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[ CAS No. 6291-01-6 ] {[proInfo.proName]}

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Chemical Structure| 6291-01-6
Chemical Structure| 6291-01-6
Structure of 6291-01-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 6291-01-6 ]

CAS No. :6291-01-6 MDL No. :MFCD00034953
Formula : C4H10ClN Boiling Point : -
Linear Structure Formula :- InChI Key :NFAZOGXQOWEWBM-UHFFFAOYSA-N
M.W : 107.58 Pubchem ID :12618374
Synonyms :

Calculated chemistry of [ 6291-01-6 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 28.9
TPSA : 26.02 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.25 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.0
Log Po/w (WLOGP) : 1.3
Log Po/w (MLOGP) : 0.76
Log Po/w (SILICOS-IT) : 0.85
Consensus Log Po/w : 0.78

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 3.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.14
Solubility : 7.85 mg/ml ; 0.0729 mol/l
Class : Very soluble
Log S (Ali) : -1.14
Solubility : 7.88 mg/ml ; 0.0732 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.26
Solubility : 59.5 mg/ml ; 0.553 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.05

Safety of [ 6291-01-6 ]

Signal Word:Danger Class:8
Precautionary Statements:P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501 UN#:1759
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 6291-01-6 ]

* 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 [ 6291-01-6 ]

[ 6291-01-6 ] Synthesis Path-Downstream   1~36

  • 1
  • [ 79-37-8 ]
  • [ 6291-01-6 ]
  • [ 37486-46-7 ]
  • 3
  • [ 7647-01-0 ]
  • [ 7732-18-5 ]
  • [ 6291-01-6 ]
  • potassium nitrite [ No CAS ]
  • [ 2516-33-8 ]
  • [ 2919-23-5 ]
  • 4
  • [ 7732-18-5 ]
  • [ 6291-01-6 ]
  • silver nitrite [ No CAS ]
  • [ 2516-33-8 ]
  • [ 2919-23-5 ]
  • 5
  • [ 6291-01-6 ]
  • eremomycin sulfate [ No CAS ]
  • C77H96ClN11O25 [ No CAS ]
  • 6
  • [ 6291-01-6 ]
  • [ 910293-47-9 ]
YieldReaction ConditionsOperation in experiment
91.56% A mixture of3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.5 g, 9.6mmol, 1.0 equiv), 1, 1'-carbonyldiimidazole (2.49 g, 15.37 mmol, 1.6 equiv) in DMF (20 mL) was stirred at50 C for 5 h. The mixture was cooled to room temperature. <strong>[6291-01-6]Cyclobutylamine hydrochloride</strong> (1.24 g, 11.52mmol, 1.2 equiv) and Et3N (1.74 mL, 12.48 mmol, 1.3 equiv) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. Purification by chromatography (1: 1 hexanes/EtOAc, then EtOAc) provided the titled compound (2.76 g, 91.56%) as a yellow solid. M. p. 69.3-71.0 C; 1H-NMR (CDCI3, 400 MHz) 8 1.51-1. 72 (m, 4H, cyclobutyl H), 2.19-2. 28 (m, 2H, cyclobutyl H), 2.37 (s, 3H,CH3), 4.39-4. 41 (m,1H, CH), 5.41 (s, 2H,OCH2Ph), 6.30 (s, 1 H, CH), 7.39-7. 49 (m, 5H, ArH), 7.86 (br, 1 H, NH), and MS(m/z) 314(M+ +1), 217,91.
  • 7
  • [ 613-69-4 ]
  • [ 6291-01-6 ]
  • N-cyclobutyl-(2-ethoxy)phenylamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium borohydrid; In ethanol; dichloromethane; chloroform; Example 9 Synthesis of alpha-(2-Ethoxyphenyl)-N-cyclobutylnitrone 2-Ethoxybenzaldehyde was combined with cyclobutylamine hydrochloride in chloroform and the solution was refluxed for 22 hours. Upon completion of the reaction, the solution was cooled to room temperature and concentrated under vacuum to give an oily residue, which was N-cyclobutyl-(2-ethoxy)phenyl imine. The oily residue was dissolved in ethanol and the solution was cooled with an ice bath. Sodium borohydride was added in portions and the reaction mixture was stirred at ambient temperature for 21 hours. The solution was then concentrated under vacuum and the residue was suspended in dichloromethane. A precipitate formed which was filtered. The filtrate was concentrated to give a liquid, which was passed through a silica gel filled funnel (eluding with hexane/ethyl acetate, 2:1) to afford N-cyclobutyl-(2-ethoxy)phenylamine.
YieldReaction ConditionsOperation in experiment
EXAMPLE 11 Synthesis of 2-Cyclobutylamino-2',6'-acetoxylidide (Compound K). To a solution of cyclobutylamine (39.8 g) in 600 ml benzene was added 2-chloro-2',6'-acetoxylidide (49.4 g), slolwy, with stirring, and the mixture was refluxed for about 5 hrs. After cooling, the mixture was filtered to remove the cyclobutylammonium chloride formed.
