanol; at 25 - 50℃; for 26h; Example 107: N-(2,4-dimethylphenyn-4-(l-hydroxy-2-((3-methyloxetan-3-ynamino)ethyl)-N- isobutyl-3-methylbenzenesulfonamide To a stirred solution of N-(2,4-dimethylphenyl)-N-isobutyl-3-methyl-4-(oxiran-2- yl)benzenesulfonamide (20 mg, 0.054 mmol) in ethanol at 25 C was added 3-methyloxetan-3- amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50 C for 18 hours. Another portion of <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50 C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 9.3 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 461 (M+H).
5.2 mg In ethanol; at 25 - 50℃; for 26h; To a stirred solution of N-(2,4-dimethylphenyl)-N-isobutyl-2-methyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.054 mmol) in ethanol at 25 C. was added <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50 C. for 18 hours. Another portion of <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50 C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 5.2 mg. LCMS [LCMS2] Rt 1.23 min, m/z (ES+) 461 (M+H).
  • 6
  • [ 874473-14-0 ]
  • [ 1429347-55-6 ]
  • N-(2,4-dimethylphenyl)-4-{1-hydroxy-2-[(3-methyloxetan-3-yl)amino]ethyl}-N-(2-methylpropyl)benzene-1-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
24% With triethylamine; In ethanol; at 50℃; Specific Example - Preparation of N-(2,4-dimethylphenyl)-4-(l-hydroxy-2-((3-methyloxetan-3- ynamino)ethyn-N-isobutylbenzenesulfonamide (Example 72) A solution of N-(2,4-dimethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (173 mg, 0.481 mmol) was prepared in ethanol (1.75 ml.) and dispensed at 0.25 mL/vial into 7 vials for each individual reaction. To one vial was added <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (0.076 mmol) as a solution in ethanol (0.25 ml_), followed by triethylamine (0.023 ml_, 0.165 mmol). The reaction was then heated at 50 C over the weekend. Solvent was concentrated under stream of nitrogen and sample purified by mass directed autoprep (ammonium carbonate modifier). Relevant fractions were evaporated under a stream of nitrogen to give the product, 7.3 mg (only one regioisomer isolated). LCMS [LCMS2] Rt 1.23 min, m/z (ES+) 447
24% With triethylamine; In ethanol; at 50℃; for 48h; A solution of N-(2,4-dimethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (173 mg, 0.481 mmol) was prepared in ethanol (1.75 mL) and dispensed at 0.25 mL/vial into 7 vials for each individual reaction. To one vial was added <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (0.076 mmol) as a solution in ethanol (0.25 mL), followed by triethylamine (0.023 mL, 0.165 mmol). The reaction was then heated at 50 C. over the weekend. Solvent was concentrated under stream of nitrogen and sample purified by mass directed autoprep (ammonium carbonate modifier). Relevant fractions were evaporated under a stream of nitrogen to give the product, 7.3 mg (only one regioisomer isolated). LCMS [LCMS2] Rt 1.23 min, m/z (ES+) 447 (M+H).
  • 7
  • [ 874473-14-0 ]
  • N-(2,4-dimethylphenyl)-N-isobutyl-3-methyl-4-(oxiran-2-yl)benzenesulfonamide [ No CAS ]
  • N-(2,4-dimethylphenyl)-4-{1-hydroxy-2-[(3-methyloxetan-3-yl)amino]ethyl}-3-methyl-N-(2-methylpropyl)benzene-1-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
5.2 mg In ethanol; at 25 - 50℃; for 26h; Example 108: N-(2^-dimethylphenyO-4-(l-hydroxy-2-((3-methyloxetan-3-yO^ isobutyl-2-methylbenzenesulfonamide To a stirred solution of N-(2,4-dimethylphenyl)-N-isobutyl-2-methyl-4-(oxiran-2- yl)benzenesulfonamide (20 mg, 0.054 mmol) in ethanol at 25 C was added 3-methyloxetan-3- amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50 C for 18 hours. Another portion of <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50 C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 5.2 mg. LCMS [LCMS2] Rt 1.23 min, m/z (ES+) 461 (M+H).
9.3 mg In ethanol; at 25 - 50℃; for 26h; To a stirred solution of N-(2,4-dimethylphenyl)-N-isobutyl-3-methyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.054 mmol) in ethanol at 25 C. was added <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50 C. for 18 hours. Another portion of <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50 C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 9.3 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 461 (M+H).
  • 8
  • [ 874473-14-0 ]
  • 2-(N-isobutyl-4-(oxiran-2-yl)phenylsulfonamido)-5-isopropylpyridine-1-oxide [ No CAS ]
  • 2-(4-(1-hydroxy-2-((3-methyloxetan-3-yl)amino)ethyl)-N-isobutylphenylsulfonamido)-5-isopropylpyridine-1-oxide [ No CAS ]
YieldReaction ConditionsOperation in experiment
71.9 mg at 50℃; for 24h; Intermediate 67: 2-(4-( 1-hvdroxv-2-((3-methvloxetan-3-vlaminoethvl-N- isobutvlihenvlsulfonamido-5-isoiroIvlIvridine 1-oxideA solution of 2-(N-isobutyl-4-(oxiran-2-yl)phenylsulfonamido)-5-isopropylpyridine 1-oxide (145 mg,0.371 mmol) was prepared in ethanol (3 mL) and <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (0.129 mL, 1.485 mmol)added. The reaction was heated to 50 C and stirred for 24 hours. The solvent was evaporated in vacuoto give the crude product which was purified by mass-directed autoprep (ammoniumcarbonate modifier). The solvent was removed under a stream of nitrogen to give the title product, 71.9 mg. LCMS (2 mm, formic) Rt 0.73 mi m/z (ESj 478 (M+H).
71.9 mg In ethanol; at 50℃; for 24h; A solution of 2-(N-isobutyl-4-(oxiran-2-yl)phenylsulfonamido)-5-isopropylpyridine 1-oxide (145 mg, 0.371 mmol) was prepared in ethanol (3 mL) and <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (0.129 mL, 1.485 mmol) added. The reaction was heated to 50 C. and stirred for 24 hours. The solvent was evaporated in vacuo to give the crude product which was purified by mass-directed autoprep (ammonium carbonate modifier). The solvent was removed under a stream of nitrogen to give the title product, 71.9 mg. LCMS (2 min, formic) Rt 0.73 min, m/z (ES+) 478 (M+H).
  • 9
  • [ 30766-11-1 ]
  • [ 874473-14-0 ]
  • [ 1403771-23-2 ]
  • 10
  • [ 874473-14-0 ]
  • [ 1403771-21-0 ]
  • [ 1428630-86-7 ]
  • 11
  • [ 874473-14-0 ]
  • C34H43F3N8O5SSi [ No CAS ]
  • {trans-3-(4-[4-[(3-methyloxetan-3-yl)amino]methyl}-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
11 mg The procedure of Example 1 was followed, using {trans-3-(4-[4- (hydroxymethyl)-6-(ti'ifluoromethyl)pyridin-2-yl]oxy}piperidin-l-yl)-l-[4-(7-[2- (trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yl]cyclobutyl}acetonitrile (21 mg, 0,031 mmol, Peak 1 from Intermediate Example A2, Step F), N,N-dusopropylethylamine (1 1 iL, 0.062 mmol) and methanesulphonic anhydride (7.5 mg, 0.043 mmol, Aldrich) in methylene chloride (0.42 niL). However, the substitution step was carried out using <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (40. , 0.46 mmol, Synthonix) in tetrahydrofuran (0.42 mL) and methanol (0.20 mL) at 55 C for 4 hours followed by 50 C overnight. Deprotection and purification carried out similarly to afford product as the free base (1 1 mg, 58%). NMR (400 MHz, d6- DMSO) delta 12.13 (s, 1H), 8.83 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.60 (d, J= 3.6 Hz, 1H), 7.46 (s, 1H), 7.15 - 7.02 (m, 2H), 5.11 - 4.89 (m, 1H), 4.45 (d, = 5.8 Hz, 2H), 4.18 (d, ./= 6.0 Hz, 2H), 3.77 (d, J= 7.4 Hz, 2H), 3.42 (s, 2H), 3.1 1 - 2.95 (m, 3H), 2.81 (p, ,7= 7.4 Hz, 1H), 2.73 - 2.55 (m, 2H), 2.44 - 2.27 (m, 2H), 2.25 - 2.08 (m, 2H), 2.08 - 1.92 (m, 2H), 1.80 - 1.54 (m, 2H), 1.37 (s, 3H). 19F NMR (376 MHz, d6- DMSO) delta -67.29 (s). LCMS (M+H)+: 622.2.
  • 12
  • [ 874473-14-0 ]
  • [ 4052-92-0 ]
  • [ 1445796-35-9 ]
  • [ 1572511-08-0 ]
YieldReaction ConditionsOperation in experiment
91.1 mg Compound 127 (2-fluoro-5-nitro-phenyl)methanol (4.3 g, 25.1 mmol) was dissolved in dichloro- methane (50 mL). Diethylaminosulfur trifluoride (4.5 g, 27.9 mmol) was added drop wise to the mixture at -30C. The mixture was stirred at 10 C for 4 hours. Methanol (10 mL) was added to the mixture and the mixture was further stirred at 10C for 30 minutes. The mixture was washed with brine (30mL) and the aqueous layer was extracted with CH2C12 (2 x 30 mL). The combined organic layers were dried over Na2S04 and concentrated in vacuo, resulting in l-fluoro-2-(fluoromethyl)-4-nitro- benzene (3.9 g). A mixture of l-fluoro-2-(fluoromethyl)-4-nitro-benzene (3.1 g, 17.9 mmol), iron (4.0 g, 71.6 mmol) and methanol (30 mL) was stirred at 65 for 8 hours. The mixture was filtrated and the filtrate was concentrated in vacuo, resulting in 4-fluoro-3-(fluoromethyl)aniline (1.5 g). 3-(chlorosulfonyl)benzoyl chloride (300 mg, 1.2 mmol) and triethylamine (150 mg, 1.5 mmol) were dissolved in dichloromethane (20 mL). 4-fluoro-3-(fluoromethyl)aniline (175 mg, 1.22 mmol) was added to the mixture at 0 C. The mixture was stirred at 10C for 30 minutes. The mixture was used to the next step without further purification.Triethylamine (152 mg, 1.5 mmol) and <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (131 mg. 1.5 mmol) were added to the above obtained reaction mixture at 0 C. The mixture was stirred at 20 C for 1 hour. The solvent was removed in vacuo and the obtained residue was purified by reversed phase high performance liquid chromatography (Column: Gemini 250*20mm*5um.. A: H2O+0.1%TFA B: MeCN. 27% to 57% B in A). The product fractions were collected and the organic solvent was removed in vacuo. The fraction was neutralized by saturated NaHC03. The mixture was extracted with dichloromethane (3 x 20 mL) and the combined organic layer was dried over Na2S04 and concentrated in vacuo, resulting in compound 127 (91.1 mg). Method A; Rt: 4.95 min. m/z : 397.3 (M+H)+ Exact mass: 396.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.41 (s, 3 H) 4.14 (d, J=6.3 Hz, 2 H) 4.56 (d, J=6.3 Hz, 2 H) 5.52 (d, J=48 Hz, 2 H) 7.31 (t, J=9.4 Hz, 1 H) 7.72 - 7.89 (m, 2 H) 7.92-7.97 (m, 1 H) 8.03 (d, J=8.0 Hz, 1 H) 8.23 (d, J=7.8 Hz, 1 H) 8.39 (s, 1 H) 8.55 (s, 1 H) 10.67 (s, 1 H).
91.1 mg Compound 127 (2-fluoro-5-nitro-phenyl)methanol (4.3 g, 25.1 mmol) was dissolved in dichloro- methane (50 mL). Diethylaminosulfur trifluoride (4.5 g, 27.9 mmol) was added drop wise to the mixture at -30C. The mixture was stirred at 10 C for 4 hours. Methanol (10 mL) was added to the mixture and the mixture was further stirred at 10C for 30 minutes. The mixture was washed with brine (30mL) and the aqueous layer was extracted with CH2C12 (2 x 30 mL). The combined organic layers were dried over Na2S04 and concentrated in vacuo, resulting in l-fluoro-2-(fluoromethyl)-4-nitro- benzene (3.9 g). A mixture of l-fluoro-2-(fluoromethyl)-4-nitro-benzene (3.1 g, 17.9 mmol), iron (4.0 g, 71.6 mmol) and methanol (30 mL) was stirred at 65 for 8 hours. The mixture was filtrated and the filtrate was concentrated in vacuo, resulting in 4-fluoro-3-(fluoromethyl)aniline (1.5 g). 3-(chlorosulfonyl)benzoyl chloride (300 mg, 1.2 mmol) and triethylamine (150 mg, 1.5 mmol) were dissolved in dichloromethane (20 mL). 4-fluoro-3-(fluoromethyl)aniline (175 mg, 1.22 mmol) was added to the mixture at 0 C. The mixture was stirred at 10C for 30 minutes. The mixture was used to the next step without further purification.Triethylamine (152 mg, 1.5 mmol) and <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (131 mg. 1.5 mmol) were added to the above obtained reaction mixture at 0 C. The mixture was stirred at 20 C for 1 hour. The solvent was removed in vacuo and the obtained residue was purified by reversed phase high performance liquid chromatography (Column: Gemini 250*20mm*5um.. A: H2O+0.1%TFA B: MeCN. 27% to 57% B in A). The product fractions were collected and the organic solvent was removed in vacuo. The fraction was neutralized by saturated NaHC03. The mixture was extracted with dichloromethane (3 x 20 mL) and the combined organic layer was dried over Na2S04 and concentrated in vacuo, resulting in compound 127 (91.1 mg). Method A; Rt: 4.95 min. m/z : 397.3 (M+H)+ Exact mass: 396.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.41 (s, 3 H) 4.14 (d, J=6.3 Hz, 2 H) 4.56 (d, J=6.3 Hz, 2 H) 5.52 (d, J=48 Hz, 2 H) 7.31 (t, J=9.4 Hz, 1 H) 7.72 - 7.89 (m, 2 H) 7.92-7.97 (m, 1 H) 8.03 (d, J=8.0 Hz, 1 H) 8.23 (d, J=7.8 Hz, 1 H) 8.39 (s, 1 H) 8.55 (s, 1 H) 10.67 (s, 1 H).
  • 13
  • [ 874473-14-0 ]
  • [ 4052-92-0 ]
  • [ 1737-69-5 ]
  • [ 1572511-30-8 ]
YieldReaction ConditionsOperation in experiment
Compound 119 Prepared similarly as described for compound 127 using 4-fluoro-2,5-dimethyl-aniline instead of 4-fluoro-3-(fluoromethyl)aniline, and DIPEA instead of NEt3. Method A; Rt: 5.27 min. m/z: 393.3 (M+H)+ Exact mass: 392.1
  • 14
  • [ 874473-14-0 ]
  • [ 1572516-10-9 ]
  • [ 1572516-14-3 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate; In tetrahydrofuran; water; at 0 - 20℃; Compound 190 Na2C03 (1.60 g, 0.0151 mol) was dissolved in water (25 mL). A solution of 3- methyloxetan-3-amine (2.63 g, 0.0302 mol) in THF (20 mL) was added, and the reaction mixture was cooled to 0C on an ice-bath. A solution of crude 5-bromo-3- chlorosulfonyl-2-fluoro-6-methyl-benzoic acid (5 g) in THF (30 mL) was added dropwise at 0C. After addition, the reaction mixture was stirred vigorously at 0C for 30 minutes, and at room temperature for 2 hours. The organic volatiles were evaporated, and the remaining ~ 30 mL was washed with Et20 (50 mL). The separated waterlayer was acidified with IN HC1 (40 mL), and the product was extracted with 2- MeTHF (2x). The combined organic layers were washed with brine, dried with Na2SC"4, filtered off, evaporated, and co-evaporated with CH3CN, resulting in crude 5-bromo-2-fluoro-6-methyl-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid (3.6 g) To a solution of crude 5-bromo-2-fluoro-6-methyl-3-[(3-methyloxetan-3- yl)sulfamoyl]benzoic acid (0.72 g, 0.00188 mol ) in CH3CN (15 mL ) under N2-atm was successively added NEt3 (0.786 mL, 0.00565 mol ), 4-fluoro-3-methylaniline (0.313 g, 0.00245 mol), and HATU (0.86 g, 0.00226 mol ). The reaction mixture was stirred at room temperature for 20 hours. More 4-fluoro-3-methylaniline (0.1 g) and HATU (0.3 g) were added, and the reaction was continued for 20 hours. The volatiles were evaporated. The residue was purified by silica gel Chromatography (heptane- EtOAc 100/0 to 0/100). The desired fractions were combined and evaporated. The residue was stirred in diisopropylether, filtered off, washed with diisopropylether (3x), and dried at 50C, resulting in compound 190 (0.38 g). m/z: 486.9 (M-H)~ Exact mass:488.0. 19F NMR (377 MHz, DMSO-d6) delta ppm -122.15 - -121.89 (m, 1 F), -116.05 (d, J=6.4 Hz, 1 F). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.47 (s, 3 H), 2.25 (d, J=1.5 Hz, 3 H), 2.40 (s, 3 H), 4.22 (d, J=6.6 Hz, 2 H), 4.62 (d, J=6.4 Hz, 2 H), 7.16 (dd, J=9.2 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 7.61 (dd, J=6.9, 2.3 Hz, 1 H), 8.01 (d, J=6.8 Hz, 1 H), 8.86 (br. s., 1 H), 10.81 (s, 1 H)
With sodium carbonate; In tetrahydrofuran; water; at 0 - 20℃; for 2.5h; Compound 190 Na2C03 (1.60 g, 0.0151 mol) was dissolved in water (25 mL). A solution of 3- methyloxetan-3-amine (2.63 g, 0.0302 mol) in THF (20 mL) was added, and the reaction mixture was cooled to 0C on an ice-bath. A solution of crude 5-bromo-3- chlorosulfonyl-2-fluoro-6-methyl-benzoic acid (5 g) in THF (30 mL) was added dropwise at 0C. After addition, the reaction mixture was stirred vigorously at 0C for 30 minutes, and at room temperature for 2 hours. The organic volatiles were evaporated, and the remaining ~ 30 mL was washed with Et20 (50 mL). The separated waterlayer was acidified with IN HC1 (40 mL), and the product was extracted with 2- MeTHF (2x). The combined organic layers were washed with brine, dried with Na2SC"4, filtered off, evaporated, and co-evaporated with CH3CN, resulting in crude 5-bromo-2-fluoro-6-methyl-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid (3.6 g) To a solution of crude 5-bromo-2-fluoro-6-methyl-3-[(3-methyloxetan-3- yl)sulfamoyl]benzoic acid (0.72 g, 0.00188 mol ) in CH3CN (15 mL ) under N2-atm was successively added NEt3 (0.786 mL, 0.00565 mol ), 4-fluoro-3-methylaniline (0.313 g, 0.00245 mol), and HATU (0.86 g, 0.00226 mol ). The reaction mixture was stirred at room temperature for 20 hours. More 4-fluoro-3-methylaniline (0.1 g) and HATU (0.3 g) were added, and the reaction was continued for 20 hours. The volatiles were evaporated. The residue was purified by silica gel Chromatography (heptane- EtOAc 100/0 to 0/100). The desired fractions were combined and evaporated. The residue was stirred in diisopropylether, filtered off, washed with diisopropylether (3x), and dried at 50C, resulting in compound 190 (0.38 g). m/z: 486.9 (M-H)~ Exact mass:488.0. 19F NMR (377 MHz, DMSO-d6) delta ppm -122.15 - -121.89 (m, 1 F), -116.05 (d, J=6.4 Hz, 1 F). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.47 (s, 3 H), 2.25 (d, J=1.5 Hz, 3 H), 2.40 (s, 3 H), 4.22 (d, J=6.6 Hz, 2 H), 4.62 (d, J=6.4 Hz, 2 H), 7.16 (dd, J=9.2 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 7.61 (dd, J=6.9, 2.3 Hz, 1 H), 8.01 (d, J=6.8 Hz, 1 H), 8.86 (br. s., 1 H), 10.81 (s, 1 H)
  • 15
  • [ 874473-14-0 ]
  • [ 434-75-3 ]
  • [ 1572516-34-7 ]
  • [ 1572516-37-0 ]
YieldReaction ConditionsOperation in experiment
Synthesis of 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid and 2- chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (2 g, 11.46 mmol) was treated with chlorosulfonic acid (10 mL, 150.44 mmol) and this was heated to 100C and stirred for 5 hours. The resulting mixture was cooled to room temperature and added dropwise to ice-water (1 liter). This was then extracted using dichloromethane (2 x 500 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo yielding an isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 gram) as a slightly yellow powder which was used as such.Method F, Rt: 0.47 min and 0.49 min. m/z : 270.9 (M-H)- Exact mass: 271.9. Sodium carbonate (1.21 g, 11.4 mmol) was dissolved in distilled water (22 mL). To this was added 3-methyl-3-oxetanamine (1.19 g, 13.68 mmol) at once followed by THF (20 mL). The obtained solution was stirred and cooled in an ice bath. An isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 g, 11.4 mmol) was dissolved in THF (30 mL) and this was added drop wise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature.The mixture was concentrated in vacuo untill only water remained. Then water (20 mL) was added and the mixture was acidified with HC1 (46 mL, 1M / aq). This was extracted using Me-THF (3 X 50 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo. The residue was purified, and isomers were separated using preparative HPLC (Stationary phase: Uptisphere CI 8 ODB - IotaOmicronmuetaiota, 200g, 5cm), Mobile phase: 0.25% NH4HC03 solution in water, MeOH) , yielding 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.40 min. m/z : 322.0 (M-H)" Exact mass: 323.0. 1H NMR (400 MHz, DMSO-d ) ppm 1.42 (s, 3 H), 4.15 (d, J=6.6 Hz, 2 H), 4.61 (d, J=5.9 Hz, 13 H), 7.29 (dd, J=8.5, 0.8 Hz, 1 H), 7.36 - 7.73 (m, 5 H). and 2-chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.34 min. m/z : 321.9 (M-H)" Exact mass: 323.0