EXAMPLE 12 Synthesis of 2-Cyclobutylamino-2',6'-acetoxylidide (Compound K). To a solution of cyclobutylamine (39.8 g) in 600 ml benzene was added 2-chloro-2',6'-acetoxylidide (49.4 g), slowly, with stirring, and the mixture was refluxed for about 5 hrs. After cooling, the mixture was filtered to remove the cyclobutylammonium chloride formed.
  • 9
  • [ 6291-01-6 ]
  • [ 78471-43-9 ]
  • 5-bromo-2-cyclobutyl-1-oxo-isoindoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In toluene; for 2h;Heating / reflux; Under nitrogen atmosphere, 200 mg of 4-bromo-2-bromomethyl methyl benzoate was dissolved in toluene. Then, 418 mg of cyclobutylamine hydrochloride and 0.4 ml of triethylamine were added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled down to room temperature, and after distilling out the solvents under reduced pressure, the residues were separated and purified by thin-layer silicagel column chromatography (ethyl acetate/hexane=1/2) to obtain 60 mg of the above compound as a white solid. 1HNMR(400MHz,CDCl3.)delta.:1.74-1.80(2H,m), 2.23-2.30(4H,m), 4.43(2H,s), 4.89-4.93(1H,m), 7.58(1H,d,J=8.0Hz), 7.62(1H,s), 7.68(1H,d,J=8.0Hz) ESI-MS Found:m/z 266.2[M+H]+
  • 10
  • [ 6291-01-6 ]
  • [ 495-75-0 ]
  • C10H17NO4 [ No CAS ]
  • 11
  • [ 1039455-20-3 ]
  • [ 6291-01-6 ]
  • [ 1039453-70-7 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 20℃; for 1h; The nitro acid derivative (see example 1; 0.70 g, 2.52 mmol) was suspended in methylene chloride (40 mL). Five drops of DMF followed by thionyl chloride (1.82 mL, 21 mmol) was added and the mixture was stirred at ambient temperature overnight. The volatiles were removed under vacuum to yield a yellow solid which was dissolved in methylene chloride (20 mL). <strong>[6291-01-6]Cyclobutylamine hydrochloride</strong> (1.45 g, 12.5 mmol) and triethyl amine (3.5 mL, 25 mmol) were dissolved in methylene chloride (30 mL) and the solution of the yellow solid was <n="38"/>slowly added. The reaction was complete after one hour of stirring at ambient temperature. The reaction mixture was washed with IN HCl, followed by a sodium bicarbonate solution. It was dried over magnesium sulfate, and concentrated to give 0.60 g of a yellow solid.The Zn/Cu reagent was prepared in the following manner: Cone. HCl (3 mL) was added to 10 g of Zinc in 100 mL water during vigorous stirring. The stirring continued for 2 min (clumps start to form), after which the water was decanted off. An additional 100 mL of water was added with vigorous stirring. Any remaining clumps were crushed with a spatula. Cone. HCl (3 mL) was added and the stirring was continued for 2 min. After removing the water by decantation, the solid was washed with an additional 100 mL of water. Water (50 mL) was added to the solid and the stirring was continued while a solution OfCuSO4 (300 mg in 50 mL water) was added slowly. After the zinc turned black, the water was removed by decantation. The residue was sequentially washed with methanol (50 mL) and THF (50 mL).The yellow solid from the previous step (0.60 g, 1.5 mmol) was dissolved in a mixture of THF (50 mL) and methanol (70 mL) by warming it to 50 C. The solution was added to freshly prepared Zn/Cu reagent (6 g, see above). Formic acid (40 drops) was added and the mixture was stirred at ambient temperature for 1 hour after which the reduction was complete. DMF (10) mL) was added and the mixture was filtered through 2 cm of silica gel. The filtrate was evaporated to dryness then dissolved in DMF (20 mL). An excess of isoamyl nitrite (8 mL) was added and the mixture was stirred over night. The DMF was removed under vacuum and the crude product was purified by column chromatography (60 g silica gel, ethyl acetate: hexane 3:1). The product fractions were combined and the solvent was removed under vacuum. The product was re crystallized from methylene chloride: methyl t-butylether to give 0.31 g of a white solid with the following properties: MP: 216 - 218 0C; 1H NMR (300 MHz, CDCl3) delta 8.75 (IH, s), 7.83 (IH, s), 5.61 (IH, m), 5.51 (IH, m), 4.0-3.6 (2H, m) and 2.9-1.9 (10H, m) ppm (4H, m).