Synthesis of 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid and 2- chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong> (2 g, 11.46 mmol) was treated with chlorosulfonic acid (10 mL, 150.44 mmol) and this was heated to 100C and stirred for 5 hours. The resulting mixture was cooled to room temperature and added dropwise to ice-water (1 liter). This was then extracted using dichloromethane (2 x 500 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo yielding an isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 gram) as a slightly yellow powder which was used as such.Method F, Rt: 0.47 min and 0.49 min. m/z : 270.9 (M-H)- Exact mass: 271.9. Sodium carbonate (1.21 g, 11.4 mmol) was dissolved in distilled water (22 mL). To this was added 3-methyl-3-oxetanamine (1.19 g, 13.68 mmol) at once followed by THF (20 mL). The obtained solution was stirred and cooled in an ice bath. An isomeric mixture of 2-chloro-3-chlorosulfonyl-6-fluoro-benzoic acid and 6-chloro-3- chlorosulfonyl-2-fluoro-benzoic acid (3.1 g, 11.4 mmol) was dissolved in THF (30 mL) and this was added drop wise to the stirring solution. The resulting mixture was stirred for 30 minutes while cooling was continued. Then, the mixture was stirred for 3 hours at room temperature.The mixture was concentrated in vacuo untill only water remained. Then water (20 mL) was added and the mixture was acidified with HC1 (46 mL, 1M / aq). This was extracted using Me-THF (3 X 50 mL). The combined organics were dried on Na2S04, filtered and concentrated in vacuo. The residue was purified, and isomers were separated using preparative HPLC (Stationary phase: Uptisphere CI 8 ODB - IotaOmicronmuetaiota, 200g, 5cm), Mobile phase: 0.25% NH4HC03 solution in water, MeOH) , yielding 6-chloro-2-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.40 min. m/z : 322.0 (M-H)" Exact mass: 323.0. 1H NMR (400 MHz, DMSO-d ) ppm 1.42 (s, 3 H), 4.15 (d, J=6.6 Hz, 2 H), 4.61 (d, J=5.9 Hz, 13 H), 7.29 (dd, J=8.5, 0.8 Hz, 1 H), 7.36 - 7.73 (m, 5 H). and 2-chloro-6-fluoro-3-[(3-methyloxetan-3-yl)sulfamoyl]benzoic acid as a white powder. Method G, Rt: 0.34 min. m/z : 321.9 (M-H)" Exact mass: 323.0
  • 16
  • [ 874473-14-0 ]
  • [ 1572516-61-0 ]
  • [ 1572514-11-4 ]
YieldReaction ConditionsOperation in experiment
1.8 g With triethylamine; In toluene; at 20℃; for 0.75h; Compound 217 A solution of 3-(difluoromethyl)-4-fluoro-aniline (1.02 mL, 8.58 mmol) in dry toluene (10 mL) was added dropwise (over 15 min) to a refluxing solution of 5- chloro-3-chlorosulfonyl-2-fluoro-benzoyl chloride (2500 mg, 8.576 mmol) in dry toluene (100 mL). After the addition, the reaction mixture was left to stir at reflux for 1 h. The reaction mixture was left to cool to room temperature under nitrogen atmosphere while stirring.The brown solution containing 5-chloro-3-[[3-(difluoromethyl)-4-fluoro- phenyl]carbamoyl]-2-fluoro-benzenesulfonyl chloride was used without further purification. <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (580 mg, 6.66 mmol) was added dropwise to the above solution at room temperature. Et3N (2.10 mL 15.14 mmol) was then added dropwise to the reaction mixture and the reaction mixture was stirred at room temperature for 45 minutes. The solvent was evaporated and the residue was taken up in EtOAc. HC1 (0.5 N, 30 mL) was added to the reaction mixture and the layers were separated. The organic layer was washed again with NaOH (0.5 N, 30 mL). The organic layer was dried on MgSC^ and was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: 100:0 -> 95:5), resulting in compound 217 (1.8 g). 1H NMR (360 MHz, DMSO-d6) delta ppm 1.45 (s, 3 H) 4.23 (d, J=6.2 Hz, 2 H) 4.63 (d, J=6.2 Hz, 2 H) 7.27 (t, J=54.3 Hz, 1 H) 7.43 (t, J=9.7 Hz, 1 H) 7.83 (dt, J=8.1, 4.0 Hz, 1 H) 7.95 (dd, J=5.9, 2.6 Hz, 1 H) 8.04 (dd, J=6.0, 2.4 Hz, 1 H) 8.13 (dd, J=5.3, 2.7 Hz, 1 H) 8.98 (s, 1 H) 10.98 (s, 1 H) Method F, Rt: 1.03 min. m/z : 465.1 (M-H)~ Exact mass: 466.0.
1.8 g With triethylamine; In toluene; at 20℃; for 0.75h; Compound 217 A solution of 3-(difluoromethyl)-4-fluoro-aniline (1.02 mL, 8.58 mmol) in dry toluene (10 mL) was added dropwise (over 15 min) to a refluxing solution of 5- chloro-3-chlorosulfonyl-2-fluoro-benzoyl chloride (2500 mg, 8.576 mmol) in dry toluene (100 mL). After the addition, the reaction mixture was left to stir at reflux for 1 h. The reaction mixture was left to cool to room temperature under nitrogen atmosphere while stirring.The brown solution containing 5-chloro-3-[[3-(difluoromethyl)-4-fluoro- phenyl]carbamoyl]-2-fluoro-benzenesulfonyl chloride was used without further purification. <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (580 mg, 6.66 mmol) was added dropwise to the above solution at room temperature. Et3N (2.10 mL 15.14 mmol) was then added dropwise to the reaction mixture and the reaction mixture was stirred at room temperature for 45 minutes. The solvent was evaporated and the residue was taken up in EtOAc. HC1 (0.5 N, 30 mL) was added to the reaction mixture and the layers were separated. The organic layer was washed again with NaOH (0.5 N, 30 mL). The organic layer was dried on MgSC^ and was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: 100:0 -> 95:5), resulting in compound 217 (1.8 g). 1H NMR (360 MHz, DMSO-d6) delta ppm 1.45 (s, 3 H) 4.23 (d, J=6.2 Hz, 2 H) 4.63 (d, J=6.2 Hz, 2 H) 7.27 (t, J=54.3 Hz, 1 H) 7.43 (t, J=9.7 Hz, 1 H) 7.83 (dt, J=8.1, 4.0 Hz, 1 H) 7.95 (dd, J=5.9, 2.6 Hz, 1 H) 8.04 (dd, J=6.0, 2.4 Hz, 1 H) 8.13 (dd, J=5.3, 2.7 Hz, 1 H) 8.98 (s, 1 H) 10.98 (s, 1 H) Method F, Rt: 1.03 min. m/z : 465.1 (M-H)~ Exact mass: 466.0.
  • 17
  • [ 874473-14-0 ]
  • 4-[(3-chloro-4,5-difluorophenyl)carbamoyl]-5-methyl-thiophene-2-sulfonyl chloride [ No CAS ]
  • N-(3-chloro-4,5-difluorophenyl)-2-methyl-5-[(3-methyloxetan-3-yl)sulfamoyl]thiophene-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
409 mg With N-ethyl-N,N-diisopropylamine; In acetonitrile; 5 -chlorosulfonyl-2 -methyl -thiophene-3-carbonyl chloride (2.4 g, 9.26 mmol) was dissolved in toluene (75 mL) and brought to reflux. 3-chloro-4,5-difiuoro-aniline (1.51 g, 9.26 mmol) was added drop wise in 2 minutes. After addition the reaction was refluxed for 5 hours. The reaction mixture was allowed to reach room temperature and the formed precipitate was filtered off yielding 4-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-5-methyl- thiophene-2-sulfonyl chloride (2.5 g). The filtrate was evaporated to dryness yielding another crop of 4-[(3-chloro-4,5-difluoro- phenyl)carbamoyl]-5-methyl-thiophene-2-sulfonyl chloride (1.1 g). 4-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-5-methyl-thiophene-2-sulfonyl chloride (500mg) was dissolved in acetonitrile (10 mL) together with <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (201.72 mg, 2.32 mmol) and diisopropylethylamine (1.2 mL, 6.95 mmol). The reaction mixture was stirred overnight. The volatiles were removed under reduced pressure and the residue was purified using silicagel column chromatography using a heptane to EtOAc gradient. The collected fractions were concentrated under reduced pressure and purified again using silicagel column chromatography using a heptane to EtOAc gradient yielding compound 19 (409 mg) as a white powder. Method B; Rt: 1.08 min. m/z : 435.1 (M-H)~ Exact mass: 436.0; 1H NMR (400 MHz, DMSO-de) delta ppm 1.55 (s, 3 H), 2.72 (s, 3 H), 4.19 (d, J=6.4 Hz, 2 H), 4.61 (d, J=6.2 Hz, 2 H), 7.75 - 7.86 (m, 2 H), 8.01 (s, 1 H), 8.65 (s, 1 H), 10.40 (s, 1 H).
  • 18
  • [ 874473-14-0 ]
  • 5-methyl-4-[[3-(trifluoromethyl)phenyl]carbamoyl]thiophene-2-sulfonyl chloride [ No CAS ]
  • 2-methyl-S-[(3-methyloxetan-3-yl)sulfamoyl]-N-[3-(trifluoromethyl)phenyl]thiophene-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
58.5 mg With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; 5-methyl-4-[[3-(trifluoromethyl)phenyl]carbamoyl]thiophene-2-sulfonyl chloride (100 mg) was dissolved in dichloromethane (10 mL). <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (34.05 mg, 0.39 mmol) and diisopropylethylamine (0.13 mL, 0.78 mmol) were added and the reaction mixture was stirred overnight at room temperature. The precipitate was filtered off, triturated with diisopropylether and dried in a vacuum oven at 50C yielding compound 22 (58.5 mg)_as a white powder. Method B; Rt: 1.05 min. m/z : 433.1 (M-H)~ Exact mass: 434.1; 1H NMR (400 MHz, DMSO-d6) delta ppm 1.55 (s, 3 H), 2.73 (s, 3 H), 4.20 (d, J=6.4 Hz, 2 H), 4.61 (d, J=5.9 Hz, 2 H), 7.46 (d, J=7.9 Hz, 1 H), 7.59 (t, J=7.9 Hz, 1 H), 7.98 (d, J=8.6 Hz, 1 H), 8.04 (s, 1 H), 8.18 (s, 1 H), 8.63 (s, 1 H), 10.42 (s, 1 H).
  • 19
  • [ 874473-14-0 ]
  • 4-[(3-cyano-4-fluoro-5-methyl-phenyl)carbamoyl]-5-methyl-thiophene-2-sulfonyl chloride [ No CAS ]
  • N-(3-cyano-4-fluoro-5-methylphenyl)-2-methyl-5-[(3-methyloxetan-3-yl)sulfamoyl]thiophene-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
56.8 mg With triethylamine; In dichloromethane; at 20℃; for 2h; 4-[(3-cyano-4-fluoro-5-methyl-phenyl)carbamoyl]-5-methyl-thiophene-2-sulfonyl chloride (175 mg, 0.47 mmol) was dissolved in CH2CI2 (10 mL). <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (52 mg, 0.6 mmol) and triethylamine (80 mg, 0.79 mmol) were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the separated organic layer was washed with water, dried over Na2S04 and evaporated to dryness to provide an oil. The residue was purified by preparative high performance liquid chromatography over RP-18 (eluent: CH3CN in H20 (0.1 % FA) from 20% to 60%, v/v). The pure fractions were collected and evaporated to dryness to provide compound 44 (56.8 mg) as a white solid. Method G; Rt: 4.63 min. m/z: 441.1 (M+NH4)+ Exact mass: 423.1. 1H NMR (400MHz, DMSO-d6) delta ppm 10.37 (s, 1H), 8.65 (s, 1H), 8.04 - 7.88 (m, 3H), 4.61 (d, J=6.0 Hz, 2H), 4.19 (d, J=6.5 Hz, 2H), 2.72 (s, 3H), 2.30 (d, J=2.0 Hz, 3H), 1.55 (s, 3H).
  • 20
  • [ 874473-14-0 ]
  • 5-[(3-bromo-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride [ No CAS ]
  • N-(3-bromo-4,5-difluoro-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
707 mg With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 120h; To one third of the above mixture containing 5-[(3-bromo-4,5-difluoro- phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride, Isopropylamine (7.3 mL, 85.4 mmol)and DIPEA (2.2 mL, 12.8 mmol) in CH2C12 (70 mL) was added. The reaction mixture was stirred at room temperature. After a few seconds the homogeneous mixture became a suspension. The solids were filtered, washed with CH2C12 (4 mL) and dried overnight in vacuo resulting in compound 46 (1.02 g) as an off white powder.Compound 48 was prepared similarly as described for compound 46 using <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (4 equiv) instead of isopropylamine. After addition of <strong>[874473-14-0]3-methyl-3-oxetanamine</strong>, the mixture was stirred for 5 days. The formed precipitate was filtered, washed with CH2C12 and dried in vacuo, resulting in compound 48 (707 mg) as an off white powder. Method B; Rt: 1.00 mi mlz :464.0 (M-H) Exact mass: 465.0. ?H NMR (400 MHz, DMSO-d6) oeppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.59 (d, J=6.2 Hz, 2 H), 7.35 (d, J=2.0 Hz, 1 H), 7.62 (d,J=1.8 Hz, 1 H), 7.84 (td, J=6.3, 2.5 Hz, 1 H), 7.89 (ddd, J=7.7, 5.1, 2.4 Hz, 1 H), 7.98 (br. s., 1 H), 10.28 (br. s., 1 H).
  • 21
  • [ 69812-32-4 ]
  • [ 874473-14-0 ]
  • methyl 1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
6.07 g With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 2h;Reflux; Methyl 4- (chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate (5 g, 1.04 mmol) was dissolved in acetonitrile (50 mL). diisopropylethylamine (9.06 mL, 52.6 mmol) was added, followed by 3- methyl-3-oxetanamine (1.92 g, 22.1 mmol) and the resulting mixture was refluxed for 2 hours. Then, the mixture was cooled to room temperature and concentrated in vacuo. The resultingresidue was dissolved in dichloromethane (250 mL) and this was washed with HC1 (2 x 150 mL).The organics were dried on sodium sulphate, filtered and concentrated in vacuo yielding methyl1 -methyl-4-[(3 -methyloxetan-3 -yl)sulfamoyl] - 1H-pyrrole-2-carboxylate (6.07 g) as a beigepowder which was used as such. Method B; Rt: 0.63 mm. mlz :287.1 (M-H) Exact mass: 288.1.
6.07 g With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 2h;Reflux; Chlorosulfonic acid (80 mL) was cooled to 0C and methyl l-methylpyrrole-2-carboxylate (20 g, 143.73 mmol) was added dropwise. After addition, the mixture was allowed to reach room temperature and stirred for another hour. The resulting mixture was added drop wise to a mechanically stirred, temperature controlled, ice-water mixture (1500 mL) keeping the temperature under 5C. A white precipitation was formed. The obtained aqueous mixture was extracted using dichloromethane (3 x 500 mL). The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo yielding methyl 4-(chlorosulfonyl)-l -methyl- 1H- pyrrole -2-carboxylate (29.4 g) as a white powder which was used as such. Methyl 4-(chloro- sulfonyl)-l -methyl- lH-pyrrole-2-carboxylate (5 g, 1.04 mmol) was dissolved in acetonitrile (50 mL). diisopropylethylamine (9.06 mL, 52.6 mmol) was added, followed by 3-methyl-3- oxetanamine (1.92 g, 22.1 mmol) and the resulting mixture was refluxed for 2 hours. Then, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (250 mL) and this was washed with HC1 (2 x 150 mL). The organics were dried on sodium sulphate, filtered and concentrated in vacuo yielding methyl l-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-lH-pyrrole-2-carboxylate (6.07 g) as a beige powder which was used as such. Method B; Rt: 0.63 min.m/z : 287.1 (M-H)" Exact mass: 288.1. Methyl l-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-lH-pyrrole-2-carboxylate (6.07 g, 21.05 mmol) was dissolved in tetrahydrofuran (60 mL). Lithium hydroxide (0.76 g, 31.58 mmol) in distilled water (8 mL) was added, followed by methanol (3 mL). The resulting mixture was stirred for 72 hours. Next, it was concentrated until only water remained and extra distilled water (15 mL) was added. After neutralization with hydrochloric acid (1M / aq / 31.6 mL, (0180) 31.58 mmol). The resulting mixture was extracted using 2-methyltetrahydrofuran (3 x 20 mL). The combined extracts were dried on sodium sulphate, filtered and concentrated in vacuo yielding l-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-lH-pyrrole-2-carboxylic acid (5.77 g) as a bright white powder which was used as such. Method B; Rt: 0.26 min. m/z : 273.1 (Mu-Eta)" Exact mass: 274.1
  • 22
  • [ 874473-14-0 ]
  • 5-[(3-cyano-5-fluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride [ No CAS ]
  • N-(3-cyano-5-fluoro-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)-sulfamoyl]pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
630 mg In acetonitrile; A solution of 5- [(3 -cyano-5 -fluoro-phenyl)carbamoyl] -1 -methyl-pyrrole-3 -sulfonyl chloride(924 mg, 2.57 mmol) and <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (559 mg, 6.4 mmol) in acetonitrile (100 mL)was stirred overnight. Water was added untill crystallisation started. The crystals were filtered ofand dried overnight in vacuo at 50C, resulting in compound 54 (630 mg) Method A, Rt: 1.52minmlz: 391.1 (M-H)Exact mass: 392.1?H NMR (400 MHz, DMSO-d6) oe ppm 1.54 (s, 3 H), 3.93 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60(d, J5.9 Hz, 2 H), 7.38 (d, J2.0 Hz, 1 H), 7.52 - 7.58 (m, 1 H), 7.64 (d, J=1.5 Hz, 1 H), 7.93 -7.98 (m, 1 H), 7.98 - 8.01 (m, 2 H), 10.46 (s, 1 H).
  • 23
  • [ 874473-14-0 ]
  • 5-[(3-cyanophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride [ No CAS ]
  • N-(3-cyanophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.43 g With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;Molecular sieve; A solution of <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (0.271 g, 3.11 mmol) in CH3CN (10 mL, p.a. dried on molecular sieves ) was added to a stirring solution of 5-[(3-cyanophenyl)carbamoyl]-1- methyl-pyrrole-3-sulfonyl chloride (1.00 g, 3.11 mmol) in CH3CN (40 mL, p.a. dried onmolecular sieves). DIPEA (1.07 mL, 6.21 mol ) was added, and the reaction mixture was stirred at room temperature for 18 hours. The volatiles were evaporated. The residue was purified by silica gel column chromatography using EtOAc-heptane 0/100 to 100/0 as eluent. The desired fractions were combined and evaporated. The residue was stirred in CH2C12 (4 mL), filtered off, washed with CH2C12 (3x), and dried in vacuo at 50C, resulting in compound 55 (0.43 g).Method A; Rt: 1.42 mi mlz: 373.0 (M-H) Exact mass: 374.1. ?H NMR (400 MHz, DMSO-d6)oe ppm 1.55 (s, 3 H), 3.93 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J5.9 Hz, 2 H), 7.38 (d, J2.0Hz, 1 H), 7.50 - 7.59 (m, 2 H), 7.61 (d, J=1.5 Hz, 1 H), 7.85-8.10 (m, 2 H), 8.16 - 8.24 (m, 1 H),10.00 - 10.67 (m, 1 H).
  • 24
  • [ 874473-14-0 ]
  • 5-[(2,6-dideuterio-4-fluoro-3-methyl-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride [ No CAS ]
  • N-(2,6-dideuterio-4-fluoro-3-methyl-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
532 mg With N-ethyl-N,N-diisopropylamine; In dichloromethane; <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (491 mg, 5.63 mmol) and DIPEA (0.97 mL, 5.63 mmol) were added to a solution of 5 -[(2,6-dideuterio-4-fluoro-3 -methyl-phenyl)carbamoyl] -1 -methyl-pyrrole-3 -sulfonylchloride (750 mg, 2.25 mmol) in dichloromethane (100 mL) and stirred overnight and concentrated in vacuo at 50C. The residue was dissolved in EtOAc (150 mL), washed twice with 1M HC1, water and saturated NaHCO3 solution. The solution was dried over sodium sulphate, filtered and concentrated. The residue was dissolved in warm EtOAc (75 mL) and the product crystallized upon addition of heptane (350 mL) The white crystals were filtered off anddried overnight in vacuo at 50C, resulting in compound 56 (532 mg). Method A, Rt: 1.56 mm mlz: 382.1 (M-H)Exact mass: 383.1. ?H NMR (400 MHz, DMSO-d6) oe ppm 1.55 (s, 3 H), 2.23 (d, J2.0 Hz, 3 H), 3.91 (s, 3 H), 4.13 (d, J6.4 Hz, 2 H), 4.60 (d, J=5.9 Hz, 2 H), 7.09 (d, J=9.5 Hz, 1 H), 7.32 (d, J=2.0 Hz, 1 H), 7.56 (d, J=1.8 Hz, 1 H), 7.94 (s, 1 H), 10.02 (s, 1 H).