  • 12
  • [ 478080-55-6 ]
  • [ 6291-01-6 ]
  • [ 530-62-1 ]
  • [ 1170668-41-3 ]
YieldReaction ConditionsOperation in experiment
25% Compound 28: (+/-)1-(6-methyl[1 ,3lthiazolo[3,2-bl[1 ,2,41triazol-5-yl)ethyl cvclobutylcarbamate; (+/-)1-(6-Methyl[1 ,3]thiazolo[3,2-b][1 ,2,4]triazol-5-yl)ethanol (Intermediate 4) (183 mg, 1 mmol) and CDI (324 mg, 2.000 mmol) in dry DCM (5 ml) were heated in a microwave reactor at 80 0C for 20 minutes. The mixture obtained was then added to a solution of cyclobutylamine hydrochloride (321 mg, 3.00 mmol) in dry DCM (5 ml) and TEA (418mul, 3.00 mmol). The resulting mixture was heated in a microwave reactor at 80 0C for 20 minutes. The crude material obtained after solvent removal was purified using MDAP to give the title compound (72.5mg 25% yield); MS: ES+ m/z: 281 [MH+] at RT 2.87 min. C12H16N4O2S requires 280 (analysed by LCMS A); 1H NMR (400 MHz, MeOD): delta 1.62 (3H,d), 1.64-1.71 (2H,m), 1.87-2.00 (2H,m), 2.17- 2.30 (2H,m), 2.59 (3H,s), 4.00-4.08 (1 H,m), 6.07-6.12 (1 H,q), 8.21 (1 H,s).
  • 13
  • [ 26032-72-4 ]
  • [ 6291-01-6 ]
  • [ 1215103-71-1 ]
YieldReaction ConditionsOperation in experiment
30.6% Step (i): Synthesis of intermediate (2-chloro-6-phenyl-pyrimidin-4-yl)-cyclobutyl-amine To <strong>[26032-72-4]2,4-dichloro-6-phenylpyrimidine</strong> (630 mg, 2.8 mmol), dissolved in 30 mL MeOH, was added DIEA (0.7 mL, 4 mmol) and was stirred for 25 min at about 20-35 C. under a nitrogen atmosphere. To this mixture was added cyclobutylamine hydrochloride (323 mg, 3 mmol) and stirred 22 h. The mixture was concentrated by rotary evaporation and purification (Biotage Horizon HPFC chromatography system, SiO2, 30:70 EtOAc: hexane) gave the title compound as a thick light yellow oil (222 mg, 30.6% yield).1H NMR (300 MHz, CDCl3, TMS): delta 7.96-7.93 (m, 2H), 7.49-7.42 (m 3H), 6.51 (s, 1H), 5.44 (br s, 1H), 2.53-2.43 (m, 2H), 2.01-1.76 (m, 5H).LC-MSD (ES+): m/z [260 (M+H)+, 100].
  • 14
  • [ 6291-01-6 ]
  • [ 3932-97-6 ]
  • [ 1187590-86-8 ]
YieldReaction ConditionsOperation in experiment
41% With potassium carbonate; In acetonitrile; at 50℃; for 2h; 2-Chloro-N-cyclobutyl-5-trifluoromethylpyrimidin-4-amineA mixture of 8.07 g (37.2 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 12.8 g (92.9 mmol) of potassium carbonate in 150 ml of acetonitrile is warmed to 50 C. 4.00 g (37.2 mmol) of cyclobutylamine hydrochloride are then added, and the mixture is stirred for 2 h. After cooling, the reaction mixture is stirred into 500 ml of ice-water and extracted with ethyl acetate (3×200 ml). The combined organic phases are separated off, washed with water (2×250 ml), dried over MgSO4 and freed from the solvent under reduced pressure. The crude product is purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 4.00 g (41%) of 2-chloro-N-cyclobutyl-5-trifluoromethylpyrimidin-4-amine (V-4). logP (pH 2.3): 3.201H NMR (400 MHz, MeCN-d) delta=8.27 (s, 1H), 6.19 (br. s, 1H), 4.64-4.56 (m, 1H), 2.40-2.32 (m, 2H), 2.14-2.04 (m, 2H), 1.82-1.74 (m, 2H).
41% With potassium carbonate; In acetonitrile; at 50℃; for 2h; 2-Chloro-N-cyclobutyl-5-trifluoromethylpyrimidin-4-amine (V-20)A mixture of 8.07 g (37.2 mmol) of 2,4-dichloro-5-trifluoropyrimidine and 12.8 g (92.9 mmol) of potassium carbonate in 150 ml of acetonitrile is warmed to 50 C. Then, 4.00 g (37.2 mmol) of cyclobutylamine hydrochloroide are added and stirring is continued for 2 h. When cold, the reaction mixture is stirred into 500 ml of ice-water and extracted with ethyl acetate (3×200 ml). The combined organic phases are separated, washed with water (2×250 ml), dried over MgSO4 and freed from solvent under reduced pressure. The crude product is purified by column chromatography over silica gel (cyclohexane/ethyl acetate). This gives 4.00 g (41%) of 2-chloro-N-cyclobutyl-5-trifluoromethylpyrimidin-4-amine. logP (pH2.3): 3.20; 1H NMR (400 MHz, MeCN-d) delta=8.27 (s, 1H), 6.19 (br. s, 1H), 4.64-4.56 (m, 1H), 2.40-2.32 (m, 2H), 2.14-2.04 (m, 2H), 1.82-1.74 (m, 2H).