  • 25
  • [ 874473-14-0 ]
  • 5-[(3-chloro-4,5-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride [ No CAS ]
  • N-(3-chloro-4,5-difluoro-phenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
677 mg In acetonitrile; for 0.5h;Reflux; A mixture of 5 -[(3 -chloro-4,5 -difluoro-phenyl)carbamoyl] -1 -methyl-pyrrole-3 -sulfonyl chloride (1.0 g, 2.57 mmol) <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (560 mg, 6.43 mmol) and acetonitrile (100 mL) was refluxed 30 minutes. The reaction mixture was cooled to 20C and diluted with water (350 mL). The product crystallized, was filtered off and dried in vacuo overnight yielding compound 59 as a beige powder (677 mg). Method A, Rt: 1.77 mm mlz: 418.0 (M-H) Exact mass: 419.1. ?HNMR (400 MHz, DMSO-d6) oe ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J=6.2 Hz, 2 H), 7.34 (d, J2.0 Hz, 1 H), 7.62 (d, J1.8 Hz, 1 H), 7.74 - 7.87 (m, 2 H), 7.98 (s, 1 H), 10.30 (s, 1 H).
  • 26
  • [ 874473-14-0 ]
  • ethyl 4-chlorosulfonyl-3-fluoro-1-methyl-pyrrole-2-carboxylate [ No CAS ]
  • ethyl 3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; at 20℃; for 1h; A mixture of crude 5-ethoxycarbonyl-4-fluoro- 1 -methyl-pyrrole-3-sulfonic acid (2318 mg) in thionylchloride (20 mL) was heated at 80C during 30 minutes. The solution was concentrated and the residue (containing ethyl 4-chlorosulfonyl-3 -fluoro- 1 -methyl-pyrrole-2-carboxylate) dissolved inacetonitrile (25 mL). <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (3035 mg, 34.84 mmol) dissolved in acetonitrile (20 mL) was added and the raction mixture was stirred 1 hour at room temperature. The reaction mixture was concentrated. The obtained residue was dissolved in dichloromethane (200 mL), washed with water, dried over sodium sulphate, filtered and concentrated. The residue was purified by column chromatography on silica using a gradient from 5 to 100% EtOAc in heptane.The product fractions were concentrated in vacuo yielding ethyl 3-fluoro-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate (1900 mg) as a white powder. ?H NMR (400MHz, DMSO-d6) oe ppm 1.28 (t, J=7.2 Hz, 3 H), 1.52 (s, 3 H), 3.83 (s, 3 H), 4.15 (d, J=6.4 Hz, 2H), 4.27 (q, J=7.0 Hz, 2 H), 4.61 (d, J=5.9 Hz, 2 H), 7.57 (d, J=4.6 Hz, 1 H), 8.28 (s, 1 H).
  • 27
  • [ 874473-14-0 ]
  • 5-[(3,5-dichloro-4-fluorophenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride [ No CAS ]
  • N-(3,5-dichloro-4-fluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (407.3 mg, 4.68 mmol) was added to crude 5-[(3,5-dichloro-4-fluoro-phenyl)carbamoyl]- 1 -methyl-pyrrole-3-sulfonyl chloride (601 mg) in acetonitrile (57 mL)and stirred overnight. Water was added untill crystallisation began. The formed white crystalswere filtered off and dried in vacuo at 50C during 4 hours. Compound 75 was recrystallizedfrom EtOAc upon addition of heptane. The white crystals (346 mg) were filtered off and dried in vacuo at 50C over weekend. ?H NMR (400 MHz, DMSO-d6) oe ppm 1.54 (s, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J5.9 Hz, 2 H), 7.35 (d, J2.0 Hz, 1 H), 7.62 (d, J=1.8 Hz, 1 H),7.95 (d, J=6.2 Hz, 2 H), 7.99 (s, 1 H), 10.27 (s, 1 H). Method A; Rt: 1.77 mi mlz :434.0 (MH) Exact mass: 435.0.
  • 28
  • [ 874473-14-0 ]
  • ethyl 4-(chlorosulfonyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxylate [ No CAS ]
  • ethyl 1,3,5-trimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100 mg In acetonitrile; at 20℃; for 2h; Crude ethyl 4-chlorosulfonyl- 1,3,5 -trimethyl-pyrrole-2-carboxylate (500 mg) was dissolved in acetonitrile (50 mL) and <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (622.9 mg, 7.15 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water (100 mL) was added and themixture was extracted with CH2C12 (3 x 50 mL) and the combined organic layers were washed with brine, dried and evaporated to afford a brown sticky oil. The oil was purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) resulting in ethyl 1,3,5- trimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate (100 mg) as a white solid. Method B; Rt: 0.83 mi mlz :329.1 (M-H) Exact mass: 330.1.
  • 29
  • [ 874473-14-0 ]
  • [ 216697-71-1 ]
  • ethyl 1,5-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 42h; Crude ethyl 4-chlorosulfonyl-1,5-dimethyl-pyrrole-2-carboxylate (1500 mg, 5.65 mmol was dissolved in acetonitrile (15 mL). Hunig?s base (2.4 mL, 14.1 mmol) and <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (639 mg, 7.33 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 42 hours. Water was added and the mixture was extracted with CH2C12 (2 x 50 mL) and EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4) and evaporatedto dryness. The obtained crude ethyl 1 ,5-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2- carboxylate (1.8 g) was used as such. Method B; Rt: 0.77 mm. mlz: 315.1 (M-H) Exact mass: 316.1.
  • 30
  • [ 874473-14-0 ]
  • ethyl 4-chlorosulfonyl-1,3-dimethyl-pyrrole-2-carboxylate [ No CAS ]
  • ethyl 1,3-dimethyl-4-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
302 mg With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 1h; Crude ethyl 4-chlorosulfonyl-1,3-dimethyl-pyrrole-2- carboxylate (1.3 g, 4.89 mmol) was dissolved in acetonitrile (5 mL) and <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (852 mg, 9.79 mmol) was adedd followed by Hunig?s base (2.11 mL, 12.23 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered. The solids were washed with CH2C12 and discarded. The filtrate was evaporated and the residue waspurified using silica gel column chromatography ethyl acetate in heptane from 0 to 100% resulting in ethyl 1,3 -dimethyl-4-[(3 -methyloxetan-3 -yl)sulfamoyl]pyrrole-2-carboxylate (302 mg) as sticky oil. Method B; Rt: 0.79 mi mlz: 315.1 (M-H) Exact mass: 316.1.
  • 31
  • [ 874473-14-0 ]
  • 5-[(3-chloro-2,4-difluoro-phenyl)carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride [ No CAS ]
  • N-(3-chloro-2,4-difluorophenyl)-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; at 20℃; for 18h;Inert atmosphere; Sealed tube; 5 -[(3 -chloro-2,4-difluoro-phenyl)carbamoyl] -1 -methyl-pyrrole-3 -sulfonyl chloride(900mg, 2.44 mmol) prepared similarly as in the synthesis for compound 57 3-chloro-2,4-difluoro-aniline (3.Sg, 14.46 mmol) was stirred in dry CH3CN (10 mL). <strong>[874473-14-0]3-methyloxetan-3-amine</strong>(255 mg, 2.93mmol) was added under N2-atm. The reaction mixture was stirred in a sealed tubeat room temperature for 18 h. The solvent was evaporated. The residue was stirred in CH2C12. The formed precipitate was filtered off [fraction 1]. The filtrate was evaporated and the residue was dissolved in CH2C12/MeOH (9/1, 5 mL) and purified by Flash Chromatography [Biotage Isolera 1/I GraceResolve Silica 12 gIl EtOAc-heptane 0/100 to 100/0 ]. The desired fractionswere combined and the solvent was evaporated leaving a white solid which was recrystallized in diisopropyl ether/CH3 CN (1:1; 6 mL), left stirring for 2 h then left standing for 18 h, filtered off and dried in vacuo at 50C yielding white powder which was combined with fraction 1. Method B; Rt: 0.88 mi mlz: 418.0 (M-H) Exact mass: 419.05.1H NMR (400 MHz, DMSO-d6) oe ppm 1.55 (s, 3 H), 3.89 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J5.9 Hz, 2 H), 7.31 - 7.38 (m, 2 H),7.53 (td, J=8.7, 5.8 6 Hz, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.98 (br. s., 1 H), 10.14 (br. s., 1 H).
  • 32
  • [ 874473-14-0 ]
  • 5-[[3-(1,1-difluoroethyl)-4-fluoro-phenyl]carbamoyl]-1-methyl-pyrrole-3-sulfonyl chloride [ No CAS ]
  • N-[3-(1,1-difluoroethyl)-4-fluorophenyl]-1-methyl-4-[(3-methyloxetan-3-yl)sulfamoyl]-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
514 mg In acetonitrile; for 17h; <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (390 mg, 4.47 mmol) was added to a solution of5 -[[3 -(1,1 -difluoroethyl)-4-fluoro-phenyl]carbamoyl] -1 -methyl-pyrrole-3 -sulfonyl chloride (605 mg, 1.49 mmol) in CH3CN (5OmL) and stirred 17 hr. Water was added untill crystallisation began. The white powder was filtered off and dried overnight in vacuo at 5 0C, resulting incompound 161 (514 mg); Method A; Rt: 1.70 mi mlz :430.1 (M-H) Exact mass: 431.11. ?H NMR (400 MHz, DMSO-d6) oe ppm 1.55 (s, 3 H), 1.95 - 2.06 (m, 3 H), 3.92 (s, 3 H), 4.14 (d, J=6.4 Hz, 2 H), 4.60 (d, J5.9 Hz, 2 H), 7.35 (d, J2.0 Hz, 2 H), 7.59 (d, J=1.8 Hz, 1 H), 7.85 - 7.92 (m, 1 H), 7.93 - 8.02 (m, 2 H), 10.23 (s, 1 H).
  • 33
  • [ 874473-14-0 ]
  • 2-(5-((3,4-difluorophenyl)carbamoyl)-1-methyl-1H-pyrrol-3-yl)-2-oxoacetic acid [ No CAS ]
  • N-(3,4-difluorophenyl)-1-methyl-4-(2-(3-methyloxetan-3-ylamino)-2-oxoacetyl)-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
221 mg Compound 11 : N-(3 ,4-difluorophenyl)- 1 -methyl-4-(2-(3 -methyloxetan-3 -ylamino)- 2- oxoacetyl)-lH-pyrrole-2-carboxamide A solution of crude 2-(5-(3,4-difluorophenylcarbamoyl)-l-methyl-lH-pyrrol-3-yl)-2- oxoacetic acid (roughly 1.4 mmol; as described in the procedure for the synthesis of Compound 10) in 10 mL DMF was mixed with triethylamine (776 mu, 5.58 mmol) and 2-(7-aza- 1 H-benzotriazole- 1 -yl)- 1,1,3,3 -tetramethyluronium hexafluorophosphate (HATU, 637 mg, 1.67 mmol) and stirred for 10 min at room temperature. 3-Methyl-3-oxetanamine (243 mg, 2.79 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured out into 100 mL water and the precipitate was filtered off and washed with water. The solid residue was re-crystallized from a mixture of 10 mL MeOH and 5 mL water, filtered off and dried in vacuum to afford N-(3,4-difluoro- phenyl)-l-methyl-4-(2-(3-methyloxetan-3-ylamino)-2-oxoacetyl)-lH-pyrrole-2-carboxamide (Compound 11, 221 mg) as a beige powder, mp = 180.7C. LC method B; Rt: 0.92 min. m/z : 376.2 (Mu-Eta)" Exact mass: 377.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.58 (s, 3 H), 3.96 (s, 3 H), 4.35 (d, J=6.6 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.36 - 7.45 (m, 1 H), 7.48 - 7.56 (m, 1 H), 7.68 (d, J=1.5 Hz, 1 H), 7.89 (ddd, J=13.4, 7.5, 2.4 Hz, 1 H), 8.20 (br. d, J=l .l Hz, 1 H), 9.27 (br. s, 1 H), 10.26 (br. s, 1 H).
  • 34
  • [ 874473-14-0 ]
  • 2-(1-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)-1H-pyrrol-3-yl)-2-oxoacetic acid [ No CAS ]
  • 1-methyl-4-(2-(3-methyloxetan-3-ylamino)-2-oxoacetyl)-N-(3-(trifluoro-methyl)phenyl)-1H-pyrrole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
316 mg Compound 13: l-methyl-4-(2-(3-methyloxetan-3-ylamino)-2-oxoacetyl)-N-(3-(trifluoro- methyl)phenyl)-lH-pyrrole-2-carboxamide A solution of crude 2-(l-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)-lH-pyrrol-3-yl)-2- oxoacetic acid (roughly 0.88 mmol; as described in the procedure for the synthesis of Compound 12) in 5 mL of DMF was mixed with triethylamine (490 mu, 2.65 mmol) and 2-(7-aza- 1 H-benzotriazole- 1 -yl)- 1,1,3,3 -tetramethyluronium hexafluorophosphate (HATU, 1005 mg, 2.65 mmol) and stirred for 10 min at room temperature. 3-Methyl-3-oxetanamine (230 mg, 2.65 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured out into 100 mL water and the precipitate was filtered off and washed with water. The solid residue was dried in vacuum to afford l-methyl-4-(2-(3-methyloxetan-3-ylamino)-2-oxoacetyl)-N-(3-(trifluoromethyl)phenyl)-lH- pyrrole-2-carboxamide (Compound 13, 316 mg) as an amorphous white powder. LC method B; Rt: 1.01 min. m/z : 408.2 (Mu-Eta)" Exact mass: 409.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.58 (s, 3 H), 3.97 (s, 3 H), 4.35 (d, J=6.6 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.43 (d, J=7.7 Hz, 1 H), 7.58 (br. t, J=7.9, 7.9 Hz, 1 H), 7.74 (d, J=1.8 Hz, 1 H), 7.98 - 8.04 (m, 1 H), 8.18 - 8.24 (m, 2 H), 9.28 (s, 1 H), 10.36 (s, 1 H).
  • 35
  • [ 874473-14-0 ]
  • methyl 4-(2-chloro-2-oxoacetyl)-1-methylpyrrole-2-carboxylat [ No CAS ]
  • methyl 1-methyl-4-[2-[(3-methyloxetan-3-yl)amino]-2-oxo-acetyl]pyrrole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
839 mg With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 1h;Inert atmosphere; Compound 16 : N-(3 -Cyano-4-fluorophenyD- 1 -methyl-4- { [(3 -methyloxetan-3 -yOamino] - (oxo)acetyll - 1 H-pyrrole-2-carboxamide Oxalylchloride (7.41 mL, 0.086 mol) was added slowly to a stirring solution of methyl l-methylpyrrole-2-carboxylate (6 g, 0.0431 mol ) in dichloroethane (30 mL ). The reaction mixture was stirred as an open vessel for 1 minute, then stirred in a closed vessel at T-int = 38C (oil-bath = 45C) for 3 hours, and at room temperature for 18 hours. Methyl 4-(2-chloro-2-oxo-acetyl)-l -methyl -pyrrole-2-carboxylate (1.45 g) was filtered off, washed with dichloroethane (2x), and used as such. Methyl 4-(2-chloro-2-oxo-acetyl)-l-methyl- pyrrole-2-carboxylate (1.45 g, 6.32 mmol) was added portionwise to a stirring solution of 3 -methyloxetan-3 -amine (1.1 g, 12.6 mmol), DIPEA (2.2 mL, 12.6 mmol), in acetonitrile (50 mL) under N2-atm. The reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated. The residue was stirred in H20 (15 mL), filtered off, washed with H20 (3x), and dried at 50C, resulting in methyl l-methyl-4-[2-[(3-methyloxetan-3-yl)- amino]-2-oxo-acetyl]pyrrole-2-carboxylate (839 mg). LC method A; Rt: 1.29 min. m/z : 278.9 (M-H)~ Exact mass:.280.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.56 (s, 3 H), 3.78 (s, 3 H), 3.93 (s, 3 H), 4.34 (d, J=6.6 Hz, 2 H), 4.70 (d, J=6.4 Hz, 2 H), 7.37 (d, J=2.0 Hz, 1 H), 8.20 (d, J=1.3 Hz, 1 H), 9.25 (s, 1 H). NaOH (1M in H20, 6.6 mL) was added to a stirring mixture of methyl l-methyl-4-[2-[(3-methyloxetan-3-yl)amino]-2-oxo-acetyl]- pyrrole-2-carboxylate (939 mg, 2.99 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 5 h. HC1 IN (7 mL) was added slowly, and precipitation occurred. After stirring for 10 minutes, the mixture was left standing for 16 hours, filtered off, washed with H20-MeOH 3/1 (2x), and dried at 50C in vacuo resulting in 1 -methyl -4- [2-[(3-methyloxetan-3-yl)amino]-2-oxo-acetyl]pyrrole-2-carboxylic acid (0.66 g). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.56 (s, 3 H), 3.92 (s, 3 H), 4.34 (d, J=6.6 Hz, 2 H), 4.70 (d, J=6.4 Hz, 2 H), 7.31 (d, J=1.8 Hz, 1 H), 8.15 (d, J=1.5 Hz, 1 H), 9.22 (s, 1 H), 12.80 (br. s., 1 H). Triethylamine (0.504 mL, 3.63 mmol ) was added to a stirring mixture of 1 -methyl -4- [2-[(3-methyloxetan-3-yl)amino]-2-oxo-acetyl]pyrrole-2-carboxylic acid (0.322 g, 1.21 mmol ), and CH3CN (dried on molecular sieves, 7.5 mL ) under N2-atm. To the resulting solution was added 5-amino-2-fluorobenzonitrile (0.187 g, 1.33 mmol) then HATU (0.483 g, 1.27 mmol ). The reaction mixture was stirred at 50C for 18 hours. The reaction mixture was allowed to reach room temperature, and poured slowly into stirring H20 (25 mL). After stirring for 10 minutes, the product was filtered off, washed with H20 (3x), and dried at 50C in vacuo, resulting in compound 16 (291 mg). LC method A; Rt: 1.55 min. m/z : 383.0 (M-H)~ Exact mass: 384.1. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.58 (s, 3 H), 3.96 (s, 3 H), 4.35 (d, J=6.6 Hz, 2 H), 4.72 (d, J=6.4 Hz, 2 H), 7.53 (dd, J=9.1 Hz, 1 H), 7.71 (d, J=1.8 Hz, 1 H), 8.04 (ddd, J=9.2, 4.8, 2.6 Hz, 1 H), 8.20 - 8.26 (m, 2 H), 9.28 (s, 1 H), 10.40 (s, 1 H).
  • 36
  • [ 874473-14-0 ]
  • (S)-ethyl 2-(3-((4-fluoro-3-methylphenyl)carbamoyl)pyrrolidin-1-yl)-2-oxoacetate [ No CAS ]
  • (3S)-N-(4-fluoro-3-methylphenyl)-1-[(3-methyloxetan-3-yl)amino](oxo)acetyl}pyrrolidine-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethanol; at 50℃; for 168h; Compound 7 was made according to the method described for compound 4 with the exception that in step 3, 3 -methyloxetan-3 -amine (2 eq.) was employed instead of isopropylamine. The reaction proceeded at 50 C for 1 week instead of at room temperature for three days as described for compound 4. Method B, Rt = 0.73 min, m/z = 364.4 (M+H)+, exact mass: 363.2. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.49 - 1.56 (m, 6 H), 1.93 - 2.22 (m, 5 H), 2.19 - 2.21 (m, 6 H), 3.07 - 3.25 (m, 2 H), 3.37 - 3.47 (m, 2 H), 3.50 - 3.60 (m, 2 H), 3.62 - 3.75 (m, 2 H), 3.76 - 3.89 (m, 2 H), 3.98 (dd, J=1 1.6, 7.6 Hz, 1 H), 4.27 - 4.35 (m, 4 H), 4.60 - 4.70 (m, 4 H), 7.01 - 7.1 1 (m, 1 H), 7.35 - 7.45 (m, 1 H), 7.49 - 7.57 (m, 2 H), 9.20 (br. s., 1 H), 9.25 (s, 1 H), 10.10 (br. s., 1 H), 10.12 (s, 1 H), as a mixture of rotamers.
  • 37
  • [ 874473-14-0 ]
  • 2-((2S,3S)-3-((4-fluoro-3-methylphenyl)carbamoyl)-2-methylpyrrolidin-1-yl)-2-oxoacetic acid [ No CAS ]
  • (2S,3S)-N-(4-fluoro-3-methylphenyl)-2-methyl-1-[(3-methyloxetan-3-yl)amino](oxo)acetyl}pyrrolidine-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; To a solution of 2-((2S,3S)-3- ((4-fluoro-3-methylphenyl)carbamoyl)-2-methylpyrrolidin-l-yl)-2-oxoacetic acid (128 mg, 0.42 mmol), HATU (236.79 mg, 1.5 eq) and DIPEA (145 mu,, 2 eq) in CH2C12 (5 mL) was added <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (36 mg, 0.42 mmol) and the reaction mixture was stirred overnight at room temperature. To the reaction mixture was added CH2CI2 and HCl (1M, aq.). The layers were separated and the organic layer was washed with NaHC03 (sat., aq.) and brine. The combined organic layers were dried over Na2S04, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude was purified by preparative HPLC (stationary phase: RP X-Bridge Prep CI 8 OBD-10 muiotaeta, 30 x 150 mm), mobile phase: 0.25% NH4HC03 solution in water, CH3CN). The best fractions were pooled and the solvent was removed under reduced pressure to afford the title compound 10. Method C, Rt = 1.46 min, m/z = 376.0 (M-H)", exact mass: 377.2. 1H NMR (400 MHz, DMSO-d6) delta ppm 0.99 - 1.05 (m, 6 H), 1.53 (m, J=4.2 Hz, 6 H), 1.86 - 2.05 (m, 2 H), 2.18 - 2.23 (m, 6 H), 2.25 - 2.36 (m, 2 H), 3.02 - 3.23 (m, 2 H), 3.38 - 3.70 (m, 3 H), 3.83 - 3.95 (m, 1 H), 4.27 - 4.35 (m, 4 H), 4.46 - 4.57 (m, 1 H), 4.60 - 4.66 (m, 4 H), 4.81 - 4.94 (m, 1 H), 6.99 - 7.12 (m, 2 H), 7.33 - 7.42 (m, 2 H), 7.45 - 7.55 (m, 2 H), 9.17 (s, 1 H), 9.26 (s, 1 H), 9.94 (s, 1 H), 10.00 (s, 1 H), as a 1/1 mixture of rotamers.