  • 15
  • [ 6291-01-6 ]
  • [ 19234-66-3 ]
  • [ 222527-42-6 ]
  • 16
  • [ 6291-01-6 ]
  • N-cyclobutylsulfamoyl chloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sulfuryl dichloride; In acetonitrile; for 16h;Reflux; Intermediate 29 :N-c clobutylsulfamoyl chloride oSulfuryl chloride (104 mmol) was dissolved in dry CH3CN (25 mL), added cyclobutylamine hydrochloride (31 mmol) and stirred at reflux for 16h. The obtained reaction mixture was cooled to rt and concentrated in vacuo. The obtained residue was trituated with Et20 (2 x 25 mL). The combined Et20-phases were concentrated in vacuo affording the title compound as oil.1H NMR (300 MHz, CDCI3) delta 5.75 (s, 1H), 4.27 - 4.04 (m, 1H), 2.64 - 2.37 (m, 2H), 2.26 - 1.96 (m, 2H), 1.93 - 1.68 (m, 2H).
  • 17
  • [ 1403771-21-0 ]
  • [ 6291-01-6 ]
  • [ 1403771-22-1 ]
YieldReaction ConditionsOperation in experiment
63% 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; Cyclobutanamine HC1 salt (645 mg, 6.0 mmol), 5-((3- fluorophenyl)ethynyl)picolinic acid (1.2 g, 5.0 mmol), HATU (2.3 g, 6.0 mmol) and N,N- diisopropylethylamine (3.5 mL, 20.0 mmol) were mixed in DMF (20.0 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 h, quenched with H20 (60.0 mL), extracted with EtOAc (40.0 mL x 3). The organic layers were combined and washed with brine (60.0 mL), dried over MgS04, and concentrated under reduced pressure. The crude material was purified by column chromatography (EtOAc:hexanes, 10-30%), affording the title compound as a while solid in 63% yield: 1H NMR (400 MHz, CDC13): delta 8.69 (d, J= 1.2 Hz, 1H), 8.12 (d, J= 8.0 Hz, 1H), 8.13 (d, J= 7.6 Hz, NH), 7.97 (dd, J= 8.0, 2.4 Hz, 1H), 7.41-7.36 (overlapped, 2H), 7.27 (m, 1H), 7.13 (m, 1H), 4.63 (sextet, J= 8.4 Hz, 1H), 2.46 (m, 2H), 2.08 (m, 2H), 2.82 (m, 2H); LC-MS (ESI), single peak, m/z 295.2 ([M+H]+); HRMS (ESI) m/z 295.1244 ([M+H]+, 100%) calculated for C18H16N2OF, 295.1247.
  • 18
  • [ 1403771-21-0 ]
  • [ 6291-01-6 ]
  • [ 1446705-64-1 ]
YieldReaction ConditionsOperation in experiment
N-cyclobutyl-5-((3-fluorophenylethynyl)picolinamide (VU0403602): To a solution of 5-((3-fluorophenyl)ethynyl)picolinic acid (VU0451326, 1.29 g, 5.0 mmol) in DMF (20 mL) was addedHATU (2.28 g, 6.0 mmol), <strong>[6291-01-6]cyclobutanamine hydrochloride</strong> (0.645 g, 6.0 mmol), anddiisopropylethylamine (3.48 mL, 20.0 mmol). The reaction stirred at room temperature untilLC/MS showed complete consumption of starting material. The reaction was quenched withH2O (60 mL) and extracted with EtOAc (60 mL x 3). The combined organics were dried overMgSO4 and concentrated under reduced pressure. The crude material was purified by silica gelcolumn chromatography (0-30% EtOAc/Hexanes). The pure free base compound was dissolvedin dioxane (5 mL) and cooled to 0C. To the solution was added 4M HCl (4mL, 16 mmol). Awhite precipitate formed and was filtered and dried in vacuo to give VU0403602 as an HCl salt:1H NMR (400 MHz, DMSO) 9.03 (d, J = 8.4 Hz, 1H), 8.83 (s, 1H), 8.19-8.16 (dd, J = 6.0, 2.0Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.56-7.48 (m, 3H), 7.38-7.33 (m, 1H), 4.51-4.43 (m, 1H),2.22-2.16 (m, 4H), 1.70-1.64 (m, 2H); LC/MS (>98%), 3.78 min, m/z = 295.1 [M+H]; HRMS =317.1066 [M+Na], calculated for C18H15FN2ONa, 317.1066.