  • 38
  • [ 874473-14-0 ]
  • N-(3-methyloxetan-3-yl)-6-[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 48 N-(3-methyloxetan-3-yl)-6-[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide The titled compound was prepared using the reaction conditions described for Example 9A, substituting <strong>[874473-14-0]3-methyloxetan-3-amine</strong> for 2,5-dihydro-1H-pyrrole. 1H NMR (300 MHz, DMSO-d6) delta ppm 9.40 (s, 1H), 8.62 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.31 (m, 1H), 8.21 (d, J=9.2 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.93 (d, J=2.7 Hz, 1H), 7.77 (m, 1H), 7.41 (d, J=8.5 Hz, 1H), 4.82 (d, J=6.4 Hz, 2H), 4.42 (d, J=6.4 Hz, 2H), 1.67 (s, 3H); MS (ESI+) m/z 404.1 [M+H]+.
  • 39
  • 6-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
  • [ 874473-14-0 ]
  • [ 7087-68-5 ]
  • 6-((4-((3-methyloxetan-3-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
  • 6-((4-(dimethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
  • 6-((4-((2-(dimethylamino)-1-methoxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
8 mg; 3 mg; 3 mg In N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; Example 220: Preparation of 6-((4-((3-methyIoxetan-3-yI)amino)-5-(trifluoromethyI) pyrimidin-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one, 6-((4-(dimethylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one and 6-((4-((2- (dimethylamino)-l-methoxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 3,4-dihydroquinolin-2(lH)-one6-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one (0.070 g, 0.204 mmol), <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (0.01 8 g, 0.204 mmol) and N-ethyl-N- isopropylpropan-2 -amine (0.036 ml, 0.204 mmol) were mixed in DMF (1 ml). The mixture was microwaved at 130 C for 30 minutes and then concentrated. Added MeOH-water and filtered off the solid. Ran two separate reverse phase columns with the solid and the filtrate (water-MeCN eluent). 8 mg of 6-((4-((3-methyloxetan-3-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 3,4-dihydroquinolin-2(lH)-one, 3 mg of 6-((4-(dimethylamino)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3,4-dihydroquinolin-2( lH)-one and 3 mg of 6-((4-((2-(dimethylamino)-l - methoxypropan-2-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroquinolin-2(lH)-one were recovered after automated reverse phase chromatography (water-MeCN eluent). MS calcd for [C1 8H,gF3N502+H]+: 394.1 5, found 394.10. MS calcd for [Ci6H16F3N50+H]+: 352.14, found 352.25. MS calcd for [C2oH25F3N602+H]+: 439.21 , found 439.00.
  • 40
  • [ 874473-14-0 ]
  • [ 66405-41-2 ]
  • methyl 2-(4-((3-methyloxetan-3-yl)amino)cyclohexyl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Step 1: methyl 2-(4-((3-methyloxetan-3-yl)amino)cyclohexyl)acetate: A mixture of 3- methyloxetan-3-amine (104 mg, 1.20 mmol) and methyl 2-(4-oxocyclohexyl)acetate (170 mg, 1.00 mmol) in THF (20 ml) was treated with titanium(IV) isopropoxide (0.585 ml, 2.00 mmol) and stirred at RT under an atmosphere of N2 for 20 h. MeOH (2 ml) was added and stirring was continued for 30 min, then sodium borohydride (98 mg, 2.59 mmol) was added. The resultant mixture was stirred at RT for 1 h. The mixture was partitioned between DCM (100 ml) and saturated NaHC03(aq) (100 ml). The phases were separated and the organic phase was washed with brine (50 ml), dried over MgS04 and concentrated in vacuo. The residue was purified by column chromatography (12 g cartridge, 0-10% (0.7 M NH3/MeOH solution)/DCM) to afford the title compound (213 mg) as a colourless oil. This material was used in subsequent reactions without analysis.
  • 41
  • [ 874473-14-0 ]
  • 2-[3-bromo-5-methyl-N-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate [ No CAS ]
  • 1-(3-bromo-5-methylphenyl)-4-(3-methyloxetan-3-yl)piperazine [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With potassium carbonate; In 1,4-dioxane; at 160℃; for 16h;Microwave irradiation; A mixture of 2- [3 -bromo-5-methyl-N-(2-methylsulfonyloxyethyl)anilino] ethyl methanesulfonate YL-4b (220 mg, 0.51 mmol), <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (54 mg, 0.62 mmol) and K2C03 (212 mg, 1.53 mmol) in dioxane (15 mL) was microwaved at 160C for 16 h. ISCO purification of the crude material (12g silica; 10 % to 50% to 100% of EtOAc in hex) gave 1-(3- bromo-5-methyl-phenyl)-4-(3-methyloxetan-3-yl)piperazine YL-4c (85 mg, 51%). ?H NMR (300 MHz, CDC13) oe 6.86 (d, J = 1.8 Hz, 1H), 6.83 (s, 1H), 6.65 (s, 1H), 4.64 (d, J = 5.4 Hz, 2H), 4.29 (d, J = 5.8 Hz, 2H), 3.29 - 3.13 (m, 4H), 2.61 - 2.44 (m, 4H), 2.35 - 2.22 (m, 3H), 1.42 (s, 3H) ppm. ESI-MS m/z calc. 324.08, found 325.39 (M+1)+; Retention time: 0.64 minutes.
51% With potassium carbonate; In 1,4-dioxane; at 160℃; for 16h;Microwave irradiation; [00298] A mixture of 2-[3-bromo-5-methyl-N-(2- methylsulfonyloxyethyl)anilino]ethyl methanesulfonate (220 mg, 0.51 mmol), 3- methyloxetan-3-amine (54 mg, 0.62 mmol) and K2CO3 (212 mg, 1.53 mmol) in 1,4- dioxane (15 mL) was microwaved at 160 C for 16 h. The reaction mixture was diluted with ethyl acetate, washed with water, saturated NaHCC , saturated NaCl and dried. The excess solvent was evaporated under reduced pressure. The crude material was subjected to flash chromatography purification (12 g silica; 10% to 50% to 100% of ethyl acetate in hexanes) to give l-(3-bromo-5-methyl-phenyl)-4-(3- methyloxetan-3-yl)piperazine (85 mg, 51%). lH NMR (300 MHz, CDC13) delta 6.86 (d, J = 1.8 Hz, 1H), 6.83 (s, 1H), 6.65 (s, 1H), 4.64 (d, J = 5.4 Hz, 2H), 4.29 (d, J = 5.8 Hz, 2H), 3.29 - 3.13 (m, 4H), 2.61 - 2.44 (m, 4H), 2.35 - 2.22 (m, 3H), 1.42 (s, 3H) ppm. ESI-MS m/z calc. 324.08, found 325.39 (M+l)+; Retention time: 0.64 minutes.
  • 42
  • [ 874473-14-0 ]
  • ethyl (S)-5-(6-(tert-butylamino)-4-(trifluoromethyl)pyridin-3-yl)-4-(2-methylpyrrolidine-1-carbonyl)thiazole-2-carboxylate [ No CAS ]
  • 5-[6-(tert-butylamino)-4-(trifluoromethyl)-3-pyridyl]-N-(3-methyloxetan-3-yl)-4-[(2S)-2-methylpyrrolidine-1-carbonyl]thiazole-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethanol; at 100℃; for 44h;Inert atmosphere; To a microwave vial under N2 was added ethyl (S)-5-(6-(tert-butylamino)-4-(trifluoromethyl)pyridin-3-yl)-4-(2-methylpyrrolidine-1-carbonyl)thiazole-2-carboxylate (100 mg, 0.21 mmol, Intermediate 107), <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (47.4 muL, 1.03 mmol) and EtOH (0.98 mL), and the reaction was stirred at 100 C. for 21 h. An additional aliquot of <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (95 muL, 2.06 mmol) was added and the mixture stirred at 100 C. for 6 h. An additional aliquot of <strong>[874473-14-0]3-methyl-3-oxetanamine</strong> (95 muL, 2.06 mmol) was added and the mixture stirred at 100 C. for 17 h. The reaction mixture was cooled to rt and partitioned between EtOAc (20 mL) and saturated aqueous NH4Cl (20 mL). The layers were separated and the aqueous further extracted with EtOAc (2*15 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude residue was dissolved in DCM and purified by FCC (0-100% EtOAc/Hexanes) to provide the title compound. MS (ESI): mass calcd. for C24H30F3N5O3S, 525.6; m/z found, 526.2 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 8.19-8.11 (s, 1H), 7.55-7.43 (m, 1H), 6.65-6.59 (m, 1H), 5.06-4.97 (m, 1H), 4.95-4.88 (m, 2H), 4.58-4.51 (d, J=6.6 Hz, 2H), 4.24-4.13 (m, 1H), 3.60-3.31 (m, 2H), 2.08-1.99 (m, 1H), 1.93-1.82 (m, 2H), 1.77-1.70 (m, 3H), 1.56-1.45 (m, 1H), 1.45-1.41 (s, 9H), 1.22-1.19 (d, J=6.3 Hz, 2H), 1.07-1.02 (d, J=6.4 Hz, 1H).
  • 43
  • [ 874473-14-0 ]
  • 3-((4-chlorophenyl)amino)-1-((1S,2S)-2-cyano-4-oxocyclohexyl)-1H-pyrazole-4-carboxamide [ No CAS ]
  • 3-((4-chlorophenyl)amino)-1-((1S,2S,4S)-2-cyano-4-((3-methyloxetan-3-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide [ No CAS ]
  • 44
  • [ 3541-37-5 ]
  • [ 874473-14-0 ]
  • C13H13NOS [ No CAS ]
  • 45
  • [ 874473-14-0 ]
  • [5-bromo-3-((S)-1-methyl-2-oxo-ethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-methyl acetate [ No CAS ]
  • {5-bromo-3-[(S)-1-methyl-2-(3-methyl-oxetan-3-ylamino)-ethyl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}-methyl acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% With sodium tris(acetoxy)borohydride; sodium cyanoborohydride; acetic acid; In dichloromethane; at 20℃; for 20h; 440 mg (1.4 mmol) of [5-bromo-3-((S)-1-methyl-2-oxo-ethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-methyl acetate, 0.1 ml (1.4 mmol) of acetic acid and 0.1 ml (1.4 mmol) of <strong>[874473-14-0]3-methyloxetan-3-amine</strong> are diluted in 8.8 ml of dichloromethane. 409 mg (1.9 mmol) of sodium triacetoxyborohydride and 87 mg (1.4 mmol) of sodium cyanoborohydride are then added. Stirring at room temperature is maintained for 20 hours. The mixture is then poured into 1N aqueous solution of sodium hydroxide and then extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulphate, then filtered and concentrated to dryness. 220 mg (41%) of [5-bromo-3-[(S)-1-methyl-2-(3-methyl-oxetan-3-ylamino)-ethyl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}-methyl acetate is obtained in the form of a colourless oil.