  • 19
  • C11H10BrN3O2 [ No CAS ]
  • [ 6291-01-6 ]
  • C15H19BrN4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
4,6-dibromobenzo[c][l ,2,5]oxadiazole (2.013 g, 7.24 mmol) and (S)-ethyl pyrrolidine-2- carboxylate hydrochloride salt (1.43 g, 7.96 mmol) were massed into a tube. The tube was evacuated and flushed with argon for three cycles. NMP (10 mL) and DIPEA (3.5 mL, 19.9 mmol) were then added and the tube was sealed and heated to 50 C overnight. Upon cooling to room temperature the mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was back-extracted with EtOAc. The combined organic layers were then washed with water (5x), brine, dried (Na2S04), filtered and concentrated to give an oil. The crude oil was then purified via flash column chromatography (15 % EtOAc / hexane) to afford 0.6105 g (25 % yield) of aniline. The aniline (1.696 g, 4.9 mmol) was dissolved in DCM (20 mL) and cooled to -78 C. DIBAL (12.5 mL, 1.0 M solution in hexanes) was added dropwise and then the reaction was allowed to warm to room temperature overnight. The reaction was quenched with MeOH and then Na2S04 was added and the mixture was stirred for 30 minutes before filtering through Celite. The organic phase was diluted with EtOAc and water. The layers were separated and the organic layer was washed with H20 (3x), brine, dried (Na2SC>4), filtered and concentrated. The crude material was purified via chromatography (30 % EtOAc / hexane) to give 1.294 g (87 % yield) of the primary alcohol. The primary alcohol (0.9956 g, 3.34 mmol) was dissolved in DCM (100 mL) and DMP (2.1249 g, 5.0 mmol) was added. The reaction was stirred for 2 hours and then it was quenched with saturated NaHCC>3 (aq) and excess Na2SC>4 (8.0 g) was added and the mixture was stirred until all solids dissolved. This mixture was then extracted with DCM and the combined organic layer was dried (Na2SC>4), filtered and concentrated. Purification (20 % EtOAc / hexane column) afforded 0.6471 g (65 % yield) of the aldehyde. This aldehyde (0.206 g, 0.696 mmol) and cyclobutylamine hydrolchloride (0.0794 g, 0.738 mmol) were dissolved in methanol (3 mL) and TEA (0.19 mL, 1.39 mmol) was added. This material was stirred for 24 hours and was then cooled to 0 C. To this mixture was then added NaBHj (0.0685 g, 1.81 mmol) portionwise. The mixture was stirred for 60 minutes and then was quenched with IN NaOH (aq). The mixture was extracted with EtOAc (3x) and the combined organics were washed with H20 (3x), brine, dried (Na2S04), filtered and concentrated to give the crude amine. To a solution of this amine in THF (5 mL) at 0 C was added TEA (0.19 mL, 1.39 mmol), DMAP (a crystal) and then BOC20 (0.1822 g, .835 mmol). The reaction was stirred at 0 C while monitoring by TLC. It was then quenched with H20 and extracted with EtOAc. The combined organics were washed with H20 (3x), brine, dried (Na2S04), filtered and concentrated to give the crude carbamate. This carbamate and 3-formylphenylboronic acid (0.1094 g, 0.73 mmol) were massed into a tube. The tube was evacuated and purged with argon (3x). DME (1.6 mL) and 2M Na2C03 (1.1 mL, 2.09 mmol) were then added followed by Pd(PPh3)4 (0.0402 g, 0.0348 mmol). The tube was then sealed and heated to 80 C overnight. Upon cooling to room temperature the mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was back-extracted with EtOAc. The combined organic layers were then washed with water (5x), brine, dried (Na2S04), filtered and concentrated to give an oil. This crude oil was then dissolved in THF (4 mL) and cooled to 0 C. CF3TMS (0.21 mL, 1.39 mmol) was added followed by TBAF (0.07 mL, 1.0 M solution in THF). The reaction was then stirred for 60 minutes before re-cooling to 0C and 4N HC1 (aq) was added and stirred for 60 minutes. The mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was basified. The aqueous layer was then re-extracted with EtOAc. The combined organic layers were was with water, brine, dried (Na2S04), filtered and concentrated to give the trifluorocarbinol, as a mixture of diastereomers. This crude material was then dissolved in DCM (15 mL) and cooled to 0 C. TFA (0.53 mL) was added and the mixture was stirred for 36 hours before quenching with saturated NaHCC>3(aq). This mixture was extracted with DCM (5x) and the combined organics were dried with NA2SO4, filtered and then concentrated. This crude material was purified via 5 % MeOH / DCM column to afford 0.130 g of the free amine. This material was then dissolved in MeOH at 0 C and treated with a large excess of methanolic HC1. The reaction mixture was stirred for 30 minutes and then concentrated to produce 0.081 g (24 % yield, 8 steps) of TRV-1458. *H NMR (MeOD, 700 MHz) delta = 7.83 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.26 (s, 1H), 6.43 (s, 1H), 5.16 (q, J = 7.1 Hz, 1H), 3.87 (m, 1H), 3.78-3.77 (m, 1H), 3.52-3.50 (m, 1H), 3.30 (s, 2H), 3.25 (dd, J = 12.5, 2.1 Hz, 1H), 3.05 (t, J = 11.0 Hz, 1H), 2.36-2.20 (m, 9H), 1.99-1...
  • 20
  • [ 793695-77-9 ]
  • [ 6291-01-6 ]
  • ethyl (3aR,3bS,4aS,5R,5aS)-5-(6-(cyclobutylamino)-2-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-3b(3aH)-carboxylate [ No CAS ]
  • 21
  • [ 1146290-19-8 ]
  • [ 6291-01-6 ]
  • 5-bromo-2-chloro-N-cyclobutylpyridine-3-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% With pyridine; In dichloromethane; at 20℃; for 16h; Step 1: 5-bromo-2-chloro-N-cyclobutylpyridine-3-sulfonamide A partial suspension of cyclobutylamine hydrochloride salt (0.39 g, 3.64 mmol) in pyridine (0.8 mL) was treated dropwise with a solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (0.52 g, 1.79 mmol) in DCM (1 mL) and the mixture was allowed to stir at rt for 16 h. The solvent was evaporated under reduced pressure and the residue was treated with ice cold 1N HCl and extracted with EtOAc. The organic solution was washed with water and dried over MgSO4, filtered and the solvent was evaporated. The crude product was purified by column chromatography to give 5-bromo-2-chloro-N-cyclobutylpyridine-3-sulfonamide (0.58 g, 58%). LCMS (FA): m/z=325.1 (M+H).
  • 22
  • [ 611-06-3 ]
  • [ 6291-01-6 ]
  • 5-chloro-N-cyclobutyl-2-nitroaniline [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.65 g With triethylamine; In tetrahydrofuran; at 100℃; for 33h;Sealed tube; Method 3: Preparation of 5-chloro-N-cyclobutyl-2-nitroaniline for use in Method 1, Step B A mixture of cyclobutylamine hydrochloride (2.15 g), triethylamine (2.8 mL), 2,4-dichloro-1-nitrobenzene (3.84 g, 20 mmol, limiting reagent) and tetrahydrofuran (40 mL) was heated in a sealed vial at 100 C. for 16 hours. The reaction mixture was cooled to room temperature, and 0.2 equivalents of both cyclobutylamine hydrochloride and triethylamine added, and the resulting mixture was heated at 100 C. for an additional 17 hours. The cooled reaction mixture was diluted with water, extracted thoroughly with dichloromethane and ethyl acetate, the organic extracts dried over anhydrous magnesium sulfate and concentrated. Purification of the crude product by chromatography on silica with 20% dichloromethane in hexanes as eluent afforded the desired product (1.65 g) as an orange solid. 1H NMR (CDCl3): delta 8.16 (NH, bs), 8.12 (1H, d), 6.70 (1H, s), 6.60 (1H, d), 4.02 (1H, m), 2.53 (2H, m), 2.03 (2H, m), 1.92 (2H, m).
  • 23
  • [ 218632-01-0 ]
  • [ 6291-01-6 ]
  • 3-(cyclobutylamino)-4-nitrobenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; A 500 mL round-bottom flask was charged with of <strong>[218632-01-0]3-fluoro-4-nitrobenzonitrile</strong> (5.00 g, 30.1 mmol) and tetrahydrofuran (100 mL) and placed in a 0 C. bath. After 5 minutes, cyclobutylamine hydrochloric acid (3.60 g, 33.0 mmol) was added in one portion with stirring before the dropwise addition of diisopropylethylamine (15 mL, 82 mmol). The mixture was allowed to stir at 0 C. for 1 hour. The ice bath was removed and the flask was allowed to warm to room temperature and allowed to stir overnight. The bulk of the tetrahydrofuran was removed on a rotary evaporator before the mixture was diluted with EtOAc (200 mL). The organic layer was washed with saturated aqueous ammonium chloride twice, saturated aqueous sodium bicarbonate, and brine and then dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated to give the desired product as a crude orange solid (6.25 g). TLC Rf=0.70-0.45 streak in 20% EtOAc in hexanes. MS (ESI) m/z 218.0 (MH+). 1H NMR (CDCl3): delta 8.24 (d, J=8.68 Hz, 1H), 8.11 (bs, 1H), 7.01 (d, J=1.48 Hz, 1H), 6.86 (dd, J=8.72, 1.64, 1H), 4.09-4.00 (m, 1H), 2.60-2.51 (m, 2H), 2.11-1.88 (m, 4H).
  • 24
  • [ 32315-10-9 ]
  • [ 6291-01-6 ]
  • [ 39126-16-4 ]
  • methyl 4-((3-cyclobutyl-1-phenylureido)methyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
83.6% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h; [422] A solution of methyl 4-((phenylamino)methyl)benzoate (0.500 g, 2.072 mmol) prepared in Step 1 , tripliosgene (0.676 g, 2.279 mmol) and N,N-diisopropylethylamine (3.619 mL, 20.722 mmol) in dichloromethane ( 10 mL) was mixed at 0 C with cy- clobutylamine hydrochloride (0.245 g. 2.279 mmol), and stirred at the room temperature for 16 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; dichloromethane / hexane = 0 % to 30 %) to give the title compound methyl 4-((3-cyclobutyl- l -phenylureido)methyl)benzoate as white solid (0.586 g, 83.6 ).