  • 46
  • [ 874473-14-0 ]
  • [ 1572516-41-6 ]
  • [ 1572509-44-4 ]
  • 47
  • [ 874473-14-0 ]
  • C15H13ClFNO3S [ No CAS ]
  • [ 1572511-17-1 ]
  • 48
  • [ 874473-14-0 ]
  • C15H13ClFNO3S [ No CAS ]
  • [ 1572511-30-8 ]
  • 49
  • [ 874473-14-0 ]
  • isopropyl N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]phenyl]carbamate [ No CAS ]
  • C27H34N4O5S2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
9.10% With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos; In toluene; at 110℃; for 16h;Inert atmosphere; A mixture of isopropyl N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl] thiazol-2- yl]phenyl]carbamate (30.00 mg, 54.30 muiotaetaomicron, 1.00 eq.), <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (23.65 mg, 271.49 muiotaetaomicron, 5.00 eq.), Pd2(dba)3 (4.97 mg, 5.43 muiotaetaomicron, 0.10 eq.), Xphos (3.88 mg, 8.14 muiotaetaomicron, 0.15 eq.) and t-BuONa (5.74 mg, 59.73 muiotaetaomicron, 1.10 eq.) in toluene (2.00 mL) was stirred at 110C for 16 hrs under N2. LCMS showed the reaction was complete. The mixture was washed with water (30 mL) and the aqueous phase was extracted with EtOAc (30 mL X 3). The combined organic phase was dried, filtered and concentrated. The residue was purified by prep-TLC (PE:EtOAc = 1: 1) and prep-HPLC (TFA condition) to give compound 14 (2.78 mg, 4.94 muetaomicron, 9.10% yield, 99.36% purity) as a brown solid. 1H NMR (400MHz, METHANOL-d4) delta = 7.88 (d, J = 8.7 Hz, 2H), 7.80 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 6.67 (dd, J = 2.4, 8.3 Hz, 1H), 5.00 (td, J = 6.2, 12.5 Hz, 1H), 4.82 (d, J = 6.0 Hz, 2H), 4.63 (d, J = 6.0 Hz, 2H), 1.71 (s, 3H), 1.33 (d, J = 6.2 Hz, 6H), 1.14 (s, 9H). ESI [M+H] = 559.2
  • 50
  • [ 874473-14-0 ]
  • methyl (R)-2-methyl-1-(1-(4-oxocyclohexyl)ethyl)-1H-indole-3-carboxylate [ No CAS ]
  • methyl (R)-2-methyl-1-(1-(4-((3-methyloxetan-3-yl)amino)cyclohexyl)ethyl)-1H-indole-3 -carboxylate [ No CAS ]
  • methyl (R)-2-methyl-1-(1-(4-((3-methyloxetan-3-yl)amino)cyclohexyl)ethyl)-1H-indole-3 -carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of methyl (R)-2-methyl-l-(l-(4-oxocyclohexyl)ethyl)-lH-indole-3- carboxylate (300 mg, 957 umol, 1 equiv) and <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (250 mg, 2.9 mmol, 3 equiv) in dichloroethane (10 mL) was added Ti(Oi-Pr)4 (816 mg, 2.9 mmol, 847 uL, 3 equiv). The mixture was stirred at 15 C for 13 h. Sodium borohydride (217 mg, 5.7 mmol, 6 equiv) was then added to the mixture and stirred at 15 C for 2 h. The mixture was then diluted with saturated sodium bicarbonate (15 mL) and water (10 mL), extracted with dichloro methane (40 mL*3). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The crude was purified by column chromatography on silica gel to give B7 as a mixture of cis/trans isomers, methyl (R)-2-methyl- l-(l-(4-((3- methyloxetan-3-yl)amino)cyclohexyl)ethyl)- lH-indole-3-carboxylate (300 mg, 749 muiotaetaomicron, 78% yield) as a white solid. LCMS [M+H]+ m/z: calc'd 385.24; found 385.1.
  • 51
  • [ 874473-14-0 ]
  • C14H19NO2 [ No CAS ]
  • C18H28N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Compound 50-A (350 mg, 1.50 mmol, 1.0 eq), <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (223 mg, 3.0 mmol, 2.0 eq) and AcOH (180 mg, 3.0 mmol, 2.0 eq) were added into the 5 mL of MeOH, and the mixture was stirred at 80 C for 18 h. NaBH3CN (123 mg, 1.95 mmol, 1.3 eq) was added under ice-bath cooling, and the resulting mixture was stirred at 50 C for 4 h. TLC (PE: EA = 1:1) showed one new spot. The mixture was concentrated to remove the solvent. The residue was diluted with water (20 mL), adjusted to pH -10, extracted with EtOAc (15 mL x 4). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography on silica gel (PE: EA = (0904) 8: 1-1 : 1) to supply crude compound 50-B (270 mg, 59.2% yield) as off-white gum. (0905) 1HNMR: (400 MHz, CDCI3) d: 8.00 (s, 1H), 4.53 ( m, 2H), 4.41 (m, 2H), 3.11 (m, 1H), 2.28 - 2.22 (m, 1H), 2.16 - 2.10 (m, 1H), 1.69 - 1.61 (m, 4H), 1.60 - 1.51 (m, 2H), 1.49 (s, 3H), (0906) 1.46 - 1.41 (m, 1H), 1.32 - 1.31 (m, 3H), 1.22 (s, 3H), 1.10 (s, 3H).
  • 52
  • [ 874473-14-0 ]
  • (R)-2-(6-chloro-4-(1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)pyridin-2-yl)-4-(trifluoromethyl)isoindolin-1-one [ No CAS ]
  • 2-{4-[(2R)-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl]-6-[(3-methyloxetan-3-yl)amino]pyridin-2-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
6% With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; General procedure: To a degassed solution of (R)-2-(6-chloro-4-(l-(4-methyl-4H-l,2,4-triazol-3- yl)propan-2-yl)pyridin-2-yl)-4-(trifluoromethyl)isoindolin-l-one (150 mg, 0.34 mmol) in dioxane (2 mL) were added RNH2 (1.02 mmol), XantPhos (20 mg, 0.03 mmol), K3PO4 (146 mg, 0.69 mmol) and Pd(OAc)2 (8 mg, 0.03 mmol). The mixture was stirred at 100 C for 12 h under N2 atmosphere. The solvent was removed under vacuum to afford residue, which was purified by Prep-HPLC to give the desired products. The coupling reaction was carried out according to General Procedure 8 using 2-{6- chloro-4-[(2R)-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl]pyridin-2-yl}-4-(trifluoromethyl)- 2,3-dihydro- lH-isoindol-l -one (100 mg, 0.23 mmol, 1.0 eq.) and <strong>[874473-14-0]3-methyloxetan-3-amine</strong> (30 mg, 0.34 mmol, 1.5 eq.) as reactants to afford the title compound (7 mg, 6%) as an off-white solid: 'H NMR (500 MHz, DMSO-d6) d 8.36 (d, J = 1.4 Hz, 1H), 8.16 (t, J = 7.1 Hz, 2H), 7.87 (t, J = 7.7 Hz, 1H), 6.90 (s, 1H), 6.65 (s, 1H), 5.36 - 5.22 (m, 2H), 5.14 (d, J = 29.0 Hz, 1H), 4.39 - 4.28 (m, 2H), 4.08 (d, J = 12.2 Hz, 1H), 3.86 - 3.72 (m, 1H), 3.59 (s, 3H), 3.39 - 3.36 (m, 1H), 3.02 (qd, J = 15.5, 7.2 Hz, 2H), 1.27 (t, J = 3.5 Hz, 3H), 1.04 (d, J = 6.1 Hz, 3H); LCMS: C24H25F3N602requires: 486, found: m/z = 487 [M+H]+.
  • 53
  • [ 67443-38-3 ]
  • [ 874473-14-0 ]
  • 5-bromo-N-(3-methyloxetan-3-yl)-3-nitropyridin-2-amine [ No CAS ]
  • 54
  • [ 98556-31-1 ]
  • [ 874473-14-0 ]
  • (9-iodo-2-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanol [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With potassium carbonate; In acetonitrile; at 25 - 90℃; for 48h;Inert atmosphere; 3-Methyloxetan-3-amine (0.204 mL, 2.30 mmol) was added to <strong>[98556-31-1]4-chloro-6-iodoquinazoline</strong>(534 mg, 1.84 mmol) and potassium carbonate (508 mg, 3.68 mmol) in acetonitrile (10 mL) at25C under nitrogen. The resulting suspension was heated to 90C for 48 hours. The reactionmixture was concentrated onto silica and purified by flash silica chromatography, elutiongradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford (9-iodo-2-methyl-2,3-dihydroimidazo[1,2-c]quinazolin-2-yl)methanol (14 mg, 32% yield) as a whitesolid.
  • 55
  • [ 874473-14-0 ]
  • [ 345-30-2 ]
  • N-{3-[(3-methyloxetan-3-yl)amino]-4-nitrophenyl}acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82.52% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20 - 100℃; for 16h; 207.2; 208.2 Step-2 To a stirred solution of N-(3-fluoro-4-nitrophenyl)acetamide (345 mg, 1.74 mmol) and N, N-Diisopropylethylamine (912 µL, 3 eq., 5.22 mmol) in N-Methyl-2-Pyrrolidone (NMP) (5.00 mL), 3- methyloxetan-3-amine (157 µL, 2 eq., 3.48 mmol) was added at room temperature and stirred at 100°C for 16h. After completion, reaction mixture quenched with ice cold water, precipitate was formed. The solid was filtered and dried to afford N-{3-[(3-methyloxetan-3-yl)amino]-4-nitrophenyl}acetamide (395 mg, 1.49 mmol) as a yellow solid. Yield: 395 mg, 85.52%
82.52% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20 - 100℃; for 16h; 207.2; 208.2 Step-2 To a stirred solution of N-(3-fluoro-4-nitrophenyl)acetamide (345 mg, 1.74 mmol) and N, N-Diisopropylethylamine (912 µL, 3 eq., 5.22 mmol) in N-Methyl-2-Pyrrolidone (NMP) (5.00 mL), 3- methyloxetan-3-amine (157 µL, 2 eq., 3.48 mmol) was added at room temperature and stirred at 100°C for 16h. After completion, reaction mixture quenched with ice cold water, precipitate was formed. The solid was filtered and dried to afford N-{3-[(3-methyloxetan-3-yl)amino]-4-nitrophenyl}acetamide (395 mg, 1.49 mmol) as a yellow solid. Yield: 395 mg, 85.52%
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