  • 25
  • [ 3899-92-1 ]
  • [ 6291-01-6 ]
  • C11H15NO [ No CAS ]
  • 26
  • [ 1006-99-1 ]
  • [ 6291-01-6 ]
  • C12H14N2S [ No CAS ]
  • 27
  • [ 5332-24-1 ]
  • [ 6291-01-6 ]
  • C13H14N2 [ No CAS ]
  • 28
  • [ 6291-01-6 ]
  • [ 116588-66-0 ]
  • 6-(cyclobutylamino)-9-methyl-8-phenyl-9H-purine [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With triethylamine; In tetrahydrofuran; at 80℃; General procedure: 9-Alkyl-6-chloro-8-phenyl-9H-purines 9-11 (1mmol) were solubilized in 12mL of dry THF. To the solution and cyclobutylamine hydrochloride (2mmol) and triethylamine (12mmol) were added and the reaction mixture left to stir at 80C for 60-70h. After in vacuo evaporation of volatiles, the reaction mixture was chromatographed on silica gel column eluting with the suitable solvent. 4.1.13 6-(Cyclobutylamino)-9-methyl-8-phenyl-9H-purine (14) Compound 14 was obtained from 9. Flash column chromatography eluting with CHCl3-cC6H12-CH3OH (70:28:2) and crystallization from acetonitrile afforded 14 as a white solid (146?mg, 52%); mp: 159-161?C; 1H NMR (400?MHz, [D6]DMSO): delta?=?1.68 (m, 2H, H-cyclobutyl), 2.20 (m, 4H, H-cyclobutyl), 3.81 (s, 3H, CH3), 4.75 (m, 1H, N6-CH), 7.59 (m, 3H, H-Ph), 7.88 (m, 2H, H-Ph), 8.10 (m, 1H, NH), 8.24 (s, 1H, H-2); Anal (C16H17N5) C, H, N.
  • 29
  • [ 868163-66-0 ]
  • [ 6291-01-6 ]
  • 6-(cyclobutylamino)-9-ethyl-8-phenyl-9H-purine [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With triethylamine; In tetrahydrofuran; at 80℃; General procedure: 9-Alkyl-6-chloro-8-phenyl-9H-purines 9-11 (1mmol) were solubilized in 12mL of dry THF. To the solution and cyclobutylamine hydrochloride (2mmol) and triethylamine (12mmol) were added and the reaction mixture left to stir at 80C for 60-70h. After in vacuo evaporation of volatiles, the reaction mixture was chromatographed on silica gel column eluting with the suitable solvent.
  • 30
  • 6-chloro-9-propyl-8-phenyl-9H-purine [ No CAS ]
  • [ 6291-01-6 ]
  • 6-(cyclobutylamino)-9-propyl-8-phenyl-9H-purine [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% With triethylamine; In tetrahydrofuran; at 80℃; General procedure: 9-Alkyl-6-chloro-8-phenyl-9H-purines 9-11 (1mmol) were solubilized in 12mL of dry THF. To the solution and cyclobutylamine hydrochloride (2mmol) and triethylamine (12mmol) were added and the reaction mixture left to stir at 80C for 60-70h. After in vacuo evaporation of volatiles, the reaction mixture was chromatographed on silica gel column eluting with the suitable solvent.
  • 31
  • 3-(6,7-dihydro-5H-pyrrolo-[1,2-a]imidazol-2-yl)benzaldehyde [ No CAS ]
  • [ 6291-01-6 ]
  • 1-cyclobutyl-N-(3-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)benzyl)methanamine [ No CAS ]
  • 32
  • [ 403-16-7 ]
  • [ 6291-01-6 ]
  • 3-chloro-N-cyclobutyl-4-fluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 4h; To the stirred solution of <strong>[403-16-7]3-chloro-4-fluoro-benzoic acid</strong> (500 mg, 2.865 mmol) in DMF (5mL), cyclobutanamine hydrochloride (369 mg, 3.438 mmol), EDC.HCl (820 mg, 4.297mmol), HOBt (580 mg, 4.297 mmol) and NMM (1.6 mL, 14.325 mmol) were added at RTand stirred for 4 h (TLC indicated complete consumption of starting material). The reactionmixture was diluted with cold water (60 mL) and extracted with EtOAc (3 x 60 mL). Thecombined organic extracts were washed with cold water (50 mL), dried over Na2S04,concentrated under reduced pressure to afford 3-chloro-N-cyclobutyl-4-fluoro-benzamide(550 mg, 84%) which was carried to the next step without any further purification.LCMS: m/z: 228.22 [M+Ht.
  • 33
  • C55H94N2O21 [ No CAS ]
  • [ 6291-01-6 ]
  • [(2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-[[(2S,5R,7R)-4-cyclobutyl-2,5-dimethyl-1,4-oxazepan-7-yl]oxy]-2-[(1S)-2-[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydropyran-2-yl]oxy-1-methylethyl]-10-[(2S,3R,4E,6R)-3-hydroxy-4-methoxyimino-6-methyltetrahydropyran-2-yl]oxy-3,5,7,9,11,13-hexamethyl-4-(3-methylbutanoyloxy)-6,14-dioxooxacyclotetradec-7-yl] (2S)-2-methylmorpholine-4-carboxylate [ No CAS ]
  • [(2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-[[(2S,5S,7R)-4-cyclobutyl-2,5-dimethyl-1,4-oxazepan-7-yl]oxy]-2-[(1S)-2-[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydropyran-2-yl]oxy-1-methylethyl]-10-[(2S,3R,4E,6R)-3-hydroxy-4-methoxyimino-6-methyltetrahydropyran-2-yl]oxy-3,5,7,9,11,13-hexamethyl-4-(3-methylbutanoyloxy)-6,14-dioxooxacyclotetradec-7-yl] (2S)-2-methylmorpholine-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65 mg; 17 mg To a mixture of compound of compound step 3A.2 (250 mg, 223,34 muetaiotaomicronIota) in THF (2.5 ml) and water (1 .25 ml) was added Nal04 (241 ,27 mg, 1 ,12 mmol). The resulting mixture was stirred at room temperature for 3h. The reaction was diluted with THF (7.5 ml) and the <strong>[6291-01-6]Cyclobutylamine hydrochloride</strong> (37,16 mg, 335,02 muetaiotaomicronIota) was added. The resulting mixture was stirred for 45 min then to the above reaction was added NaBH3CN (44,32 mg, 670,03 muetaiotaomicronIota) and stirred at room temperature for 16h. The reaction was diluted with EtOAc (20 ml), washed with NaHC03 solution (15 ml), dried with anhydrous MgS04, filtered. The filtrate was concentrated under reduced pressure to afford 0.268 g of crude product. The residue was purified by silica gel column (20 g SiOH 15-40 muetaiota, EtOAC-TEA 98.5/1 .5) to afford 0,180 g of mixture 3A and 3A'. The mixture was purified by silica gel column (10 g of 15-40 muetaiota silica) eluted with the following elution solvent: DCM-MeOH- NH4OH 96/4/0.2) to afford 65 mg of the desired compound example 3A and 17 mg of 3A'. (0380) Example 3A (0381) NMR 1 H (500MHz, delta in ppm , DMSO-d6): 0.78 (d, J=6.8 Hz, 3 H); 0.93 (m, 15 H); 1 .04 (m, 12 H); 1 .1 1 (d, J=6.1 Hz, 6 H); 1 .15 (d, J=6.1 Hz, 3 H); 1 .52 (m, 2 H); 1 .66 to 2.07 (m, 16 H); 2.14 (m, 3 H); 2.23 (dd, J=7.5 et 14.6 Hz, 1 H); 2.42 (m, 0.5 H); 2.58 (m, 0.5 H); 2.71 (m, 1 H); 2.76 to 2.95 (m, 5 H); 3.01 (m, 2 H); 3.26 to 3.42 (m, 7 H); 3.46 (s, 3 H); 3.52 (m, 1 H); 3.59 to 3.99 (m, 13 H); 4.45 (d, J=8.0 Hz, 1 H); 4.58 (m, 2 H); 4.66 (d, J=9.5 Hz, 1 H); 4.88 (m, 2 H); 5.15 (m, 1 H). (0382) MS method d: (0383) Retention time Tr (min): 1 .1 ; [M+H]+ 1 156 ; [M-H+HCOOH]-: m/z 1200 (base peak). Example 3A' (0384) NMR 1 H (500MHz, delta in ppm , DMSO-d6): 0.78 (d, J=6.9 Hz, 3 H); 0.93 (m, 15 H); 1 .00 to 1 .16 (m, 21 H); 1 .47 to 2.07 (m, 18 H); 2.14 (m, 3 H); 2.28 (dd, J=9.2 et 13.5 Hz, 1 H); 2.42 (m, 1 H); 2.71 (m, 1 H); 2.85 (m, 4 H); 3.05 (m, 3 H); 3.25 to 3.42 (m, 7 H); 3.45 (s, 3 H); 3.52 (m, 1 H); 3.57 to 3.99 (m, 12 H); 4.15 (m, 1 H); 4.44 (d, J=8.0 Hz, 1 H); 4.57 (m, 2 H); 4.65 (m, 1 H); 4.86 (d, J=7.1 Hz, 1 H); 4.94 (t, J=6.9 Hz, 1 H); 5.41 (m, 1 H) (0385) MS method d: (0386) Retention time Tr (min): 1 .1 ; [M+H]+ 1 156 ; [M-H+HCOOH]-: m/z 1200 (base peak).
  • 34
  • [ 6291-01-6 ]
  • [ 98-88-4 ]
  • [ 120218-51-1 ]
  • 35
  • 5-(5-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one [ No CAS ]
  • [ 6291-01-6 ]
  • 5-(5-(cyclobutylamino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one [ No CAS ]
  • 36
  • 5-(6-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one [ No CAS ]
  • [ 6291-01-6 ]
  • 5-(6-(cyclobutylamino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one [ No CAS ]
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